An 8-week feeding experiment was conducted to investigate the effect of dietary histamine on growth performance, digestive physiology function and muscle quality in a hybrid grouper (Epinephelus fuscoguttatus♀ × Epinephelus lanceolatus♂). Seven isoproteic (50%) and isolipidic (11%) diets were prepared with various histamine inclusion levels of 0, 30, 60, 120, 240, 480 and 960 mg/kg in diets (actual contents were 72.33, 99.56, 138.60, 225.35, 404.12, 662.12 and 1245.38 mg/kg), respectively. Each diet was randomly assigned to triplicates of 30 juveniles (average body weight 14.78 g) per tank in a flow-through mariculture system. The increase in the dietary histamine level up to 1245.38 mg/kg made no significant difference on the growth rate and feed utilization of the grouper. However, the increased histamine content linearly decreased the activities of digestive enzymes, while no differences were observed in groups with low levels of histamine (≤404.12 mg/kg). Similarly, high levels of histamine (≥404.12 mg/kg) significantly damaged the gastric and intestinal mucosa, disrupted the intestinal tight junction structure, and raised the serum diamine oxidase activity and endotoxin level. Meanwhile, high doses of histamine (≥662.12 mg/kg) significantly reduced the activities of antioxidant enzymes, upregulated the relative expression of Kelch-like ECH-associated protein 1, and hardened and yellowed the dorsal muscle of grouper. These results showed that dietary histamine was detrimental to the digestive physiology function and muscle quality of the grouper, although it did compromise its growth performance. Full article

Potato sprouts, an underutilized by-product of potato processing, could be exploited for the recovery of caffeoyl-quinic acids (CQAs), a family of polyphenols with well-recognized biological activities. In this work, the predominant compound of this class, 5-CQA, was extracted by Ultrasound-Assisted Extraction (UAE) under conditions optimized by an Experimental Design. The investigated variables solid/solvent ratio (1:10–1:50 g/mL), water content in ethanol (30–100% v/v) and UAE time (5–20 min) highlighted a critical influence of the last two factors on the extraction efficiency: extracts richer in 5-CQA were obtained with lower water content (30%) and time (5 min). The addition of ascorbic acid (1.7 mM) as anti-browning agent to the extraction solvent improved the extraction efficiency of 5-CQA compared to acetic and citric acids (3158.71 μg/mL, 1766.71 μg/mL, 1468.20 μg/mL, respectively). A parallel trend for the three acids and an increase in 5-CQA recovery was obtained with the use of freeze-dried sprouts (4980.05 μg/mL, 4795.62, 4211.25 μg/mL, respectively). Total antioxidant capacity (TAC) in vitro demonstrated UAE being a more valuable technique than conventional maceration. Furthermore, three-times-higher values of TPC (7.89 mg GAE/g) and TAC (FRAP: 24.01 mg TE/g; DPPH: 26.20 mg TE/g; ABTS 26.72 mg TE/g) were measured for the optimized extract compared to the initial one. An HPLC-DAD method was applied to monitor 5-CQA recovery, while an LC-HRMS/MS investigation allowed us to perform analyte identity confirmation along with detection of the glycoalkaloids α-solanine and α-chaconine. This evidence underlines the necessity to develop purification strategies in order to maximize the potential of potato sprout waste as a source of 5-CQA. Full article

Plants and brown algae avoid photoinhibition (decline in photosystem II efficiency, Fv/Fm) caused by excess light energy and oxidative stress through several photoprotective mechanisms, such as antioxidant xanthophyll production and heat dissipation. The heat dissipation can be measured as non-photochemical quenching (NPQ) and is strongly driven by de-epoxidation of xanthophyll cycle pigments (XCP). Although NPQ is known to increase under high light acclimation and nutrient-deficient conditions, a few studies have investigated the combined effects of the conditions on both NPQ and associated xanthophyll-to-chlorophyll (Chl) a ratio. The present study investigated the photosynthetic parameters of the brown alga Sargassum fusiforme acclimated to three irradiance levels combined with three nutrient levels. Elevated irradiance decreased Fv/Fm but increased NPQ, XCP/Chl a ratio, and fucoxanthin/Chl a ratio, suggesting the photoprotective role of antioxidant fucoxanthin in brown algae. Reduced nutrient availability increased NPQ but had no effect on the other variables, including XCP/Chl a ratio and its de-epoxidation state. The results indicate that NPQ can be used as a sensitive stress marker for nutrient deficiency, but cannot be used to estimate XCP pool size and state. Full article

