Ercan Cacan

Objective: Periodontal and peri‐implant tissues differ histologically and biomechanically, which may be reflected in local osteogenic and mechanosensitive signaling. This exploratory cross‐sectional study aimed to compare expression profiles of Osteolectin (CLEC11A) and related signaling molecules across periodontal health, peri‐implant health, periodontitis, and peri‐implantitis. Methods: There were four groups: Periodontal Health (PH), Peri‐Implant Health (PIH), Periodontitis (P), and Peri‐Implantitis (PID). CLEC11A, integrin alpha‐11 (ITGA11), glycogen synthase kinase‐3β (GSK‐3β), and piezo‐type mechanosensitive ion channel component‐1 (PIEZO1) levels in gingival/peri‐implant crevicular fluids (GCF/PICF) were assessed using ELISA. CLEC11A, ITGA11, GSK‐3β, β‐catenin, runt‐related transcription factor‐2 (RUNX2), and PIEZO1 expressions in gingival and peri‐implant mucosa tissues were assessed using qRT‐PCR. Results: GCF/PICF CLEC11A levels differed significantly among the groups, with higher levels in P and PID than in PH. Similarly, ITGA11 expression was significantly higher in P and PID relative to PH. β‐catenin expression varied significantly, with higher levels in PIH and P than in PH. Additionally, RUNX2 expression differed significantly, with higher expression in PIH, P, and PID than in PH. Furthermore, PIEZO1 expression was significantly higher in P compared to PIH. Conclusion: Within the limitations of this study, CLEC11A‐related signals appear to be differentially associated with periodontal and peri‐implant inflammatory conditions.

Colorectal cancer (CRC) continues to be one of the deadliest cancers worldwide, mainly due to late diagnosis, chemoresistance, and the complex interactions within the tumor microenvironment. Recent studies suggest that the gut bacterium Akkermansia muciniphila plays a key role in maintaining intestinal health and may influence the effectiveness of cancer therapies. Therefore, the main aim of this study was to explore whether a lyophilized form of A. muciniphila could support CRC treatment. First, we analyzed A. muciniphila abundance in healthy, adenoma, and CRC tissues using public datasets. Next, CRC cell lines (HT29, HCT116, and SW620) and normal stromal cells (Hs738 St/Int) were treated with increasing doses of the bacterial extract, alone and with 5‐fluorouracil (5‐FU). Then, cell viability measured by MTT assay, apoptosis by BAX/BCL2 expression via RT‐qPCR, and physicochemical properties by zeta potential analysis. The results showed a marked reduction of A. muciniphila abundance in CRC samples, with an early decline from healthy to adenoma tissues and a slight recovery in advanced tumors. In vitro, the extract demonstrated dose‐dependent cytotoxicity toward cancer cells, with HT29 showing strong sensitivity at low doses, HCT116 responding at higher concentrations, and SW620 exhibiting greater resistance. Importantly, the extract was well tolerated by normal cells, unlike 5‐FU. Combining the extract with 5‐FU resulted in a synergistic effect, indicating the possibility of reducing 5‐FU dosage to limit its toxicity. The extract significantly upregulated BAX, downregulated BCL2, and displayed strong negative zeta potential, supporting enhanced apoptotic activation and selective interaction with cancer cell membranes. These findings suggest that A. muciniphila and its derived products may serve as promising adjuncts in personalized microbiome‐based CRC therapy.

MicroRNAs (miRNAs) are critical post-transcriptional regulators of gene expression and play key roles in cancer progression and chemoresistance. In this study, we investigated the expression profiles of selected cancer-associated miRNAs in response to two chemotherapeutic agents, docetaxel and lapatinib, in colorectal cancer cell lines. We also explored the potential regulatory interaction between miR-595 and the oncogene E2F7. Colorectal cancer cells (HT-29 and HCT-116) were treated with the IC₅₀ concentrations of docetaxel and lapatinib. RT-qPCR analysis revealed that docetaxel treatment significantly upregulated miR-718, miR-206, miR-1199, and miR-595 in HT-29 cells. In contrast, only miR-206 was upregulated, while the other genes were downregulated in HCT-116 cells. Lapatinib moderately increased the expression of the selected miRNAs in HT-29 cells but consistently downregulated all four miRNAs in HCT-116 cells. Bioinformatic analysis using TargetScan identified E2F7 as a potential target of miR-595. E2F7 expression was found to be elevated in colorectal cancer and further increased in docetaxel-treated HT-29 cells, suggesting a role in drug resistance. Overexpression of miR-595 resulted in the downregulation of E2F7, supporting a regulatory interaction. These findings suggest that miR-595 negatively regulates E2F7 and may contribute to modulating chemoresistance in colorectal cancer. Targeting the miR-595/E2F7 axis may offer a novel therapeutic strategy to enhance the efficacy of chemotherapy in colorectal cancer treatment.

