Neurofibromatosis type 1: Expanded variant spectrum with multiplex ligation-dependent probe amplification and genotype-phenotype correlation in 138 Turkish patients

Objective To investigate the variant spectrum and genotype-phenotype correlations in a Turkish cohort with Neurofibromatosis Type-1 (NF1)

SAHA induce hippo pathway in CCA cells without increasing cell proliferation

Background Cholangiocarcinoma is a malignant tumor originating from bile duct epithelial cells. Since tumor metastasis is associated with poor prognosis and short-term survival of patients, there is an urgent need for alternative therapeutic approaches for CCA. Because of that reason, we aimed to investigate effect of SAHA which is known as HDAC inhibitor on extrahepatic cholangiocarcinoma cell line (TFK-1). Methods Cell cycle was measured by Muse Cell Analyzer. YAP, TAZ, TGF-beta protein levels were determined by western-blotting method. TEAD (1-3), TIMP2 and TIMP3 genes level were determined by real-time PCR analysis. Results We have seen the positive effects of SAHA on the TFK-1 cell line as it reduces cell viability and arresting cells in the G0/G1 phase. We also observed the negative effects of SAHA, as it increases the expression levels of YAP, TAZ, TGF-beta protein and TEAD (1-3) gene. We also found that SAHA reduced the expression levels of TIMP2 and TIMP3 in TFK-1 cells, but was not statistically significant. Conclusions Although observing its antiproliferative effects, these negative effects may be related to the cells being resistant to the drug or the remaining cells having a more aggressive phenotype. Therefore, we think that caution should be exercised in the use of this drug for CCA treatment

SAHA modulates cell proliferation, colony forming and epithelial-mesenchymal transition in CCA cells

Background: Therapeutic options for advanced cholangiocarcinoma (CCA) are limited and ineffective due to the largely incomplete understanding of the molecular pathogenesis of this deadly tumor. So that, we planned to investigate epigenetic regulation of epithelial-mesenchymal transition (EMT) in cholangiocarcinoma cell line by applying Suberoylanilide hydroxamic acid (SAHA). We studied the effect of SAHA on cell proliferation, colony forming, migration and protein level of E-cadherin (E-cad) as an epithelial EMT marker, N-cadherin (N-cad) and Vimentin (Vim), as a mesenchymal markers of EMT, in human CCA cell line

Expressions of glutathione S-transferase alpha, mu, pi, and theta in the skin samples of patients with acne rosacea

Takci, Zennure/0000-0001-7257-5792WOS:000539720000001PubMed: 32433803Background Data point to the importance of oxidative stress in rosacea. Glutathione S-transferases (GSTs) have substantial roles in a wide variety of oxidative stress-related conditions. Aim To evaluate the immunohistochemical staining characteristics of GST alpha (GSTA), mu (GSTM), pi (GSTP), and theta (GSTT) in patients with rosacea. Patients/Methods The study included 23 women and 7 men with rosacea (mean +/- SD age 49 +/- 11 year) and 15 healthy control subjects (10 women, 5 men; mean +/- SD age 47.86 +/- 10.88 year). For each patient, the average disease duration, disease subtype, ocular involvement, and severity score were recorded. A 3-mm punch biopsy was taken from the facial skin of each patient and control. Expression of GST isoenzymes was analyzed immunohistochemically. Results Expressions of GSTM1, GSTP1, and GSTT1 were significantly elevated in patients with rosacea compared to those in the control group (P = .0001,P = .0002,P .05). Conclusions In rosacea, the significant increase of GSTT1, GSTP1, and GSTM1 expressions might result from activation of GST as an outcome of extreme free radical generation from triggered neutrophils or ultraviolet vulnerability. These findings support the relevance of oxidant stress in the pathogenesis of rosacea.Yuzuncu Yil University Scientific ProjectYuzuncu Yil University [2012-TF-B014]This work was supported by Yuzuncu Yil University Scientific Project (2012-TF-B014)