Idiopathic pulmonary fibrosis (IPF) has a detrimental prognosis despite antifibrotic therapies to which individual responses vary. IPF pathology is associated with oxidative stress, inflammation and increased activation of SRC family kinases (SFK). This pilot study evaluates individual responses to pirfenidone, nintedanib and SFK inhibitor saracatinib, markers of redox homeostasis, fibrosis and inflammation, in IPF-derived human bronchial epithelial (HBE) cells. Differentiated HBE cells from patients with and without IPF were analyzed for potential alterations in redox and profibrotic genes and pro-inflammatory cytokine secretion. Additionally, the effects of pirfenidone, nintedanib and saracatinib on these markers were determined. HBE cells were differentiated into a bronchial epithelium containing ciliated epithelial, basal, goblet and club cells. NOX4 expression was increased in IPF-derived HBE cells but differed on an individual level. In patients with higher NOX4 expression, pirfenidone induced antioxidant gene expression. All drugs significantly decreased NOX4 expression. IL-6 (p = 0.09) and IL-8 secretion (p = 0.014) were increased in IPF-derived HBE cells and significantly reduced by saracatinib. Finally, saracatinib significantly decreased TGF-β gene expression. Our results indicate that treatment responsiveness varies between IPF patients in relation to their oxidative and inflammatory status. Interestingly, saracatinib tends to be more effective in IPF than standard antifibrotic drugs. Full article

Dialysis prevents death from uremia in patients with end-stage renal disease (ESRD). Nevertheless, during hemodialysis, circulating levels of di-(2-ethylhexyl) phthalate (DEHP) are increased due to phthalates leaching from medical tubes. Statins are an effective therapy for reducing the risks associated with cardiovascular diseases in patients with chronic kidney disease; however, the mechanism by which statins fail to reduce cardiovascular events in hemodialysis ESRD patients remains unclear. In this study, we investigated whether DEHP and its metabolites interfere with the lipid-lowering effect of statins in hepatocytes. In Huh7 cells, treatment with DEHP and its metabolites abolished the simvastatin-conferred lipid-lowering effect. Mechanistically, DEHP down-regulated the expression of low-density lipoprotein receptor (LDLR) and led to a decrease in LDL binding, which was mediated by the activation of the PPARγ-PCSK9 and LXRα-IDOL signaling pathways. Additionally, the NOX-ROS-TRPA1 pathway is involved in the DEHP-mediated inhibition of LDLR expression and LDL binding activity. Blockage of this pathway abrogated the DEHP-mediated inhibition in the LDLR expression and LDL binding of simvastatin. Collectively, DEHP induces the activation of the NOX-ROS-TRPA1 pathway, which in turn activates PPARγ-PCSK9- and LXRα-IDOL-dependent signaling, and, ultimately, diminishes the statin-mediated lipid-lowering effect in hepatocytes. Full article

White wines’ oxidative stability is related to a flow of chemical reactions involving a number of native wine compounds comprising their antioxidant metabolome. By applying the combination of powerful and modern analytical approaches (EPR, DPPH, and UPLC-qToF-MS-based metabolomics), we could define wine antioxidant metabolome as the sum of molecular antioxidant markers (AM) characterized by their radical scavenging (AM-RS) and nucleophilic (AM-Nu) properties. The impact of on-lees barrel aging of chardonnay wines on the antioxidant metabolome was studied for two consecutive vintages. The identification of wines’ antioxidant metabolome allows for a detailed understanding of the transient chemical interplays involved in the antioxidant chemistry associated with well-known antioxidants and opens an avenue towards personalized winemaking. The present study gathers for the first time the dynamics of wines’ antioxidant metabolome during on-lees aging. Monitoring the variations of the wine antioxidant metabolome can provide an avenue to better control the winemaking process using the knowledge of how to optimize the wine aging potential. Full article

