Juglanin administration protects skin against UVB­induced injury by reducing Nrf2­dependent ROS generation.

Extensive solar ultraviolet B (UVB) exposure of the skin results in inflammation and oxidative stress, which may contribute to skin cancer. Natural products have attracted attention for their role in the effective treatment of cutaneous neoplasia. Juglanin is purified from the crude extract of Polygonum aviculare, exhibiting anti­oxidant, anti­inflammatory and anti­cancer activities. Jugalanin was used in the current study to investigate whether it may ameliorate UVB irradiation­induced skin damage by reducing oxidative stress and suppressing the inflammatory response in vivo and in vitro. In the present study, hairless mice were exposed to UVB irradiation in the absence or presence of juglanin administration for 10 weeks. The findings indicated that juglanin inhibited UVB­induced hyperplasia and decreased infiltration in the skin of mice. UVB exposure­induced oxidative stress in mice and cells was inhibited by juglanin via enhancing anti­oxidant activity. Additionally, juglanin markedly reduced pro­inflammatory cytokine release, including cyclic oxidase 2, interleukin­1ß and tumor necrosis factor­α, triggered by chronic UVB irradiation. Juglanin­ameliorated skin damage was associated with its suppression of mitogen activated protein kinases (MAPKs), including p38, extracellular signal regulated 1/2, and c­Jun N­terminal kinases, as well as nuclear factor (NF)­κB signaling pathways, which was dependent on nuclear factor­E2­related factor 2 (Nrf2)­modulated reactive oxygen species generation. Taken together, these data indicate that juglanin protected against UVB­triggered oxidative stress and inflammatory responses by suppressing MAPK and NF­κB activation via enhancing Nrf2 activity.

Fisetin inhibits pristine-induced systemic lupus erythematosus in a murine model through CXCLs regulation.

Systemic lupus erythematosus (SLE) is associated with an increased risk of vascular complications. Lupus nephritis is a major manifestation of SLE in the clinic. Lupus nephritis is elevated by T helper type 17 (Th17) cells, the major pro­inflammatory T­cell subset, leading to autoimmunity modulation. Therapeutic treatments targeting leukocyte recruitment may be useful in attenuating vascular complications linked to SLE progression. 3,7,3',4'­Tetrahydroxyflavone (fisetin) is a flavonol and a member of the flavonoid polyphenols. It is present in various fruits and vegetables, including persimmons, apples, kiwis, grapes, onions, strawberries and cucumbers. In the present study, the effects of fisetin against SLE induced by pristane (PRI) were evaluated in mice. Fisetin was indicated to reduce PRI­induced anti­double stranded DNA, anti­ small nuclear ribonucleoprotein and the ratio of albumin to creatinine in urine. In addition, the chemokine (C­X­C motif) ligand (CXCL) signaling pathway was activated for PRI treatment, which was reversed by fisetin administration by reducing CXCL­1 and 2, chemokine (C­C motif) ligand 3, as well as CXC receptor 2 expression. In addition, the induction of inflammatory cytokines, including interleukin (IL)­6, tumor necrosis factor­α, IL­1ß, as well as the chemokine interferon­Î³, by PRI were downregulated by fisetin treatment in mice. Furthermore, Th17 cells and their associated cytokines were highly induced by PRI treatment, which was inhibited by fisetin administration. The present results indicated that fisetin may be an effective management for SLE by targeting the CXCL signaling pathway and regulating Th17 differentiation during lupus nephritis development.

Salidroside prevents skin carcinogenesis induced by DMBA/TPA in a mouse model through suppression of inflammation and promotion of apoptosis.

Salidroside (SR) is a main component of Rhodiola rosea L. and exhibits a variety of pharmacologic properties. The present study was carried out to explore the potential effect of SR against skin cancer induced by 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13­acetate (TPA) in female Institute for Cancer Research (ICR) mice and to reveal the underlying molecular targets regulated by SR. The mice were randomly divided into 4 groups: control, DMBA/TPA, DMBA/TPA+SR (20 mg/kg) and DMBA/TPA+SR (40 mg/kg). SR was administered to mice five times a week after DMBA treatments. In our study, we found that SR dose-dependently ameliorated skin cancer incidence and the multiplicity in the animal models by reducing the release of inflammation-related cytokines, including tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), interleukin-18 (IL-18), interleukin-6 (IL-6), cyclooxygenase 2 (COX2) and transforming growth factor ß-1 (TGF-ß1). Suppression of the nuclear factor (NF)-κB signaling pathway by SR was effective to prevent skin carcinogenesis. Furthermore, TUNEL analysis indicated that compared to the DMBA/TPA group, enhanced apoptosis was observed in the DMBA/TPA+SR group. In addition, p53 expression levels were increased by SR in the DMBA/TPA-induced mice. Therefore, SR was effective for inducing apoptosis during skin cancer progression triggered by DMBA/TPA. Consistently, p21, p53 upregulated modulator of apoptosis (PUMA), Bax and caspase-3 were highly induced by SR to enhance the apoptotic response for preventing skin cancer. Moreover, in vitro, we found that SR dramatically reduced the inflammatory response, while enhancing the aoptotic response by blocking NF-κB and activating caspase-3 pathways, respectively. In addition, flow cytometric analysis further confirmed the induction of apoptosis by SR in DMBA-treated cells in vitro. Taken together, the in vivo and in vitro studies illustrated that SR might be a promising compound to reduce skin cancer risk.

