Zearalenone (ZEA), one of the non-steroidal estrogen mycotoxin, can cause male reproductive damage and genotoxicity in mammals. Testicular oxidative injury is an important factor causing male sterility. Testicular Sertoli cells are essential for spermatogenesis and male fertility. At present, the mechanism of oxidative injury in dairy goat Sertoli cells after exposure to ZEA remains unclear. This study explored the effects of ZEA on oxidative stress and autophagy in dairy goat Sertoli cells. It was found that treatment of primary Sertoli cells with 25, 50 and 100 μmol/L ZEA for 24 h can promote ROS production, decrease cell viability, antioxidant enzyme activity and mitochondrial membrane potential, induce caspase-dependent cell apoptosis and autophagy activity. ZEA-induced autophagy was confirmed by LC3-I/LC3-II transformation. More importantly, N-acetylcysteine (NAC) pretreatment can remarkably inhibit ZEA-induced oxidative stress, apoptosis and autophagy in Sertoli cells by eliminating ROS. In conclusion, this study indicates that ZEA induces oxidative stress and autophagy in dairy goat Sertoli cells by promoting ROS production.

Alloimperatorin (Alloi) has been shown to have anti-proliferative effects in our previous studies. we aimed to investigate whether Alloimperatorin induces autophagy through the reactive oxygen species (ROS) pathway and anticancer activity in vivo. The anti-proliferative effect of Alloimperatorin was evaluated using a cell counting kit (CCK-8 kit). Apoptosis was detected using flow cytometry. Confocal microscopy, immunofluorescence, and mRFP-GFP-LC3 lentivirus transfection were used to verify autophagy. Electron microscopy detection of autophagosomes was induced by Alloimperatorin. Western blotting was used to detect autophagy proteins in HeLa and SiHa cells. A xenograft model was used to monitor the inhibitory effect of Alloimperatorin on tumor growth in nude mice. The results showed that Alloimperatorin induced ROS production and inhibited the proliferation of HeLa and SiHa cells. Furthermore, Alloimperatorin increased the apoptosis rate in HeLa and SiHa cells. Confocal microscopy fluorescence indicated that Alloimperatorin increased autophagy fluorescence of HeLa and SiHa cells. mRFP-GFP-LC3 lentivirus transfection and electron microscopy demonstrated that Alloimperatorin increased autophagy in HeLa and SiHa cells. Western blotting showed that Alloimperatorin induced the expression of autophagy proteins in HeLa and SiHa cells. However, N-acetylcysteine reversed the autophagy. These results demonstrate that Alloimperatorin can induce autophagy in HeLa and SiHa cells through the ROS pathway. In vivo xenograft experiments showed that Alloimperatorin could inhibit tumor growth in nude mice. Alloimperatorin is expected to be an effective new drug for cervical cancer treatment.Abbreviations: ROS, reactive oxygen species; Alloi, Alloimperatorin; CCK-8, Cell Counting Kit-8; NAC, N-acetyl-L-cysteine; DCFH-DA, 2,7-dichlorodihydrofluorescein diacetate; OD, optical density; PBS, phosphate buffer solution; BCA, bicinchoninic acid; DAPI, 4,6-diamidino-2-phenylindole; DMSO, dimethyl sulfoxide.

Genipin (GP), the reactive metabolite of geniposide (GE), is responsible for GE-induced hepatotoxicity. As a potential detoxification pathway, the inactivation of GP by glutathione S-transferases (GSTs) has not yet been characterized. In this study, the thiol-GSH conjugates of GP, M532-1 and M532-2 were first identified and the catalytic activities of GSTs were investigated both in vitro and in vivo. GSTA1-1 and GSTA4-4 showed high activity in the formation of both thiol-GSH conjugates, whereas GSTA4-4 specifically catalyzed M532-2 formation in vitro. The active GST isoforms protect against alkylation of N-acetylcysteine (NAC), a classic model nucleophile. GST inhibition attenuated M532-1 formation in rat bile, confirming the in vivo catalytic role of GSTs. In conclusion, this study demonstrated the inactivation of GP by GSTs and implied that interindividual variability of GSTs may be a risk factor for susceptibility to GE-induced hepatotoxicity.

