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Shikonin, an herbal naphthoquinone, demonstrates a broad spectrum of pharmacological properties. Owing to increasingly adverse environmental conditions, human skin is vulnerable to harmful influences from dust particles. This study explored the antioxidant capabilities of shikonin and its ability to protect human keratinocytes from oxidative stress induced by fine particulate matter (PM2.5). We found that shikonin at a concentration of 3 µM was nontoxic to human keratinocytes and effectively scavenged reactive oxygen species (ROS) while increasing the production of reduced glutathione (GSH). Furthermore, shikonin enhanced GSH level by upregulating glutamate-cysteine ligase catalytic subunit and glutathione synthetase mediated by nuclear factor-erythroid 2-related factor. Shikonin reduced ROS levels induced by PM2.5, leading to recovering PM2.5-impaired cellular biomolecules and cell viability. Shikonin restored the GSH level in PM2.5-exposed keratinocytes via enhancing the expression of GSH-synthesizing enzymes. Notably, buthionine sulphoximine, an inhibitor of GSH synthesis, diminished effect of shikonin against PM2.5-induced cell damage, confirming the role of GSH in shikonin-induced cytoprotection. Collectively, these findings indicated that shikonin could provide substantial cytoprotection against the adverse effects of PM2.5 through direct ROS scavenging and modulation of cellular antioxidant system.
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Exposure to fine particulate matter with an aerodynamic diameter of less than 2.5 µm (PM2.5) can cause oxidative damage and apoptosis in the human skin. Chlorogenic acid (CGA) is a bioactive polyphenolic compound with antioxidant, antifungal, and antiviral properties. The objective of this study was to identify the ameliorating impact of CGA that might protect human HaCaT cells against PM2.5. CGA significantly scavenged the reactive oxygen species (ROS) generated by PM2.5, attenuated oxidative cellular/organelle damage, mitochondrial membrane depolarization, and suppressed cytochrome c release into the cytosol. The application of CGA led to a reduction in the expression levels of Bcl-2-associated X protein, caspase-9, and caspase-3, while simultaneously increasing the expression of B-cell lymphoma 2. In addition, CGA was able to reverse the decrease in cell viability caused by PM2.5 via the inhibition of extracellular signal-regulated kinase (ERK). This effect was further confirmed by the use of the mitogen-activated protein kinase kinase inhibitor, which acted upstream of ERK. In conclusion, CGA protected keratinocytes from mitochondrial damage and apoptosis via ameliorating PM2.5-induced oxidative stress and ERK activation.
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Apoptosis , Ácido Clorogénico , Queratinocitos , Estrés Oxidativo , Material Particulado , Ácido Clorogénico/farmacología , Humanos , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Material Particulado/toxicidad , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Queratinocitos/patología , Especies Reactivas de Oxígeno/metabolismo , Células HaCaT , Supervivencia Celular/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacosRESUMEN
Specific sensitivity of the skin to ultraviolet B (UVB) rays is one of the mechanisms responsible for widespread skin damage. This study tested whether 1,3,5-trihydroxybenzene (THB), a compound abundant in marine products, might inhibit UVB radiation-induced NADPH oxidase 4 (NOX4) in both human HaCaT keratinocytes and mouse dorsal skin and explore its cytoprotective mechanism. The mechanism of action was determined using western blotting, immunocytochemistry, NADP+/NADPH assay, reactive oxygen species (ROS) detection, and cell viability assay. THB attenuated UVB-induced NOX4 expression both in vitro and in vivo, and suppressed UVB-induced ROS generation via NADP+ production, resulting in increased cell viability with decreased apoptosis. THB also reduced the expression of UVB-induced phosphorylated AMP-activated protein kinase (AMPK) and phosphorylated c-Jun N-terminal kinase (JNK). THB suppressed UVB-induced NOX4 expression and ROS generation by inhibiting AMPK and JNK signaling pathways, thereby inhibiting cellular damage. These results showed that THB could be developed as a UV protectant.
