1,4-Dihydropyridine Derivatives: Dihydronicotinamide Analogues—Model Compounds Targeting Oxidative Stress

Many 1,4-dihydropyridines (DHPs) possess redox properties. In this review DHPs are surveyed as protectors against oxidative stress (OS) and related disorders, considering the DHPs as specific group of potential antioxidants with bioprotective capacities. They have several peculiarities related to antioxidant activity (AOA). Several commercially available calcium antagonist, 1,4-DHP drugs, their metabolites, and calcium agonists were shown to express AOA. Synthesis, hydrogen donor properties, AOA, and methods and approaches used to reveal biological activities of various groups of 1,4-DHPs are presented. Examples of DHPs antioxidant activities and protective effects of DHPs against OS induced damage in low density lipoproteins (LDL), mitochondria, microsomes, isolated cells, and cell cultures are highlighted. Comparison of the AOA of different DHPs and other antioxidants is also given. According to the data presented, the DHPs might be considered as bellwether among synthetic compounds targeting OS and potential pharmacological model compounds targeting oxidative stress important for medicinal chemistry

Expression of Sirtuin 1 and 2 Is Associated with Poor Prognosis in Non-Small Cell Lung Cancer Patients

Sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) are NAD+-dependent protein deacetylases involved in the regulation of key cancer-associated genes. In this study we evaluated the relevance of these deacetylases in lung cancer biology

Loss of imprinting and promoter usage of the IGF2 in laryngeal squamous cell carcinoma

The gene for insulin-like growth factor two, IGF2 is maternally imprinted. Fifteen heterozygous samples were analyzed for the IGF2 imprinting status and promoter usage. IGF2 LOI was detected in four non-tumorous tissues and in six laryngeal squamous cell carcinoma (LSCC) tumors. There was no clear pattern of specific promoter activity in LSCC tumors and the adjacent normal tissues. P1 promoter usage was active in eight LSCCs, among them four with LOI. As it was activated in four tumors with maintenance of imprinting (MOI) and four non-tumors, we concluded that P1 promoter is not exclusively connected with IGF2 LOI in LSCC

Influence of 4-hydroxynonenal and spleen cells on primary hepatocyte culture and a novel liver-derived cell line resembling hepatocyte stem cells

Liver is a unique mammalian organ with a great capacity of regeneration related to its function. After surgical resection or injury, hepatic cells, especially hepatocytes, can proliferate rapidly to repair the damage and to regenerate the structure without affecting the function of the liver. Loss of catalase activity during regeneration indicates that oxidative stress is present in the liver not only in pathological conditions but also as a 'physiological' factor during regeneration. As we have shown in our previous work, liver stem cell-like cells treated with 4-hydroxynonenal (HNE), a cytotoxic and growth regulating lipid peroxidation product, recover in the presence of spleen cells. In the current study we characterized this novel cell line as liver-derived progenitor/oval-like cells, (LDP/OCs), i.e. functional liver stem-like cells. We showed that LDP/OC were OV6 positive, with abundant glycogen content in the cytoplasm and expressed α-fetoprotein, albumin, biliverdin reductase and γ-glutamyl transferase. Also, we compared their growth in vitro with the growth of cultured primary hepatocytes stressed with HNE and co-cultured with autologous spleen cells. The influence of spleen cells on HNE-treated primary hepatocytes and on LDP/OCs showed that spleen cells support in a similar manner the recovery of both types of liver cells indicating their important role in regeneration. Hence, LDP/OC cells may provide a valuable tool to study cell interactions and the role on HNE in liver regeneration

Downregulation of SIRT1 and SIRT2 inhibits proliferation of NSCLC cells.

<p>A, immunoblotting of SIRT1, SIRT2 and β-actin in A549 and H1299 cells transfected with scrambled siRNA (scr), siRNA targeting SIRT1 (siSIRT1 #1 or siSIRT1 #2) or SIRT2 (siSIRT2 #1 and siSIRT2 #2). The inhibition was verified after 72 h by Western blotting. B, A549 and H1299 cells were transfected with different siRNAs as indicated. MTT assay was performed 72 h post-transfection. The figure is representative of three different experiments: *, P < 0.05; **, P < 0.01.</p

Treatment with tnv-1 decreases growth of NSCLC cell lines.

<p>A, NSCLC cell lines were treated with 10 μM tnv-1. After three (3 d) and five (5 d) days the proliferation was measured by MTT assay. Relative proliferation values were obtained by dividing the absorbance values with those of the DMSO controls. Error bars represent standard deviation (SD). **, P < 0.01. B, Representative image of clonogenic assays (anchorage dependent growth). Cells were seeded and treated with tnv-1 (10 μM). After 10 days, colony formation was determined. C, Quantification of soft agar colony formation (anchorage independent growth) after tnv-1 treatment (10 μM) of NSCLC cell lines. Mean relative colony numbers and SD are shown. **, P < 0.01. D, Cell cycle distribution of NSCLC cells. Cells were treated with tnv-1 (10 μM) for 72 h, collected and analyzed by flow cytometry. E, Effect of tnv-1 (10 μM) on apoptosis. Cells were treated (48 h), collected and the cell death was assessed by Annexin V labeling. Error bars, SD.</p

SIRT1 and SIRT2 are upregulated in NSCLC.

<p>(A, B) Immunoblotting of SIRT1 (A) and SIRT2 (B) in NSCLC cell lines and normal immortalized lung epithelial HBEC-3KT cells. The figure is representative of three different experiments. β-actin was used as control. (C-H) Representative immunohistochemical staining for SIRT1 (C, D, G) and SIRT2 (E, F, H) in normal human lung (C-F) and tumor (G, H) specimens expressing different levels of SIRT1 and SIRT2 proteins. In tumors, SIRT1 expression is predominantly nuclear whereas SIRT2 immunoreactivity is mostly localized in the cytoplasm. Bar = 50 μm.</p