Acetaminophen (N-acetyl-p-aminophenol, APAP) is a common antipyretic agent and analgesic. An overdose of APAP can result in acute liver injury (ALI). Oxidative stress and inflammation are central to liver injury. N-acetylcysteine (NAC), a precursor of glutathione, is used commonly in clinical settings. However, the window of NAC treatment is limited, and more efficacious alternatives must be found. Endogenous cytokines such as fibroblast growth factor (FGF) 21 can improve mitochondrial function while decreasing intracellular oxidative stress and inflammatory responses, thereby exhibiting antioxidant-like effects. In this study, self-assembled nanoparticles comprising chitosan and heparin (CH) were developed to deliver FGF21 (CH-FGF21) to achieve the sustained release of FGF21 and optimize the in vivo distribution of FGF21. CH-FGF21 attenuated the oxidative damage and intracellular inflammation caused by APAP to hepatocytes effectively. In a murine model of APAP-induced hepatotoxicity, CH-FGF21 could alleviate ALI progression and promote the recovery of liver function. These findings demonstrated that a simple assembly of CH nanoparticles carrying FGF21 could be applied for the treatment of liver diseases.

Bipolar-disorder's pathophysiology and the mechanism by which medications exert their beneficial effect is yet unknown, but others' and our data implicate patients' brain mitochondrial-dysfunction and its amendment by mood-stabilizers. We recently designed a novel mouse bipolar-disorder-like model using chronic administration of a low-dose of the oxidative-phosphorylation complex I inhibitor, rotenone. Four and eight weeks rotenone treatment induced manic- and depressive-like behavior, respectively, accompanied by mood-related neurochemical changes. Here we aimed to investigate whether each of the autophagy-enhancers lithium (a mood-stabilizer), trehalose and resveratrol and/or each of the reactive oxygen species (ROS)-scavengers, resveratrol and N-acetylcystein and/or the combinations lithium+resveratrol or trehalose+N-acetylcystein, can ameliorate behavioral and neurochemical consequences of neuronal mild mitochondrial-dysfunction. We observed that lithium, trehalose and N-acetylcystein reversed rotenone-induced manic-like behavior as well as deviations in protein levels of mitochondrial complexes and the autophagy marker LC3-II. This raises the possibility that mild mitochondrial-dysfunction accompanied by impaired autophagy and a very mild increase in ROS levels are related to predisposition to manic-like behavior. On the other hand, although, as expected, most of the drugs tested eliminated the eight weeks rotenone-induced increase in protein levels of all hippocampal mitochondrial complexes, only lithium ubiquitously ameliorated the depressive-like behaviors. We cautiously deduce that aberrant autophagy and/or elevated ROS levels are not involved in predisposition to the depressive phase of bipolar-like behavior. Rather, that amending the depressive-like characteristics requires different mitochondria-related interventions. The latter might be antagonizing N-methyl-D-aspartate receptors (NMDARs), thus protecting from disruption of mitochondrial calcium homeostasis and its detrimental consequences. In conclusion, our findings suggest that by-and-large, among the autophagy-enhancers and ROS-scavengers tested, lithium is the most effective in counteracting rotenone-induced changes. Trehalose and N-acetylcystein may also be effective in attenuating manic-like behavior.

In order to improve the stability of oxytetracycline hydrochloride, a polymorphic antibiotic set of novel binary systems were developed using β-cyclodextrin and amino acids with different acid-basic characteristics as ligands. The formation constants for each system containing β-cyclodextrin, L-aspartic acid, histidine and N-acetylcysteine were determined by Scott's method and statistical studies. The structure of the binary systems with β-cyclodextrin and N-acetylcysteine was elucidated by NMR experiments. The effect β-cyclodextrin and N-acetylcysteine on the polymorph's chemical stability in aqueous and phosphate buffered saline solutions at 25 °C was monitored by an optimized and validated high-performance liquid chromatography method. The combination of N-acetylcysteine with the three polymorphs and the β-cyclodextrin system obtained with the form III demonstrated a reduction in the degradation rate of oxytetracycline hydrochloride in the aqueous solution when compared to each free form, with an increase of 20 h in the half time. It evidences that the use of amino acids as ligands constitutes an interesting alternative for pharmaceutical areas. In conclusion, based on the results obtained, these pharmaceutical systems could be candidates for the development of a pharmaceutical formulation for the administration of the drug through reconstituted solutions using the binary system as a promising tool for improving the stability of oxytetracycline hydrochloride polymorphs in solution.