Besides the clinically proven superior antimalarial activity, artemisinins (ARTs) are also associated with anticancer properties, albeit at much lower potency. Iron and heme have been proposed as possible activators of ARTs against cancer cells. Here we show that zinc protoporphyrin-9 (ZnPPIX), a heme homolog and a natural metabolite for heme synthesis during iron insufficiency, greatly enhanced the anticancer activity of dihydroartemisinin (DHA) in multiple cell lines. Using melanoma B16 and breast cancer 4T1 cells, we demonstrated ZnPPIX dramatically elevated intracellular free heme levels, accompanied by heightened reactive oxidative species (ROS) production. The tumor-suppression activity of ZnPPIX and DHA is mitigated by antioxidant vitamin E or membrane oxidation protectant ferrostatin. In vivo xenograft animal models confirmed that ZnPPIX significantly potentiated the tumor-inhibition capability of DHA while posing no apparent toxicity to the mice. The proliferating index and growth of tumors after the combinatory treatment of DHA and ZnPPIX were evidently reduced. Considering the clinical safety profiles of both DHA and ZnPPIX, their action synergy offers a promising strategy to improve the application of ARTs in our fight against cancer. Full article

Non-small cell lung cancer (NSCLC), the most common type of lung cancer, etiologically associates with tobacco smoking which mechanistically contributes to oxidative stress to facilitate the occurrence of mutations, oncogenic transformation and aberrantly activated signaling pathways. Our previous reports suggested an essential role of Sulfiredoxin (Srx) in promoting the development of lung cancer in humans, and was causally related to Peroxiredoxin IV (Prx4), the major downstream substrate and mediator of Srx-enhanced signaling. To further explore the role of the Srx-Prx4 axis in de novo lung tumorigenesis, we established Prx4^−/− and Srx^−/−/Prx4^−/− mice in pure FVB/N background. Together with wild-type litter mates, these mice were exposed to carcinogenic urethane and the development of lung tumorigenesis was evaluated. We found that disruption of the Srx-Prx4 axis, either through knockout of Srx/Prx4 alone or together, led to a reduced number and size of lung tumors in mice. Immunohistological studies found that loss of Srx/Prx4 led to reduced rate of cell proliferation and less intratumoral macrophage infiltration. Mechanistically, we found that exposure to urethane increased the levels of reactive oxygen species, activated the expression of and Prx4 in normal lung epithelial cells, while knockout of Prx4 inhibited urethane-induced cell transformation. Moreover, bioinformatics analysis found that the Srx-Prx4 axis is activated in many human cancers, and their increased expression is tightly correlated with poor prognosis in NSCLC patients. Full article

Nonalcoholic fatty liver disease (NAFLD) encompasses nonalcoholic steatohepatitis (NASH) and affects 25% of the global population. Although a plethora of experimental models for studying NASH have been proposed, still scarce findings regarding the hepatic metabolomic/molecular profile. In the present study, we sought to unravel the hepatic metabolomic profile of mice subjected to a hybrid model of NASH, by combining a Western diet and carbon tetrachloride administration, for 8 weeks, in male C57BL/6J and BALB/c mice. In both mouse strains, the main traits of NASH—metabolic (glucose intolerance profile), morphologic (extensive microvesicular steatosis and fibrosis, lobular inflammation, and adipose tissue-related inflammation/hypertrophy), and molecular (impaired Nrf2/NF-κB pathway dynamics and altered metabolomic profile)—were observed. The hepatic metabolomic profile revealed that the hybrid protocol impaired, in both strains, the abundance of branched chain-aromatic amino acids, carboxylic acids, and glycosyl compounds, that might be linked to the Nrf2 pathway activation. Moreover, we observed a strain-dependent hepatic metabolomic signature, in which the tricarboxylic acid metabolites and pyruvate metabolism were dissimilarly modulated in C57BL/6J and BALB/c mice. Thus, we provide evidence that the strain-dependent hepatic metabolomic profile might be linked to the distinct underlying mechanisms of NASH, also prospecting potential mechanistic insights into the corresponding disease. Full article

