The chronic disease psoriasis is associated with severe inflammation and abnormal keratinocyte propagation in the skin. Tranexamic acid (TXA), a plasmin inhibitor, is used to cure serious bleeding. ...We investigated whether TXA ointment mitigated Imiquimod (IMQ)-induced psoriasis-like inflammation. Furthermore, this study investigated the effect of noncytotoxic concentrations of TXA on IL-17-induced human keratinocyte (HaCaT) cells to determine the status of proliferative psoriatic keratinocytes. We found that TXA reduced IMQ-induced psoriasis-like erythema, thickness, scaling, and cumulative scores (erythema plus thickness plus scaling) on the back skin of BALB/c mice. Additionally, TXA decreased ear thickness and suppressed hyperkeratosis, hyperplasia, and inflammation of the ear epidermis in IMQ-induced BALB/c mice. Furthermore, TXA inhibited IMQ-induced splenomegaly in BALB/c mouse models. In IL-17-induced HaCaT cells, TXA inhibited ROS production and IL-8 secretion. Interestingly, TXA suppressed the IL-17-induced NFκB signaling pathway via IKK-mediated IκB degradation. TXA inhibited IL-17-induced activation of the NLRP3 inflammasome through caspase-1 and IL1β expression. TXA inhibited IL-17-induced NLRP3 inflammasome activation by enhancing autophagy, as indicated by LC3-II accumulation, p62/SQSTM1 expression, ATG4B inhibition, and Beclin-1/Bcl-2 dysregulation. Notably, TXA suppressed IL-17-induced Nrf2-mediated keratin 17 expression. N-acetylcysteine pretreatment reversed the effects of TXA on NFκB, NLRP3 inflammasomes, and the Nrf2-mediated keratin 17 pathway in IL-17-induced HaCaT cells. Results further confirmed that in the ear skin of IMQ-induced mice, psoriasis biomarkers such as NLRP3, IL1β, Nrf2, and keratin 17 expression were downregulated by TXA treatment. TXA improves IMQ-induced psoriasis-like inflammation in vivo and psoriatic keratinocytes in vitro. Tranexamic acid is a promising future treatment for psoriasis.
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Although gastric cancer (GC) is one of the most common cancers, knowledge of its development and carcinogenesis is limited. To date, expression of ubiquitin‐specific protease 3 (USP3) in all types of ...cancer, including GC, is still unknown. The present study explored the involvement of USP3 in the carcinogenesis and prognosis of GC. We measured USP3 expression in normal and GC tissues and cell lines. Correlations between USP3 protein level and clinicopathological parameters, as well as the significance of USP3 protein level for disease‐free survival were assessed. Small hairpin RNA technology and transfection were used to investigate the effect of USP3 manipulation on cell proliferation and spreading. Moreover, xenograft proliferation and metastasis were used to explore the influence of USP3 on tumor growth and metastasis in animals. An increase in USP3 expression was observed in GC cells and tissues. The overexpression of USP3 was significantly correlated with several clinicopathological parameters and poor disease‐free survival. Multivariate Cox regression analysis showed that the overexpression of USP3 was an independent prognostic biomarker. Silencing of USP3 suppressed GC cell proliferation and spreading in vitro as well as xenograft proliferation and metastasis in vivo; however, opposite results were obtained when USP3 was overexpressed. Further studies showed that USP3 influenced cell proliferation and spreading by regulating the cell cycle control‐ and epithelial‐mesenchymal transition‐related molecules. This study suggests that USP3 overexpression can be a useful biomarker for predicting the outcomes of GC patients and that USP3 targeting represents a potential modality for treating GC.
USP3 was overexpressed in gastric cancer tissues and cells and was significantly correlated with several clinicopathological parameters and poor disease‐free survival. Mechanistic studies further showed that USP3 influenced gastric cancer cell proliferation and spread in vitro and in vivo. The results indicate that USP3 overexpression can be a useful biomarker for predicting the outcomes of gastric cancer patients and that USP3 targeting represents a potential modality for treating gastric cancer.
