Wnt signaling pathways constitute a group of signal transduction pathways that direct many physiological processes, such as development, growth, and differentiation. Dysregulation of these pathways is thus associated with many pathological processes, including neurodegenerative diseases, metabolic disorders, and cancer. At the same time, alterations are observed in plasma membrane compositions, lipid organizations, and ordered membrane domains in brain and metabolic diseases that are associated with Wnt signaling pathway activation. Here, we discuss the relationships between plasma membrane components—specifically ligands, (co) receptors, and extracellular or membrane-associated modulators—to activate Wnt pathways in several brain and metabolic diseases. Thus, the Wnt–receptor complex can be targeted based on the composition and organization of the plasma membrane, in order to develop effective targeted therapy drugs.

Hepatocyte dedifferentiation is a major source of hepatocellular carcinoma (HCC), but its mechanisms are unknown. We explored the p73 expression in HCC tumors and studied the effects of transcriptionally active p73β (TAp73β) in HCC cells. Expression profiles of p73 and patient clinical data were collected from the Genomic Data Commons (GDC) data portal and the TSVdb database, respectively. Global gene expression profiles were determined by pan-genomic 54K microarrays. The Gene Set Enrichment Analysis method was used to identify TAp73β-regulated gene sets. The effects of TAp73 isoforms were analyzed in monolayer cell culture, 3D-cell culture and xenograft models in zebrafish using western blot, flow cytometry, fluorescence imaging, real-time polymerase chain reaction (RT-PCR), immunohistochemistry and morphological examination. TAp73 isoforms were significantly upregulated in HCC, and high p73 expression correlated with poor patient survival. The induced expression of TAp73β caused landscape expression changes in genes involved in growth signaling, cell cycle, stress response, immunity, metabolism and development. Hep3B cells overexpressing TAp73β had lost hepatocyte lineage biomarkers including ALB, CYP3A4, AFP, HNF4α. In contrast, TAp73β upregulated genes promoting cholangiocyte lineage such as YAP, JAG1 and ZO-1, accompanied with an increase in metastatic ability. Our findings suggest that TAp73β may promote malignant dedifferentiation of HCC cells.

Background: Phenylurenyl chalcone structures have the potential to act as a scaffold in anticancer drug discovery. Methods: N-Phenethyl-N'-{4-[(2E)-3-phenylprop-2-enoyl]phenyl}urea, 4/3-[(2E)-3-substitutedphenylprop-2-enoyl]phenyl}-N-phenylurea,4/3-[(2E)-3-substitutedphenyl prop-2-enoyl]phenyl}-N-methylphenyl urea and {4/3-[(2E)-3-substitutedphenylprop-2-enoyl]phenyl}-N-ethylphenyl urea derivatives(1-35)were prepared and evaluated for their anticancer and antimicrobial activity against A-549 Hep-3B, HT-29, CF-7, PC-3, K-562 NIH-3T3 and Huh-7 cell lines and against Staphylococcus aureus (ATCC 6538), Pseudomonas aeruginosa (ATCC 9027), Escherichia coli (ATCC 8739) and Candida albicans (ATCC 10231), respectively. Results: While compounds 2, 26, 29, and 34 showed moderate cytotoxic activity on cell line Huh 7, compounds 14 (IC50: 6.42 µM), 16 (IC50: 5.64 µM), 19 (IC50: 6.95 µM) and 34 (IC50: 6.87 µM) showed good cytotoxic activity on Huh-7 cell line close to Sorafenib (IC50: 4.29 µM) (as reference). MIC values of compounds 4 and 22 against E. coli were 25 μg/ml, of compounds 3, 14 and 29 against P. aeruginosa 25 μg/ml and of compounds 11 and 33 against S. aureus 25 μg/ml. On the other hand, the minimum inhibitory concentration of all tested compounds against C. albicans was 25 μg/ml. Conclusion: N-Phenethyl-N'-{4-[(2E)-3-phenylprop-2-enoyl]phenyl}urea may be a new candidate to be developed as an anticancer compound.

