Phytochemical profiles, phototoxic and antioxidant properties of eleven Hypericum species - A comparative study.

The purpose of the current study was to investigate the effect of dietary dihydroquercetin (DHQ) supplementation on dextran sodium sulfate (DSS)-induced colitis in mice. Mice were given DHQ supplementation (3 g kg−1) throughout the study, starting 14 days prior to DSS treatment for 1 week followed by 2 days without DSS. The results showed that dietary DHQ supplementation restored DSS-induced disease activity index (DAI), colon length and histopathology scores of the colon tissue. Additionally, supplementation with DHQ reduced the pro-inflammatory cytokine levels, and enhanced the level of IL-10 in the serum. qPCR results indicated that DHQ supplementation significantly downregulated IL-1β, IL-6, and TNF-α, and upregulated IL-10 gene mRNA expression. Western blot results proved that DHQ supplementation upregulated ZO-1 and occludin levels. Using amplicon sequencing technology, 16S rRNA sequencing results showed that DHQ supplementation increased the fecal Firmicutes/Bacteroidetes ratio and the relative abundance of Lactobacillus and Dubosiella, and decreased the relative abundance of Bacteroidetes. Additionally, DHQ supplementation restored the decreased fecal acetic acid and butyric acid concentrations in DSS-induced colitis mice. Besides, Spearman's correlation analysis showed that Dubosiella was positively correlated with the butyric acid level and Bacteroidetes was positively correlated with the mRNA expression of IL-1β and IL-6. Both Lactobacillus and Dubosiella showed a negative correlation with the mRNA expression of IL-1β, IL-6, and TNF-α, and Dubosiella was positively correlated with IL-10. In summary, it was found that DHQ supplementation alleviated DSS-induced colitis which may be potentially associated with altered fecal microbiota communities in mice.

Dihydroquercetin supplement alleviates colonic inflammation potentially through improved gut microbiota community in mice.

Caffeic acid (CA) is found abundantly in fruits, vegetables, tea, coffee, oils, and more. CA and its derivatives have been used for many centuries due to their natural healing and medicinal properties. CA possesses various biological and pharmacological activities, including antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. The potential therapeutic effects of CA are mediated via repression and inhibition of transcription and growth factors. CA possesses potential anticancer and neuroprotective effects in human cell cultures and animal models. However, the biomolecular interactions and pathways of CA have been described highlighting the target binding proteins and signaling molecules. The current review focuses on CA’s chemical, physical, and pharmacological properties, including antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. We further described CA’s characteristics and therapeutic potential and its future directions.

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Therapeutic Implications of Caffeic Acid in Cancer and Neurological Diseases

Many pathological problems are initiated by ultraviolet radiation (UVR), such as skin cancer, the most commonly diagnosed cancer worldwide. The UVA (320–400 nm) and UVB (290–320 nm) wavelengths may cause effects such as photoaging, DNA damage, and a series of cellular alterations. The UVA radiation can damage the DNA, oxidize the lipids, and produce dangerous free radicals, which can cause inflammation, modify the gene expression in response to stress, and weaken the skin immune response. With a minor penetration, the UVB radiation is more harmful, being responsible for immediate damage. Ultraviolet radiation light emitted by the sun is considered necessary for the existence of life but cause radiation problems, especially in the skin. The photoprotective activities of plant extracts and isolated composts were evaluated by many reports, as well as the correlation of these compounds with the antioxidant activity. This review presents plant compounds with interest to the cosmetic industry to be used in sunscreens such as flavonoids and cinnamates.

https://downloads.hindawi.com/journals/aps/2018/5341487.pdf

Use of Flavonoids and Cinnamates, the Main Photoprotectors with Natural Origin

Silybum marianum (L.) is a medicinal plant traditionally used in treatment of liver disorders. In last decades, silymarin (SM), a standardized extract from S. marianum seeds has been studied for its dermatological application, namely for UVB-protective properties. However, information on SM and its polyphenols effect on activity of enzymes participating in the (photo)aging process is limited. Therefore, evaluation of SM and its flavonolignans potential to inhibit collagenase, elastase, and hyaluronidase in tube tests was the goal of this study. The antioxidant and UV screening properties of SM and its flavonolignans silybin, isosilybin, silydianin, silychristin and 2,3-dehydrosilybin (DHSB) were also evaluated by a DPPH assay and spectrophotometrical measurement. DHSB showed the highest ability to scavenge DPPH radical and also revealed the highest UVA protection factor (PF-UVA) that corresponds with its absorption spectrum. SM and studied flavonolignans were found to exhibit anti-collagenase and anti-elastase activity. The most potent flavonolignan was DHSB. None of studied flavonolignans or SM showed anti-hyaluronidase activity. Our results suggest that SM and its flavonolignans may be useful agents for skin protection against the harmful effects of full-spectrum solar radiation including slowing down skin (photo)aging.

https://www.mdpi.com/1420-3049/24/6/1022/pdf

Skin Protective Activity of Silymarin and its Flavonolignans.