Parenteral N-acetylcysteine has a wide variety of clinical applications, but its use can be limited by a poor chemical stability. We managed to control parenteral N-acetylcysteine stability, and to study the influence of additives on the decrease of N-acetylcysteine degradation. First, an HPLC-UV dosing method of N-acetylcysteine and its main degradation product, a dimer, was validated and the stability without additive was studied. Then, the influence of several additives (ascorbic acid, sodium edetate, tocopherol and zinc) and of temperature on N-acetylcysteine dimerization was evaluated. Finally, the influence of zinc gluconate at different concentrations (administrable to patients) was investigated. Zinc gluconate at 62.5 µg·mL-1 allows the stabilization of 25 mg·mL-1 N-acetylcysteine solution for at least 8 days when stored at 5 ± 3 °C.

The impact of long-term sleep deprivation on the heart and its underlying mechanisms are poorly understood. The present study aimed to investigate the impact of chronic sleep deprivation (CSD) on the heart and mitochondrial function and explore an effective drug for treating CSD-induced heart dysfunction. We used a modified method to induce CSD in mice; lipoic acid (LA) and N-acetylcysteine (NAC) were used to treat CSD mice. Echocardiography, hematoxylin-eosin (H&E) staining, Sirius red staining, and immunohistochemistry were used to determine heart function and cardiac fibrosis. The serum levels of brain natriuretic peptide (BNP), superoxide Dismutase (SOD), micro malondialdehyde (MDA), and glutathione (GSH) were measured to determine cardiovascular and oxidative stress-related damage. Transmission electron microscopy was used to investigate mitochondrial damage. RNA-seq and Western blotting were used to explore related pathways. We found that the left ventricular ejection fraction (LVEF) and fraction shortening (LVFS) values were significantly decreased and myocardial hypertrophy was induced, accompanied by damaged mitochondria, elevated reactive oxygen species (ROS), and reduced SOD levels. RNA-sequence analysis of the heart tissue showed that various differentially expressed genes in the metabolic pathway were enriched. Sirtuin 1 (Sirt1) and Glutathione S-transferase A3 (Gsta3) may be responsible for CSD-induced heart and mitochondrial dysfunction. Pharmacological inhibition of ROS by treating CSD mice with LA and NAC effectively reduced heart damage and mitochondrial dysfunction by regulating Sirt1 and Gsta3 expression. Our data contribute to understanding the pathways of CSD-induced heart dysfunction, and pharmacological targeting to ROS may represent a strategy to prevent CSD-induced heart damage.

Cyanidin-3-O-glucoside (C3G), an active ingredient in anthocyanins, mainly exists in dark cereals. C3G was investigated for its effect on human gastric cancer (GC) cells, together with its molecular mechanism. The CCK-8 assay results showed that C3G had significant antiproliferative effects on GC cells, but it had little effect on normal cells. Western blot and flow cytometry results showed that C3G regulated the reduction of mitochondrial membrane potential and arrested the cell cycle in the G2/M phase through the AKT signaling pathway, causing the cells to undergo apoptosis. Additionally, in MKN-45 cells, C3G markedly raised intracellular reactive oxygen species (ROS) levels. The wound healing assay and Transwell assay results showed that MKN-45 cell migration was significantly inhibited. Western blot results showed that the expression of E-cadherin protein was upregulated and the expressions of β-catenin, N-cadherin, and Vimentin were downregulated. Additionally, following N-acetylcysteine treatment, the expression levels of these proteins were reduced. In conclusion, C3G caused MKN-45 cells to undergo apoptosis; arrested the cell cycle in the G2/M phase; hindered cell migration; and activated the MAPK, STAT3, and NF-κB signaling pathways, by inducing an increase in ROS levels. Thus, C3G may be a promising new medication for the treatment of GC.

There is accumulating evidence that mitochondria and mitochondrial STAT3 are involved in the activation of mast cells. The mitochondria-targeted curcuminoids Mitocur-1 and Mitocur-3 have been suggested to reduce antigen-dependent mast cell activation by inhibiting mitochondrial STAT3. The aim of the current work was to investigate the mechanisms of action of these mitocurcuminoids on mast cells and mitochondrial functions. The pretreatment of rat basophilic leukemia cells RBL-2H3 with Mitocur-1 and Mitocur-3 decreased antigen-dependent degranulation but did not affect spontaneous degranulation. Both compounds caused mitochondrial fragmentation and increased mitochondrial ROS. Inhibition of Drp1 prevented mitochondrial fragmentation induced by Mitocur-3 but not by Mitocur-1. The antioxidant N-acetylcysteine inhibited mitochondrial fission induced by Mitocur-1 but not Mitocur-3. Mitochondrial fragmentation caused by Mitocur-3 but not Mitocur-1 was accompanied by activation of Drp1 and AMPK. These data suggest a distinct mechanism of action of mitocurcuminoids on the mitochondria of RBL-2H3 cells: Mitocur-3 stimulated AMPK and caused Drp1-dependent mitochondrial fragmentation, while Mitocur-1-induced mitochondrial fission was ROS-dependent. This difference may contribute to the higher toxicity of Mitocur-3 compared to Mitocur-1. The findings contribute to further drug development for inflammatory and allergic diseases.

