Multiple Roles of Mitochondria in Aging Processes

Aging is a multifactorial process influenced by genetic factors, nutrition, and lifestyle. According to mitochondrial theory of aging, mitochondrial dysfunction is widely considered a major contributor to age-related processes. Mitochondria are both the main source and targets of detrimental reactions initiated in association with age-dependent deterioration of the cellular functions. Reactions leading to increased reactive oxygen species generation, mtDNA mutations, and oxidation of mitochondrial proteins result in subsequent induction of apoptotic events, impaired oxidative phosphorylation capacity, mitochondrial dynamics, biogenesis and autophagy. This review summarizes the major changes of mitochondria related to aging, with emphasis on mitochondrial DNA mutations, the role of the reactive oxygen species, and structural and functional changes of mitochondria.</jats:p

Role of Polymorphisms of NKG2D Receptor and Its Ligands in Acute Myeloid Leukemia and Human Stem Cell Transplantation

Natural killer cells possess key regulatory function in various malignant diseases, including acute myeloid leukemia. NK cell activity is driven by signals received through ligands binding activating or inhibitory receptors. Their activity towards elimination of transformed or virally infected cells can be mediated through MICA, MICB and ULBP ligands binding the activating receptor NKG2D. Given the efficiency of NK cells, potential target cells developed multiple protecting mechanisms to overcome NK cells killing on various levels of biogenesis of NKG2D ligands. Targeted cells can degrade ligand transcripts via microRNAs or modify them at protein level to prevent their presence at cell surface via shedding, with added benefit of shed ligands to desensitize NKG2D receptor and avert the threat of destruction via NK cells. NK cells and their activity are also indispensable during hematopoietic stem cell transplantation, crucial treatment option for patients with malignant disease, including acute myeloid leukemia. Function of both NKG2D and its ligands is strongly affected by polymorphisms and particular allelic variants, as different alleles can play variable roles in ligand-receptor interaction, influencing NK cell function and HSCT outcome differently. For example, role of amino acid exchange at position 129 in MICA or at position 98 in MICB, as well as the role of other polymorphisms leading to different shedding of ligands, was described. Finally, match or mismatch between patient and donor in NKG2D ligands affect HSCT outcome. Having the information beyond standard HLA typing prior HSCT could be instrumental to find the best donor for the patient and to optimize effects of treatment by more precise patient-donor match. Here, we review recent research on the NKG2D/NKG2D ligand biology, their regulation, description of their polymorphisms across the populations of patients with AML and the influence of particular polymorphisms on HSCT outcome

Dynamic Changes of Inhibitory Killer-Immunoglobulin-Like Receptors on NK Cells after Allogeneic Hematopoietic Stem Cell Transplantation: An Initial Study

Killer-immunoglobulin-like receptors (KIRs) are critical natural killer (NK) cell regulators. The expression of KIRs is a dynamic process influenced by many factors. Their ligands—HLA(Human Leukocyte Antigen) class I molecules—are expressed on all nucleated cells that keep NK cells under control. In hematopoietic stem cell transplantation (HSCT), NK cells play an essential role in relapse protection. In the presented pilot study, we characterized the dynamic expression of inhibitory KIRS (iKIRs), which protect cells against untoward lysis, in donors and patients during the first three months after HSCT using flow cytometry. The expression of all iKIRs was highly variable and sometimes correlated with patients’ clinical presentation and therapy regiment. Cyclophosphamide (Cy) in the graft-versus-host disease (GvHD) prevention protocol downregulated KIR2DL1 to just 25% of the original donor value, and the FEAM (Fludarabine + Etoposid + Ara-C + Melphalan) conditioning protocol reduced KIR2DL3. In lymphoid neoplasms, there was a slightly increased KIR2DL3 expression compared to myeloid malignancies. Additionally, we showed that the ex vivo activation of NK cells did not alter the level of iKIRs. Our study shows the influence of pre- and post-transplantation protocols on iKIR expression on the surface of NK cells and the importance of monitoring their cell surface

Molecular profile of 5-fluorouracil pathway genes in colorectal carcinoma

BACKGROUND: This study addresses involvement of major 5-fluorouracil (5-FU) pathway genes in the prognosis of colorectal carcinoma patients. METHODS: Testing set and two validation sets comprising paired tumor and adjacent mucosa tissue samples from 151 patients were used for transcript profiling of 15 5-FU pathway genes by quantitative real-time PCR and DNA methylation profiling by high resolution melting analysis. Intratumoral molecular profiles were correlated with clinical data of patients. Protein levels of two most relevant candidate markers were assessed by immunoblotting. RESULTS: Downregulation of DPYD and upregulation of PPAT, UMPS, RRM2, and SLC29A1 transcripts were found in tumors compared to adjacent mucosa in testing and validation sets of patients. Low RRM2 transcript level significantly associated with poor response to the first-line palliative 5-FU-based chemotherapy in the testing set and with poor disease-free interval of patients in the validation set irrespective of 5-FU treatment. UPP2 was strongly methylated while its transcript absent in both tumors and adjacent mucosa. DPYS methylation level was significantly higher in tumor tissues compared to adjacent mucosa samples. Low intratumoral level of UPB1 methylation was prognostic for poor disease-free interval of the patients (P = 0.0002). The rest of the studied 5-FU genes were not methylated in tumors or adjacent mucosa. CONCLUSIONS: The observed overexpression of several 5-FU activating genes and DPYD downregulation deduce that chemotherapy naïve colorectal tumors share favorable gene expression profile for 5-FU therapy. Low RRM2 transcript and UPB1 methylation levels present separate poor prognosis factors for colorectal carcinoma patients and should be further investigated. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2826-8) contains supplementary material, which is available to authorized users

Additional file 1: Table S1. of Molecular profile of 5-fluorouracil pathway genes in colorectal carcinoma

Lists TaqMan Gene Expression Assays used in the study. Table S2 shows sequence of primers and PCR conditions used for promoter CpG methylation profiling. Table S3 shows results of stage-adjusted Cox regression of associations between transcript levels and DFI of colorectal cancer patients from the combined testing and validation I sets. Figure S1 depicts 5-Fluorouracil pathway gene expression levels in the studied sets of colorectal cancer patients. Figure S2 shows results of analysis of associations between transcript levels and disease-free survival of colorectal cancer patients from the validation set I. Figure S3 shows results of analysis of associations between transcript levels and disease-free survival of colorectal cancer patients from the testing set. Figure S4 shows results of analysis of associations between transcript levels and disease-free survival of colorectal cancer patients from the combined testing and validation I set. Figure S5 shows results of analysis of associations between transcript levels and disease-free survival of 5-fluorouracil-treated colorectal cancer patients from the combined testing and validation I set. Figure S6 shows results of analysis of associations between transcript levels and disease-free survival of untreated colorectal cancer patients from the validation I set. Figure S7 shows results of analysis of associations between UPB1 methylation levels and disease-free survival of colorectal cancer patients. Figure S8 shows analysis of association of RRM2 expression with disease-free survival of colorectal cancer patients based on publicly available GEO database. Figure S9 shows analysis of methylation profiles of 5-FU pathway genes in human colorectal tumor (red boxes) and mucosa (green boxes) tissues from publicly available MethHC database. (DOC 1916 kb