Exposure to solar radiation is a major cause of environmental human skin damage. The main constituent of solar UV light is UVA radiation (320–400 nm); however, the need for protection against UVA has been marginalized for a long time. As a result, there is still a lack of useful agents for UVA protection. In this study, the effect of silymarin (SM) and its main constituent silybin (SB) pre-treatment on UVA-stimulated damage to primary human dermal fibroblasts were carried out. The cells were pre-treated for 1 h with SB or SM and then were exposed to UVA light, using a solar simulator. The effect of SB and SM on reactive oxygen species (ROS) and glutathione (GSH) level, caspase-3 activity, single-strand breaks (SSB) formation and protein level of matrix metalloproteinase-1 (MMP-1), heme oxygenase-1 (HO-1), and heat shock protein (HSP70) was evaluated. Treatment with both SM and SB resulted in a reduction in UVA-stimulated ROS generation and SSB production, as well as in the prevention of GSH depletion, a decrease in the activation of caspase-3 and protein level of MMP-1. They also moderately increased HO-1 level and reduced HSP70 level. Our data showed that both SM and SB are non-phototoxic and have UVA-photoprotective potential and could be useful agents for UV-protective dermatological preparations.

UVA-photoprotective potential of silymarin and silybin

PURPOSE Excessive exposure of skin to solar radiation is associated with greatly increased production of reactive oxygen and nitrogen species (ROS, RNS) resulting in oxidative stress (OS), inflammation, immunosuppression, the production of matrix metalloproteinase, DNA damage and mutations. These events lead to increased incidence of various skin disorders including photoaing and both non-melanoma and melanoma skin cancers. The ultraviolet (UV) part of sunlight, in particular, is responsible for structural and cellular changes across the different layers of the skin. Among other effects, UV photons stimulate oxidative damage to biomolecules via the generation of unstable and highly reactive compounds. In response to oxidative damage, cytoprotective pathways are triggered. One of these is the pathway driven by the nuclear factor erythroid-2 related factor 2 (Nrf2). This transcription factor translocates to the nucleus and drives the expression of numerous genes, among them various detoxifying and antioxidant enzymes. Several studies concerning the effects of UV radiation on Nrf2 activation have been published, but different UV wavelengths, skin cells or tissues and incubation periods were used in the experiments that complicate the evaluation of UV radiation effects. CONCLUSIONS This review summarizes the effects of UVB (280-315 nm) and UVA (315-400 nm) radiation on the Nrf2 signaling pathway in dermal fibroblasts and epidermal keratinocytes and melanocytes. The effects of natural compounds (pure compounds or mixtures) on Nrf2 activation and level as well as on Nrf2-driven genes in UV irradiated human skin fibroblasts, keratinocytes and melanocytes are briefly mentioned as well.HighlightsUVB radiation is a rather poor activator of the Nrf2-driven pathway in fibroblastsUVA radiation stimulates Nrf2 activation in dermal fibroblastsEffects of UVA on the Nrf2 pathway in keratinocytes and melanocytes remain unclearLong-term Nrf2 activation in keratinocytes disturbs their normal differentiationPharmacological activation of Nrf2 in the skin needs to be performed carefully.

Effect of ultraviolet radiation on the Nrf2 signaling pathway in skin cells.

