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1.
Marzena Ułamek-Kozioł Wanda Furmaga-Jabłońska Sławomir Januszewski Judyta Brzozowska Małgorzata Ściślewska Mirosław Jabłoński Ryszard Pluta 《Neurochemical research》2013,38(9):1769-1773
Autophagy is a major intracellular degeneration pathway involved in the elimination and recycling of damaged organelles and long-lived proteins by lysosomes. Many of the pathological factors, which trigger neurodegenerative diseases, can perturb the autophagy activity, which is associated with misfolded protein aggregates accumulation in these disorders. Alzheimer’s disease, the first neurodegenerative disorder between dementias, is characterized by two aggregating proteins, β-amyloid peptide (plaques) and τ-protein (tangles). In Alzheimer’s disease autophagosomes dynamically form along neurites within neuronal cells and in synapses but effective clearance of these structures needs retrograde transportation towards the neuronal soma where there is a major concentration of lysosomes. Maturation of autophago-lysosomes and their retrograde trafficking are perturbed in Alzheimer’s disease, which causes a massive concentration of autophagy elements along degenerating neurites. Transportation system is disturbed along defected microtubules in Alzheimer’s disease brains. τ-protein has been found to control the stability of microtubules, however, phosphorylation of τ-protein or an increase in the total level of τ-protein can cause dysfunction of neuronal cells microtubules. Current evidence has shown that autophagy is developing in Alzheimer’s disease brains because of ineffective degradation of autophagosomes, which hold amyloid precursor protein-rich organelles and secretases important for β-amyloid peptides generation from amyloid precursor. The combination of raised autophagy induction and abnormal clearance of β-amyloid peptide-generating autophagic vacuoles creates circumstances helpful for β-amyloid peptide aggregation and accumulation in Alzheimer’s disease. However, the key role of autophagy in Alzheimer’s disease development is still under consideration today. One point of view suggests that abnormal autophagy induction causes a concentration of autophagic vacuoles rich in amyloid precursor protein, β-amyloid peptide and the elements crucial for its formation, whereas other hypothesis points to marred autophagic clearance or even decrease in autophagic effectiveness playing a role in maturation of Alzheimer’s disease. In this review we present the recent evidence linking autophagy to Alzheimer’s disease and the role of autophagic regulation in the development of full-blown Alzheimer’s disease. 相似文献
2.
Chong Li Marzena Pazgier Changqing Li Min Liu Gang Wei Wei-Yue Lu 《Journal of molecular biology》2010,398(2):200-213
Inhibition of the interaction between the tumor suppressor protein p53 and its negative regulators MDM2 and MDMX is of great interest in cancer biology and drug design. We previously reported a potent duodecimal peptide inhibitor, termed PMI (TSFAEYWNLLSP), of the p53-MDM2 and -MDMX interactions. PMI competes with p53 for MDM2 and MDMX binding at an affinity roughly 2 orders of magnitude higher than that of 17-28p53 (ETFSDLWKLLPE) of the same length; both peptides adopt nearly identical α-helical conformations in the complexes, where the three highlighted hydrophobic residues Phe, Trp, and Leu dominate PMI or 17-28p53 binding to MDM2 and MDMX. To elucidate the molecular determinants for PMI activity and specificity, we performed a systematic Ala scanning mutational analysis of PMI and 17-28p53. The binding affinities for MDM2 and MDMX of a total of 35 peptides including 10 truncation analogs were quantified, affording a complete dissection of energetic contributions of individual residues of PMI and 17-28p53 to MDM2 and MDMX association. Importantly, the N8A mutation turned PMI into the most potent dual-specific antagonist of MDM2 and MDMX reported to date, registering respective Kd values of 490 pM and 2.4 nM. The co-crystal structure of N8A-PMI-25-109MDM2 was determined at 1.95 Å, affirming that high-affinity peptide binding to MDM2/MDMX necessitates, in addition to optimized intermolecular interactions, enhanced helix stability or propensity contributed by non-contact residues. The powerful empirical binding data and crystal structures present a unique opportunity for computational studies of peptide inhibition of the p53-MDM2/MDMX interactions. 相似文献
3.
Abdullah Mohib Sliwinska Elwira Góralski Grzegorz Latocha Piotr Tuleja Monika Widyna Patrycja Popielarska-Konieczna Marzena 《Plant Cell, Tissue and Organ Culture》2021,147(3):569-582
Plant Cell, Tissue and Organ Culture (PCTOC) - Endosperm, an ephemeral and storage tissue, serves as a source of nutrition and protection during embryo development and germination. It can be used... 相似文献
4.