Ischemia/reperfusion injury is a process associated with cardiologic interventions, such as percutaneous coronary angioplasty after an acute myocardial infarction. Blood flow restoration causes a quick burst of reactive oxygen species (ROS), which generates multiple organelle damage, leading to the activation of cell death pathways. Therefore, the intervention contributes to a greater necrotic zone, thus increasing the risk of cardiovascular complications. A major cardiovascular ROS source in this setting is the activation of multiple NADPH oxidases, which could result via the occupancy of type 1 angiotensin II receptors (AT1R); hence, the renin angiotensin system (RAS) is associated with the generation of ROS during reperfusion. In addition, ROS can promote the expression of NF-κΒ, a proinflammatory transcription factor. Recent studies have described an intracellular RAS pathway that is associated with increased intramitochondrial ROS through the action of isoform NOX4 of NADPH oxidase, thereby contributing to mitochondrial dysfunction. On the other hand, the angiotensin II/ angiotensin type 2 receptor (Ang II/AT2R) axis exerts its effects by counter-modulating the action of AT1R, by activating endothelial nitric oxide synthase (eNOS) and stimulating cardioprotective pathways such as akt. The aim of this review is to discuss the possible use of AT1R blockers to hamper both the Ang II/AT1R axis and the associated ROS burst. Moreover; we suggest that AT1R antagonist drugs should act synergistically with other cardioprotective agents, such as ascorbic acid, N-acetylcysteine and deferoxamine, leading to an enhanced reduction in the reperfusion injury. This therapy is currently being tested in our laboratory and has shown promising outcomes in experimental studies.

Current pharmacotherapy options of drug-induced liver injury (DILI) remain under discussion and are now evaluated in this analysis. Needless to say, the use of the offending drug must be stopped as soon as DILI is suspected. Normal dosed drugs may cause idiosyncratic DILI, and drugs taken in overdose commonly lead to intrinsic DILI. Empirically used but not substantiated regarding efficiency by randomized controlled trials (RCTs) is the intravenous antidote treatment with N-acetylcysteine (NAC) in patients with intrinsic DILI by N-acetyl-p-aminophenol (APAP) overdose. Good data recommending pharmacotherapy in idiosyncratic DILI caused by hundreds of different drugs are lacking. Indeed, a recent analysis revealed that just eight RCTs have been published, and in only two out of eight trials were DILI cases evaluated for causality by the worldwide used Roussel Uclaf Causality Assessment Method (RUCAM), representing overall a significant methodology flaw, as results of DILI RCTs lacking RUCAM are misleading since many DILI cases are known to be attributable erroneously to nondrug alternative causes. In line with these major shortcomings and mostly based on anecdotal reports, glucocorticoids (GCs) and other immuno-suppressants may be given empirically in carefully selected patients with idiosyncratic DILI exhibiting autoimmune features or caused by immune checkpoint inhibitors (ICIs), while some patients with cholestatic DILI may benefit from ursodeoxycholic acid use; in other patients with drug-induced hepatic sinusoidal obstruction syndrome (HSOS) and coagulopathy risks, the indication for anticoagulants should be considered. In view of many other mechanistic factors such as the hepatic microsomal cytochrome P450 with a generation of reactive oxygen species (ROS), ferroptosis with toxicity of intracellular iron, and modification of the gut microbiome, additional therapy options may be available in the future. In summation, stopping the offending drug is still the first line of therapy for most instances of acute DILI, while various therapies are applied empirically and not based on good data from RCTs awaiting further trials using the updated RUCAM that asks for strict exclusion and inclusion details like liver injury criteria and provides valid causality rankings of probable and highly probable grades.