UVA irradiation-induced skin damage and redox imbalance have been shown to be ameliorated by ergothioneine (EGT), a naturally occurring sulfur-containing amino acid. However, the responsible ...molecular mechanism with nanomolar concentrations of EGT remains unclear. We investigated the dermato protective efficacies of EGT (125–500nM) against UVA irradiation (15J/cm2), and elucidated the underlying molecular mechanism in human keratinocyte-derived HaCaT cells. We found that EGT treatment prior to UVA exposure significantly increased the cell viability and prevented lactate dehydrogenase release into the medium. UVA-induced ROS and comet-like DNA formation were remarkably suppressed by EGT with a parallel inhibition of apoptosis, as evidenced by reduced DNA fragmentation (TUNEL), caspase-9/-3 activation, and Bcl-2/Bax dysregulation. Furthermore, EGT alleviated UVA-induced mitochondrial dysfunction. Dose-dependent increases of antioxidant genes, HO-1, NQO-1, and γ-GCLC and glutathione by EGT were associated with upregulated Nrf2 and downregulated Keap-1 expressions. This was confirmed by increased nuclear accumulation of Nrf2 and inhibition of Nrf2 degradation. Notably, augmented luciferase activity of ARE may explain Nrf2/ARE-mediated signaling pathways behind EGT dermato-protective properties. We further demonstrated that Nrf2 translocation was mediated by PI3K/AKT, PKC, or ROS signaling cascades. This phenomenon was confirmed with suppressed nuclear Nrf2 activation, and consequently diminished antioxidant genes in cells treated with respective pharmacological inhibitors (LY294002, GF109203X, and N-acetylcysteine). Besides, increased basal ROS by EGT appears to be crucial for triggering the Nrf2/ARE signaling pathways. Silencing of Nrf2 or OCTN1 (EGT carrier protein) signaling with siRNA showed no such protective effects of EGT against UVA-induced cell death, ROS, and apoptosis, which is evidence of the vitality of Nrf2 translocation and protective efficacy of EGT in keratinocytes. Our findings conclude that EGT at nanomolar concentrations effectively ameliorated UVA-induced skin damage, and may be considered as a desirable food supplement for skin protection and/or preparation of skin care products.
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•EGT (nM) attenuated UVA-induced ROS, apoptosis, and mitochondrial dysfunction.•EGT-mediated Nrf2/ARE signaling pathway triggered the antioxidant genes.•EGT increased Nrf2 nuclear accumulation, and inhibited degradation in keratinocytes.•Activation of Nrf2 relies on PI3K/AKT, PKC, and ROS signaling cascades.•Nrf2 and OCTN1 knockdown cells showed no EGT protection on UVA irradiation.
Breast cancer is the most prevalent cancer among women. In triple-negative breast cancer (TNBC) cells, a novel quinone derivative, coenzyme Q
(CoQ
), promotes apoptosis and cell-cycle arrest. This ...study explored the anti-epithelial-mesenchymal transition (EMT) and antimetastatic attributes of CoQ
in TNBC (MDA-MB-231).
Invasion, as well as MTT assays were conducted. Lipofectamine RNAiMAX was used to transfect cells with β-catenin siRNA. Through Western blotting and RT-PCR, the major signaling pathways' protein expressions were examined, and the biopsied tumor tissues underwent immunohistochemical and hematoxylin and eosin staining as well as Western blotting.
CoQ
(0.5-2 μM) hindered tumor migration, invasion, and progression. Additionally, it caused MMP-2/- 9, uPA, uPAR, and VEGF downregulation. Furthermore, in highly metastatic MDA-MB-231 cells, TIMP-1/2 expression was subsequently upregulated and MMP-9 expression was downregulated. In addition, CoQ
inhibited metastasis and EMT in TGF-β/TNF-α-stimulated non-tumorigenic MCF-10A cells. Bioluminescence imaging of MDA-MB-231 luciferase-injected live mice demonstrated that CoQ
significantly inhibited metastasis of the breast cancer to the lungs and inhibited the development of tumors in MDA-MB-231 xenografted nude mice. Silencing of β-catenin with siRNA stimulated CoQ
-inhibited EMT. Western blotting as well as histological analysis established that CoQ0 reduced xenografted tumor development because apoptosis induction, cell-cycle inhibition, E-cadherin upregulation, β-catenin downregulation, and metastasis and EMT regulatory protein modulation were observed.
CoQ
inhibited the progression of metastasis as well as EMT (in vitro and in vivo). The described approach has potential in treating human breast cancer metastasis.
Chalcones found in fruits and vegetables have promising cancer chemopreventive properties. This study attempts to identify the anticancer efficacies of chalcone flavokawain B (FKB) in the rhizomes of ...Alpinia pricei Hayata by examining key molecular events in non‐small‐cell lung cancer (A549) cells. Our results indicated that in human A549 cells, FKB (0–15 μg/ml) decreases cell viability and colony formation, dysregulates the Bax:B‐cell lymphoma 2 ratio and increases apoptotic DNA fragmentation. Mitochondrial (caspase‐9/‐3 and poly ADP ribose polymerase PARP) signaling was found to be involved in FKB‐induced apoptosis. In addition, FKB‐induced reactive oxygen species (ROS) generation, and N‐acetylcysteine attenuated FKB‐induced apoptotic cell death. Moreover, FKB triggered autophagy, as evidenced by the improved acidic vesicular organelle formation, lipidated light chain 3 (microtubule‐related light chain 3) accumulation, and ATG7 expression and the decreased mammalian target of rapamycin phosphorylation. Furthermore, FKB suppressed ROS‐mediated ATG4B expression. Inhibiting autophagy using 3‐methyladenine/chloroquine diminished FKB‐induced cell death, indicating that autophagy is triggered as a death mechanism by FKB. In summary, FKB has a crucial role in the execution and propagation of ROS‐mediated apoptotic and autophagic cell death of lung adenocarcinoma cells.