Anna Juras Edvard Ehler Maciej Chyleński Łukasz Pospieszny Anna Elżbieta Spinek Helena Malmström Maja Krzewińska Krzysztof Szostek Wojciech Pasterkiewicz Marek Florek Stanisław Wilk Barbara Mnich Janusz Kruk Marzena Szmyt Sławomir Kozieł Anders Götherström Mattias Jakobsson Miroslawa Dabert 《American journal of physical anthropology》2021,176(2):223-236
5.
Marzena Wieczorkowska Jacek Zielonka Joanna Celińska Jan Adamus Ewa Ciesielska Andrzej Marcinek 《Free radical research》2013,47(11):1157-1162
It is shown that NADH can be effectively oxidized by 1-methyl-3-nitropyridine in non-enzymatic and enzyme-mediated processes. Mechanistic issues of these reactions are discussed. These processes seem to contribute to the observed cytotoxicity of 1-methyl-3-nitropyridine. A key role of 1-methyl-3-nitropyridinyl radical formed in the enzyme-mediated processes is emphasized. 相似文献
6.
Aleksandra Markiewicz Marzena We?nicka-Ja?kiewicz Jaros?aw Skokowski Janusz Ja?kiewicz Jolanta Szade Jacek Jassem Anna J. ?aczek 《PloS one》2013,8(8)
Introduction
Amplification of the ESR1 gene, coding for estrogen receptor alpha, was shown to predict responsiveness to tamoxifen, however its prognostic impact in breast cancer patients has not been thoroughly investigated. Other factors that could contribute to responsiveness to tamoxifen treatment are polymorphisms in ESR1 gene and genes involved in tamoxifen metabolism.The aim of this study was to assess the prognostic role of ESR1 gene dosage in a consecutive group of breast cancer patients and to correlate this feature with clinico-pathological factors. Additionally, ESR1 PvuII, CYP2C19*2 and UGT2B15*2 polymorphisms were analyzed in the tamoxifen-treated subgroup of patients.Materials and Methods
Primary tumor samples from 281 stage I-III consecutive breast cancer patients were analyzed for ESR1 gene dosage using real-time PCR with locked nucleic acids hydrolysis probes. In the tamoxifen-treated subgroup of patients, ESR1 PvuII, CYP2C19*2 and UGT2B15*2 polymorphism in leukocytes genomic DNA were analyzed. Results were correlated with clinico-pathological factors and with disease-free survival (DFS) and overall survival (OS).Results
ESR1 amplification (with a cut-off level of 2.0) was found in 12% of the entire group of breast cancer patients, and in 18% of the ER-negative subgroup. This feature was associated with decreased DFS both in the entire group (P=0.007) and in the ER-negative subgroup (P=0.03), but not in the tamoxifen-treated patients.Patients with ESR1 PvuII wt/wt genotype and at least one UGT2B15 wt allele had a worse DFS (P=0.03) and showed a trend towards decreased Os (P=0.08) in comparison to patients with ESR1 PvuII wt/vt or vt/vt genotype and UGT2B15 *2/*2 genotype.Conclusions
ESR1 amplification can occur in ER-negative tumors and may carry poor prognosis. In the tamoxifen-treated subgroup, poor prognosis was related to the combined presence of ESR1 PvuII wt/wt and UGT2B15wt/wt or wt/*2 genotype. 相似文献7.
Kristen M. Varney Alexandre M. J. J. Bonvin Marzena Pazgier Jakob Malin Wenbo Yu Eugene Ateh Taiji Oashi Wuyuan Lu Jing Huang Marlies Diepeveen-de Buin Joseph Bryant Eefjan Breukink Alexander D. MacKerell Jr Erik P. H. de Leeuw 《PLoS pathogens》2013,9(11)
We have previously reported on the functional interaction of Lipid II with human alpha-defensins, a class of antimicrobial peptides. Lipid II is an essential precursor for bacterial cell wall biosynthesis and an ideal and validated target for natural antibiotic compounds. Using a combination of structural, functional and in silico analyses, we present here the molecular basis for defensin-Lipid II binding. Based on the complex of Lipid II with Human Neutrophil peptide-1, we could identify and characterize chemically diverse low-molecular weight compounds that mimic the interactions between HNP-1 and Lipid II. Lead compound BAS00127538 was further characterized structurally and functionally; it specifically interacts with the N-acetyl muramic acid moiety and isoprenyl tail of Lipid II, targets cell wall synthesis and was protective in an in vivo model for sepsis. For the first time, we have identified and characterized low molecular weight synthetic compounds that target Lipid II with high specificity and affinity. Optimization of these compounds may allow for their development as novel, next generation therapeutic agents for the treatment of Gram-positive pathogenic infections. 相似文献
8.
