8-Shogaol inhibits rheumatoid arthritis through targeting TAK1.

Rheumatoid arthritis (RA) is a chronic immune-mediated disorder, mainly characterized by synovial inflammation and joint damage. If insufficiently treated, RA can lead to irreversible joint destruction and decreased life expectancy. While better understanding of the pathologies and the development of new antirheumatic drugs have improved the outcome of individuals with RA, many patients still cannot achieve remission and experience progressive disability. Fibroblast-like synoviocytes (FLS) have gained attention due to its pivotal role in RA pathogenesis and thus targeting FLS has been suggested as an attractive therapeutic strategy. To identify candidate molecules with strong inhibitory activity against FLS inflammation, we tested the effect of 315 natural extracts against IL-17-mediated IL-6 production. Zingiber officinale was found as the top hit and further analysis on the active compound responsible led to the discovery of 8-shogaol as a potent molecule against synovitis. 8-Shogaol displayed significant inhibitory effects against TNF-α-, IL-1ß-, and IL-17-mediated inflammation and migration in RA patient-derived FLS (RA-FLS) and 3D synovial culture system. 8-Shogaol selectively and directly inhibited TAK1 activity and subsequently suppressed IKK, Akt, and MAPK signaling pathways. Moreover, treatment with 8-shogaol reduced paw thickness and improved walking performance in the adjuvant-induced arthritic (AIA) rat model. 8-Shogaol also reversed pathologies of joint structure in AIA rats and decreased inflammatory biomarkers in the joints. Collectively, we report a novel natural compound that inhibits RA through reversing pathologies of the inflamed synovium via targeting TAK1.

Red Ginseng Improves Exercise Endurance by Promoting Mitochondrial Biogenesis and Myoblast Differentiation.

Red ginseng has been reported to elicit various therapeutic effects relevant to cancer, diabetes, neurodegenerative diseases, and inflammatory diseases. However, the effect of red ginseng on exercise endurance and skeletal muscle function remains unclear. Herein, we sought to investigate whether red ginseng could affect exercise endurance and examined its molecular mechanism. Mice were fed with red ginseng extract (RG) and undertook swimming exercises to determine the time to exhaustion. Animals fed with RG had significantly longer swimming endurance. RG treatment was also observed to enhance ATP production levels in myoblasts. RG increased mRNA expressions of mitochondrial biogenesis regulators, NRF-1, TFAM, and PGC-1α, which was accompanied by an elevation in mitochondrial DNA, suggesting an enhancement in mitochondrial energy-generating capacity. Importantly, RG treatment induced phosphorylation of p38 and AMPK and upregulated PGC1α expression in both myoblasts and in vivo muscle tissue. In addition, RG treatment also stimulated C2C12 myogenic differentiation. Our findings show that red ginseng improves exercise endurance, suggesting that it may have applications in supporting skeletal muscle function and exercise performance.

Caffeic Acid Phenethyl Ester Inhibits UV-Induced MMP-1 Expression by Targeting Histone Acetyltransferases in Human Skin.

Caffeic acid phenethyl ester (CAPE), a naturally occurring bioactive compound, displays anti-inflammatory, anti-carcinogenic, and anti-microbial effects. However, the effect of CAPE on skin photoaging is unknown. Herein, we investigated the inhibitory effect of CAPE against ultraviolet (UV) irradiation-mediated matrix metalloproteinase (MMP)-1 expression and its underlying molecular mechanism. CAPE treatment suppressed UV-induced MMP-1 levels in both human dermal fibroblasts (HDF) and human skin tissues. While CAPE did not display any significant effects against the upstream regulatory pathways of MMP-1, CAPE was capable of reversing UV-mediated epigenetic modifications. CAPE suppressed UV-induced acetyl-histone H3 (Lys9) as well as total lysine acetylation in HDF cells. Similarly, CAPE also attenuated UV-induced lysine acetylations in human skin tissues, suggesting that the CAPE-mediated epigenetic alterations can be recapitulated in ex vivo conditions. CAPE was found to attenuate UV-induced histone acetyltransferase (HAT) activity in HDF. Notably, CAPE was able to directly inhibit the activity of several HATs including p300, CREP-binding protein (CBP), and p300/CBP-associated factor (PCAF), further confirming that CAPE can function as an epigenetic modulator. Thus, our study suggests that CAPE maybe a promising agent for the prevention of skin photoaging via targeting HATs.

