Rosarugosides A and D from Rosa rugosa Flower Buds: Their Potential Anti-Skin-Aging Effects in TNF-α-Induced Human Dermal Fibroblasts.

This present study investigated the anti-skin-aging properties of Rosa rugosa. Initially, phenolic compounds were isolated from a hot water extract of Rosa rugosa's flower buds. Through repeated chromatography (column chromatography, MPLC, and prep HPLC), we identified nine phenolic compounds (1-9), including a previously undescribed depside, rosarugoside D (1). The chemical structure of 1 was elucidated via NMR, HR-MS, UV, and hydrolysis. Next, in order to identify bioactive compounds that are effective against TNF-α-induced NHDF cells, we measured intracellular ROS production in samples treated with each of the isolated compounds (1-9). All isolates reduced the level of ROS at a concentration of 10 µM. Particularly, two depsides-rosarugosides A and D (2 and 1)-significantly inhibited ROS expression in TNF-α-induced NHDFs compared to the other phenolic compounds. Subsequently, the production of MMP-1 and procollagen type Ι α1 by these two depsides was examined. Remarkably, rosarugoside A (2) significantly decreased MMP-1 secretion at all concentrations. In contrast, rosarugoside D (1) regulated the expression of procollagen type Ι α1. These findings collectively suggest that Rosa rugosa extracts and their isolated compounds, rosarugosides A (2) and D (1), hold significant potential for protecting against aging and skin damage. Overall, these findings suggest that Rosa rugosa extracts and their isolated compounds, rosarugosides A (2) and D (1), have the potential to prevent and protect against aging and skin damage, although more specific quantitative analysis is needed.

The Effects of Flavonol and Flavone Glucuronides from Potentilla chinensis Leaves on TNF-α-Exposed Normal Human Dermal Fibroblasts.

Skin aging is a complex biological process influenced by a variety of factors, including UV radiation. UV radiation accelerates collagen degradation via the production of reactive oxygen species (ROS) and cytokines, including TNF-α. In a prior investigation, the inhibitory properties of flavonol and flavone glucuronides derived from Potentilla chinensis on TNF-α-induced ROS and MMP-1 production were explored. Consequently, we verified the skin-protective effects of these flavonol and flavone glucuronides, including potentilloside A, from P. chinensis, and conducted a structure-activity relationship analysis as part of our ongoing research. We investigated the protective effects of the extract and its 11 isolates on TNF-α-stimulated normal human dermal fibroblasts (NHDFs). Ten flavonol and flavone glucuronides significantly inhibited ROS generation (except for 7) and suppressed MMP-1 secretion, except for 2. In contrast, six isolates (1, 5, 6, 11, 9, 10, and 11) showed a significant reverse effect on COLIA1 secretion. Comparing the three experimental results of each isolate, potentilloside A (1) showed the most potent skin cell-protective effect among the isolates. Evaluation of the signaling pathway of potentilloside A in TNF-α-stimulated NHDF revealed that potentilloside A inhibits the phosphorylation of ERK, JNK, and c-Jun. Taken together, these results suggest that compounds isolated from P. chinensis, especially potentilloside A, can be used to inhibit skin damage, including aging.

Laricitrin 3-Rutinoside from Ginkgo biloba Fruits Prevents Damage in TNF-α-Stimulated Normal Human Dermal Fibroblasts.

