Redox Chemistry: Implications for Necrotizing Enterocolitis.

Reduction-oxidation (redox) chemistry plays a vital role in human homeostasis. These reactions play critical roles in energy generation, as part of innate immunity, and in the generation of secondary messengers with various functions such as cell cycle progression or the release of neurotransmitters. Despite this cornerstone role, if left unchecked, the body can overproduce reactive oxygen species (ROS) or reactive nitrogen species (RNS). When these overwhelm endogenous antioxidant systems, oxidative stress (OS) occurs. In neonates, OS has been associated with retinopathy of prematurity (ROP), leukomalacia, and bronchopulmonary dysplasia (BPD). Given its broad spectrum of effects, research has started to examine whether OS plays a role in necrotizing enterocolitis (NEC). In this paper, we will discuss the basics of redox chemistry and how the human body keeps these in check. We will then discuss what happens when these go awry, focusing mostly on NEC in neonates.

Stability of a Multiresponsive Sulfonium Vinyl Sulfide Linker toward Nucleophilic/Radical Thiols, Reactive Nitrogen Species, and in Cells under Pro-inflammatory Stimulation.

Chemical linkages that respond to biological stimuli are important for many pharmaceutical and biotechnological applications, making it relevant to explore new variants with different responsivity profiles. This work explores the responsiveness of a TAT peptide-based sulfonium vinyl sulfide probe that responds to nucleophilic thiols, radical thiol species (RTS), and reactive nitrogen species (RNS). Under model conditions, response to nucleophilic thiols was very slow (hours/days), though fast with down to molar equivalents of either RTS or RNS (minutes). These reactions led to the traceless release of a methionine-containing peptide in the first two cases and to a hydroxy nitration adduct in the third case. Despite the sensitive nature of the probe, it remained stable for at least ∼2 h in the presence of cells during TAT-mediated trafficking, even under pro-inflammatory stimulation. The thiol-responsiveness is intermediate to that observed for disulfide linkers and conventional cysteine-maleimide linkers, presenting opportunities for biotechnological applications.

The Key Targets of NO-Mediated Post-Translation Modification (PTM) Highlighting the Dynamic Metabolism of ROS and RNS in Peroxisomes.

Nitric oxide (NO) has been firmly established as a key signaling molecule in plants, playing a significant role in regulating growth, development and stress responses. Given the imperative of sustainable agriculture and the urgent need to meet the escalating global demand for food, it is imperative to safeguard crop plants from the effects of climate fluctuations. Plants respond to environmental challenges by producing redox molecules, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), which regulate cellular, physiological, and molecular processes. Nitric oxide (NO) plays a crucial role in plant stress tolerance, acting as a signaling molecule or free radical. NO is involved in various developmental processes in plants through diverse mechanisms. Exogenous NO supplementation can alleviate the toxicity of abiotic stresses and enhance plant resistance. In this review we summarize the studies regarding the production of NO in peroxisomes, and how its molecule and its derived products, (ONOO-) and S-nitrosoglutathione (GSNO) affect ROS metabolism in peroxisomes. Peroxisomal antioxidant enzymes including catalase (CAT), are key targets of NO-mediated post-translational modification (PTM) highlighting the dynamic metabolism of ROS and RNS in peroxisomes.

High serum levels of reactive nitrogen species and low total antioxidant capacity in patients with resistant hypertension compared to those in age- gender matched healthy controls, controlled hypertension and follow up with propranolol treatment in the extended APPROPRIATE trial.

OBJECTIVES: To perform a comparative analysis of the extended APPROPRIATE trial of measures of reactive nitrogen species and antioxidant capacity in patients having resistant hypertension with controlled hypertension and healthy controls. RESULTS: Mean serum NO2- and NOx levels were significantly lower and mean AOC was significantly higher in patients with controlled hypertension (n = 38) and healthy controls (n = 38) compared to resistant hypertension (RHTN) patients (n = 40) at the pre-intervention stage (p < 0.001). The serum NO2-, NOx and AOC levels of both controlled hypertension and healthy controls were comparable to those of the RHTN patients following treatment with propranolol (n = 18). Considering all samples (n = 114) we noted that there were significant weak and moderate positive correlations between NO2- levels with systolic blood pressure (SBP) and diastolic blood pressure (DBP) (r = 0.396, p < 0.001 and r = 0.292, p = 0.004) as well as total NOx levels with SBP and DBP (r = 0.636 and r = 0.480 respectively, p < 0.001). Conversely, there was a significant negative correlation between AOC levels with SBP and DBP (r= -0.846 and r = -0.626 respectively, p < 0.001).