Oxidative stress (OS) on tissues is a major pathological insult leading to elevated intraocular pressure (IOP) and primary open-angle glaucoma (POAG). Aqueous humor (AH) produced by the non-pigmentary ciliary epithelium (NPCE) drains out via the trabecular meshwork (TM) outflow pathway in the anterior chamber. The exosomes are major constituents of AH, and exosomes can modulate the signaling events, as well as the responses of their target TM tissue. Despite the presence of molecular mechanisms to negate OS, oxidative damage directly, as well as indirectly, influences TM health, AH drainage, and IOP. We proposed that the expression of microRNA (miRNAs) carried by exosomes in the AH can be affected by OS, and this can modulate the pathways in target cells. To assess this, we subjected NPCE to acute and chronic OS (A-OS and C-OS), enriched miRNAs, performed miRNA microarray chip analyses, and miRNA-based gene targeting pathway prediction analysis. We found that various miRNA families, including miR27, miR199, miR23, miR130b, and miR200, changed significantly. Based on pathway prediction analysis, we found that these miRNAs can regulate the genes including Nrf2, Keap1, GSK3B, and serine/threonine-protein phosphatase2A (PP2A). We propose that OS on the NPCE exosomal miRNA cargo can modulate the functionality of the TM tissue. Full article

As a selenium-enriched plant, Cardamine violifolia (SEC) has an excellent antioxidant function. The edibility of SEC is expected to develop new sources of organic Se supplementation for human and animal nutrition. This study was conducted to investigate the effects of SEC on laying performance and ovarian antioxidant capacity in aging laying hens. A total of 450 laying hens were assigned to five treatments. Dietary treatments included the following: a basal diet (diet without Se supplementation, CON) and basal diets supplemented with 0.3 mg/kg Se from sodium selenite (SS), 0.3 mg/kg Se from Se-enriched yeast (SEY), 0.3 mg/kg Se from SEC, or 0.3 mg/kg Se from SEC and 0.3 mg/kg Se from SEY (SEC + SEY). Results showed that supplementation with SEC tended to increase the laying rate, increased the Haugh unit of eggs, and reduced the FCR. SEC promoted ovarian cell proliferation, inhibited apoptosis, and ameliorated the maintenance of follicles. SEC, SEY, or SEC + SEY increased ovarian T-AOC and decreased MDA levels. SEC increased the mRNA abundance of ovarian selenoproteins. SEC and SEC + SEY increased the mRNA abundance of Nrf2, HO-1, and NQO1, and decreased the mRNA abundance of Keap1. These results indicate that SEC could potentially to improve laying performance and egg quality via the enhancement of ovarian antioxidant capacity. SEC exerts an antioxidant function through the modulation of the Nrf2/Keap1 signaling pathway. Full article

Lemon verbena infusions are widely appreciated due to their agreeable lemony flavor and medicinal properties. In this study, the antioxidant potential, phenolic profile, and free amino acid profile of lemon verbena infusions from different commercial brands were studied. Characterization by UHPLC-QTOF-HRMS allowed the identification of 34 phenolics. The free amino acid profile (by RP-HPLC-FLD) was assessed for the first time, allowing the quantification of 16 amino acids. Furthermore, the infusions showed high antioxidant activity by different assays (ferric reducing antioxidant power, DPPH^• scavenging, and oxygen radical absorbance capacity assays), which in turn were significantly correlated with total phenolics and total flavonoid contents. Notwithstanding, phenylalanine seemed to have also an impact on the antioxidant activity of the infusions, with significant correlations found. Finally, significant differences were found in all the evaluated parameters for one of the four commercial brands herein studied, which was possibly related to the different geographical origins of this sample. Overall, these lemon verbena infusions proved to be rich in a huge variety of bioactive compounds that can provide therapeutic potential. Full article

