Source Of Adenosine Triphosphate Research Articles

Ligand-Based Virtual Screening and Molecular Docking of Benzimidazoles as Potential Inhibitors of Triosephosphate Isomerase Identified New Trypanocidal Agents.

Trypanosoma cruzi (T. cruzi) is a parasite that affects humans and other mammals. T. cruzi depends on glycolysis as a source of adenosine triphosphate (ATP) supply, and triosephosphate isomerase (TIM) plays a key role in this metabolic pathway. This enzyme is an attractive target for the design of new trypanocidal drugs. In this study, a ligand-based virtual screening (LBVS) from the ZINC15 database using benzimidazole as a scaffold was accomplished. Later, a molecular docking on the interface of T. cruzi TIM (TcTIM) was performed and the compounds were grouped by interaction profiles. Subsequently, a selection of compounds was made based on cost and availability for in vitro evaluation against blood trypomastigotes. Finally, the compounds were analyzed by molecular dynamics simulation, and physicochemical and pharmacokinetic properties were determined using SwissADME software. A total of 1604 molecules were obtained as potential TcTIM inhibitors. BP2 and BP5 showed trypanocidal activity with half-maximal lytic concentration (LC50) values of 155.86 and 226.30 µM, respectively. Molecular docking and molecular dynamics simulation analyzes showed a favorable docking score of BP5 compound on TcTIM. Additionally, BP5 showed a low docking score (−5.9 Kcal/mol) on human TIM compared to the control ligand (−7.2 Kcal/mol). Both compounds BP2 and BP5 showed good physicochemical and pharmacokinetic properties as new anti-T. cruzi agents.

Transcriptome and Proteome Analysis Revealed Key Pathways Regulating Final Stage of Oocyte Maturation of the Turkey (Meleagris gallopavo).

In birds, the zona pellucida (ZP) matrix that surrounds the ovulated oocyte—called the inner perivitelline layer—is involved in sperm–zona interaction and successful fertilization. To identify the important genes and proteins connected with the final step of egg development, next-generation sequencing and two-dimensional electrophoresis, combined with mass spectrometry, were used for the analysis of mature oocytes at the F1 developmental stage. A total of 8161 genes and 228 proteins were annotated. Six subfamilies of genes, with codes ZP, ZP1–4, ZPD, and ZPAX, were identified, with the dominant expression of ZPD. The main expression site for ZP1 was the liver; however, granulosa cells may also participate in local ZP1 secretion. A ubiquitination system was identified in mature oocytes, where ZP1 was found to be the main ubiquitinated protein. Analysis of transcripts classified in estrogen receptor (ESR) signaling indicated the presence of ESR1 and ESR2, as well as a set of estrogen-dependent genes involved in both genomic and nongenomic mechanisms for the regulation of gene expression by estrogen. Oxidative phosphorylation was found to be a possible source of adenosine triphosphate, and the nuclear factor erythroid 2-related factor 2 signaling pathway could be involved in the response against oxidative stress. Oocyte–granulosa cell communication by tight, adherens, and gap junctions seems to be essential for the final step of oocyte maturation.

Heterogeneity in Cancer Metabolism: New Concepts in an Old Field.

Significance: In the last years, metabolic reprogramming, fluctuations in bioenergetic fuels, and modulation of oxidative stress became new key hallmarks of tumor development. In cancer, elevated glucose uptake and high glycolytic rate, as a source of adenosine triphosphate, constitute a growth advantage for tumors. This represents the universally known Warburg effect, which gave rise to one major clinical application for detecting cancer cells using glucose analogs: the positron emission tomography scan imaging.Recent Advances: Glucose utilization and carbon sources in tumors are much more heterogeneous than initially thought. Indeed, new studies emerged and revealed a dual capacity of tumor cells for glycolytic and oxidative phosphorylation (OXPHOS) metabolism. OXPHOS metabolism, which relies predominantly on mitochondrial respiration, exhibits fine-tuned regulation of respiratory chain complexes and enhanced antioxidant response or detoxification capacity.Critical Issues: OXPHOS-dependent cancer cells use alternative oxidizable substrates, such as glutamine and fatty acids. The diversity of carbon substrates fueling neoplastic cells is indicative of metabolic heterogeneity, even within tumors sharing the same clinical diagnosis. Metabolic switch supports cancer cell stemness and their bioenergy-consuming functions, such as proliferation, survival, migration, and invasion. Moreover, reactive oxygen species-induced mitochondrial metabolism and nutrient availability are important for interaction with tumor microenvironment components. Carcinoma-associated fibroblasts and immune cells participate in the metabolic interplay with neoplastic cells. They collectively adapt in a dynamic manner to the metabolic needs of cancer cells, thus participating in tumorigenesis and resistance to treatments.Future Directions: Characterizing the reciprocal metabolic interplay between stromal, immune, and neoplastic cells will provide a better understanding of treatment resistance. Antioxid. Redox Signal. 26, 462–485.