Sphingolipids participate in the structure of the cell membrane and have bioactive roles in many cellular events, including cell proliferation, differentiation, and programmed cell death. Changes in sphingolipid metabolism contribute to the formation and progression of the cancer phenotype in different cancer types and multi-drug resistance. In this study, we aimed to examine the antiproliferative effects of ceramide and sphingomyelin on different cancer cell lines. The results showed that ceramide and sphingomyelin act similarly and have antiproliferative effects on three different cancer cell lines and a normal cell line in a dose-dependent manner. In contrast, this effect decreases when low concentrations are applied. In DMSO solvent, ceramide was most effective in C6 cells (IC50 = 32.7 μM) and least in CCD-18Co (IC50 = 56.91 μM). In ethanol, it showed highest sensitivity in CCD-18Co (IC50 = 0.33 μM). Sphingomyelin in DMSO had IC50 values of 0.25 μM in C6 and HT29 and 0.45 μM in CCD-18Co. In ethanol, it was more effective in cancer cells (IC50 = 0.25–0.28 μM) but less cytotoxic in CCD-18Co. In conclusion, these two molecules have antiproliferative activities in a dose-dependent manner, however, further molecular investigations are needed to understand the mechanism of actions.

Pancreatic cancer is among the most lethal cancers with a 5-year survival rate of only 13%. Due to its late-stage diagnosis and high metastatic potential, there is a critical need to better understand its molecular mechanisms to develop effective treatments. Tripartite motif containing 15 (TRIM15), a member of the TRIM protein family, plays a role in tumor progression, immune evasion, and lipid metabolism reprogramming, but its role in apoptosis and immune-related pathways remains unclear. Moreover, immune checkpoint proteins such as PD-L1 and VISTA have been associated with cancer progression and poor survival by contributing significantly to the tumor microenvironment. In this context, in order to better understand the effects of TRIM15 and its neighboring genes on pancreatic cancer, other genes interacting with these genes were obtained from NCBI and BioGRID databases. In the topological analysis of the protein-protein interaction network, 191 proteins in which TRIM15 is involved were identified and the expression profiles of these proteins in pancreatic cancer were analyzed using the Expression Atlas database. These analyses revealed 73 differentially expressed proteins compared to normal individuals, and high accuracy (> 0.90) was achieved with machine learning algorithms. These proteins were identified as drug targets and 50 drug candidates were identified through the L1000CSD2 database. As a result of the TF-IDF calculations performed for innovation, impartozole with a TF-IDF value of 0 was selected as a potential drug candidate for the treatment of pancreatic cancer. Importin-β1, which is overexpressed in many cancers, is associated with tumor progression and its inhibitor, importazole, exhibits antitumor activity by inducing G2/M cell cycle arrest and apoptosis. Here, TRIM15 regulation, apoptosis mechanism and immune checkpoint mechanisms were investigated to reveal the role of importazole on the underlying mechanisms of pancreatic cancer progression. The findings show that importazole administration suppressed the expression level of TRIM15 and VISTA in AsPC-1 pancreatic cancer cells and triggered the apoptosis mechanism. These results suggest that importazole may be a potential therapeutic target for TRIM15 and VISTA in pancreatic cancer and may contribute to the development of innovative strategies for cancer treatment.