Franciszek Burdan Agnieszka Mocarska Marzena Janczarek Robert Klepacz Marek ?osicki Krzysztof Patyra Agnieszka Brodzik Joanna Kiszka Aneta Chru?cicka Iwonna ?elzowska-Cie?lińska El?bieta Staros?awska 《PloS one》2013,8(8)
The spinal perineurial cyst (Tarlov) is a dilatation between the perineurium and endoneurium of spinal nerve roots, located at level of the spinal ganglion and filled with cerebrospinal fluid but without communication with the perineurial subarachnoid space. The aim of the study was to evaluate it incidence among East-European patients. The retrospective data collected during various magnetic resonance spinal examinations and stored on the picture archiving and communication system was analyzed for an incidence of perineurial cysts. From among 842 patients that underwent examination, 75 cases perineurial cysts were revealed. In 22 cases single anomalies were found. In remaining 53 cases, multiple uni- or less frequently bilateral changes were noted. The most common position was the sacral canal, particularly the level of S2 and S3. Occasionally, cysts were also visible on the cervical, thoracic and lumbar level. Incidence of sacral perineurial cysts was significantly higher in females than in males. Similar data was found for single and multiple changes despite of their localization. Insignificant changes were seen for patient age and cyst size. Perineurial spinal cysts were the most frequently observed on the sacral level and such changes were more common in females. 相似文献
9.
Le Zhao W. David Tolbert Bryan Ericksen Changyou Zhan Xueji Wu Weirong Yuan Xu Li Marzena Pazgier Wuyuan Lu 《PloS one》2013,8(11)
HNP1 is a human alpha defensin that forms dimers and multimers governed by hydrophobic residues, including Tyr16, Ile20, Leu25, and Phe28. Previously, alanine scanning mutagenesis identified each of these residues and other hydrophobic residues as important for function. Here we report further structural and functional studies of residues shown to interact with one another across oligomeric interfaces: I20A-HNP1 and L25A-HNP1, plus the double alanine mutants I20A/L25A-HNP1 and Y16A/F28A-HNP1, and the quadruple alanine mutant Y16A/I20A/L25A/F28A-HNP1. We tested binding to HIV-1 gp120 and HNP1 by surface plasmon resonance, binding to HIV-1 gp41 and HNP1 by fluorescence polarization, inhibition of anthrax lethal factor, and antibacterial activity using the virtual colony count assay. Similar to the previously described single mutant W26A-HNP1, the quadruple mutant displayed the least activity in all functional assays, followed by the double mutant Y16A/F28A-HNP1. The effects of the L25A and I20A single mutations were milder than the double mutant I20A/L25A-HNP1. Crystallographic studies confirmed the correct folding and disulfide pairing, and depicted an array of dimeric and tetrameric structures. These results indicate that side chain hydrophobicity is the critical factor that determines activity at these positions. 相似文献
10.
Malgorzata Stec Jarosław Baran Rafał Szatanek Bożenna Mytar Marzena Lenart Antoni Czupryna Antoni Szczepanik Maciej Siedlar Marek Zembala 《Cancer immunology, immunotherapy : CII》2013,62(4):705-713
Monocytes exhibit direct and indirect antitumour activities and may be potentially useful for various forms of adoptive cellular immunotherapy of cancer. However, blood is a limited source of them. This study explored whether monocytes can be obtained from bone marrow haematopoietic CD34+ stem cells of colon cancer patients, using previously described protocol of expansion and differentiation to monocytes of cord blood-derived CD34+ haematopoietic progenitors. Data show that in two-step cultures, the yield of cells was increased approximately 200-fold, and among these cells, up to 60 % of CD14+ monocytes were found. They consisted of two subpopulations: CD14++CD16+ and CD14+CD16?, at approximately 1:1 ratio, that differed in HLA-DR expression, being higher on the former. No differences in expression of costimulatory molecules were observed, as CD80 was not detected, while CD86 expression was comparable. These CD14+ monocytes showed the ability to present recall antigens (PPD, Candida albicans) and neoantigens expressed on tumour cells and tumour-derived microvesicles (TMV) to autologous CD3+ T cells isolated from the peripheral blood. Monocytes also efficiently presented the immunodominant HER-2/neu369–377 peptide (KIFGSLAFL), resulting in the generation of specific cytotoxic CD8+ T lymphocytes (CTL). The CD14++CD16+ subset exhibited enhanced cytotoxicity, though nonsignificant, towards tumour cells in vitro. These observations indicate that generation of monocytes from CD34+ stem cells of cancer patients is feasible. To our knowledge, it is the first demonstration of such approach that may open a way to obtain autologous monocytes for alternative forms of adaptive and adoptive cellular immunotherapy of cancer. 相似文献