Clasmatodendrosis (an autophagic astroglial degeneration) plays an important role in the regulation of spontaneous seizure duration but not seizure frequency or behavioral seizure severity in chronic epilepsy rats. Recently, it has been reported that N-acetylcysteine (NAC), a precursor to glutathione (GSH), attenuates clasmatodendritic degeneration and shortens spontaneous seizure duration in chronic epilepsy rats, although the underlying mechanisms of its anti-convulsive effects are not fully understood. To elucidate this, the present study was designed to investigate whether NAC affects astroglial glutamine synthase (GS) expression mediated by GSH peroxidase 1 (GPx1) and/or peroxiredoxin 6 (Prdx6) in the epileptic hippocampus. As compared to control animals, GS and GPx1 expressions were upregulated in reactive CA1 astrocytes of chronic epilepsy rats, while their expressions were significantly decreased in clasmatodendritic CA1 astrocytes and reactive astrocytes within the molecular layer of the dentate gyrus. Prdx6 expression was increased in reactive CA1 astrocytes as well as clasmatodendritic CA1 astrocytes. In the molecular layer of the dentate gyrus, Prdx6 expression levels were similar to those in control animals. NAC ameliorated clasmatodendrosis through the increment of GS and GPx1 expressions, while it abolished Prdx6 upregulation. 1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol (MJ33, a selective inhibitor of aiPLA2 activity of Prdx6) alleviated clasmatodendrosis by enhancing GPx1 and GS expressions in clasmatodendritic CA1 astrocytes without changing the Prdx6 level. NAC or MJ33 did not affect GS, GPx1 and Prdx6 expression in astrocytes within the molecular layer of the dentate gyrus. These findings indicate that upregulated aiPLA2 activity of Prdx6 may abolish GPx1-mediated GS preservation and lead to clasmatodendrosis in CA1 astrocytes, which would extend spontaneous seizure duration due to impaired glutamate-glutamine conversion regulated by GS. Therefore, the present data suggest that aiPLA2 activity of Prdx6 in astrocytes may be one of the upstream effectors of seizure duration in the epileptic hippocampus.

As the blood-brain barrier (BBB) prevents most compounds from entering the brain, nanocarrier delivery systems are frequently being explored to potentially enhance the passage of drugs due to their nanometer sizes and functional characteristics. This study aims to investigate whether Pluronic® F68 (P68) and dequalinium (DQA) nanocarriers can improve the ability of curcumin, n-acetylcysteine (NAC) and/or deferoxamine (DFO), to access the brain, specifically target mitochondria and protect against rotenone by evaluating their effects in a combined Transwell® hCMEC/D3 BBB and SH-SY5Y based cellular Parkinson's disease (PD) model. P68 + DQA nanoformulations enhanced the mean passage across the BBB model of curcumin, NAC and DFO by 49%, 28% and 49%, respectively (p < 0.01, n = 6). Live cell mitochondrial staining analysis showed consistent co-location of the nanocarriers within the mitochondria. P68 + DQA nanocarriers also increased the ability of curcumin and NAC, alone or combined with DFO, to protect against rotenone induced cytotoxicity and oxidative stress by up to 19% and 14% (p < 0.01, n = 6), as measured by the MTT and mitochondrial hydroxyl radical assays respectively. These results indicate that the P68 + DQA nanocarriers were successful at enhancing the protective effects of curcumin, NAC and/or DFO by increasing the brain penetrance and targeted delivery of the associated bioactives to the mitochondria in this model. This study thus emphasises the potential effectiveness of this nanocarrier strategy in fully utilising the therapeutic benefit of these antioxidants and lays the foundation for further studies in more advanced models of PD.

Ionizing radiation (IR) can induce some associated pathological conditions due to numerous cell damages. The influence of sex is scarcely known, and even less known is whether the effect of antioxidants is sex-dependent. Given the increased use of IR, we investigated whether male human umbilical vein endothelial cells (MHUVECs) and female human umbilical vein endothelial cells (FHUVECs) respond differently to IR exposure and whether the antioxidants 10 mM taurine (TAU) and 5 mM N-acetylcysteine (NAC) can prevent IR-induced damage in a sex-dependent way. In untreated cells, sex differences were observed only during autophagy, which was higher in FHUVECs. In non-irradiated cells, preincubation with TAU and NAC did not modify viability, lactate dehydrogenase (LDH) release, migration, or autophagy, whereas only NAC increased malondialdehyde (MDA) levels in FHUVECs. X-ray irradiation increased LDH release and reduced viability and migration in a sex-independent manner. TAU and NAC did not affect viability while reduced LDH release in irradiated cells: they have the same protective effect in FHUVECs, while, TAU was more protective than NAC in male cells.. Moreover, TAU and NAC significantly promoted the closure of wounds in both sexes in irradiated cells, but NAC was more effective at doing this in FHUVECs. In irradiated cells, TAU did not change autophagy, while NAC attenuated the differences between the sexes. Finally, NAC significantly decreased MDA in MHUVECs and increased MDA in FHUVECs. In conclusion, FHUVECs appear to be more susceptible to IR damage, and the effects of the two antioxidants present some sex differences, suggesting the need to study the influence of sex in radiation mitigators.

