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Background Interleukin-6 (IL-6) is involved in fibroblast-like synoviocyte (FLS) activation and promotes pannus formation and bone and cartilage destruction in rheumatoid arthritis (RA). Cysteine-rich 61 (Cyr61) protein regulates cell proliferation, migration, and differentiation. The aim of this study was to investigate the role of Cyr61 in RA-FLS migration and invasion after IL-6 stimulation. Methods Western blotting, immunohistochemistry, reverse transcription-polymerase chain reaction, and real time-polymerase chain reaction were used to examine protein and mRNA levels of Cyr61, matrix metalloproteinases (MMPs), and other signalling proteins. Knockdown of gene expression was performed with siRNA, and RNA sequencing was performed for differential gene analysis. Migration and invasion were assessed by wound healing and Boyden chamber assays. Results Cyr61 levels were elevated in FLSs from RA patients compared to those in osteoarthritis patients. Control and IL-6-treated FLSs showed differential gene expression. IL-6 stimulated protein synthesis of Cyr61, which was attenuated by the extracellular signal-related kinase 1/2 (ERK 1/2) inhibitor, PD98059, and knockdown of early growth response 3 ( EGR3 ), but not of JUN . IL-6-induced Cyr61 protein synthesis increased expression of MMP2 . Cyr61 promoted FLS migration and invasion in an autocrine manner. Knockdown of CYR61 and a neutralising antibody attenuated Cyr61 synthesis and IL-6-induced FLS migration. Conclusions By modulating the ERK/EGR3 pathway, IL-6 stimulated Cyr61 production and in turn increased invasiveness of FLS. Our data suggest that Cyr61 might be a potential target to prevent the progression of joint damage in RA.

PurposeProbiotics and prebiotics are commonly used to improve the gut microbiota. Since prebiotics can support the growth of probiotics, co-administration of these is called synbiotics. It has been demonstrated that obesity-induced gut dysbiosis can worsen inflammatory bowel disease symptoms. This study evaluated how modulation of gut microbiota with Schizophyllum commune-derived β-glucan (BG), probiotics (PRO), and synbiotics containing both BG and PRO (SYN) could improve the symptoms of obesity-associated colitis and hepatic manifestation.MethodsMice were fed a normal diet (ND), high-fat diet (HFD), and HFD with different additives (BG, PRO, and SYN) for 12 weeks, followed by 5 days of colitis induction. Mice were sacrificed before and after colitis induction. During the experiment, body weight, food and water consumption, and rectal bleeding were monitored. Proteins from the colon were subjected to western blotting, and serum biomarkers such as alanine transaminase, alkaline phosphatase, triglycerides, and total cholesterol were analyzed. Colon and liver samples were sectioned for histological analysis. The fecal microbiota was analyzed based on partial 16S rRNA gene sequences.ResultsAlthough BG and PRO secured intestinal tight junctions, these two treatments did not modulate inflammatory cell infiltration and inflammatory markers (i.e., IL-6 and TNF-α). In contrast, SYN demonstrated stronger and broader effects in reducing colonic inflammation. While BG treatment increased the abundance of indigenous Lactobacillus, PRO treatment decreased bacterial diversity by suppressing the growth of several species of bacteria. SYN treatment groups, however, supported the growth of both indigenous and supplemented bacteria while maintaining bacterial diversity.ConclusionObesity-associated colitis can be improved by modulating gut bacteria with β-glucan and probiotics. The co-administration of both outperformed β-glucan and probiotic treatment alone by fostering both indigenous and supplemented probiotic strains.

Beta-glucans, which existed in the cell walls of cereals, bacteria, and fungi, comprise a group of β- d -glucose polysaccharides. We investigated the effects of four kinds of beta-glucan, that are derived from barley, yeast, mushroom, and euglena on wound healing. The migration and viability of keratinocyte or fibroblast were analyzed using the in vitro scratch wound healing assay, invasion assay, MTT assay, and in vivo assay. All the beta-glucans had a significant effect on keratinocyte migration at 20 μM and showed no toxicity on dermal fibroblast. Moreover, treatment of keratinocytes with the beta-glucan derived from the mushroom ( Schizophyllum commune ) promoted in vivo wound closure. The Integrin/FAK/Src pathway is known to affect cell migration by forming lamellipodia. Beta-glucan from S. commune activates the Integrin/FAK/Src signaling pathway in a time-dependent. Reactive oxygen species are associated with fibroblast differentiation to contract dermal layer and synthesize collagens. We found that fibroblast was activated by increasing NOX4 expression. We propose that beta-glucan derived from mushroom is capable of promoting keratinocyte migration via the induction of FAK/Src phosphorylation there by accelerating wound closure and activating dermal fibroblast differentiation through NADPH oxidase for matrix remodeling.

