The key role of nitric oxide in hypoxia: hypoxic vasodilation and energy supply-demand matching

Significance: a mismatch between energy supply and demand induces tissue hypoxia with the potential to cause cell death and organ failure. Whenever arterial oxygen concentration is reduced, increases in blood flow - 'hypoxic vasodilation' - occur in an attempt to restore oxygen supply. Nitric oxide is a major signalling and effector molecule mediating the body's response to hypoxia, given its unique characteristics of vasodilation (improving blood flow and oxygen supply) and modulation of energetic metabolism (reducing oxygen consumption and promoting utilization of alternative pathways). Recent advances: this review covers the role of oxygen in metabolism and responses to hypoxia, the hemodynamic and metabolic effects of nitric oxide, and mechanisms underlying the involvement of nitric oxide in hypoxic vasodilation. Recent insights into nitric oxide metabolism will be discussed, including the role for dietary intake of nitrate, endogenous nitrite reductases, and release of nitric oxide from storage pools. The processes through which nitric oxide levels are elevated during hypoxia are presented, namely (i) increased synthesis from nitric oxide synthases, increased reduction of nitrite to nitric oxide by heme- or pterin-based enzymes and increased release from nitric oxide stores, and (ii) reduced deactivation by mitochondrial cytochrome c oxidase. Critical issues: several reviews covered modulation of energetic metabolism by nitric oxide, while here we highlight the crucial role NO plays in achieving cardiocirculatory homeostasis during acute hypoxia through both vasodilation and metabolic suppression Future directions: we identify a key position for nitric oxide in the body's adaptation to an acute energy supply-demand mismatc

Investigation of antibacterial and antiinflammatory activities of proanthocyanidins from pelargonium sidoides dc root extract

The study explores antibacterial, antiinflammatory and cytoprotective capacity of Pelargonium sidoides DC root extract (PSRE) and proanthocyanidin fraction from PSRE (PACN) under conditions characteristic for periodontal disease. Following previous finding that PACN exerts stronger suppression of Porphyromonas gingivalis compared to the effect on commensal Streptococcus salivarius, the current work continues antibacterial investigation on Staphylococcus aureus, Staphylococcus epidermidis, Aggregatibacter actinomycetemcomitans and Escherichia coli. PSRE and PACN are also studied for their ability to prevent gingival fibroblast cell death in the presence of bacteria or bacterial lipopolysaccharide (LPS), to block LPS-or LPS + IFNγ-induced release of inflammatory mediators, gene expression and surface antigen presentation. Both PSRE and PACN were more efficient in suppressing Staphylococcus and Aggregatibacter compared to Escherichia, prevented A. actinomycetemcomitans-and LPS-induced death of fibroblasts, decreased LPS-induced release of interleukin-8 and prostaglandin E2 from fibroblasts and IL-6 from leukocytes, blocked expression of IL-1β, iNOS, and surface presentation of CD80 and CD86 in LPS + IFNγ-treated macrophages, and IL-1β and COX-2 expression in LPS-treated leukocytes. None of the investigated substances affected either the level of secretion or expression of TNFα. In conclusion, PSRE, and especially PACN, possess strong antibacterial, antiinflammatory and gingival tissue protecting properties under periodontitis-mimicking conditions and are suggestable candidates for treatment of the disease

Probucol Suppresses Enterocytic Accumulation of Amyloid-β Induced by Saturated Fat and Cholesterol Feeding

Amyloid-β (Aβ) is secreted from lipogenic organs such as intestine and liver as an apolipoprotein of nascent triacylglycerol rich lipoproteins. Chronically elevated plasma Aβ may compromise cerebrovascular integrity and exacerbate amyloidosis—a hallmark feature of Alzheimer’s disease (AD). Probucol is a hypocholesterolemic agent that reduces amyloid burden in transgenic amyloid mice, but the mechanisms for this effect are presently unclear. In this study, the effect of Probucol on intestinal lipoprotein-Aβ homeostasis was explored. Wild-type mice were fed a control low-fat diet and enterocytic Aβ was stimulated by high-fat (HF) diet enriched in 10% (w/w) saturated fat and 1% (w/w) cholesterol for the duration of 1 month. Mice treated with Probucol had the drug incorporated into the chow at 1% (w/w). Quantitative immunofluorescence was utilised to determine intestinal apolipoprotein B (apo B) and Aβ abundance. We found apo B in both the perinuclear region of the enterocytes and the lacteals in all groups. However, HF feeding and Probucol treatment increased secretion of apo B into the lacteals without any change in net villi abundance. On the other hand, HF-induced enterocytic perinuclear Aβ was significantly attenuated by Probucol. No significant changes in Aβ were observed within the lacteals. The findings of this study support the notion that Probucol suppresses dietary fat induced stimulation of Aβ biosynthesis and attenuate availability of apo B lipoprotein-Aβ for secretion

Exploration of Clustering Force Through Scale

Materialisation / Complex ProjectsArchitecture and The Built Environmen

Širdies perfuzija NO donoru S-nitrozoglutationu sukelia nuo mitochondrijų pralaidumo priklausančią kardiomiocitų apoptozę