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Particulate matter 2.5 (PM2.5) causes skin aging, inflammation, and impaired skin homeostasis. Hyperoside, a flavanol glycoside, has been proposed to reduce the risk of diseases caused by oxidative stress. This study evaluated the cytoprotective potential of hyperoside against PM2.5-induced skin cell damage. Cultured human HaCaT keratinocytes were pretreated with hyperoside and treated with PM2.5. Initially, the cytoprotective and antioxidant ability of hyperoside against PM2.5 was evaluated. Western blotting was further employed to investigate endoplasmic reticulum (ER) stress and cellular senescence and for evaluation of cell cycle regulation-related proteins. Hyperoside inhibited PM2.5-mediated ER stress as well as mitochondrial damage. Colony formation assessment confirmed that PM2.5-impaired cell proliferation was restored by hyperoside. Moreover, hyperoside reduced the activation of PM2.5-induced ER stress-related proteins, such as protein kinase R-like ER kinase, cleaved activating transcription factor 6, and inositol-requiring enzyme 1. Hyperoside promoted cell cycle progression in the G0/G1 phase by upregulating the PM2.5-impaired cell cycle regulatory proteins. Hyperoside significantly reduced the expression of PM2.5-induced senescence-associated ß-galactosidase and matrix metalloproteinases (MMPs), such as MMP-1 and MMP-9. Overall, hyperoside ameliorated PM2.5-impaired cell proliferation, ER stress, and cellular senescence, offering potential therapeutic implications for mitigating the adverse effects of environmental pollutants on skin health.
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Senescencia Celular , Estrés del Retículo Endoplásmico , Queratinocitos , Material Particulado , Quercetina , Humanos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Material Particulado/toxicidad , Senescencia Celular/efectos de los fármacos , Quercetina/farmacología , Quercetina/análogos & derivados , Queratinocitos/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Células HaCaT , Antioxidantes/farmacología , Piel/efectos de los fármacos , Piel/metabolismo , Piel/citologíaRESUMEN
This study investigated the mechanism of silver nanoparticle (AgNP) cytotoxicity from a mitochondrial perspective. The effect of AgNP on manganese superoxide dismutase (MnSOD), a mitochondrial antioxidant enzyme, against oxidative stress has not been studied in detail. We demonstrated that AgNP decreased MnSOD mRNA level, protein expression, and activity in human Chang liver cells in a time-dependent manner. AgNP induced the production of mitochondrial reactive oxygen species (mtROS), particularly superoxide anion. AgNP was found to increase mitochondrial calcium level and disrupt mitochondrial function, leading to reduced ATP level, succinate dehydrogenase activity, and mitochondrial permeability. AgNP induced cytochrome c release from the mitochondria into the cytoplasm, attenuated the expression of the anti-apoptotic proteins phospho Bcl-2 and Mcl-1, and induced the expression of the pro-apoptotic proteins Bim and Bax. In addition, c-Jun N-terminal kinase (JNK) phosphorylation was significantly increased by AgNP. Treatment with elamipretide (a mitochondria-targeted antioxidant) and SP600125 (a JNK inhibitor) showed the involvement of MnSOD and JNK in these processes. These results indicated that AgNP damaged human Chang liver cells by destroying mitochondrial function through the accumulation of mtROS.
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Nanopartículas del Metal , Especies Reactivas de Oxígeno , Superóxido Dismutasa , Humanos , Nanopartículas del Metal/toxicidad , Superóxido Dismutasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Línea Celular , Plata/toxicidad , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Supervivencia Celular/efectos de los fármacos , Mitocondrias Hepáticas/efectos de los fármacos , Mitocondrias Hepáticas/enzimología , Mitocondrias Hepáticas/metabolismo , Mitocondrias Hepáticas/patología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/enzimología , Hepatocitos/patologíaRESUMEN
Particulate matter 2.5 (PM2.5) imposes a heavy burden on the skin and respiratory system of human beings, causing side effects such as aging, inflammation and cancer. Astaxanthin (ATX) is a well-known antioxidant widely used for its anti-inflammatory and anti-aging properties. However, few studies have investigated the protective effects of ATX against PM2.5-induced senescence in HaCaT cells. In the present study, the levels of reactive oxygen species (ROS) and antioxidant enzymes were measured after treatment with PM2.5. The results revealed that PM2.5 generated excessive ROS and reduced the translocation of nuclear factor erythroid 2-related factor 2 (NRF2), subsequently reducing the expression of antioxidant enzymes. However, pretreatment with ATX reversed the ROS levels as well as the expression of antioxidant enzymes. In addition, ATX protected cells from PM2.5-induced DNA damage and rescued PM2.5-induced cell cycle arrest. The levels of senescence-associated phenotype markers, such as interleukin-1ß, matrix metalloproteinases, and ß-galactosidase, were increased by exposure to PM2.5, however these effects were reversed by ATX. After interfering with NRF2 mRNA expression and exposing cells to PM2.5, the levels of ROS and ß-galactosidase were higher compared with siControl RNA cells exposed to PM2.5. However, ATX inhibited ROS and ß-galactosidase levels in both the siControl RNA and the siNRF2 RNA groups. Thus, ATX protects HaCaT keratinocytes from PM2.5-induced senescence by partially inhibiting excessive ROS generation via the NRF2 signaling pathway.