Ex Tenebris Lux: Illuminating Reactive Oxygen and Nitrogen Species with Small Molecule Probes.

Reactive oxygen and nitrogen species are small reactive molecules derived from elements in the air─oxygen and nitrogen. They are produced in biological systems to mediate fundamental aspects of cellular signaling but must be very tightly balanced to prevent indiscriminate damage to biological molecules. Small molecule probes can transmute the specific nature of each reactive oxygen and nitrogen species into an observable luminescent signal (or even an acoustic wave) to offer sensitive and selective imaging in living cells and whole animals. This review focuses specifically on small molecule probes for superoxide, hydrogen peroxide, hypochlorite, nitric oxide, and peroxynitrite that provide a luminescent or photoacoustic signal. Important background information on general photophysical phenomena, common probe designs, mechanisms, and imaging modalities will be provided, and then, probes for each analyte will be thoroughly evaluated. A discussion of the successes of the field will be presented, followed by recommendations for improvement and a future outlook of emerging trends. Our objectives are to provide an informative, useful, and thorough field guide to small molecule probes for reactive oxygen and nitrogen species as well as important context to compare the ecosystem of chemistries and molecular scaffolds that has manifested within the field.

Multiple RONS-Loaded Plasma-Activated Ice Microneedle Patches for Transdermal Treatment of Psoriasis.

Cold atmospheric plasma (CAP) is a fledgling therapeutic technique for psoriasis treatment with noninvasiveness, but clinical adoption has been stifled by the insufficient production and delivery of plasma-generated reactive oxygen and nitrogen species (RONS). Herein, patches of air-discharge plasma-activated ice microneedles (PA-IMNs) loaded with multiple RONS are designed for local transdermal delivery to treat psoriasis as an alternative to direct CAP irradiation treatment. By mixing two RONS generated by the air-discharge plasma in the NOx mode and O3 mode, abundant high-valence RONS are produced and incorporated into PA-IMNs via complex gas-gas and gas-liquid reactions. The PA-IMNs abrogate keratinocyte overproliferation by inducing reactive oxygen species (ROS)-mediated loss of the mitochondrial membrane potential and apoptosis of keratinocytes. The in vivo transdermal treatment confirms that PA-IMNs produce significant anti-inflammatory and therapeutic actions for imiquimod (IMQ)-induced psoriasis-like dermatitis in mice by inhibiting the release of associated inflammatory factors while showing no evident systemic toxicity. Therefore, PA-IMNs have a large potential in transdermal delivery platforms as they overcome the limitations of using CAP directly in the clinical treatment of psoriasis.

Orally administrated liquid metal agents for inflammation-targeted alleviation of inflammatory bowel diseases.

Rapid drug clearance and off-target effects of therapeutic drugs can induce low bioavailability and systemic side effects and gravely restrict the therapeutic effects of inflammatory bowel diseases (IBDs). Here, we propose an amplifying targeting strategy based on orally administered gallium (Ga)-based liquid metal (LM) nano-agents to efficiently eliminate reactive oxygen and nitrogen species (RONS) and modulate the dysregulated microbiome for remission of IBDs. Taking advantage of the favorable adhesive activity and coordination ability of polyphenol structure, epigallocatechin gallate (EGCG) is applied to encapsulate LM to construct the formulations (LM-EGCG). After adhering to the inflamed tissue, EGCG not only eliminates RONS but also captures the dissociated Ga to form EGCG-Ga complexes for enhancive accumulation. The detained composites protect the intestinal barrier and modulate gut microbiota for restoring the disordered enteral microenvironment, thereby relieving IBDs. Unexpectedly, LM-EGCG markedly decreases the Escherichia_Shigella populations while augmenting the abundance of Akkermansia and Bifidobacterium, resulting in favorable therapeutic effects against the dextran sulfate sodium-induced colitis.

Deciphering molecular regulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) signalling networks in Oryza genus amid environmental stress.

