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Microbiology and Molecular Biology... Nov 2020Brucellosis is a bacterial disease of domestic animals and humans. The pathogenic ability of organisms relies on their stealthy strategy and their capacity to replicate... (Review)
Review
Brucellosis is a bacterial disease of domestic animals and humans. The pathogenic ability of organisms relies on their stealthy strategy and their capacity to replicate within host cells and to induce long-lasting infections. organisms barely induce neutrophil activation and survive within these leukocytes by resisting microbicidal mechanisms. Very few -infected neutrophils are found in the target organs, except for the bone marrow, early in infection. Still, induces a mild reactive oxygen species formation and, through its lipopolysaccharide, promotes the premature death of neutrophils, which release chemokines and express "eat me" signals. This effect drives the phagocytosis of infected neutrophils by mononuclear cells that become thoroughly susceptible to replication and vehicles for bacterial dispersion. The premature death of the infected neutrophils proceeds without NETosis, necrosis/oncosis, or classical apoptosis morphology. In the absence of neutrophils, the Th1 response exacerbates and promotes bacterial removal, indicating that -infected neutrophils dampen adaptive immunity. This modulatory effect opens a window for bacterial dispersion in host tissues before adaptive immunity becomes fully activated. However, the hyperactivation of immunity is not without a price, since neutropenic -infected animals develop cachexia in the early phases of the disease. The delay in the immunological response seems a requirement for the development of long-lasting brucellosis. This property may be shared with other pathogenic alphaproteobacteria closely related to We propose a model in which -infected polymorphonuclear neutrophils (PMNs) function as "Trojan horse" vehicles for bacterial dispersal and as modulators of the Th1 adaptive immunity in infection.
Topics: Animals; Apoptosis; Brucella; Brucellosis; Host-Pathogen Interactions; Humans; Immunity, Innate; Lipopolysaccharides; Neutrophils; Phagocytosis; Th1 Cells; Virulence
PubMed: 33055283
DOI: 10.1128/MMBR.00048-20 -
Frontiers in Physiology 2020Ouabain is of cardiotonic steroids (CTS) family that is plant-derived compounds and is known for many years as therapeutic and cytotoxic agents. They are specific... (Review)
Review
Ouabain is of cardiotonic steroids (CTS) family that is plant-derived compounds and is known for many years as therapeutic and cytotoxic agents. They are specific inhibitors of Na,K-ATPase, the enzyme, which pumps Na and K across plasma membrane of animal cells. Treatment of cells by CTS affects various cellular functions connected with the maintenance of the transmembrane gradient of Na and K. Numerous studies demonstrated that binding of CTS to Na,K-ATPase not only suppresses its activity but also induces some signal pathways. This review is focused on different mechanisms of two ouabain effects: their ability (1) to protect rodent cells from apoptosis through the expression of [Na]-sensitive genes and (2) to trigger death of non-rodents cells (so-called «oncosis»), possessing combined markers of «classic» necrosis and «classic» apoptosis. Detailed study of oncosis demonstrated that the elevation of the [Na]/[K] ratio is not a sufficient for its triggering. Non-rodent cell death is determined by the characteristic property of "sensitive" to ouabain α1-subunit of Na,K-ATPase. In this case, ouabain binding leads to enzyme conformational changes triggering the activation of p38 mitogen-activated protein kinases (MAPK) signaling. The survival of rodent cells with ouabain-«resistant» α1-subunit is connected with another conformational transition induced by ouabain binding that results in the activation of ERK 1/2 signaling pathway.
PubMed: 33013454
DOI: 10.3389/fphys.2020.01060 -
American Journal of Physiology.... Sep 2020How low-level psychological stress and overnutrition interact in influencing cardiometabolic disease is unclear. Mechanistic overlaps suggest potential synergies;...
How low-level psychological stress and overnutrition interact in influencing cardiometabolic disease is unclear. Mechanistic overlaps suggest potential synergies; however, findings are contradictory. We test whether low-level stress and Western diet (WD) feeding synergistically influence homeostasis, mood, and myocardial ischemic tolerance. Male C57BL6/J mice were fed a control diet or WD (32%/57%/11% calories from fat/carbohydrates/protein) for 12 wk, with subgroups restrained for 30 min/day over the final 3 wk. Metabolism, behavior, tolerance of perfused hearts to ischemia-reperfusion (I/R), and cardiac "death proteins" were assessed. The WD resulted in insignificant trends toward increased body weight (+5%), glucose (+40%), insulin (+40%), triglycerides (+15%), and cholesterol (+20%) and reduced leptin (-20%) while significantly reducing insulin sensitivity [100% rise in homeostasis model assessment of insulin resistance (HOMA-IR), < 0.05]. Restraint did not independently influence metabolism while increasing HOMA-IR a further 50% (and resulting in significant elevations in insulin and glucose to 60-90% above control) in WD mice ( < 0.05), despite blunting weight gain in control and WD mice. Anxiogenesis with restraint or WD was nonadditive, whereas anhedonia (reduced sucrose consumption) only arose with their combination. Neuroinflammation markers (hippocampal TNF-α, Il-1b) were unchanged. Myocardial I/R tolerance was unaltered with stress or WD alone, whereas the combination worsened dysfunction and oncosis [lactate dehydrogenase (LDH) efflux]. Apoptosis (nucleosome accumulation) and death protein expression (BAK, BAX, BCL-2, RIP-1, TNF-α, cleaved caspase-3, and PARP) were unchanged. We conclude that mild, anxiogenic yet cardio-metabolically "benign" stress interacts synergistically with a WD to disrupt homeostasis, promote anhedonia (independently of neuroinflammation), and impair myocardial ischemic tolerance (independently of apoptosis and death protein levels).