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Physiological stress such as excessive reactive oxygen species (ROS) production may contribute normal fibroblasts activation into cancerassociated fibroblasts, which serve a crucial role in certain types of cancer such as pancreatic, breast, liver and lung cancer. The present study aimed to examine the cytoprotective effects of luteolin (3',4',5,7tetrahydroxyflavone) against hydrogen peroxide (H2O2)generated oxidative stress in lung fibroblasts. To examine the effects of luteolin against H2O2induced damages, cell viability, subG1 cell population, nuclear staining with Hoechst 33342, lipid peroxidation and comet assays were performed. To evaluate the effects of luteolin on the protein expression level of apoptosis, western blot assay was performed. To assess the antioxidant effects of luteolin, detection of ROS using H2DCFDA staining, O2 and ·OH using electron spin resonance spectrometer and antioxidant enzyme activity was performed. In a cellfree chemical system, luteolin scavenges superoxide anion and hydroxyl radical generated by xanthine/xanthine oxidase and the Fenton reaction (FeSO4/H2O2). Furthermore, Chinese hamster lung fibroblasts (V794) treated with H2O2 showed a significant increase in cellular ROS. Intracellular ROS levels and damage to cellular components such as lipids and DNA in H2O2treated cells were significantly decreased by luteolin pretreatment. Luteolin increased cell viability, which was impaired following H2O2 treatment and prevented H2O2mediated apoptosis. Luteolin suppressed active caspase9 and caspase3 levels while increasing Bcl2 expression and decreasing Bax protein levels. Additionally, luteolin restored levels of glutathione that was reduced in response to H2O2. Moreover, luteolin enhanced the activity and protein expressions of superoxide dismutase, catalase, glutathione peroxidase, and heme oxygenase1. Overall, these results indicated that luteolin inhibits H2O2mediated cellular damage by upregulating antioxidant enzymes.
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Antioxidantes , Apoptosis , Supervivencia Celular , Fibroblastos , Peróxido de Hidrógeno , Luteolina , Estrés Oxidativo , Especies Reactivas de Oxígeno , Luteolina/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/farmacología , Peróxido de Hidrógeno/farmacología , Peróxido de Hidrógeno/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Línea Celular , Cricetinae , Peroxidación de Lípido/efectos de los fármacos , CricetulusRESUMEN
Particulate matter 2.5 (PM2.5) poses a serious threat to human health and is responsible for respiratory disorders, cardiovascular diseases, and skin disorders. 3-Bromo-4,5-dihydroxybenzaldehyde (3-BDB), abundant in marine red algae, exhibits anti-inflammatory, antioxidant, and antidiabetic activities. In this study, we investigated the protective mechanisms of 3-BDB against PM2.5-induced cell cycle arrest and autophagy in human keratinocytes. Intracellular reactive oxygen species generation, DNA damage, cell cycle arrest, intracellular Ca2+ level, and autophagy activation were tested. 3-BDB was found to restore cell proliferation and viability which were reduced by PM2.5. Furthermore, 3-BDB reduced PM2.5-induced reactive oxygen species levels, DNA damage, and attenuated cell cycle arrest. Moreover, 3-BDB ameliorated the PM2.5-induced increases in cellular Ca2+ level and autophagy activation. While PM2.5 treatment reduced cell growth and viability, these were restored by the treatment with the autophagy inhibitor bafilomycin A1 or 3-BDB. The findings indicate that 3-BDB ameliorates skin cell death caused by PM2.5 via inhibiting cell cycle arrest and autophagy. Hence, 3-BDB can be exploited as a preventive/therapeutic agent for PM2.5-induced skin impairment.