The Oryza genus, containing Oryza sativa L., is quintessential to sustain global food security. This genus has a lot of sophisticated molecular mechanisms to cope with environmental stress, particularly during vulnerable stages like flowering. Recent studies have found key involvements and genetic modifications that increase resilience to stress, including exogenous application of melatonin, allantoin, and trehalose as well as OsSAPK3 and OsAAI1 in the genetic realm. Due to climate change and anthropogenic reasons, there is a rise in sea level which raises a concern of salinity stress. It is tackled through osmotic adjustment and ion homeostasis, mediated by genes like P5CS, P5CR, GSH1, GSH2, and SPS, and ion transporters like NHX, NKT, and SKC, respectively. Oxidative damage is reduced by a complex action of antioxidants, scavenging RONS. A complex action of genes mediates cold stress with studies highlighting the roles of OsWRKY71, microRNA2871b, OsDOF1, and OsICE1. There is a need to research the mechanism of action of proteins like OsRbohA in ROS control and the action of regulatory genes in stress response. This is highly relevant due to the changing climate which will raise a lot of environmental changes that will adversely affect production and global food security if certain countermeasures are not taken. Overall, this study aims to unravel the molecular intricacies of ROS and RNS signaling networks in Oryza plants under stress conditions, with the ultimate goal of informing strategies for enhancing stress tolerance and crop performance in this important agricultural genus.

Reactive nitrogen species act as the enhancers of glutathione pool in embryonic axes of apple seeds subjected to accelerated ageing.

MAIN CONCLUSION: Reactive nitrogen species mitigate the deteriorative effect of accelerated seed ageing by affecting the glutathione concentration and activities of GR and GPX-like. The treatment of apple (Malus domestica Borkh.) embryos isolated from accelerated aged seeds with nitric oxide-derived compounds increases their vigour and is linked to the alleviation of the negative effect of excessive oxidation processes. Reduced form of glutathione (GSH) is involved in the maintenance of redox potential. Glutathione peroxidase-like (GPX-like) uses GSH and converts it to oxidised form (GSSG), while glutathione reductase (GR) reduces GSSG into GSH. The aim of this work was to investigate the impact of the short-time NOx treatment of embryos isolated from apple seeds subjected to accelerated ageing on glutathione-related parameters. Apple seeds were subjected to accelerated ageing for 7, 14 or 21 days. Isolated embryos were shortly treated with NOx and cultured for 48 h. During ageing, in the axes of apple embryos, GSH and GSSG levels as well as half-cell reduction potential remained stable, while GR and GPX-like activities decreased. However, the positive effect of NOx in the vigour preservation of embryos isolated from prolonged aged seeds is linked to the increased total glutathione pool, and above all, higher GSH content. Moreover, NOx increased the level of transcripts encoding GPX-like and stimulated enzymatic activity. The obtained results indicate that high seed vigour related to the mode of action of NO and its derivatives is closely linked to the maintenance of higher GSH levels.

NIR-Mediated Pyroelectric Catalysis for Sustained ROS/RNS Generation and Advanced Cancer Therapy In Vivo via Injectable Hydrogel.

Exogenous electrical stimulation has attracted considerable attention due to the advantages of microelectric induction and subsequent biological effects such as actin reorganization and reactive oxygen species (ROS) generation. Herein, an injectable hydrogel of BPR-ARG@Gel (BAG) with pyroelectric BPR nanoparticle loading and l-arginine (ARG) introduction was fabricated for advanced cancer therapy in vivo. Due to the photothermal effect, the holes and electrons in BPR nanoparticles were separated to produce an open-circuit voltage and consequently catalyze water H2O to generate toxic superoxide (•O2-) and hydroxyl radicals (•OH). These ROS substances further oxidize ARG to produce NO for synergistic tumor treatments. The mice experiments indicated that the employment of BAG hydrogel incorporation with a near-infrared laser downregulated the heat shock protein and recruited immune cells with 5-fold-enhanced expression of proinflammatory cytokines of interferon-γ. It was also noteworthy that the injectable hydrogel of BAG substantially induced the generation of reactive oxygen/nitrogen species (ROS/RNS) with reliable biosafety and strong tumor inhibition. Overall, these findings have provided potentially new inspirations and a feasible strategy to translate this multifunctional hydrogel toward tumor therapy in a pyroelectric stimulation manner.

Bitter Taste Receptor 46 (hTAS2R46) Protects Monocytes/Macrophages from Oxidative Stress.