IRF1 up-regulates isg15 gene expression in dsRNA stimulation or CSFV infection by targeting nucleotides -487 to -325 in the 5' flanking region.

Interferon (IFN)-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that is heavily involved in immune response elicitation. As an important member of interferon regulatory factor (IRF) family, IRF1 can activate the expression of multiple genes, including the human optineurin gene (Sudhakar et al., 2013). In this study, a sequence in the promoter region of the optineurin gene was compared to the 5' flanking region of the porcine isg15 gene. Porcine IRF1 also possesses antiviral activity against several swine viruses (Li et al., 2015), but the mechanism is not well understood. Herein, we report that porcine IRF1 and ISG15 were up-regulated in porcine kidney (PK-15) cells following stimulation with double-stranded RNA (dsRNA) or classical swine fever virus (CSFV) infection. We also found that siRNA-mediated knockdown of IRF1 expression resulted in lower ISG15 expression in response to polyinosinic:polycytidylic acid [poly(I:C)] or CSFV infection. The overexpression of IRF1 resulted in ISG15 up-regulation. IRF1 was shown to translocate to the nucleus in response to dsRNA stimulation. To further identify the functional domain of the isg15 gene that promotes IRF1 transcriptional activity, firefly luciferase and ISG15 reporter systems were constructed. The results of the firefly luciferase and ISG15 reporter assay suggested that IRF1 mediates the up-regulation of ISG15. Nucleotides -487 to -325, located in the 5' flanking region of the isg15 gene, constituted the promoter region of IRF1. ChIP assay indicated that IRF1 protein was able to interact with the DNA in the 5'fr of isg15 gene in cells. As an innate immune response protein with broad-spectrum antiviral activity, the up-regulation of ISG15 mediated by IRF1 in porcine cells is reported for the first time. These results warrant further investigation into the antiviral activity of porcine IRF1 against reported swine viruses.

Galangin inhibits the cell progression and induces cell apoptosis through activating PTEN and Caspase-3 pathways in retinoblastoma.

Retinoblastoma is reported as a rare cancer that occurs during childhood. Although several treatments are available for retinoblastoma, there is a need for alternative new treatment modalities for retinoblastoma with better safety and efficacy profile. Galangin (3,5,7-trihydroxyflavone), is a flavonoid compound, which is found in high concentration in lesser galangal. Galangin has been reported to have various bioactivities, including anti-inflammation, anti-oxidative stress and anti-cancer through various pathways. The objective of our study was to explore the effects of galangin on the suppression of retinoblastoma in vitro and in vivo. Using MTT analysis, transwell-chamber migration analysis, colony-forming analysis, wound healing analysis, immunofluorescent assay of KI-67, we found that galangin exhibited a suppressive effect on human retinoblastoma cell proliferation and migration. Moreover, PTEN, a tumor-suppressor, was increased by galangin in cancer cells and in tumor tissues isolated from retinoblastoma xenograft models. Additionally, galangin reduced protein kinase B (Akt) phosphorylation, which was associated with PTEN up-regulation. Galangin-reduced Akt activation and cell proliferation was abolished by PTEN knockdown, which might be associated with the over-expression of phosphatidylinositol-3,4,5-triphosphate (PIP3)/diphosphate product (PIP2). Furthermore, flow cytometry, Hoechst 33258 staining and western blot assays indicated that galangin could induce apoptosis through promoting Caspase-3 pathway, which was, at least partly, dependent on PTEN expression. Our data illustrated that galangin treatment suppressed the growth of retinoblastoma tumor in vivo by anti-proliferative and apoptogenic mechanisms. Thus, galangin might be a safe and promising non-chemotherapeutic drug, which could be useful as an adjuvant against retinoblastoma.