Bjerregaardbonner3862

These results suggested that plant polyphenols MO and QU both promote eNOS-mediated NO production and vasodilation in diabetic aorta, MO via Akt pathway activation and QU via PI3K/Akt and AMPK pathway activation. Elucidation of these pathways may define effective therapeutic targets for diabetic vascular dysfunction.Triple-negative breast cancer (TNBC) is a highly lethal subtype of breast cancer associated with early relapse and metastasis. Epithelial to mesenchymal transition (EMT) plays pivotal roles in the progression of TNBC, including inducing cancer stem cell (CSC) properties, chemoresistance, tumor metastasis, and recurrence. Abnormally activated YAP/TAZ induces EMT in TNBC, making it a promising target for drug development. Our goal is to identify potential YAP/TAZ inhibitors from naturally derivative molecules and further study its effects on inhibiting EMT and metastasis of TNBC. In the current study, we demonstrate that luteolin significantly inhibits YAP/TAZ activity by promoting YAP/TAZ degradation in TNBC cells. Luteolin treatment leads to a decrease of mesenchymal markers and an increase of epithelial markers in both TNBC cells and TAZ-induced mesenchymal cells. Consistently, luteolin treatment inhibits cell migration in TNBC cells. Additionally, luteolin inhibits tumor growth in mice xenografted with TNBC cells. Collectively, our results support luteolin as a novel YAP/TAZ inhibitor for development as a new agent for the treatment of TNBC.Non-small cell lung cancer (NSCLC) is the primary subtype of lung cancer with high mortality. Circular RNAs (circRNAs) play a crucial role in tumor development and progression. This study aimed to explore the function of circ_0067934 in NSCLC progression and its molecular basis. The levels of circ_0067934, miR-1182 and kruppel like factor 8 (KLF8) were measured by quantitative real-time polymerase chain reaction or western blot assay. Cell viability was detected by Cell Counting Kit-8 (CCK-8) assay. Cell migration and invasion were assessed by transwell assay. Cell apoptosis was monitored by flow cytometry. The protein levels of epithelial-to-mesenchymal transition (EMT)-related markers and Wnt/β-catenin pathway-related proteins were examined by western blot. Dual-luciferase reporter assay, RNA Immunoprecipitation (RIP) assay or RNA pull-down assay was performed to verify the interaction among circ_0067934, miR-1182 and KLF8. Xenograft assay was used to detect tumor growth in vivo. We found that circ_0067934 and KLF8 were up-regulated, while miR-1182 was down-regulated in NSCLC tissues and cells. Circ_0067934 knockdown blocked proliferation, migration, invasion and EMT and induced apoptosis in NSCLC cells. Circ_0067934 regulated NSCLC progression by sponging miR-1182. MiR-1182 targeted KLF8 to hinder NSCLC development. In addition, depletion of circ_0067934 restrained tumor growth in vivo. In conclusion, Circ_0067934 acted as a competing endogenous RNA to facilitate NSCLC progression by regulating the miR-1182/KLF8 axis and activating Wnt/β-catenin pathway.Radiation is a current standard treatment of glioma. The fractionated radiotherapy with low dose of radiation over weeks has been employed in glioma patients, while radiotherapy can only offer palliation due to the radioresistance. We cumulatively radiated a glioblastoma cell line, U87MG, and screened radioresistant glioma cells. A transcriptome sequencing was performed to analyze the transcription differences between the raidoresistant and control cells, which showed the mitochondria NADH-ubiquinone oxidoreductase (Complex I) subunits were up-regulated in the radioresistant cells. The copy numbers of mitochondria were increased in the radioresistant glioma cells. After using mitochondria Complex I inhibitors, rotenone and metformin, to treat glioma cells, we found the resistant glioma cells re-sensitized to radiation. These results demonstrate that Complex I is associated with the fractioned radiation-induced radioresistance of glioma and would be a potent target for clinical radiotherapy of glioma.Studying prostate cancer is important due to its high annual incidences and mortality rates in the world. Although prostate cancer mortality rates are reduced using new therapy, complicated routes and side effects of these current drugs require a daily available treatment for prevention. Lycopene is a natural, prominent, and effective product which has a high value in diet. The anti-cancer effect, non-toxicity, safety and preventive or therapeutic roles of lycopene have been investigated in several studies. In the current review, we have collected information about the anti-cancer, anti-progressive and apoptotic effects of lycopene on prostate cancer. This article is a summary of the most important original and review articles on lycopene and its anticancer effects that are systematically categorized and presents information about the molecular structure, different sources, biological functions, and its in-vivo and in-vitro effects of lycopene on variety of cancerous and normal cells. The clinical studies provide a clear image for continuous use of this adjunctive dietary for different type of cancers, especially prostate cancer in men. In addition, this article discusses the various molecular pathways activated by lycopene that eventually prevent or suppress cancer. Lycopene has been found to effectively suppress the progression and proliferation, arrest in-cell cycle, and induce apoptosis of prostate cancer cells in both in-vivo and in-vitro conditions. Additionally, lycopene showed that it could modulate the signaling pathways and their protein for the treatment or prevention of prostate cancer.Hepatic ischemia-reperfusion (IR) injury is characterized by severe inflammation and cell