Human skin comprises the epidermis and dermis, which perform interactive functional activities with each other in order to maintain the skin's tensile strength. In particular, the dermal layer is crucial for skin protection. However, skin aging destroys collagen and elastin fibers, causing wrinkles, pigments, and sagging. Skin aging-related factors, such as tumor necrosis factor-α (TNF-α), promote the generation of intercellular reactive oxygen species (ROS). These are known to stimulate the hypersecretion of matrix metalloproteinase-1 (MMP-1), which degrades collagen and inhibits collagen synthesis. In this study, as part of our ongoing discovery of natural products, we investigated potential natural products derived from ginkgo fruit (Ginkgo biloba fruit) with protective effects against TNF-α-induced skin aging. Phytochemical investigation of the MeOH extract of G. biloba fruits, aided by liquid chromatography-mass spectrometry, led to the isolation of 14 compounds (1-14) from the n-butanol-soluble fraction. These were structurally determined to be: (E)-coniferin (1), syringin (2), 4-hydroxybenzoic acid 4-O-ß-D-glucopyranoside (3), vanillic acid 4-O-ß-D-glucopyranoside (4), glucosyringic acid (5), (E)-ferulic acid 4-O-ß-D-glucoside (6), (E)-sinapic acid 4-O-ß-D-glucopyranoside (7), ginkgotoxin-5-glucoside (8), ginkgopanoside (9), (Z)-4-coumaric acid 4-O-ß-D-glucopyranoside (10), (1'R,2'S,5'R,8'S,2'Z,4'E)-dihydrophaseic acid 3'-O-ß-D-glucopyranoside (11), eucomic acid (12), rutin (13), and laricitrin 3-rutinoside (L3R) (14). Biological evaluation of the isolated compounds for their effects on intracellular ROS generation showed that, of these 14 compounds, L3R (14) inhibited TNF-α-stimulated ROS generation (p < 0.001 at 100 µM). Inhibition of ROS generation by L3R led to the suppression of MMP-1 secretion and protection against collagen degradation. The inhibitory effect of L3R was mediated by the inhibition of extracellular signal regulated kinase (ERK) phosphorylation. Furthermore, L3R diminished the secretion of pro-inflammatory cytokines interleukin 6 (IL-6) and interleukin 8 (IL-8). Based on these experimental results, L3R is a potential bioactive natural product that can be used to protect against skin damage, including aging, in cosmetics and pharmaceuticals.

2-O-ß-d-Glucopyranosyl-4,6-dihydroxybenzaldehyde Isolated from Morus alba (Mulberry) Fruits Suppresses Damage by Regulating Oxidative and Inflammatory Responses in TNF-α-Induced Human Dermal Fibroblasts.

Human skin is composed of three layers, of which the dermis is composed of an extracellular matrix (ECM) comprising collagen, elastin, and other proteins. These proteins are reduced due to skin aging caused by intrinsic and extrinsic factors. Among various internal and external factors related to aging, ultraviolet (UV) radiation is the main cause of photoaging of the skin. UV radiation stimulates DNA damage, reactive oxygen species (ROS) generation, and pro-inflammatory cytokine production such as tumor necrosis factor-alpha (TNF-α), and promotes ECM degradation. Stimulation with ROS and TNF-α upregulates mitogen-activated protein kinases (MAPKs), nuclear factor kappa B (NF-κB), and activator protein 1 (AP-1) transcription factors that induce the expression of the collagenase matrix metalloproteinase-1 (MMP-1). Moreover, TNF-α induces intracellular ROS production and several molecular pathways. Skin aging progresses through various processes and can be prevented through ROS generation and TNF-α inhibition. In our previous study, 2-O-ß-d-glucopyranosyl-4,6-dihydroxybenzaldehyde (GDHBA) was isolated from the Morus alba (mulberry) fruits and its inhibitory effect on MMP-1 secretion was revealed. In this study, we focused on the effect of GDHBA on TNF-α-induced human dermal fibroblasts (HDFs). GDHBA (50 µM) inhibited ROS generation (18.8%) and decreased NO (58.4%) and PGE2 levels (53.8%), significantly. Moreover, it decreased MMP-1 secretion (55.3%) and increased pro-collagen type I secretion (207.7%). GDHBA (50 µM) decreased the expression of different MAPKs as per western blotting; p-38: 35.9%; ERK: 47.9%; JNK: 49.5%; c-Jun: 32.1%; NF-κB: 55.9%; and cyclooxygenase-2 (COX-2): 31%. This study elucidated a novel role of GDHBA in protecting against skin inflammation and damage through external stimuli, such as UV radiation.

Potentilloside A, a New Flavonol-bis-Glucuronide from the Leaves of Potentilla chinensis, Inhibits TNF-α-Induced ROS Generation and MMP-1 Secretion.