Topics: Animals; Diet, High-Fat; Energy Intake; Heart; Homeostasis; Insulin Resistance; Mice, Inbred C57BL; Myocardial Ischemia; Myocardium; Obesity
PubMed: 32755463
DOI: 10.1152/ajpregu.00322.2019 -
Medical Hypotheses Mar 2020Cancer is one of the leading causes of death worldwide, and metastasis is the major cause of death in cancer, therefore, treatments to attenuate metastasis are urgently...
Cancer is one of the leading causes of death worldwide, and metastasis is the major cause of death in cancer, therefore, treatments to attenuate metastasis are urgently needed. Cell migration is indispensable in metastatic cascade, and aquaporins (AQPs) promote cell migration by facilitating water influx at cell front (lamellipodia). In fact, AQPs overexpressed widely among many cancer types. Accordingly, previous efforts of targeting AQPs as strategies of cancer treatments were based on AQP inhibitors, yet the efficacy of AQP inhibition was limited based on recent surveys. On the contrary, whether AQP agonist has role in cancer treatments has not been explored. AqF026, an AQP1 agonist, was initially applied to a mouse model of peritoneal dialysis. Herein, we aimed to apply AqF026 to magnify the water influx into lamellipodia of migrating cancer cells so as to induce oncosis by causing overloaded cancer cell swelling in advance of metastatic cascade. Cell swelling is a characteristic of oncosis. With impairment or insufficient regulatory volume decrease (RVD), cell swelling can lead to oncosis. Cancer cells with metastatic potentials shared the same population of cancer cells with multidrug resistance (MDR) lineage, and the impairment or insufficient RVD is shown in cancer cells with MDR. Taken together, the author hypothesized that given appropriate concentration or dose of AQP1 agonist AqF026, the AqF026 may induce oncosis of cancer cells preferentially rather than normal cells by causing overloaded water influx via AQP1 and consequent irreversible cell swelling.
PubMed: 32220711
DOI: 10.1016/j.mehy.2020.109685 -
Cell Death and Differentiation Jun 2020In contrast to the "Warburg effect" or aerobic glycolysis earlier generalized as a phenomenon in cancer cells, more and more recent evidence indicates that functional...
In contrast to the "Warburg effect" or aerobic glycolysis earlier generalized as a phenomenon in cancer cells, more and more recent evidence indicates that functional mitochondria are pivotal for ensuring the energy supply of cancer cells. Here, we report that cancer cells with reduced autophagy-related protein 12 (ATG12) expression undergo an oncotic cell death, a phenotype distinct from that seen in ATG5-deficient cells described before. In addition, using untargeted metabolomics with ATG12-deficient cancer cells, we observed a global reduction in cellular bioenergetic pathways, such as β-oxidation (FAO), glycolysis, and tricarboxylic acid cycle activity, as well as a decrease in mitochondrial respiration as monitored with Seahorse experiments. Analyzing the biogenesis of mitochondria by quantifying mitochondrial DNA content together with several mitochondrion-localizing proteins indicated a reduction in mitochondrial biogenesis in ATG12-deficient cancer cells, which also showed reduced hexokinase II expression and the upregulation of uncoupling protein 2. ATG12, which we observed in normal cells to be partially localized in mitochondria, is upregulated in multiple types of solid tumors in comparison with normal tissues. Strikingly, mouse xenografts of ATG12-deficient cells grew significantly slower as compared with vector control cells. Collectively, our work has revealed a previously unreported role for ATG12 in regulating mitochondrial biogenesis and cellular energy metabolism and points up an essential role for mitochondria as a failsafe mechanism in the growth and survival of glycolysis-dependent cancer cells. Inducing oncosis by imposing an ATG12 deficiency in solid tumors might represent an anticancer therapy preferable to conventional caspase-dependent apoptosis that often leads to undesirable consequences, such as incomplete cancer cell killing and a silencing of the host immune system.
Topics: Animals; Autophagy-Related Protein 12; Cell Line, Tumor; Energy Metabolism; Glycolysis; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Mitochondria; Neoplasms
PubMed: 31844253
DOI: 10.1038/s41418-019-0476-5 -
International Journal of Molecular... Sep 2019The term necrosis is commonly applied to cells that have died via a non-specific pathway or mechanism but strictly is the description of the degradation processes...