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Autofagia , Benzaldehídos , Puntos de Control del Ciclo Celular , Queratinocitos , Material Particulado , Especies Reactivas de Oxígeno , Autofagia/efectos de los fármacos , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Material Particulado/toxicidad , Benzaldehídos/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Proliferación Celular/efectos de los fármacos , Calcio/metabolismo , Supervivencia Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacosRESUMEN
The skin is directly exposed to atmospheric pollutants, especially particulate matter 2.5 (PM2.5) in the air, which poses significant harm to skin health. However, limited research has been performed to identify molecules that can confer resistance to such substances. Herein, we analyzed the effect of fermented sea tangle (FST) extract on PM2.5-induced human HaCaT keratinocyte damage. Results showed that FST extract, at concentrations less than 800 µg/mL, exhibited non-significant toxicity to cells and concentration-dependent inhibition of PM2.5-induced reactive oxygen species (ROS) production. PM2.5 induced oxidative stress by stimulating ROS, resulting in DNA damage, lipid peroxidation, and protein carbonylation, which were inhibited by the FST extract. FST extract significantly suppressed the increase in calcium level and apoptosis caused by PM2.5 treatment and significantly restored the reduced cell viability. Mitochondrial membrane depolarization occurred due to PM2.5 treatment, however, FST extract recovered mitochondrial membrane polarization. PM2.5 inhibited the expression of the anti-apoptotic protein Bcl-2, and induced the expression of pro-apoptotic proteins Bax and Bim, the apoptosis initiator caspase-9, as well as the executor caspase-3, however, FST extract effectively protected the changes in the levels of these proteins caused by PM2.5. Interestingly, pan-caspase inhibitor Z-VAD-FMK treatment enhanced the anti-apoptotic effect of FST extract in PM2.5-treated cells. Our results indicate that FST extract prevents PM2.5-induced cell damage via inhibition of mitochondria-mediated apoptosis in human keratinocytes. Accordingly, FST extract could be included in skin care products to protect cells against the harmful effects of PM2.5.
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Queratinocitos , Piel , Humanos , Especies Reactivas de Oxígeno , Apoptosis , Material Particulado/toxicidadRESUMEN
Runt domain transcription factor 3 (RUNX3) suppresses many different cancer types and is disabled by mutations, epigenetic repression, or cytoplasmic mislocalization. In this study, we investigated whether oxidative stress is associated with RUNX3 accumulation from the nucleus to the cytoplasm in terms of histone modification. Oxidative stress elevated histone deacetylase (HDAC) level and lowered that of histone acetyltransferase. In addition, oxidative stress decreased the expression of mixed lineage leukemia (MLL), a histone methyltransferase, but increased the expression of euchromatic histone-lysine N-methyltransferase 2 (EHMT2/G9a), which is also a histone methyltransferase. Moreover, oxidative stress-induced RUNX3 phosphorylation, Src activation, and Jun activation domain-binding protein 1 (JAB1) expression were inhibited by knockdown of HDAC and G9a, restoring the nuclear localization of RUNX3 under oxidative stress. Cytoplasmic RUNX3 localization was followed by oxidative stress-induced histone modification, activated Src along with RUNX3 phosphorylation, and induction of JAB1, resulting in RUNX3 inactivation.