Bitter taste receptors (TAS2Rs) are not only responsible for taste perception in the oral cavity, but are spread throughout the body, generating a widespread chemosensory system. In humans, 25 subtypes have been identified and are differentially expressed in tissues and organs, including in the immune system. In fact, several TAS2R subtypes have been detected in neutrophils, lymphocytes, B and T cells, NK cells, and monocytes/macrophages, in which they regulate various protective functions of the innate immune system. Given its recognized anti-inflammatory and antioxidant activity, and the generally protective role of bitter taste receptors, in this work, we studied TAS2R46's potential in the protection of human monocyte/macrophage DNA from stress-induced damage. Through both direct and indirect assays and a single-cell gel electrophoresis assay, we demonstrated that absinthin, a specific TAS2R46 agonist, counteracts the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and reduces DNA damage in both cell types. Even though the release of ROS from monocytes/macrophages is fundamental for contrast pathogen agents, supraphysiological ROS production impairs their function, finally leading to cell death. Our results highlight TAS2R46 as a novel player involved in the protection of monocytes and macrophages from oxidative stress damage, while simultaneously supporting their antimicrobial activity.

Cold atmospheric plasma-activated medium for potential ovarian cancer therapy.

Cold atmospheric plasma (CAP) has emerged as an innovative tool with broad medical applications, including ovarian cancer (OC) treatment. By bringing CAP in close proximity to liquids such as water or cell culture media, solutions containing reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated, called plasma-activated media (PAM). In this systematic review, we conduct an in-depth analysis of studies focusing on PAM interactions with biological substrates. We elucidate the diverse mechanisms involved in the activation of different media and the complex network of chemical reactions underlying the generation and consumption of the prominent reactive species. Furthermore, we highlight the promises of PAM in advancing biomedical applications, such as its stability for extended periods under appropriate storage conditions. We also examine the application of PAM as an anti-cancer and anti-metastatic treatment for OC, with a particular emphasis on its ability to induce apoptosis via distinct signaling pathways, inhibit cell growth, suppress cell motility, and enhance the therapeutic effects of chemotherapy. Finally, the future outlook of PAM therapy in biomedical applications is speculated, with emphasis on the safety issues relevant to clinical translation.

Plasma-generated RONS in liquid transferred into cryo-microneedles patch for skin treatment of melanoma.

Malignant melanoma is the most lethal form of skin cancer. As a promising anti-cancer agent, plasma-activated water (PAW) rich in reactive oxygen and nitrogen species (RONS) has shown significant potential for melanoma treatment. However, rapid decay of RONS and inefficient delivery of PAW in conventional injection methods limit its practical applications. To address this issue, here we report a new approach for the production of plasma-activated cryo-microneedles (PA-CMNs) patches using custom-designed plasma devices and processes. Our innovation is to incorporate PAW into the PA-CMNs that are fabricated using a fast cryogenic micro-molding method. It is demonstrated that PA-CMNs can be easily inserted into skin to release RONS and slow the decay of RONS thereby prolonging their bioactivity and effectiveness. The new insights into the effective melanoma treatment suggest that the rich mixture of RONS within PA-CMNs prepared by custom-developed hybrid plasma-assisted configuration induces both ferroptosis and apoptosis to selectively kill tumor cells. A significant inhibition of subcutaneous A375 melanoma growth was observed in PA-CMNs-treated tumor-bearing nude mice without any signs of systemic toxicity. The new approach based on PA-CMNs may potentially open new avenues for a broader range of disease treatments.

The emerging role of oxidative stress in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic immune-mediated condition that affects the digestive system and includes Crohn's disease (CD) and ulcerative colitis (UC). Although the exact etiology of IBD remains uncertain, dysfunctional immunoregulation of the gut is believed to be the main culprit. Amongst the immunoregulatory factors, reactive oxygen species (ROS) and reactive nitrogen species (RNS), components of the oxidative stress event, are produced at abnormally high levels in IBD. Their destructive effects may contribute to the disease's initiation and propagation, as they damage the gut lining and activate inflammatory signaling pathways, further exacerbating the inflammation. Oxidative stress markers, such as malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and serum-free thiols (R-SH), can be measured in the blood and stool of patients with IBD. These markers are elevated in patients with IBD, and their levels correlate with the severity of the disease. Thus, oxidative stress markers can be used not only in IBD diagnosis but also in monitoring the response to treatment. It can also be targeted in IBD treatment through the use of antioxidants, including vitamin C, vitamin E, glutathione, and N-acetylcysteine. In this review, we summarize the role of oxidative stress in the pathophysiology of IBD, its diagnostic targets, and the potential application of antioxidant therapies to manage and treat IBD.

Regulation of nitro-oxidative homeostasis: an effective approach to enhance salinity tolerance in plants.