Pancreatic cancer is one of the deadliest malignant tumours worldwide. Despite the developments in the treatments of pancreatic cancer, survival rates remain at a low level, and the mechanisms underlying the aggressive course of the cancer are not fully understood. VISTA is an immune checkpoint and has recently become a significant target in cancer treatment; however, the roles of VISTA in the development of pancreatic cancer have largely remained unknown. Histone deacetylase inhibitors (HDACi) have been reported to reverse the epithelial‐mesenchymal transition (EMT) and may enhance the efficacy of anti‐PD‐1 therapy. The PD‐L1/PD‐1 immune checkpoint targeted by this therapy shares structural similarity with VISTA. Moreover, combination therapy of vorinostat and anti‐PD‐1 has been shown to significantly reduce tumour growth by suppressing the transcription factor c‐Myc. Therefore, in this study, we aim to investigate the genes that are associated with EMT and explore the potential mechanism involving Twist1, a proto‐oncogene, and VISTA in pancreatic cancer. We also sought to determine the synergistic effects of an HDACi, vorinostat, in combination with Twist1‐siRNA on VISTA expression in pancreatic cancer cells’ viability and proliferation. Our results revealed that Twist1 blockade in combination with vorinostat in pancreatic cancer cells suppresses EMT‐associated genes and the immune checkpoint VISTA compared to treatments administered alone. As a result, identifying the genes associated with EMT in pancreatic cancer and understanding the role of Twist1 in this process is a crucial step to contribute to the identification of new targets for pancreatic cancer treatment and the improvement of existing treatment strategies.

Mammalian colostrum (liquid gold) is a commercially valuable and potentially future functional food with high levels of essential nutrients. In this study, we obtained colostrums from Karayaka sheep (Ovis aries), Saanen goats (Capra aegagrus hircus), Danish red cows (Bos taurus), and buffaloes (Bubalus bubalis) and determined the effect of these colostrums on MCF–7 breast cancer and AsPC–1 pancreatic cancer cell lines at different doses. In addition, the potential antimicrobial activity of these colostrums against five different bacteria/moulds was determined. For this purpose, antimicrobial activities of lyophilized and dried colostrums were determined by the disc diffusion method, cell viability and cytotoxicity were determined by the MTT test, and migration potentials were determined by wound healing assays. The results showed that these colostrums had similar cytotoxic activities in both AsPC–1 and MCF–7 cancer cell lines, with some minor differences. In addition, in cell migration assays, the MCF–7 cell line treated with cow colostrum showed the most wound closure compared to other colostrums used in the study. We also found that goat and sheep colostrums have a higher antimicrobial effect on Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, Aspergillus flavus, and Aspergillus niger than cow and buffalo colostrums. Goat colostrum had the highest antimicrobial effect on S. aureus, while buffalo colostrum had the lowest antimicrobial effect on E. coli. In conclusion, analyses of the anticancer and antimicrobial activities of colostrum between species shed light on potential health benefits and functional food production.

Background SARS-CoV-2 infection is marked by an excessive inflammatory response, leading to elevated production of pro-inflammatory cytokines through activation of intracellular pathways like mitogen-activated protein kinase (MAPK). Viruses can use the MAPK signaling pathway to their advantage, but the relationship of this pathway to the severe SARS-CoV-2 period has not been fully elucidated. MAP2K4 is involved in the MAPK signaling pathway and affects cellular processes such as cell-cell junction, cell proliferation, differentiation and apoptosis. Methods and results In this study, we sought to determine the associated biomarkers that are involved in the MAP2K4 pathway and elucidate its possible roles in terms of some clinical features associated with COVID-19. We evaluated the expressions of MAP2K4, SNAI1, SLUG, ZEB1 and E-Cadherin. For this purpose, we prospectively recruited 66 individuals, 39 of whom were women and had a mean age of 65 years. The results revealed that MAP2K4 upregulation increased SNAI1 gene expression level whereas E- Cadherin level was decreased in SARS-CoV-2 positive participants. In addition, negative correlations were determined with PLT, Lymphocyte and CKMB and E- Cadherin levels in positive participants. We also observed a negative correlation between the MAP2K4 and AST, and a positive correlation between SLUG and BUN, ZEB1 and CK. Conclusions We conclude that SARS-CoV-2 infection triggers fibrosis by increasing MAP2K4 regulation. Additionally, this is the first study to demonstrate the possible contribution of MAP2K4 in influencing COVID-19 clinical features, which may be relevant for identifying COVID-19 positive participants with severe complications.