The major contributor to skin aging is UV radiation, which activates pro-inflammatory cytokines including TNF-α. TNF-α is involved in the acceleration of skin aging via ROS generation and MMP-1 secretion. In our preliminary study, a 30% EtOH extract from the leaves of Potentilla chinensis (LPCE) significantly inhibited TNF-α-induced ROS generation in human dermal fibroblasts (HDFs). Therefore, the objective of this study is to identify the active components in LPCE. A new flavonol-bis-glucuronide (potentilloside A, 1) and 14 known compounds (2-15) were isolated from an LPCE by repeated chromatography. The chemical structure of the new compound 1 was determined by analyzing its spectroscopic data (NMR and HRMS) and by acidic hydrolysis. Nine flavonols (2-9 and 11) and two flavone glycosides (12 and 13) from P. chinensis were reported for the first time in this study. Next, we evaluated the effects of the isolates (1-15) on TNF-α-induced ROS generation in HDFs. As a result, all compounds significantly inhibited ROS generation. Furthermore, LPCE and potentilloside A (1) remarkably suppressed MMP-1 secretion in HDFs stimulated by TNF-α. The data suggested that LPCE and potentilloside A (1) are worthy of further experiments for their potential as anti-skin aging agents.

Protective Effects of Withagenin A Diglucoside from Indian Ginseng (Withania somnifera) against Human Dermal Fibroblast Damaged by TNF-α Stimulation.

Human skin is constructed with many proteins such as collagen and elastin. Collagen and elastin play a key role in providing strength and elasticity to the human skin and body. However, damage to collagen causes various symptoms such as wrinkles and freckles, which suggests that they are important to maintain skin condition. Extrinsic or intrinsic skin aging produces an excess of skin destructive factors such as tumor necrosis factor (TNF)-α, which is a major mediator of the aging process. In aged skin, TNF-α provokes the generation of intracellular ROS (reactive oxygen species). It triggers the excessive secretion of MMP-1, which is a collagen-degrading enzyme that causes the collapse of skin collagen. Therefore, we aimed to search for a natural-product-derived candidate that inhibits the skin damage caused by TNF-α in human dermal fibroblasts. In this study, the protective effect of withagenin A diglucoside (WAD) identified from Withania somnifera against TNF-α-stimulated human dermal fibroblasts is investigated. W. somnifera (Solanaceae), well-known as 'ashwagandha', is an Ayurvedic medicinal plant useful for promoting health and longevity. Our experimental results reveal that WAD from W. somnifera suppresses the generation of intercellular ROS. Suppressing intracellular ROS generation inhibits MMP-1 secretion and the collapse of type 1 collagen. The effect of WAD is shown to depend on the inhibition of MAPK phosphorylation, Akt phosphorylation, c-Jun phosphorylation, COX-2 expression, and NF-κB phosphorylation. Further, WAD-depressed expression of the pro-inflammatory cytokines IL-6 and IL-8 triggers various inflammatory reactions in human skin. These findings suggest that WAD has protective effects against skin damage. Accordingly, our study provides experimental evidence that WAD can be a potential agent that can be applied in various industrial fields, such as cosmetics and pharmaceuticals related to skin aging.

Antiskin Aging Effects of Indole Alkaloid N-Glycoside from Ginkgo Fruit (Ginkgo biloba fruit) on TNF-α-Exposed Human Dermal Fibroblasts.

Human skin aging has internal and external factors, both of which are characterized by TNF-α overproduction. Therefore, we aimed to identify a natural product that suppresses the damage that occurs in cutaneous dermal fibroblasts exposed to TNF-α. The protective effects of the indole alkaloid N-glycoside, ginkgoside B dimethyl ester (GBDE), isolated from ginkgo fruit (Ginkgo biloba fruit) were evaluated in TNF-α stimulated human dermal fibroblasts (HDFs). GBDE inhibited TNF-α-induced MMP-1 expression to 2.2 ± 0.1-fold (p < 0.01) and reversed the decrease in collagen levels to 0.4 ± 0.00-fold (p < 0.01) at 50 µM. The effect of GBDE was due to the suppression of the phospolylaton of MAPKs (ERK, 0.47 ± 0.05; JNK, 1.21 ± 0.07; p38, 0.77 ± 0.07-folds, p < 0.001) and Akt (0.14 ± 0.03-fold, p < 0.001) compared to the TNF-α group. GBDE also reduced the expression of COX-2 to 2.06 ± 0.12-fold (p < 0.001) and increased the expression of HO-1 to 10.64 ± 0.2-fold (p < 0.001). In addition, GBDE inhibited the expression of the pro-inflammatory cytokines (IL-8, 2.2 ± 0.0; IL-1ß, 1.6 ± 0.0; IL-6, 2.0 ± 0.10-folds, p < 0.05). These results provide experimental evidence that GBDE can protect against skin damage, including aging.