Altered Glucose Metabolism In Rituximab-Chemotherapy Resistant Cells Is a Potential Target For Future Therapeutic Development

Although treatment of lymphoma has greatly improved over recent years, acquired rituximab-chemotherapy resistance is an emerging clinical challenge for physicians treating relapsed/refractory diffuse large B-cell lymphoma and other aggressive histological subtypes. The discovery and characterization of cellular pathways up-regulated or down-regulated in rituximab-chemotherapy resistant B-cell lymphoma cells can potentially identify prognostic biomarkers and/or the development of novel therapeutic strategies. Differences in cellular metabolism exist between normal and malignant cells. Cancer cells are known to have an increase in aerobic glycolysis as a source of adenosine triphosphate (ATP) generation (a.k.a. Warburg effect). Inhibition of glucose uptake or its metabolism has been shown to induce cytotoxicity in solid tumor cancer cells. Therefore, we evaluated differences in the glucose metabolism between rituximab-sensitive (RSCL) or rituximab-resistant cell lines (RRCL) representing aggressive subtypes of B-cell lymphoma. Differences in the baseline cell proliferation rate, ATP generation, lactic acid dehydrogenase (LDH) activity, glucose uptake and lactic acid production between RSCL and RRCL were determined. We then blocked glucose uptake in RSCL and RRCL by exposing these cells to 2-deoxy-D-glucose (2-DG), a glycolytic inhibitor, and measured changes in cell viability, cell cycle distribution, mitochondrial potential and induction of apoptosis using the MTT assay and flow cytometry (propidium iodine [PI], DiOC6, and PI/AnnexinV staining, respectively. Finally, we evaluated the cytotoxic effects of 2-DG in combination with multiple chemotherapy agents in RSCL and RRCL. Significant differences in metabolic rate and glucose metabolism were identified. RRCL had a lower proliferation rate, but alternatively had a higher: 1) intracellular concentrations of ATP, 2) LDH activity, 3) production of Lactate, and 4) glucose uptake/consumption. Together these data suggest that RRCL are more dependent on glucose metabolism for generation of energy (i.e. ATP). In vitro exposure of RRCL, and to a lesser degree of RSCL to 2-DG, resulted in a dose- and time-dependent cell death. As expected, in vitro exposure of RRCL to 2-DG resulted in a decrease in: 1) glucose uptake, 2) lactate production, 3) ATP production and subsequent depletion of ATP intracellular reserves. In addition, 2-DG induced greater G1-phase arrest in RRCL. The baseline mitochondrial potential was higher in RRCL than RSCL and correlated with resistance to multiple chemotherapy agents commonly used in the treatment of B-cell lymphoma. Caspase inhibition did not rescue RRCL to the cytotoxic effects of 2-DG, suggesting the execution of as caspase-independent cell death pathway (i.e. autophagy or senescence). In addition, 2-DG exhibited additive/synergistic effects when combined with doxorubicin in RRCL. In summary, our data suggests that the acquirement of rituximab-chemotherapy resistance in RRCL is associated with deregulation in the mitochondrial potential leading to chemotherapy resistance and an altered cellular metabolism that is primarily dependent on glucose uptake and glycolysis to generate ATP. Developing therapeutic strategies that selectively inhibit glucose uptake or glucose metabolism in cancer cells could prove to be a promising strategy for the treatment of relapsed/refractory lymphoid malignancies in the future. (Research, in part, supported by a NIH grant R01 CA136907-01A1 awarded to Roswell Park Cancer Institute and The Eugene and Connie Corasanti Lymphoma Research Fund) Disclosures: Czuczman: Genetech, Onyx, Celgene, Astellas, Millennium, Mundipharma: Advisory Committees Other.

An interdisciplinary systems approach to study sperm physiology and evolution

Optical trapping is a noninvasive biophotonic tool that has been developed to study the physiological and biomechanical properties of cells. The custom-designed optical system is built to direct near-infrared laser light into an inverted microscope to create a single-point three-dimensional gradient laser trap at the microscope focal point. A real-time automated tracking and trapping system (RATTS) is described that provides a remote user-friendly robotic interface. The combination of laser tweezers, fluorescent imaging, and RATTS can measure sperm swimming speed and swimming force simultaneously with mitochondrial membrane potential (MMP). The roles of two sources of adenosine triphosphate in sperm motility/energetics are studied: oxidative phosphorylation, which occurs in the mitochondria located in the sperm midpiece, and glycolysis, which occurs along the length of the sperm tail (flagellum). The effects of glucose, oxidative phosphorylation inhibitors, and glycolytic inhibitors on human sperm motility are studied. This combination of photonic physical and engineering tools has been used to examine the evolutionary effect of sperm competition in primates. The results demonstrate a correlation between mating type and sperm motility: sperm from polygamous (multi-partner) primate species swim faster and with greater force than sperm from polygynous (single partner) primate species. In summary, engineering and biological systems are combined to provide a powerful interdisciplinary approach to study the complex biological systems that drive the sperm toward the egg.