death. However, very few effective therapies are presently available for hepatic IR injury treatment. Here, we reported a protective function and the underlying mechanism of myotubularin-related protein 14 (MTMR14) during hepatic IR injury. Hepatocyte-specific MTMR14 knockout (HKO) and transgenic (TG) mice were subjected to hepatic IR operation to explore MTMR14 function in vivo. Primary hepatocytes isolated from MTMR14-HKO and MTMR14-TG mice were subjected to hypoxia/reoxygenation (HR) insult in vitro. We found that MTMR14 expression in liver tissues from individuals with hepatic IR was markedly decreased, and similar results were detected in mice with hepatic IR surgery. MTMR14-TG mice following hepatic IR operation had obviously ameliorated liver pathological changes, along with improved hepatic dysfunction, which was proved by the decreased serum alanine amino transferase (ALT) and aspartate amino transferase (AST) levels. MTMR14-HKO and MTMR14-TG animal models indicated that MTMR14 alleviated cell death and inflammatory response. In addition, MTMR14 inhibited nuclear transcription factor κB (NF-κB) signaling. Of note, promoting MTMR14 expression improved phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) pathway through a physical interaction with AKT, subsequently reducing cell death and inflammation. Therefore, MTMR14 is a protective factor during hepatic IR injury, and the MTMR14/AKT signaling is involved the pathogenesis hepatic IR injury. Improvement of this axis might be a novel therapeutic strategy for the prevention of this pathological process.HDAC6 is a crucial epigenetic modifier that plays a vital role in tumor progression and carcinogenesis due to its multiple biological functions. It is a unique member of class-II HDAC enzymes. It possesses two catalytic domains, which function independently of the overall enzyme activity. Up to date, there are only a few selective HDAC6 inhibitors with anti-cancer activity. In this study, 175,204 ligands obtained from the ZINC15 and OTAVAchemical databases were used for virtual drug screening against HDAC6. Molecular docking studies were performed for 100 selected compounds. Furthermore, the top 10 compounds obtained from docking were tested for their efficacy to inhibit the function of HDAC6. Five compounds (N-(9-oxo-9H-fluoren-3-yl)benzamide, 2-hydroxy-5-[(5-oxo-6-phenyl-4,5-dihydro-1,2,4-triazin-3-yl)amino]benzoic acid, 5-(4-bromonaphthalene-1-sulfonamido)-2-hydroxybenzoic acid, 2-(naphthalen-2-yl)-N-(1H-1,2,3,4-tetrazol-5-yl)cyclopropane-1-carboxamide, and 4-oxa-5,6 diazapentacyclo[10.7.1.0³,⁷.0⁸,²⁰.0¹⁴,¹⁹]icosa-1,3(7),5,8(20),9,11,14,16,18-nonaen-13-one) inhibited enzymatic activity by more than 50 % compared to DMSO as the control. Two candidates, (N-(9-oxo-9H-fluoren-3-yl)benzamide and 5-(4-bromonaphthalene-1-sulfonamido)-2-hydroxybenzoic acid), were identified with considerable cytotoxicity towards drug-sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells. Microscale thermophoresis revealed the binding of N-(9-oxo-9H-fluoren-3-yl)benzamide and 5-(4-bromonaphthalene-1-sulfonamido)-2-hydroxybenzoic acid to purified HDAC6 protein. Both compounds induced apoptosis in a dose-dependent manner as analyzed by flow cytometry. In conclusion, we demonstrate for the first time that these two compounds bind to HDAC6, inhibit its function, and exert cytotoxic activity by apoptosis induction.Osteoarthritis (OA) is the most prevalent joint degenerative disease leading to irreversible structural and functional changes in the joint and is a major cause of disability and reduced life expectancy in ageing population. Despite the high prevalence of OA, there is no disease modifying drug available for the management of OA. Oxidative stress, a result of an imbalance between the production of reactive oxygen species (ROS) and their clearance by antioxidant defense system, is high in OA cartilage and is a major cause of chronic inflammation. Inflammatory mediators, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are highly upregulated in OA joints and induce ROS production and expression of matrix degrading proteases leading to cartilage extracellular matrix degradation and joint dysfunction. ROS and inflammation are interdependent, each being the target of other and represent ideal target/s for the treatment of OA. Plant polyphenols possess potent antioxidant and anti-inflammatory properties and can inhibit ROS production and inflammation in chondrocytes, cartilage explants and in animal models of OA. buy Rutin The aim of this review is to discuss the chondroprotective effects of polyphenols and modulation of different molecular pathways associated with OA pathogenesis and limitations and future prospects of polyphenols in OA treatment.

Astilbin exerts immunoregulatory activities and plays anti-inflammatory effects in inflammation-associated diseases. IL-10-producing B cells are the major subset of regulatory B cells (Bregs) and inhibit inflammation and autoimmune diseases. This study aimed to analyse the inducing effect of astilbin on Bregs and investigate the involved molecular mechanisms.

The frequencies and activities of IL-10-producing Bregs were observed using the co-treatment of astilbin and lipopolysaccharide (LPS) ex vivo. The protective effect of astilbin/LPS-induced Bregs on dextran sulphate sodium (DSS)-induced colitis was confirmed in vivo. The molecular signalling events of Breg induction were checked via Western blot. CD40

and toll-like receptor (TLR) 4

B cells were treated with astilbin/LPS to determine the modulatory role of CD40 or TLR4 on astilbin/LPS-induced Bregs.

Although astilbin alone could not affect Bregs, the co-treatment of astilbin and LPS remarkably induced CD19

CD1d

and CD19

TIM-1

cells which produced IL-10 ex vivo.