The harmful effects of low energy UVA photons (315–400 nm) are associated with the massive production of reactive oxygen species resulting in oxidative stress. In response to oxidative damage, NF-E2-related factor 2 (Nrf2) is translocated to the nucleus and drives the expression of detoxication and antioxidant enzymes. UVA's effect on Nrf2 has been quite well characterised in dermal fibroblasts. However, there is a dearth of such information for keratinocytes. This study aimed to evaluate and compare the effect of UVA radiation on the Nrf2 pathway and oxidative stress related proteins in primary human dermal fibroblasts (NHDF), epidermal keratinocytes (NHEK) and human keratinocyte cell line HaCaT. NHDF were exposed to doses of 2.5–7.5 J/cm2, NHEK and HaCaT to 10–20 J/cm2 using a solar simulator. Effects on Nrf2 translocation were evaluated after 1, 3 and 6 h and Nrf2-controlled proteins (heme oxygenase 1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione reductase (GSR), glutathione-S-transferase (GST), interleukine-6 (IL-6), and matrix metalloproteinases (MMP-1, MMP-2)) after 3, 6 and 24 h. The results showed the fastest Nrf2 translocation was in UVA-irradiated HaCaT (1 h), persisting until the subsequent time interval (3 h), while in primary keratinocytes the effect of radiation was minimal. In NHDF, UVA-stimulated Nrf2 translocation was conspicuous 3 h after UVA treatment. In NHDF, most of the studied proteins (NQO1, HO-1, GSR, GSTM1 and MMP-1) showed the highest level 24 h after UVA exposure, except for MMP-2 and IL-6 which had their highest level at a shorter time incubation interval (3 h). In NHEK, NQO1, HO-1 and GST were increased 6 h after UVA exposure, GSR and MMP-2 level was slightly below or above the control level, and MMP-1 and IL-6 increased at shorter time intervals. When comparing NHEK and HaCaT, these cells displayed contrary responses in most of the Nrf2-controlled proteins. Thus, primary keratinocytes cannot be replaced with HaCaT when studying cell signalling such as the Nrf2 driven pathway and Nrf2-controlled proteins.

Effect of UVA radiation on the Nrf2 signalling pathway in human skin cells.

Quercetin, one of the most abundant polyphenols in the plant kingdom has been shown to be photodegraded on exposure to UV light. Despite the fact, it is a component of several dermatological preparations. Its phototoxic potential has not been evaluated to date. The aim of this study was to assess whether photo-induced degradation of quercetin is linked to phototoxic effects on living cells. Its dihydro derivative, taxifolin, was included in the study. For evaluation, the 3T3 Neutral Red Uptake Phototoxicity Test according to OECD TG 432 was used. To better approximate human skin, HaCaT keratinocytes, normal human epidermal keratinocytes and dermal fibroblasts were used, apart from the Balb/c 3T3 cell line. Quercetin showed a dose-dependent photodegradation in aqueous and organic environments and a phototoxic effect on all used cells. Quercetin pretreatment and following UVA exposure resulted in increased reactive oxygen species production and intracellular glutathione level depletion in human dermal fibroblasts. Taxifolin was found completely nonphototoxic and photostable. As only in vitro methodology was used, further studies using 3D skin models and/or human volunteers are needed to confirm whether exposure to sunlight, tanning sunbeds and/or phototherapy in people using cosmetics containing quercetin is a health risk.

The Phototoxic Potential of the Flavonoids, Taxifolin and Quercetin

The ultraviolet (UV) part of solar radiation can permanently affect skin tissue. UVA photons represent the most abundant UV component and stimulate the formation of intracellular reactive oxygen species (ROS), leading to oxidative damage to various biomolecules. Several plant-derived polyphenols are known as effective photoprotective agents. This study evaluated the potential of quercetin (QE) and its structurally related flavonoid taxifolin (TA) to reduce UVA-caused damage to human primary dermal fibroblasts (NHDF) and epidermal keratinocytes (NHEK) obtained from identical donors. Cells pre-treated with QE or TA (1 h) were then exposed to UVA light using a solar simulator. Both flavonoids effectively prevented oxidative damage, such as ROS generation, glutathione depletion, single-strand breaks formation and caspase-3 activation in NHDF. These protective effects were accompanied by stimulation of Nrf2 nuclear translocation, found in non-irradiated and irradiated NHDF and NHEK, and expression of antioxidant proteins, such as heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1 and catalase. For most parameters, QE was more potent than TA. On the other hand, TA demonstrated protection within the whole concentration range, while QE lost its protective ability at the highest concentration tested (75 μM), suggesting its pro-oxidative potential. In summary, QE and TA demonstrated UVA-protective properties in NHEK and NHDF obtained from identical donors. However, due to the in vitro phototoxic potential of QE, published elsewhere and discussed herein, further studies are needed to evaluate QE safety in dermatological application for humans as well as to confirm our results on human skin ex vivo and in clinical trials.

Alena Ryšavá

Papers

UVA-photoprotective potential of silymarin and silybin

Effect of ultraviolet radiation on the Nrf2 signaling pathway in skin cells.

Effect of UVA radiation on the Nrf2 signalling pathway in human skin cells.

The Phototoxic Potential of the Flavonoids, Taxifolin and Quercetin

Effect of the flavonoids quercetin and taxifolin on UVA-induced damage to human primary skin keratinocytes and fibroblasts