TNF-α is a ligand that induces both intrinsic and extrinsic apoptotic pathways in HeLa cells by modulating complex gene regulatory mechanisms. However, the full spectrum of TNF-α-modulated epitranscriptomic m ⁶ A marks is unknown. We employed a genomewide approach to examine the extent of m ⁶ A RNA modifications under TNF-α-modulated apoptotic conditions in HeLa cells. miCLIP-seq analyses revealed a plethora of m ⁶ A marks on 632 target mRNAs with an enrichment on 99 mRNAs associated with apoptosis. Interestingly, the m ⁶ A RNA modification patterns were quite different under cisplatin- and TNF-α-mediated apoptotic conditions. We then examined the abundance and translational efficiencies of several mRNAs under METTL3 knockdown and/or TNF-α treatment conditions. Our analyses showed changes in the translational efficiency of TP53INP1 mRNA based on the polysome profile analyses. Additionally, TP53INP1 protein amount was modulated by METTL3 knockdown upon TNF-α treatment but not CP treatment, suggesting the existence of a pathway-specific METTL3-TP53INP1 axis. Congruently, METLL3 knockdown sensitized HeLa cells to TNF-α-mediated apoptosis, which was also validated in a zebrafish larval xenograft model. These results suggest that apoptotic pathway-specific m ⁶ A methylation marks exist in cells and TNF-α-METTL3-TP53INP1 axis modulates TNF-α-mediated apoptosis in HeLa cells.

Amaç: Hipertrofik skar travma, geçirilen ameliyatlar, yanık ve bazı cilt enfeksiyonları sonrası yaygın olarak görülebilen bir cilt sorunudur. Mevcut tedaviye verilen zayıf yanıt ve yüksek nüks oranları göz önüne alındığında hipertrofik skarların oluşumunun engellenmesinde hedeflenmiş, etkili topikal moleküler tedavi stratejilerinin belirlenmesine ve geliştirilmesine ihtiyaç vardır. YAP/TAZ, Hippo sinyal yolağı hedef molekülleridir. Bu çalışmada, mekanik stres kaynaklı hipertrofik skar oluşumunda rol alan YAP/TAZ hedef genlerinin belirlenmesi amaçlanmaktadır. Gereç ve Yöntemler: Mekanik stres kaynaklı hipertrofik skar oluşumunda rol oynayan genlerin ifade verisine 'Gene Expression Omnibus' veri tabanından erişildi. p<0,05 anlamlılık düzeyinde, 2 kat ve üzerinde değişim gösteren genlerin listesi oluşturuldu. Oluşturulan gen listesinde, YAP/TAZ sinyal yolağı hedef genleri belirlendi. Literatür taraması sonucunda, YAP/TAZ hedef genlerinin fonksiyonları belirlendi. Belirlenen genlerin etkileşim ağlarını ve rol oynadıkları sinyal yolaklarını bulmak için STRING protein etkileşim veritabanı kullanıldı. Bulgular: Anlamlı düzeyde değişim olan genlerin içinde YAP/TAZ sinyal yolağı hedef genlerinden; tenascin C, trombospondin 1, serin proteaz inhibitör 1'in ifadesinde artış gözlendi. Literatür taraması sonucunda bu genlerin yara iyileşmesi, hücre proliferasyonu, hücre farklılaşması ve hücre dışı matriksin yeniden yapılanmasında rol oynadıklarını gösterdik. Sonuç: Bu çalışmada, mekanik stres ile uyarılan hipertrofik skarlarda, YAP/TAZ sinyal iletim yolağının hedef genlerinin ifadesinin değiştiğini göstermiş bulunmaktayız. Hipertrofik skar oluşumunda YAP/TAZ sinyal yolağının rolünün belirlenmesine yönelik daha ileri çalışmaların yapılmasına ihtiyaç vardır.