Soil salinity is a major constraint for sustainable agricultural productivity, which together with the incessant climate change may be transformed into a severe threat to the global food security. It is, therefore, a serious concern that needs to be addressed expeditiously. The overproduction and accumulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the key events occurring during salt stress, consequently employing nitro-oxidative stress and programmed cell death in plants. However, very sporadic studies have been performed concerning different aspects of nitro-oxidative stress in plants under salinity stress. The ability of plants to tolerate salinity is associated with their ability to maintain the cellular redox equilibrium mediated by both non-enzymatic and enzymatic antioxidant defense mechanisms. The present review emphasizes the mechanisms of ROS and RNS generation in plants, providing a detailed evaluation of how redox homeostasis is conserved through their effective removal. The uniqueness of this article stems from its incorporation of expression analyses of candidate genes for different antioxidant enzymes involved in ROS and RNS detoxification across various developmental stages and tissues of rice, utilizing publicly available microarray data. It underscores the utilization of modern biotechnological methods to improve salinity tolerance in crops, employing different antioxidants as markers. The review also explores how various transcription factors contribute to plants' ability to tolerate salinity by either activating or repressing the expression of stress-responsive genes. In summary, the review offers a thorough insight into the nitro-oxidative homeostasis strategy for extenuating salinity stress in plants.

Dynamic interplay of reactive oxygen and nitrogen species (ROS and RNS) in plant resilience: unveiling the signaling pathways and metabolic responses to biotic and abiotic stresses.

KEY MESSAGE: Plants respond to environmental challenges by producing reactive species such as ROS and RNS, which play critical roles in signaling pathways that lead to adaptation and survival strategies. Understanding these pathways, as well as their detection methods and effects on plant development and metabolism, provides insight into increasing crop tolerance to combined stresses. Plants encounter various environmental stresses (abiotic and biotic) that affect plant growth and development. Plants sense biotic and abiotic stresses by producing different molecules, including reactive species, that act as signaling molecules and stimulate secondary messengers and subsequent gene transcription. Reactive oxygen and nitrogen species (ROS and RNS) are produced in both physiological and pathological conditions in the plasma membranes, chloroplasts, mitochondria, and endoplasmic reticulum. Various techniques, including spectroscopy, chromatography, and fluorescence methods, are used to detect highly reactive, short-half-life ROS and RNS either directly or indirectly. In this review, we highlight the roles of ROS and RNS in seed germination, root development, senescence, mineral nutrition, and post-harvest control. In addition, we provide information on the specialized metabolism involved in plant growth and development. Secondary metabolites, including alkaloids, flavonoids, and terpenoids, are produced in low concentrations in plants for signaling and metabolism. Strategies for improving crop performance under combined drought and pathogen stress conditions are discussed in this review.

Differential effects of angiotensin II and aldosterone on human neutrophil adhesion and concomitant secretion of proteins, free amino acids and reactive oxygen and nitrogen species.

Invasion and adhesion of neutrophils into tissues and their concomitant secretion play an important role in the development of vascular pathologies, including abdominal aortic aneurysm (AAA). Chronic administration of angiotensin II is used to initiate AAA formation in mice. The role of aldosterone in this process is being studied. We conducted for the first time a complex comparative study of the effects of angiotensin II and aldosterone on the adhesion of human neutrophils to fibronectin and the concomitant secretion of proteins, free amino acids as well as reactive oxygen (ROS) and nitrogen (NO) species. Neither angiotensin II nor aldosterone affected the attachment of neutrophils to fibronectin and the concomitant production of ROS. We showed for the first time that aldosterone stimulated the release of amino acid hydroxylysine, a product of lysyl hydroxylase, the activity of which is positively correlated with cell invasiveness. Aldosterone also initiates the secretion of matrix metalloproteinase 9 (MMP-9) and cathepsin G, which may reorganize the extracellular matrix and stimulate the recruitment and adhesion of neutrophils to the aortic walls. Angiotensin II did not affect protein secretion. It may contribute to neutrophil-induced vascular injury by inhibiting the production of NO or by increasing the secretion of isoleucine. Our results suggest that it is aldosterone-induced neutrophil secretion that may play a significant role in neutrophil-induced vascular wall destruction in angiotensin II-induced AAA or other vascular complications.

NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer.