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Background: The exposure of the human skin to particulate matter 2.5 (PM2.5) results in adverse health outcomes, such as skin aging, wrinkle formation, pigment spots, and atopic dermatitis. It has previously been shown that rosmarinic acid (RA) can protect keratinocytes from ultraviolet B radiation by enhancing cellular antioxidant systems and reducing oxidative damage; however, its protective action against the adverse effects of PM2.5 on skin cells remains unclear. Therefore, in this study, we explored the mechanism underlying the protective effects of RA against PM2.5-mediated oxidative stress in HaCaT keratinocytes. Methods: HaCaT keratinocytes were pretreated with RA and exposed to PM2.5. Thereafter, reactive oxygen species (ROS) production, protein carbonylation, lipid peroxidation, DNA damage, and cellular apoptosis were investigated using various methods, including confocal microscopy, western blot analysis, and flow cytometry. Results: RA significantly inhibited PM2.5-induced lipid peroxidation, protein carbonylation, DNA damage, increases in intracellular Ca2+ level, and mitochondrial depolarization. It also significantly attenuated PM2.5-induced apoptosis by downregulating Bcl-2-associated X, cleaved caspase-9, and cleaved caspase-3 protein levels, while upregulating B-cell lymphoma 2 protein level. Further, our results indicated that PM2.5-induced apoptosis was associated with the activation of the mitogen-activated protein kinase (MAPK) signaling pathway and that MAPK inhibitors as well as RA exhibited protective effects against PM2.5-induced apoptosis. Conclusion: RA protected HaCaT cells from PM2.5-induced apoptosis by lowering oxidative stress.
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Material Particulado , Ácido Rosmarínico , Humanos , Material Particulado/toxicidad , Línea Celular , Queratinocitos , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , ApoptosisRESUMEN
Stimulation of human keratinocytes with particulate matter 2.5 (PM2.5) elicits complex signaling events, including a rise in the generation of reactive oxygen species (ROS). However, the mechanisms underlying PM2.5-induced ROS production remain unknown. Here, we show that PM2.5-induced ROS production in human keratinocytes is mediated via the NADPH oxidase (NOXs) system and the Ca2+ signaling pathway. PM2.5 treatment increased the expression of NOX1, NOX4, and a calcium-sensitive NOX, dual oxidase 1 (DUOX1), in human epidermal keratinocyte cell line. PM2.5 bound to aryl hydrocarbon receptor (AhR), and this complex bound to promoter regions of NOX1 and DUOX1, suggesting that AhR acted as a transcription factor of NOX1 and DUOX1. PM2.5 increased the transcription of DUOX1 via epigenetic modification. Moreover, a link between DNA demethylase and histone methyltransferase with the promoter regions of DUOX1 led to an elevation in the expression of DUOX1 mRNA. Interestingly, PM2.5 increased NOX4 expression and promoted the interaction of NOX4 and Ca2+ channels within the cytoplasmic membrane or endoplasmic reticulum, leading to Ca2+ release. The increase in intracellular Ca2+ concentration activated DUOX1, responsible for ROS production. Our findings provide evidence for a PM2.5-mediated ROS-generating system network, in which increased NOX1, NOX4, and DUOX1 expression serves as a ROS signal through AhR and Ca2+ activation.
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NADPH Oxidasas , Receptores de Hidrocarburo de Aril , Humanos , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Oxidasas Duales/genética , Oxidasas Duales/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Material Particulado/toxicidad , Epigénesis GenéticaRESUMEN
BACKGROUND/AIM: Melanoma is a prevalent malignant tumor that arises from melanocytes. The treatment of malignant melanoma has become challenging due to the development of drug resistance. It is, therefore, imperative to identify novel therapeutic drug candidates for controlling malignant melanoma. Naringenin is a flavonoid abundant in oranges and other citrus fruits and recognized for its numerous medicinal benefits. The objective of the study was to assess the anti-carcinogenic potential of naringenin by evaluating its ability to regulate the cellular production of reactive oxygen species (ROS) and its effect on mitochondrial function and apoptosis in melanoma cells. MATERIALS AND METHODS: Cell viability, intracellular ROS levels, cell apoptosis, and mitochondrial functions were evaluated. RESULTS: Naringenin decreased melanoma cell viability and triggered generation of ROS, leading to cell apoptosis. In addition, it stimulated mitochondrial damage in melanoma cells by elevating the levels of Ca2+ and ROS in the mitochondria and decreasing cellular ATP. Naringenin stimulated the expression of proapoptotic proteins, including phospho p53, B-cell lymphoma-2 (Bcl-2)-associated X protein, cleaved caspase-3, and cleaved caspase-9, in melanoma cells in a time-dependent manner. Furthermore, it reduced the expression of the anti-apoptotic protein Bcl-2. Naringenin triggered cell apoptosis by phosphorylating c-Jun N-terminal kinase and stimulating cellular autophagy. CONCLUSION: Naringenin caused oxidative stress and mitochondrial damage, and activated autophagy in melanoma cells, leading to cell apoptosis. These findings indicate the potential of naringenin as a new therapeutic candidate for melanoma.