Flavokawain B (FKB)‐induced autophagy was evidenced by a large accumulation of lipidated light chain 3 and acidic vesicular organelles. Mitochondrial (caspase‐9, capase‐3, and PARP) signaling was found to be critically involved in FKB‐induced apoptosis. FKB plays a crucial role in the execution and propagation of ROS‐mediated apoptotic and autophagic cell death of lung adenocarcinoma cells.
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•CoQ0, a quinone derivative of Antrodia camphorata, inhibits UVA-induced α-MSH level in HaCaT cells.•CoQ0 facilitated Nrf2 activation via autophagy-mediated p62/Keap-1 degradation in ...HaCaT cells.•Nrf2-activated antioxidant HO-1, γ-GCLC, and NQO-1 enzyme is major for antimelanogenesis of CoQ0.•CoQ0 inhibited UVA-induced ROS-mediated photoaging by activating Nrf2 pathway in HaCaT cells.•CoQ0 ameliorated UVB-induced ROS-mediated inflammation through Nrf2 activation in HaCaT cells.
We discovered that Coenzyme Q0 (CoQ0), a major quinone derivative from Antrodia camphorata, exerts antimelanogenic, antiphotoaging, and anti-inflammatory effects by activating Nrf2-mediated antioxidant pathways on UVA (3 or 10 J/cm2)/UVB (80 mJ/cm2)-irradiated keratinocyte (HaCaT) cells. CoQ0 downregulated p53/POMC-mediated α-MSH expression in UVA (3 J/cm2)-irradiated HaCaT cells. Additionally, conditioned medium (containing α-MSH) derived from CoQ0-pretreated and UVA-irradiated HaCaT cells inhibited melanogenesis and melanin generation in melanoma B16F10 cells. CoQ0 enhanced Nrf2 nuclear translocation, resulting in antioxidant HO-1, γ-GCLC, and NQO-1 expression in HaCaT cells. Silencing of Nrf2 reversed CoQ0-inhibited ROS (H2O2) and α-MSH expression in UVA (3 J/cm2)-irradiated HaCaT cells. Furthermore, CoQ0 exerted antiphotoaging by activating Nrf2 pathway, leading to the inhibition of ROS-mediated apoptosis in UVA (10 J/cm2)-irradiated HaCaT cells. CoQ0 ameliorated UVB (80 mJ/cm2)-induced ROS-mediated inflammation (NFκB, iNOS, and COX-2 levels) by activating Nrf2 pathway in HaCaT cells. CoQ0 could be used in formulations as a topical cosmetic application.
We assayed skin hydration and anti-inflammatory efficacies of zerumbone (Zer, 2.5–10 μM), a natural sesquiterpene of Zingiber zerumbet, using non– or UVB (30 mJ/cm2)-irradiated keratinocytes (HaCaT). ...& Zer increased cell viability, upregulated hyaluronic acid, and inhibited ROS generation in UVB-irradiated HaCaT cells. Zer promoted antioxidant Nrf2 nuclear translocation resulting in HO-1 and γ-GCLC expression. Zer promotes skin hyaluronic acid by increasing protein and mRNA expression of HAS-2 and AQP-3 in non– or UVB-irradiated HaCaT cells. Furthermore, Zer increased Src and ERK phosphorylation. Src silencing or ERK inhibitor (PD98059) diminished Zer-mediated skin hydration, as evidenced by decreased HAS-2 and AQP-3 expression. Interestingly, UVB-induced Src/ERK inhibition was reversed by Zer or N-acetylcysteine. Additionally, Zer inhibited inflammatory iNOS, COX-2, and IL-1β expression through NFκB (p65) and AP-1 (c-Jun/c-Fos) pathway in UVB-irradiated HaCaT cells. HaCaT cells treated with Zer enhanced the growth factors PDGF-A, VEGF, and EGFR expressions. Zerumbone might be utilized in cosmetic formulations.