The term necrosis is commonly applied to cells that have died via a non-specific pathway or mechanism but strictly is the description of the degradation processes involved once the plasma membrane of the cell has lost integrity. The signalling pathways potentially involved in accidental cell death (ACD) or oncosis are under-studied. In this study, the flow cytometric analysis of the intracellular antigens involved in regulated cell death (RCD) revealed the phenotypic nature of cells undergoing oncosis or necrosis. Sodium azide induced oncosis but also classic apoptosis, which was blocked by zVAD (z-Vla-Ala-Asp(OMe)-fluoromethylketone). Oncotic cells were found to be viability/caspase-3/RIP3 (Receptor-interacting serine/threonine protein kinase 3). These two cell populations also displayed a DNA damage response (DDR) phenotype pH2AX/PARP, cleaved PARP induced caspase independent apoptosis H2AX/PARP and hyper-activation or parthanatos H2AX/PARP. Oncotic cells with phenotype cell viability/RIP3/caspase-3 showed increased DDR and parthanatos. Necrostatin-1 down-regulated DDR in oncotic cells and increased sodium azide induced apoptosis. This flow cytometric approach to cell death research highlights the link between ACD and the RCD processes of programmed apoptosis and necrosis.
Topics: Apoptosis; Biomarkers; Caspases; Flow Cytometry; Humans; Immunophenotyping; Models, Biological; Neoplasms
PubMed: 31489916
DOI: 10.3390/ijms20184379 -
Journal of Enzyme Inhibition and... Dec 2019In this paper, a series of novel 1-dibenzo[,]carbazole derivatives of dehydroabietic acid bearing different -(piperazin-1-yl)alkyl side chains were designed, synthesised...
In this paper, a series of novel 1-dibenzo[,]carbazole derivatives of dehydroabietic acid bearing different -(piperazin-1-yl)alkyl side chains were designed, synthesised and evaluated for their anticancer activities against three human hepatocarcinoma cell lines (SMMC-7721, HepG2 and Hep3B). Among them, compound exhibited the most potent activity against three cancer cell lines with IC values of 1.39 ± 0.13, 0.51 ± 0.09 and 0.73 ± 0.08 µM, respectively. In the kinase inhibition assay, compound could significantly inhibit MEK1 kinase activity with IC of 0.11 ± 0.02 µM, which was confirmed by western blot analysis and molecular docking study. In addition, compound could elevate the intracellular ROS levels, decrease mitochondrial membrane potential, destroy the cell membrane integrity, and finally lead to the oncosis and apoptosis of HepG2 cells. Therefore, compound could be a potent MEK inhibitor and a promising anticancer agent worthy of further investigations.
Topics: Abietanes; Antineoplastic Agents; Carbazoles; Cell Cycle; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; MAP Kinase Kinase 1; Membrane Potential, Mitochondrial; Models, Molecular; Molecular Structure; Piperazine; Protein Kinase Inhibitors; Structure-Activity Relationship
PubMed: 31448648
DOI: 10.1080/14756366.2019.1655407 -
Biological & Pharmaceutical Bulletin Aug 2019The purpose of the paper is to study the differences in cell death mechanism of MGC-803 induced by "dextran-magnetic layered double hydroxide-fluorouracil" (DMF) drug...
The purpose of the paper is to study the differences in cell death mechanism of MGC-803 induced by "dextran-magnetic layered double hydroxide-fluorouracil" (DMF) drug delivery system and 5-Fluorouracil (5-Fu), respectively. The inhibitory effect on the proliferation was detected via CCK-8. The morphology of cell death was detected by transmission electron microscopy (TEM). Intracellular ATP, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) and Cytosolic Free Ca (Ca) level were detected via some methods. The result showed that DMF had more obvious effect in suppressing proliferation compared with 5-Fu, and changed cell death pattern of 5-Fu from apoptosis to oncosis. The ATP decrease, MMP loss, Ca increase, the activation of uncoupling protein-2 (UCP-2) and calpain-1 were significant after DMF exposure. However, DMF did not result in ROS accumulation. DMF could involve in activation of porimin, and the cascade reaction of caspases-3, -7, -9, and -12 and poly ADP-ribose polymerase (PARP) through Western blot. DMF showed a stronger injury on nuclear membrane in the cascade reaction of caspases-6, -8 and lamin-A. DMF triggered rapid depletion of ATP, which was consistent with the phenotype of oncosis. Endogenous mitochondrial apoptosis might not be the main cause of cell swelling. DMF could induce strong endoplasmic reticulum stress (ERS) effect, there might be some signaling pathways related with ERS during the process of oncosis. The calpain system might not be a key factor for structural damage in oncosis induced by DMF. DMF could induce the caspases cascade reactions similar to apoptosis, but inflicted a more strong damage on nuclear membrane and PARP.
Topics: Apoptosis; Calpain; Caspases; Cell Death; Cell Line, Tumor; Cell Proliferation; Dextrans; Drug Delivery Systems; Fluorouracil; Humans; Hydroxides; Lamin Type A; Mitochondria; Phenotype; Poly (ADP-Ribose) Polymerase-1; Reactive Oxygen Species; Stomach Neoplasms
PubMed: 31105116
DOI: 10.1248/bpb.b18-00938