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Flavanonas , Melanoma , Humanos , Especies Reactivas de Oxígeno/metabolismo , Melanoma/patología , Línea Celular Tumoral , Apoptosis , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Potencial de la Membrana MitocondrialRESUMEN
Rosmarinic acid (RA) is a phenolic ester that protects human keratinocytes against oxidative damage induced by ultraviolet B (UVB) exposure, however, the mechanisms underlying its effects remain unclear. This study aimed to elucidate the cell signaling mechanisms that regulate the antioxidant activity of RA and confirm its cyto-protective role. To explore the signaling mechanisms, we used the human keratinocyte cell line HaCaT and SKH1 hairless mouse skin. RA enhanced glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase (GSS) expression in HaCaT cells in a dose- and time-dependent manner. Moreover, RA induced nuclear factor erythroid-2-related factor 2 (NRF2) nuclear translocation and activated the signaling kinases protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, the ERK inhibitor U0126, and small interfering RNA (siRNA) gene silencing suppressed RA-enhanced GCLC, GSS, and NRF2 expression, respectively. Cell viability tests showed that RA significantly prevented UVB-induced cell viability decrease, whereas the glutathione (GSH) inhibitors buthionine sulfoximine, LY294002, and U0126 significantly reduced this effect. Moreover, RA protected against DNA damage and protein carbonylation, lipid peroxidation, and apoptosis caused by UVB-induced oxidative stress in a concentration-dependent manner in SKH1 hairless mouse skin tissues. These results suggest that RA protects against UVB-induced oxidative damage by activating AKT and ERK signaling to regulate NRF2 signaling and enhance GSH biosynthesis. Thus, RA treatment may be a promising approach to protect the skin from UVB-induced oxidative damage.
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In the original publication [...].
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Skin is a direct target of fine particulate matter (PM2.5), as it is constantly exposed. Herein, we investigate whether Korean red ginseng (KRG) can inhibit PM2.5-induced senescence in skin keratinocytes. PM2.5-treated human keratinocyte cell lines and normal human epidermal keratinocytes showed characteristics of cellular senescence, including flat and enlarged forms; however, KRG suppressed them in both cell types. Moreover, while cells exposed to PM2.5 showed a higher level of p16INK4A expression (a senescence inducer), KRG inhibited its expression. Epigenetically, KRG decreased the expression of the ten-eleven translocation (TET) enzyme, a DNA demethylase induced by PM2.5, and increased the expression of DNA methyltransferases suppressed by PM2.5, resulting in the decreased methylation of the p16INK4A promoter region. Additionally, KRG decreased the expression of mixed-lineage leukemia 1 (MLL1), a histone methyltransferase, and histone acetyltransferase 1 (HAT1) induced by PM2.5. Contrastingly, KRG increased the expression of the enhancer of zeste homolog 2, a histone methyltransferase, and histone deacetyltransferase 1 reduced by PM2.5. Furthermore, KRG decreased TET1, MLL1, and HAT1 binding to the p16INK4A promoter, corresponding with the decreased mRNA expression of p16INK4A. These results suggest that KRG exerts protection against the PM2.5-induced senescence of skin keratinocytes via the epigenetic regulation of p16INK4A.