Lucidone, which comprises a naturally occurring cyclopentenedione, has been investigated for its in vitro and in vivo wound healing properties, and the underlying molecular signaling cascades in the ...wound healing mechanism have been elucidated. We demonstrated the cell-/dose-specific responses of lucidone (0.5-8μM) on proliferation and migration/invasion of keratinocyte HaCaT and fibroblast Hs68 cells. In keratinocytes, lucidone-induced nuclear translocation of β-catenin was accompanied by increased transcriptional target genes, including c-Myc and cyclin-D1, through GSK3β-dependent pathway. Correspondingly, lucidone promoted the cell-cycle by increasing PCNA/CDK4 and decreasing p21/p27 expressions. Lucidone induced EMT through the downregulation of epithelial (E-cadherin/occludin) and upregulation of mesenchymal (vimentin/Twist/Snail) marker proteins. Activated MMP-9/-2 and uPA/uPAR as well as suppressed TIMP-1/-2 and PAI-1 expressions by lucidone may promote the migration/invasion of keratinocytes. Notably, lucidone activated NF-κB signaling via IKK-mediated-IκB degradation, and its inhibition abolished MMP-9 activation and keratinocyte migration. Inhibition of PI3K/AKT signaling impaired the lucidone-induced proliferation/migration with corresponding suppression of β-catenin/c-Myc/cyclin-D1 and NF-κB/MMP-9 expressions. Results indicate that lucidone-induced PI3K/AKT signaling anchored the β-catenin/NF-κB-mediated healing mechanism. β-catenin knockdown substantially diminished lucidone-induced keratinocyte migration. Furthermore, lucidone increased endothelial cell proliferation/migration and triggered angiogenesis (MMP-9/uPA/ICAM-1). In macrophages, lucidone-activated NF-κB-mediated inflammation (COX-2/iNOS/NO) and VEGF, which may contribute to the growth of keratinocytes/fibroblasts and endothelial cells. Punched wounds on mice were rapidly healed with the topical application of lucidone (5mM) compared with control ointment-treated mice. Taken together, lucidone accelerates wound healing through the cooperation of keratinocyte/fibroblast/endothelial cell growth and migration and macrophage inflammation via PI3K/AKT, Wnt/β-catenin and NF-κB signaling cascade activation.
Glioblastoma (GBM) is the most mortality brain cancer in the world. Due to high invasion and drug resistance cause the poor prognosis of GBM. Naringenin, an ingredient of citrus, exhibits many ...cellular functions such as antioxidant, anti-inflammation, and anticancer. Naringenin inhibits the migration of bladder and lung cancer via modulation of MMP-2 and/or MMP-9 activities, Naringenin inhibits migration and trigger apoptosis in gastric cancer cells through downregulation of AKT pathway. However, the effects of naringenin in GBM still remain to be elucidated. In this study, we reveal the molecular mechanisms of naringenin in the inhibition of migration and invasion in GBM. No overt alternation of cell proliferation was found in of GBM 8901 cells treated with different concentration of naringenin. Slight decreased cell viability was found in GBM 8401 cell treated with 200 and 300 μM naringenin. Significant reduction of migration and invasion as assayed by Boyden chamber analysis was found in of GBM cells treated with 100, 200, and 300 μM naringenin. Zymography analysis also revealed that the activities of MMP-2 and MMP-9 of GBM cells were significantly inhibited in response to 100, 200, or 300 μM naringenin treatment. Proteins of MMP-2 and MMP-9 were downregulated in naringenin treated GBM cells. In addition, naringenin also attenuated the activities of ERK and p38. Naringenin decreased mesenchymal markers (snail and slug) expression as revealed by Western blot analysis. Taken together, our findings indicated that naringenin eliminated the migration and invasion of GBM cells through multiple mechanisms including inhibition of MMPs, ERK, and p38 activities and modulation of EMT markers. Our results also suggested that naringenin may be a potential agent to prevent metastasis of GBM.
Spiropyran‐4‐quinolines were synthesized in two steps from exo‐glycals. The first step involved the double additions of aniline (or substituted anilines) to produce C,N‐glycosides. The next step was ...to eliminate the anomeric N‐aryl group by formation of benzophenone‐derived imine, followed by in situ intramolecular Friedel−Crafts alkylation. The resulting (1S)‐spiropyran‐4‐quinolines were obtained in 60–72 % overall yields with exclusive (from the reactions of exo‐galactals) or high stereoselectivity (from those of exo‐glucals with m‐substituted anilines), respectively. Additionally, exo‐galactals were found suitable to perform the two steps consecutively in one‐pot at 75 °C.
Spiropyran‐4‐quinolines were synthesized in two steps from exo‐glycals. The two steps could be performed consecutively in one‐pot manner at 75 °C, leading to formation of (1S)‐spiropyran‐4‐quinolines in 60–72 % overall yields with exclusive stereoselectivity (from the reactions of exo‐galactals). A plausible mechanism was proposed to explain how the products were generated in a stereoselective manner.
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