IL-6, interleukin-6; sIL-6R, soluble IL-6 receptor; FBS, foetal bovine serum Full size image Fig. 3 figure2 Signalling pathways involved in IL-6-regulated protein synthesis of Cyr61 in rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLSs). a, c, e Cells were pretreated with inhibitors for 2 h before IL-6 (20 ng/mL) stimulation for 2 h. LY294002 (10 μM): PI3K/AKT inhibitor, AG490 (50 μM): JAK2/STAT3 inhibitor, SB203580 (10 μM): p38 MAPK inhibitor, PD98059 (1 μM): ERK inhibitor. d, f RA-FLSs transfected with either small interfering RNA (c-Jun or EGR3) or siNC (control) (20 pmol/L) stimulated by IL-6 (20 ng/mL) for 2 h. Data are representative of at least three independent experiments. a–f Protein levels were determined by western blotting. FLSs were incubated overnight in 1% FBS-containing medium before treatment with IL-6/sIL-6R Full size image Fig. 4 figure3 Cyr61 secretion induced by IL-6. a, b Extracellular protein levels of Cyr61 in culture supernatants of IL-6-treated RA-FLSs measured by western blotting. b IL-6 (20 ng/mL). c, d FLSs stimulated by extracellular Cyr61 (100 ng/mL) for indicated time periods. c Protein levels were determined by western blotting. d The mRNA levels of Cyr61 were determined through real time polymerase chain reaction. e–h The mRNA levels of Cyr61, MMP1, 2, and GAPDH induced by IL-6 (20 ng/mL) and extracellular Cyr61 protein (100 ng/mL) for 2 h. e, f The mRNA levels were determined by reverse-transcription polymerase chain reaction. g, h The mRNA levels were determined through real time polymerase chain reaction. Data are representative of at least three independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001 Full size image Fig. 5 figure4 Migration and invasion of rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLSs) promoted by IL-6 and Cyr61 secretion. a, d, e, g Wound-closure over 17 h. b ECIS proliferation analysis over 72 h. c, f Western blotting for Cyr61 protein detection. h, i Cyr61-stimulated invasion of RA-FLSs in transwells over 24 h ± antiCyr61 ab. f, g transfection with 20 pmol/L of small-interfering Cyr61 RNA (siCyr61) or siNC (negative control).

Synbiotics synergistically favors beneficial effects of prebiotics and probiotics towards host metabolic health by modulating gut ecosystem. In this study, we sought to examine the effects of prebiotics ( Schizophyllum commune derived β-(1,3/1,6)-glucan), probiotics (concoction made of eight different bacterial strains) and synbiotics (prebiotics + probiotics) on gut microbiota and its associated metabolic functions through 16S rRNA gene sequences analysis. Results showed that probiotics strains used in this study were detected more in the synbiotic and probiotic treatments, while prebiotic dietary intervention increased the total bacterial abundance and metabolisms related to host immune strengthening. Probiotics and synbiotics dietary interventions enhanced similar metabolisms relating to butanediol and s -adenosyl- l -methionine biosynthesis. Probiotics treatment also showed depleted metabolic activities related to SCFA productions, that were not depleted in prebiotics treatment. With varying differential abundance patterns and metabolic activities across the treatments, our results suggest that synbiotic treatment provide more beneficial effects over probiotics and prebiotics.

ABSTRACT Apigenin, a natural flavonoid, exhibits diverse pharmacological effects including antioxidant property. The present study evaluated the protective effects of apigenin on human HaCaT keratinocytes against damage induced by particulate matter 2.5 (PM2.5). Apigenin suppressed PM2.5-induced production of reactive oxygen species (ROS). Apigenin mitigated excessive accumulation of mitochondrial Ca2+ caused by PM2.5, along with a reduction in ATP, production of mitochondrial ROS, and depolarization of the mitochondrial membrane potential, thereby inhibiting cytochrome c release from mitochondria to the cytosol. Apigenin decreased the cellular apoptosis and the levels of proapoptotic phosphorylated p53, B-cell lymphoma-2-associated X protein, cleaved caspase-9, and cleaved caspase-3, which were all elevated by PM2.5. Furthermore, apigenin reversed the negative effects of PM2.5 on cell proliferation and the levels of proteins involved in advancing the G0/G1 phase of cell cycle. These findings indicate that apigenin can potentially mitigate skin cell damage induced by PM2.5.

Background Wound healing is an intricate process whereby the skin repairs itself after injury. The epithelial-mesenchymal transition (EMT) is associated with wound healing and tissue regeneration. Naphthochalcone derivatives have various pharmaceutical properties. We investigated the effect of a novel naphthochalcone derivative, 2-(5-(2,4,6-trimethoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)naphthalen-1-ol (TDPN), on dermal wound healing in vivo and the migration of keratinocytes in vitro. Result We investigated the effect of TDPN on signaling pathway and epithelial-mesenchymal transition through protein and transcriptional expression. The TDPN treatment accelerated dermal closure about 3 days and remodeling of dermis. We found that treatment with TDPN induced the migration of keratinocytes but not cytotoxicity. TDPN induced the phosphorylation of ERK and AKT. TDPN-treated cells showed loss of adherence protein and showed induction of the transcriptional factor Slug, mesenchymal marker, and fibronectin. Moreover, TDPN treatment induced the expression of matrix metalloproteinase-1 (MMP-1), which degrades specific components of the extracellular matrix, thereby providing new substrates that facilitate migration and invasion. MMP expression is considered to be one of the major attributes acquired by cells after EMT. Conclusion We propose that a novel naphthochalcone derivative TDPN is capable of promoting keratinocyte migration via the induction of EMT resulting acceleration of wound closure and matrix remodeling.