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Excessive UVB exposure causes development of both malignant and non-malignant melanoma via the secretion of α-melanocyte-stimulating hormone (α-MSH). We investigated whether baicalein (5,6,7-trihydroxyflavone) could inhibit α-MSH-stimulated melanogenesis. Baicalein prevented UVB- and α-MSH-induced melanin production and attenuated α-MSH-stimulated tyrosinase (monophenol monooxygenase) activity, and expression of tyrosinase and tyrosine-related protein-2. In addition, baicalein prevented melanogenesis and pigmentation via the p38 mitogen-activated protein kinases signaling pathway. These findings suggest that baicalein represents a natural compound for attenuating melanogenesis.
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Cellular senescence can be activated by several stimuli, including ultraviolet radiation and air pollutants. This study aimed to evaluate the protective effect of marine algae compound 3-bromo-4,5-dihydroxybenzaldehyde (3-BDB) on particulate matter 2.5 (PM2.5)-induced skin cell damage in vitro and in vivo. The human HaCaT keratinocyte was pre-treated with 3-BDB and then with PM2.5. PM2.5-induced reactive oxygen species (ROS) generation, lipid peroxidation, mitochondrial dysfunction, DNA damage, cell cycle arrest, apoptotic protein expression, and cellular senescence were measured using confocal microscopy, flow cytometry, and Western blot. The present study exhibited PM2.5-generated ROS, DNA damage, inflammation, and senescence. However, 3-BDB ameliorated PM2.5-induced ROS generation, mitochondria dysfunction, and DNA damage. Furthermore, 3-BDB reversed the PM2.5-induced cell cycle arrest and apoptosis, reduced cellular inflammation, and mitigated cellular senescence in vitro and in vivo. Moreover, the mitogen-activated protein kinase signaling pathway and activator protein 1 activated by PM2.5 were inhibited by 3-BDB. Thus, 3-BDB suppressed skin damage induced by PM2.5.
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Neurodegenerative diseases are associated with neuronal cell death through apoptosis. Apoptosis is tightly associated with the overproduction of reactive oxygen species (ROS), and high glucose levels contribute to higher oxidative stress in diabetic patients. Hesperidin, a natural active compound, has been reported to scavenge free radicals. Only a few studies have explored the protective effects of hesperidin against high glucose-induced apoptosis in SH-SY5Y neuronal cells. Glucose stimulated neuronal cells to generate excessive ROS and caused DNA damage. In addition, glucose triggered endoplasmic reticulum stress and upregulated cytoplasmic as well as mitochondrial calcium levels. Hesperidin inhibited glucose-induced ROS production and mitigated the associated DNA damage and endoplasmic reticulum stress. The downregulation of antiapoptotic protein Bcl-2 following glucose treatment was reversed by a hesperidin treatment. Furthermore, hesperidin repressed the glucose-induced Bcl-2-associated X protein, cleaved caspase-9, and cleaved caspase-3. Hesperidin also suppressed the glucose-induced phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase. The current results confirmed that hesperidin could protect neuronal cells against glucose-induced ROS. Mechanistically, hesperidin was shown to promote cell viability via attenuation of the mitogen-activated protein kinase signaling pathway.
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Ginseng (Panax ginseng Meyer) has been used in East Asian traditional medicine for a long time. Korean red ginseng (KRG) is effective against several disorders, including cancer. The cytotoxic effects of KRG extract in terms of autophagy- and apoptosis-mediated cell death and its mechanisms were investigated using human colorectal cancer lines. KRG induced autophagy-mediated cell death with enhanced expression of Atg5, Beclin-1, and LC3, and formed characteristic vacuoles in HCT-116 and SNU-1033 cells. An autophagy inhibitor prevented cell death induced by KRG. KRG generated mitochondrial reactive oxygen species (ROS); antioxidant countered this effect and decreased autophagy. KRG caused apoptotic cell death by increasing apoptotic cells and sub-G1 cells, and by activating caspases. A caspase inhibitor suppressed cell death induced by KRG. KRG increased phospho-Bcl-2 expression, but decreased Bcl-2 expression. Moreover, interaction of Bcl-2 with Beclin-1 was attenuated by KRG. Ginsenoside Rg2 was the most effective ginsenoside responsible for KRG-induced autophagy- and apoptosis-mediated cell death. KRG induced autophagy- and apoptosis-mediated cell death via mitochondrial ROS generation, and thus its administration may inhibit colon carcinogenesis.