Kauno medicinos universitetasKauno medicinos universiteto Biomedicininių tyrimų institutasVytauto Didžiojo universiteta

Fibrillar beta-amyloid peptide A beta(1-40) activates microglial proliferation via stimulating TNF-alpha release and H2O2 derived from NADPH oxidase: a cell culture study

Background: Alzheimer's disease is characterized by the accumulation of neuritic plaques, containing activated microglia and beta-amyloid peptides (A beta). Fibrillar A beta can activate microglia, resulting in production of toxic and inflammatory mediators like hydrogen peroxide, nitric oxide, and cytokines. We have recently found that microglial proliferation is regulated by hydrogen peroxide derived from NADPH oxidase. Thus, in this study, we investigated whether A beta can stimulate microglial proliferation and cytokine production via activation of NADPH oxidase to produce hydrogen peroxide.|Methods: Primary mixed glial cultures were prepared from the cerebral cortices of 7-day-old Wistar rats. At confluency, microglial cells were isolated by tapping, replated, and treated either with or without A beta. Hydrogen peroxide production by cells was measured with Amplex Red and peroxidase. Microglial proliferation was assessed under a microscope 0, 24 and 48 hours after plating. TNF-alpha and IL-1 beta levels in the culture medium were assessed by ELISA.|Results: We found that 1 mu M fibrillar (but not soluble)A beta(1-40) peptide induced microglial proliferation and caused release of hydrogen peroxide, TNF-alpha and IL-1 beta from microglial cells. Proliferation was prevented by the NADPH oxidase inhibitor apocynin (10 mu M), by the hydrogen peroxide-degrading enzyme catalase (60 U/ml), and by its mimetics EUK-8 and EUK-134 (20 mu M); as well as by an antibody against TNF-alpha and by a soluble TNF receptor inhibitor. Production of TNF-alpha and IL-1 beta, measured after 24 hours of A beta treatment, was also prevented by apocynin, catalase and EUKs, but the early release (measured after 1 hour of A beta treatment)of TNF-alpha was insensitive to apocynin or catalase.|Conclusion: These results indicate that A beta(1-40)-induced microglial proliferation is mediated both by microglial release of TNF-alpha and production of hydrogen peroxide from NADPH oxidase. This suggests that TNF-alpha and NADPH oxidase, and its products, are potential targets to prevent A beta-induced inflammatory neurodegeneration

Extracellular matrix mimetics by crosslinked peptide hydrogels: application to neural 3D cell cultures

Self-supporting, shapeable hydrogels that consist of self-assembling synthetic peptides mimic the structural blocks of the extracellular matrix (ECM). Although they have been developed for regenerative medicine purposes, with a potential of grafting into patients without transplantation from organ donors, this class of materials are attractive as scaffolds for advanced cell culture/ in vitro tissue applications. In the present study, we have combined a series of peptides with functional motives (collagen, fibronectin, and laminin-like) for promoting granule layer-like organization of primary cerebellar cells and for controlling the cell attachment, neuritogenesis, cluster size and organization. We show that the micro/nanofabricated hydrogel scaffolds are applicable as multiwell plate inserts helping to analyse cell migration, differentiation, proliferation, adhesion, ultimately forming organotypic cell culture and artificial tissue structures

Extracellular matrix mimetics by crosslinked peptide hydrogels: application to neural 3D cell cultures

Self-supporting, shapeable hydrogels that consist of self-assembling synthetic peptides mimic the structural blocks of the extracellular matrix (ECM). Although they have been developed for regenerative medicine purposes, with a potential of grafting into patients without transplantation from organ donors, this class of materials are attractive as scaffolds for advanced cell culture/ in vitro tissue applications. In the present study, we have combined a series of peptides with functional motives (collagen, fibronectin, and laminin-like) for promoting granule layer-like organization of primary cerebellar cells and for controlling the cell attachment, neuritogenesis, cluster size and organization. We show that the micro/nanofabricated hydrogel scaffolds are applicable as multiwell plate inserts helping to analyse cell migration, differentiation, proliferation, adhesion, ultimately forming organotypic cell culture and artificial tissue structures

Extracellular matrix mimetics by crosslinked peptide hydrogels: application to neural 3D cell cultures

Self-supporting, shapeable hydrogels that consist of self-assembling synthetic peptides mimic the structural blocks of the extracellular matrix (ECM). Although they have been developed for regenerative medicine purposes, with a potential of grafting into patients without transplantation from organ donors, this class of materials are attractive as scaffolds for advanced cell culture/ in vitro tissue applications. In the present study, we have combined a series of peptides with functional motives (collagen, fibronectin, and laminin-like) for promoting granule layer-like organization of primary cerebellar cells and for controlling the cell attachment, neuritogenesis, cluster size and organization. We show that the micro/nanofabricated hydrogel scaffolds are applicable as multiwell plate inserts helping to analyse cell migration, differentiation, proliferation, adhesion, ultimately forming organotypic cell culture and artificial tissue structures