Rosa gallica and its active compound, cyanidin-3,5-O-diglucoside, improve skin hydration via the GLK signaling pathway.

Rosa gallica has been previously reported to display anti-inflammatory, anti-oxidative, and anti-skin wrinkle activities. However, the effect of Rosa gallica on skin hydration and its active components are largely unknown. Herein, we aimed to investigate the skin hydration effect of rose petal extract (RPE) in humans and elucidate the underlying molecular mechanism. A double-blinded clinical study was performed to investigate the effect of RPE on skin hydration. Stratum corneum moisture analysis demonstrated that RPE treatment significantly improved hydration levels in human skin. Furthermore, HAS2 and hyaluronic acid levels were notably increased by RPE in keratinocytes and 3D human skin equivalent model. By comparing the modulatory effect on HAS2 expression, cyanidin-3,5-O-diglucoside (CDG) was identified as the most potent compound in RPE likely responsible for skin hydration. The kinase activity of GLK, an upstream regulator of MAPK signaling, was increased by CDG in a dose-dependent manner. Importantly, silencing GLK reversed CDG-mediated HAS2 upregulation, further supporting the involvement of GLK in the CDG-mediated effects. Binding of CDG to GLK was confirmed by pull-down assay and computer modeling. These findings suggest that RPE and its active component CDG increases skin hydration by upregulating HAS2 expression through modulating the GLK-MAP2K-MAPK signaling pathway.

Immunomodulatory functional foods and their molecular mechanisms.

The immune system comprises a complex group of processes that provide defense against diverse pathogens. These defenses can be divided into innate and adaptive immunity, in which specific immune components converge to limit infections. In addition to genetic factors, aging, lifestyle, and environmental factors can influence immune function, potentially affecting the susceptibility of the host to disease-causing agents. Chemical compounds in certain foods have been shown to regulate signal transduction and cell phenotypes, ultimately impacting pathophysiology. Research has shown that the consumption of specific functional foods can stimulate the activity of immune cells, providing protection against cancer, viruses, and bacteria. Here, we review a number of functional foods reported to strengthen immunity, including ginseng, mushrooms, chlorella, and probiotics (Lactobacillus plantarum). We also discuss the molecular mechanisms involved in regulating the activity of various types of immune cells. Identifying immune-enhancing functional foods and understanding their mechanisms of action will support new approaches to maintain proper health and combat immunological diseases.

Oral Administration of Rosa gallica Prevents UVB-Induced Skin Aging through Targeting the c-Raf Signaling Axis.

Rosa gallica is a widely used Rosa species for medicinal and culinary purposes. Rosa gallica has been reported to display antioxidant, anti-inflammatory, and antibacterial activities. However, the effect of Rosa gallica against skin aging in vivo is unknown and its active components have not been fully understood. Oral administration of Rosa gallica prevented UVB-mediated skin wrinkle formation and loss of collagen/keratin fibers in the dorsal skin of mice. Examination of biomarkers at the molecular level showed that Rosa gallica downregulates UVB-induced COX-2 and MMP-1 expression in the skin. Through a direct comparison of major compounds identified using the UHPLC-MS/MS system, we discovered gallic acid as the primary component contributing to the anti-skin aging effect exhibited by Rosa gallica. Examination of the molecular mechanism revealed that gallic acid can potently and selectively target the c-Raf/MEK/ERK/c-Fos signaling axis. In addition, both gallic acid and MEK inhibitor blocked UVB-induced MMP-1 expression and restored collagen levels in a reconstructed 3D human skin model. Collectively, Rosa gallica could be used as a functional ingredient in the development of nutraceuticals against skin aging.