Metabolomics and Physiological Insights into the Ability of Exogenously Applied Chlorogenic Acid and Hesperidin to Modulate Salt Stress in Lettuce Distinctively

Recent studies in the agronomic field indicate that the exogenous application of polyphenols can provide tolerance against various stresses in plants. However, the molecular processes underlying stress mitigation remain unclear, and little is known about the impact of exogenously applied phenolics, especially in combination with salinity. In this work, the impacts of exogenously applied chlorogenic acid (CA), hesperidin (HES), and their combination (HES + CA) have been investigated in lettuce (Lactuca sativa L.) through untargeted metabolomics to evaluate mitigation effects against salinity. Growth parameters, physiological measurements, leaf relative water content, and osmotic potential as well as gas exchange parameters were also measured. As expected, salinity produced a significant decline in the physiological and biochemical parameters of lettuce. However, the treatments with exogenous phenolics, particularly HES and HES + CA, allowed lettuce to cope with salt stress condition. Interestingly, the treatments triggered a broad metabolic reprogramming that involved secondary metabolism and small molecules such as electron carriers, enzyme cofactors, and vitamins. Under salinity conditions, CA and HES + CA distinctively elicited secondary metabolism, nitrogen-containing compounds, osmoprotectants, and polyamines

Synthesis and Structure of Novel Phenothiazine Derivatives, and Compound Prioritization via In Silico Target Search and Screening for Cytotoxic and Cholinesterase Modulatory Activities in Liver Cancer Cells and In Vivo in Zebrafish

Phenothiazines (PTZ) are antipsychotics known to modulate a variety of neurotransmitter activities that include dopaminergic and cholinergic signaling and have been identified as potential anticancer agents in vitro. However, it is important to also test whether a highly cytotoxic, repurposed, or novel PTZ has low toxicity and neuromodulatory activity in vivo using vertebrate model organisms, such as zebrafish. In this study, we synthesized novel phenothiazines and screened them in vitro in liver cancer and in vivo in zebrafish embryos/larvae. The syntheses of several intermediate PTZ 10-yl acyl chlorides were followed by elemental analysis and determination of 1H NMR and 13C NMR mass (ESI+) spectra of a large number of novel PTZ 10-carboxamides. Cytotoxicities of 28 PTZ derivatives (1-28) screened against Hep3B and SkHep1 liver cancer cell lines revealed five intermediate and five novel leads along with trifluoperazine (TFP), prochlorperazine (PCP), and perphenazine, which are relatively more cytotoxic than the basic PTZ core. Overall, the derivatives were more cytotoxic to Hep3B than SkHep1 cells. Moreover, in silico target screening identified cholinesterases as some of the commonest targets of the screened phenothiazines. Interestingly, molecular docking studies with acetylcholinesterase (AChE) and butyrylcholinesterase proteins showed that the most cytotoxic compounds 1, 3, PCP, and TFP behaved similar to Huprin W in their amino acid interactions with the AChE protein. The highly cytotoxic intermediate PTZ derivative 1 exhibited a relatively lower toxicity profile than those of 2 and 3 during the zebrafish development. It also modulated in vivo the cholinesterase activity in a dose-dependent manner while significantly increasing the total cholinesterase activity and/or ACHE mRNA levels, independent of the liver cancer cell type. Our screen also identified novel phenothiazines, i.e., 8 and 10, with significant cytotoxic and cholinesterase modulatory effects in liver cancer cells; yet both compounds had low levels of toxicity in zebrafish. Moreover, they modulated the cholinesterase activity or expression of ACHE in a cancer cell line-specific manner, and compound 10 significantly inhibited the cholinesterase activity in zebrafish. Accordingly, using a successful combination of in silico, in vitro, and in vivo approaches, we identified several lead anticancer and cholinesterase modulatory PTZ derivatives for future research