Nitric oxide (NO) and reactive nitrogen species (RNS) exert profound biological impacts dictated by their chemistry. Understanding their spatial distribution is essential for deciphering their roles in diverse biological processes. This review establishes a framework for the chemical biology of NO and RNS, exploring their dynamic reactions within the context of cancer. Concentration-dependent signaling reveals distinctive processes in cancer, with three levels of NO influencing oncogenic properties. In this context, NO plays a crucial role in cancer cell proliferation, metastasis, chemotherapy resistance, and immune suppression. Increased NOS2 expression correlates with poor survival across different tumors, including breast cancer. Additionally, NOS2 can crosstalk with the proinflammatory enzyme cyclooxygenase-2 (COX-2) to promote cancer progression. NOS2 and COX-2 co-expression establishes a positive feed-forward loop, driving immunosuppression and metastasis in estrogen receptor-negative (ER-) breast cancer. Spatial evaluation of NOS2 and COX-2 reveals orthogonal expression, suggesting the unique roles of these niches in the tumor microenvironment (TME). NOS2 and COX2 niche formation requires IFN-γ and cytokine-releasing cells. These niches contribute to poor clinical outcomes, emphasizing their role in cancer progression. Strategies to target these markers include direct inhibition, involving pan-inhibitors and selective inhibitors, as well as indirect approaches targeting their induction or downstream effectors. Compounds from cruciferous vegetables are potential candidates for NOS2 and COX-2 inhibition offering therapeutic applications. Thus, understanding the chemical biology of NO and RNS, their spatial distribution, and their implications in cancer progression provides valuable insights for developing targeted therapies and preventive strategies.

A Cascade-Amplified Pyroptosis Inducer: Optimizing Oxidative Stress Microenvironment by Self-Supplying Reactive Nitrogen Species Enables Potent Cancer Immunotherapy.

Selective generation of sufficient pyroptosis inducers at the tumor site without external stimulation holds immense significance for a longer duration of immunotherapy. Here, we report a cascade-amplified pyroptosis inducer CSCCPT/SNAP that utilizes reactive nitrogen species (RNS), self-supplied from the diffusion-controlled reaction between reactive oxygen species (ROS) and nitric oxide (NO) to potentiate pyroptosis and immunotherapy, while both endogenous mitochondrial ROS stimulated by released camptothecin and released NO initiate pyroptosis. Mechanistically, cascade amplification of the antitumor immune response is prompted by the cooperation of ROS and NO and enhanced by RNS with a long lifetime, which could be used as a pyroptosis trigger to effectively compensate for the inherent drawbacks of ROS, resulting in long-lasting pyroptosis for favoring immunotherapy. Tumor growth is efficiently inhibited in mouse melanoma tumors through the facilitation of reactive oxygen/nitrogen species (RONS)-NO synergy. In summary, our therapeutic approach utilizes supramolecular engineering and nanotechnology to integrate ROS producers and NO donors of tumor-specific stimulus responses into a system that guarantees synchronous generation of these two reactive species to elicit pyroptosis-evoked immune response, while using self-supplied RNS as a pyroptosis amplifier. RONS-NO synergy achieves enhanced and sustained pyroptosis and antitumor immune responses for robust cancer immunotherapy.

Protective Effects of Adropin in Experimental Subarachnoid Hemorrhage.

PURPOSE: We aimed to investigate early effects of exogenously administered adropin (AD) on neurological function, endothelial nitric oxide synthase (eNOS) expression, nitrite/nitrate levels, oxidative stress, and apoptosis in subarachnoid hemorrhage (SAH). METHODS: Following intracerebroventricular AD administration (10 µg/5 µl at a rate of 1 µl/min) SAH model was carried out in Sprague-Dawley rats by injection of autologous blood into the prechiasmatic cistern. The effects of AD were assessed 24 h following SAH. The modified Garcia score was employed to evaluate functional insufficiencies. Adropin and caspase-3 proteins were measured by ELISA, while nitrite/nitrate levels, total antioxidant capacity (TAC) and reactive oxygen/nitrogen species (ROS/RNS) were assayed by standard kits. eNOS expression and apoptotic neurons were detected by immunohistochemical analysis. RESULTS: The SAH group performed notably lower on the modified Garcia score compared to sham and SAH + AD groups. Adropin administration increased brain eNOS expression, nitrite/nitrate and AD levels compared to SHAM and SAH groups. SAH produced enhanced ROS/RNS generation and reduced antioxidant capacity in the brain. Adropin boosted brain TAC and diminished ROS/RNS production in SAH rats and no considerable change amongst SHAM and SAH + AD groups were detected. Apoptotic cells were notably increased in intensity and number after SAH and were reduced by AD administration. CONCLUSIONS: Adropin increases eNOS expression and reduces neurobehavioral deficits, oxidative stress, and apoptotic cell death in SAH model. Presented results indicate that AD provides protection in early brain injury associated with SAH.