Moringa oleifera Lam. is known to have significant antioxidant properties. Because of this, the development of an optimal extraction method is crucial to obtain pharmacological products based on the bioactive compounds produced by this tree. Through a Plackett–Burman and a Box–Behnken design, enzymatic extraction conditions (temperature, agitation, solvent pH and composition, sample-to-solvent ratio, enzyme-to-sample ratio and extraction time) have been optimized using normalized areas (UA/g) as response variable and relative mass (mg/g) as quantification variable. Extractions were performed in an incubator, where all the extraction conditions could be digitally controlled. Thus, 58.9 °C, 50 rpm, 4.0 pH, 32.5% EtOH, 0.2 g sample in 15 mL solvent and 106 U/g were established as the optimal extraction conditions for the extraction with a mix of pectinases coming from Aspergillus niger. Under these optimal conditions, two-minute extractions were performed and evaluated through a single factor design. The enzymatic extraction method demonstrated its suitability to produce extracts with good antioxidant power (antioxidant activity 4.664 ± 0.059 mg trolox equivalent/g sample and total phenolic compounds 6.245 ± 0.101 mg gallic acid equivalent/g sample). The method was also confirmed to have good repeatability (1.39%) and intermediate precision (2.37%) levels. Full article

Hypertension is the most common complication of chronic kidney disease (CKD) in children but is still poorly controlled. Nitric oxide (NO) deficiency plays a pivotal role in CKD and hypertension. NO is known to have health benefits, while NO typically has a short half-life and is not specifically targeted. In this study, we used a pediatric CKD model, which was induced in young rats by feeding them 0.25% adenine. We investigated two different NO donors, namely S-nitrosoglutathione (GSNO) and diethylenetriamine/NO adduct (DETA NONOate) via intraperitoneal injection at 10 mg/kg/day daily for 3 weeks. GSNO was delivered by Cu²⁺-doped zeolitic imidazolate framework (Cu/ZIF-8) nanoparticles to generate NO. As a result, we observed Cu/ZIF-8 nanoparticles were successfully loaded with GSNO and were able to release NO. Young rats fed with adenine displayed kidney dysfunction and hypertension at 9 weeks of age, which were prevented by GSNO-loaded nanoparticle or DETA NONOate treatment. GSNO-loaded nanoparticles reduced CKD-induced hypertension, which was related to an enhanced endogenous NO-generating system, reduced renal oxidative stress, and downregulated several components belonging to the classic renin–angiotensin (RAS) system. Our results cast new light on targeting NO delivery through the use of nanoparticles aiming to improve child-focused outcomes related to CKD worthy of clinical translation. Full article

Background: Varronia curassavica Jacq. (Boraginaceae) is traditionally used in the treatment of inflammatory processes. The ethanolic extract of its leaves (EEVc) showed anti-inflammatory properties and low toxicity. Medicinal plants have aroused interest for their antiglycation activities. The formation and accumulation of advanced glycation end products (AGEs) are associated with several chronic diseases. The objective of this study was to evaluate the antiglycation potential of EEVc and two isolated compounds. Methods: The compounds brickellin and cordialin A were obtained by chromatographic methods and identified by spectrometric techniques. Analysis of fluorescent AGEs, biomarkers of amino acid residue oxidation, protein carbonyl groups and crosslink formation were performed in samples obtained from an in vitro model system of protein glycation with methylglyoxal. Results: EEVc, brickellin and cordialin A significantly reduced the in vitro formation of AGEs, and reduced the damage caused by oxidative damage to the protein. Conclusions: According to the results, EEVc, brickellin and cordialin A are potential candidates against AGEs formation, which opens the way to expand the therapeutic arsenal for many pathologies resulting from glycoxidative stress. Full article