Keratinocyte-fibroblast interactions are critical for skin repair after injury. During the proliferative phase of wound healing, proliferation, migration and differentiation of these cells are the major mechanisms leading to tissue remodeling. We have previously reported that glycitin, a major soy isoflavone, stimulates dermal fibroblast proliferation; and the phytochemical, 4′,6,7-trimethoxyisoflavone (TMF), induces migration of HaCaT keratinocyte cells. We therefore investigated whether these compounds display synergistic effects on skin cells during wound healing in vitro and in vivo . Co-treatment with TMF and glycitin synergistically promotes the proliferation and migration of both keratinocytes and dermal fibroblasts, with a 1:1 ratio of these compounds showing the greatest efficacy in our co-culture system. This keratinocyte-fibroblast interaction occurred via the secretion of TGF-β, and the induction of differentiation and proliferation was confirmed in both indirect and direct co-culture assays. In an excisional and burn wound animal model, mice treated with a 1:1 ratio of TMF and glycitin showed faster wound closure, regeneration and scar reduction than even the positive control drug. These data indicate that two isoflavones, TMF and glycitin, act synergistically to promote wound healing and anti-scarring and could potentially be developed together as a bioactive therapeutic for wound treatment. Wound healing: Plant compound pair aids skin repair Two plant-derived compounds work together to promote wound healing and reduce scar formation in a mouse model. Co-treatment with these two compounds — glycitin from soybeans and TMF from the roots of an African plant used medicinally — could help people with cuts and other skin injuries. A team led by Moonjae Cho and Young Mee Kim from Jeju National University, South Korea, had previously shown that glycitin stimulates fibroblast cell growth in the inner skin and TMF induces the migration of keratin-producing cells in the outer skin. In this study, they demonstrated that glycitin and TMF work synergistically to promote proliferation and migration of these cells, with a 1:1 concentration ratio showing the greatest efficacy in cell culture. The same ratio also produced the fastest wound closure and scar reduction in mice with burnt skin.

Hepatic stellate cells (HSCs) are the main extra cellular matrix-producing cells in the liver. Several reports have indicated that activated HSCs are involved in hepatic carcinogenesis by way of transforming growth factor β (TGF-β) secretion. This study aimed to investigate the effects of TGF-β, derived from HSCs activated by the chronic hepatitis B virus x protein (HBx), on the transdifferentiation of hepatocytes into hepatocarcinoma cells. Normal hepatocytes (the Chang liver cell line) were treated with a low concentration of TGF-β for 2 weeks, after which cell cycle- and cell signaling- related protein expression was analyzed. Lon-term treatment of TGF-β clearly induced the proliferation and the expression of cancer signaling proteins in the Chang cell line. TGF-β treatment also increased the expression of c-Jun N-terminal kinase (JNK) and c-Myc, indicating that induction of the JNK/pSmad3/c-Myc oncogenic signaling pathway is involved in hepatocyte transformation. Similar results were observed after culturing Chang cells with conditioned media derived from the activated LX-2 hepatic stellate cell line, suggesting that TGF-β paracrine effects are involved in the transformation of hepatocyte cells into hepatocarcinoma cells. Immunohistochemical results showed that the livers from HBx transgenic mice were composed of more activated HSCs and produced more TGF-β compared with those from normal mice. The TGF-β secreted from HBx-infected HSCs might induce transdifferentiation of hepatocytes into hepatocarcinoma, which is the fact that suggested a potential knowledge on liver cancer inhibition.

Keratinocyte-fibroblast interactions are critical for skin repair after injury. During the proliferative phase of wound healing, proliferation, migration and differentiation of these cells are the major mechanisms leading to tissue remodeling. We have previously reported that glycitin, a major soy isoflavone, stimulates dermal fibroblast proliferation; and the phytochemical, 4′,6,7-trimethoxyisoflavone (TMF), induces migration of HaCaT keratinocyte cells. We therefore investigated whether these compounds display synergistic effects on skin cells during wound healing in vitro and in vivo. Co-treatment with TMF and glycitin synergistically promotes the proliferation and migration of both keratinocytes and dermal fibroblasts, with a 1:1 ratio of these compounds showing the greatest efficacy in our co-culture system. This keratinocyte-fibroblast interaction occurred via the secretion of TGF-β, and the induction of differentiation and proliferation was confirmed in both indirect and direct co-culture assays. In an excisional and burn wound animal model, mice treated with a 1:1 ratio of TMF and glycitin showed faster wound closure, regeneration and scar reduction than even the positive control drug. These data indicate that two isoflavones, TMF and glycitin, act synergistically to promote wound healing and anti-scarring and could potentially be developed together as a bioactive therapeutic for wound treatment. KCI Citation Count: 39