The three endogenous gaseous transmitters - nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) - regulate a number of key biological functions. Emerging data have revealed several new ...mechanisms for each of these three gasotransmitters in tumour biology. It is now appreciated that they show bimodal pharmacological character in cancer, in that not only the inhibition of their biosynthesis but also elevation of their concentration beyond a certain threshold can exert anticancer effects. This Review discusses the role of each gasotransmitter in cancer and the effects of pharmacological agents - some of which are in early-stage clinical studies - that modulate the levels of each gasotransmitter. A clearer understanding of the pharmacological character of these three gases and the mechanisms underlying their biological effects is expected to guide further clinical translation.
Nitric oxide (NO) vascular signaling has long been considered an independent, self-sufficient pathway. However, recent data indicate that the novel gaseous mediator, hydrogen sulfide (H
S), serves as ...an essential enhancer of vascular NO signaling. The current article overviews the multiple levels at which this enhancement takes place. The first level of interaction relates to the formation of biologically active hybrid S/N species and the H
S-induced stimulation of NO release from its various stable "pools" (e.g., nitrite). The next interactions occur on the level of endothelial calcium mobilization and PI3K/Akt signaling, increasing the specific activity of endothelial NO synthase (eNOS). The next level of interaction occurs on eNOS itself; H
S directly interacts with the enzyme: sulfhydration of critical cysteines stabilizes it in its physiological, dimeric state, thereby optimizing eNOS-derived NO production and minimizing superoxide formation. Yet another level of interaction, further downstream, occurs at the level of soluble guanylate cyclase (sGC): H
S stabilizes sGC in its NO-responsive, physiological, reduced form. Further downstream, H
S inhibits the vascular cGMP phosphodiesterase (PDE5), thereby prolonging the biological half-life of cGMP. Finally, H
S-derived polysulfides directly activate cGMP-dependent protein kinase (PKG). Taken together, H
S emerges an essential endogenous enhancer of vascular NO signaling, contributing to vasorelaxation and angiogenesis. The functional importance of the H
S/NO cooperative interactions is highlighted by the fact that H
S loses many of its beneficial cardiovascular effects when eNOS is inactive.
The process of poly(ADP-ribosyl)ation and the major enzyme that catalyses this reaction, poly(ADP-ribose) polymerase 1 (PARP1), were discovered more than 50 years ago. Since then, advances in our ...understanding of the roles of PARP1 in cellular processes such as DNA repair, gene transcription and cell death have allowed the investigation of therapeutic PARP inhibition for a variety of diseases - particularly cancers in which defects in DNA repair pathways make tumour cells highly sensitive to the inhibition of PARP activity. Efforts to identify and evaluate potent PARP inhibitors have so far led to the regulatory approval of four PARP inhibitors for the treatment of several types of cancer, and PARP inhibitors have also shown therapeutic potential in treating non-oncological diseases. This Review provides a timeline of PARP biology and medicinal chemistry, summarizes the pathophysiological processes in which PARP plays a role and highlights key opportunities and challenges in the field, such as counteracting PARP inhibitor resistance during cancer therapy and repurposing PARP inhibitors for the treatment of non-oncological diseases.
Hydrogen sulfide (H
S) has a long history as toxic gas and environmental hazard; inhibition of cytochrome c oxidase (mitochondrial Complex IV) is viewed as a primary mode of its cytotoxic action. ...However, studies conducted over the last two decades unveiled multiple biological regulatory roles of H
S as an endogenously produced mammalian gaseous transmitter. Cystathionine -lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST) are currently viewed as the principal mammalian H
S-generating enzymes. In contrast to its inhibitory (toxicological) mitochondrial effects, at lower (physiological) concentrations, H
S serves as a stimulator of electron transport in mammalian mitochondria, by acting as an electron donor-with sulfide:quinone oxidoreductase (SQR) being the immediate electron acceptor. The mitochondrial roles of H
S are significant in various cancer cells, many of which exhibit high expression and partial mitochondrial localization of various H
S producing enzymes. In addition to the stimulation of mitochondrial ATP production, the roles of endogenous H
S in cancer cells include the maintenance of mitochondrial organization (protection against mitochondrial fission) and the maintenance of mitochondrial DNA repair (via the stimulation of the assembly of mitochondrial DNA repair complexes). The current article overviews the state-of-the-art knowledge regarding the mitochondrial functions of endogenously produced H
S in cancer cells.
Translational research on endogenous gaseous mediators--nitric oxide, carbon monoxide, and hydrogen sulfide--has exploded over the past decade. Drugs that modulate either the gaseous mediators ...themselves or their related intracellular signaling pathways are already in use in the clinics, and still more are being tested in preclinical models and clinical trials. Discussed here are the chemical and pharmacological properties that present challenges for the translation of these potentially toxic molecules.
Here we overview the role of reactive nitrogen species (nitrosative stress) and associated pathways in the pathogenesis of diabetic vascular complications. Increased extracellular glucose ...concentration, a principal feature of diabetes mellitus, induces a dysregulation of reactive oxygen and nitrogen generating pathways. These processes lead to a loss of the vascular endothelium to produce biologically active nitric oxide (NO), which impairs vascular relaxations. Mitochondria play a crucial role in this process: endothelial cells placed in increase extracellular glucose respond with a marked increase in mitochondrial superoxide formation. Superoxide, when combining with NO generated by the endothelial cells (produced by the endothelial isoform of NO synthase), leads to the formation of peroxynitrite, a cytotoxic oxidant. Reactive oxygen and nitrogen species trigger endothelial cell dysfunction through a multitude of mechanisms including substrate depletion and uncoupling of endothelial isoform of NO synthase. Another pathomechanism involves DNA strand breakage and activation of the nuclear enzyme poly(ADP‐ribose) polymerase (PARP). PARP‐mediated poly(ADP‐ribosyl)ation and inhibition of glyceraldehyde‐3‐phosphate dehydrogenase importantly contributes to the development of diabetic vascular complications: it induces activation of multiple pathways of injury including activation of nuclear factor kappa B, activation of protein kinase C and generation of intracellular advanced glycation end products. Reactive species generation and PARP play key roles in the pathogenesis of ‘glucose memory’ and in the development of injury in endothelial cells exposed to alternating high/low glucose concentrations.
Review: Zsuzsanna Turcsán-Tóth, Alapvetés az Artemis Ephesia-szobrok ikonográfiai elemzéséhez (Notes on the iconographic analysis of the Artemis Ephesia statues), Martin Opitz: Budapest, 2023, p. ...368. ISBN: 978-615-6388-07-0
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