DTP3 It has been demonstrated that

It has been demonstrated that HO-1 inhibits the production of proinflammatory mediators including TNF-α and IL-6 in response to sepsis [35], and the expression of iNOS and COX-2 [36,37]. An inverse association between HO-1 and iNOS has previously been described: the NO levels decline with increases in HO-1 activity [38]. Moreover, HO-1 has been reported to negatively regulate NF-κB activation [39], which initiates the expression of many inflammation-related genes, such as TNF-α, IL-6, COX-2, and iNOS [40]. The up-regulation of HO-1 promotes catabolism of cellular heme to biliverdin, CO, and iron, which are all considered to play important roles in HO-induced anti-inflammation and cytoprotection: CO inactivates existing iNOS by interacting with its heme iron moiety [41,42]. HO-1 itself could degrade directly the heme located in the activity site of iNOS, because iNOS is a hemoprotein that contains 2 heme molecules in the activity site [42]. HO-1 induction exerts anti-inflammatory effects by inhibition of COX-2 activity and decrease of PGE2 production [43,44]. Induction of HO-1 leads to heme depletion and consequently decreased expression of other important heme proteins, such as COX-2 and NADPH oxidase [45]. Its product CO binds to promoter elements of the COX-2 gene to decrease its transcription [46]. In the present study, the levels of HO-1 enzymatic activity and protein expression in the lung and RAW264.7 cells were found to be increased after LPS challenge. GYY4137 augmented these increased levels. SnPP, a competitive HO-1 inhibitor, reversed the anti-inflammatory responses of GYY4137 observed in GYY4137-treated mice and cells, providing compelling evidence that GYY4137-mediated HO-1 activity participates in its protection against LPS-induced lung injury. GYY4137 has been suggested as a novel H2S donor with anti-inflammatory effect [47,48], thus the effect of GYY4137 on HO-1 in LPS-evoked inflammation may be secondary to H2S. To further define HO-1 induction by GYY4137-derived H2S, we found that HO-1 protein expression and enzymatic activity were both up-regulated by GYY4137 but not GYY4137(-) in LPS-stimulated RAW264.7 cells. Similar results were also obtained in mice (Supplementary Fig.2). Not a few studies has demonstrated that H2S can induce HO-1 in various cells and tissues [[49], [50], [51]]. Moreover, H2S could induce HO-1 expression in RAW264.7 macrophages at least in part through the ERK1/2-dependent pathway [49]. In summary, GYY4137 protects the lung against LPS-induced injury via HO-1 modulation, inhibits the NF-κB signaling pathway and the production of pro-inflammatory mediators. Furthermore, our study clarifies novel anti-inflammatory mechanisms of GYY4137 in ALI and indicates that GYY4137 is a potential therapeutic H2S-releasing drug to treat LPS-induced lung inflammatory injury.
Conflicts of interest
Acknowledgments This work was supported by the National Natural Science Foundation of China (Grant No. 81570010 and 81772045).
Introduction Degenerative and developmental human DTP3 disorders vary with respect to age of onset, sex predilections, neurological and behavioral symptoms, risk factors, neuraxial distribution, hallmark cytopathology (if any), neurochemical alterations, electrophysiology and neuroimaging. In spite of this diversity, there is ample pathological overlap and shared molecular pathways among the common aging-related neurodegenerative and neuroinflammatory disorders (Alzheimer disease (AD), Parkinson disease (PD), dementia with Lewy bodies (DLB), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), etc.), as well as within the spectrum of major neurodevelopmental conditions (schizophrenia, autism, etc.). Several ‘core’ neuropathological features shared among these and related entities include: i) oxidative stress and associated protein, lipid and nucleic acid modifications, (ii) excessive deposition of non-transferrin bound iron, iii) mitochondrial membrane damage and bioenergetic failure, and iv) macroautophagy (mitophagy) in the affected neural tissues. We previously surmised that this ‘core’ tetrad of features may constitute a single neuropathological ‘lesion’, with self-reinforcing positive feedback loops ensuring that the development of one component obligates the establishment of the others, thereby driving the degenerative process even following dissipation of the offending stimuli (Schipper, 2004a). In this article, we review evidence adduced from cell culture, whole animal and human neuropathological studies that sustained upregulation of the stress protein, heme oxygenase-1 (HO-1) in astroglia of the aging and diseased CNS is a prime transducer of deleterious stimuli into precisely this core cytopathological signature. We begin by outlining key aspects of the regulation and physiology of mammalian HO-1. We acknowledge that HO-1 is Janus-faced and allude to an extensive literature attesting to the beneficial roles of neural HO-1 under various experimental conditions. Thereafter, detailed information largely adduced by our laboratory is provided implicating HO-1 overexpression in astrocytes as a necessary and sufficient cause of intracellular oxidative stress, iron sequestration, mitochondrial damage and macroautophagy (mitophagy) - the ‘core’ neuropathological tetrad mentioned above. We then garner support for this ‘transducer’ role of HO-1 in the aging CNS, drawing on examples from the rodent (Gomori-positive glial system) and human corpora amylacea (CA) literature. Next, we demonstrate how HO-1 transduction of stressful stimuli may contribute to the etiopathogenesis of human developmental and degenerative CNS disorders, with particular emphasis on AD, PD and schizophrenia. In the final section, several major implications of the ‘HO-1 transducer’ model vis-à-vis our understanding and management of chronic human CNS afflictions are considered. The latter is informed by the principle, often disregarded in the HO-1 literature, that successful exploitation of HO-1 modulation as a therapeutic target presupposes a nuanced appreciation of its specific (beneficial or dystrophic) role in the tissue, condition or process under consideration.