This study investigated whether high-intensity exercise training alters the effect of N-acetylcysteine (a precursor of antioxidant glutathione) on exercise-related muscle ionic shifts. We assigned 20 recreationally-active men to 6 weeks of high-intensity exercise training, comprising three weekly sessions of 4-10 × 20-s all-out bouts interspersed by 2 min recovery (SET, n = 10), or habitual lifestyle maintenance (n = 10). Before and after SET, we measured ionic shifts across the working muscle, using leg arteriovenous balance technique, during one-legged knee-extensor exercise to exhaustion with and without N-acetylcysteine infusion. Furthermore, we sampled vastus lateralis muscle biopsies for analyses of metabolites, mitochondrial respiratory function, and proteins regulating ion transport and antioxidant defense. SET lowered exercise-related H+, K+, lactate-, and Na+ shifts and enhanced exercise performance by ≈45%. While N-acetylcysteine did not affect exercise-related ionic shifts before SET, it lowered H+, HCO3-, and Na+ shifts after SET. SET enhanced muscle mitochondrial respiratory capacity and augmented the abundance of Na+/K+-ATPase subunits (α1 and β1), ATP-sensitive K+ channel subunit (Kir6.2), and monocarboxylate transporter-1, as well as superoxide dismutase-2 and glutathione peroxidase-1. Collectively, these findings demonstrate that high-intensity exercise training not only induces multiple adaptations that enhance the ability to counter exercise-related ionic shifts but also potentiates the effect of N-acetylcysteine on ionic shifts during exercise.

Our previous study reported that N-acetylcysteine (NAC) administration improved the function of intestinal absorption in piglets infected with porcine epidemic diarrhea virus (PEDV). However, the effects of NAC administration on the functions of other tissues and organs in PEDV-infected piglets have not been reported. In this study, the effects of NAC on the liver, spleen, lung, lymph node, and gastrocnemius muscle in PEDV-infected piglets were investigated. Thirty-two 7-day-old piglets with similar body weights were randomly divided into one of four groups: Control group, NAC group, PEDV group, and PEDV+NAC group (eight replicates per group and one pig per replicate). The trial had a 2 × 2 factorial design consisting of oral administration of 0 or 25 mg/kg body weight NAC and oral administration of 0 or 1.0 × 104.5 TCID50 PEDV. The trial lasted 12 days. All piglets were fed a milk replacer. On days 5-9 of the trial, piglets in the NAC and PEDV + NAC groups were orally administered NAC once a day; piglets in the control and PEDV groups were orally administered the same volume of saline. On day 9 of trial, piglets in the PEDV and PEDV+NAC groups were orally administrated 1.0 × 104.5 TCID50 PEDV, and the piglets in the control and NAC groups were orally administrated the same volume of saline. On day 12 of trial, samples, including of the liver, spleen, lung, lymph node, and gastrocnemius muscle, were collected. PEDV infection significantly increased catalase activity but significantly decreased the mRNA levels of Keap1, Nrf2, HMOX2, IFN-α, MX1, IL-10, TNF-α, S100A12, MMP3, MMP13, TGF-β, and GJA1 in the spleens of piglets. NAC administration ameliorated abnormal changes in measured variables in the spleens of PEDV-infected piglets. In addition, NAC administration also enhanced the antioxidant capacity of the mesenteric lymph nodes and gastrocnemius muscles in PEDV-infected piglets. Collectively, these novel results revealed that NAC administration improved the redox and functional gene expression levels in the spleen, mesenteric lymph nodes, and gastrocnemius muscle in PEDV-infected piglets.

Acetaminophen (APAP), a widely used antipyretic and analgesic drug in clinics, is relatively safe at therapeutic doses; however, APAP overdose may lead to fatal acute liver injury. Currently, N-acetylcysteine (NAC) is clinically used as the main antidote for APAP poisoning, but its therapeutic effect remains limited owing to rapid disease progression and the general diagnosis of advanced poisoning. As is well known, APAP-induced hepatotoxicity (AIH) is mainly caused by the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), and the toxic mechanisms of AIH are complicated. Several cellular processes are involved in the pathogenesis of AIH, including liver metabolism, mitochondrial oxidative stress and dysfunction, sterile inflammation, endoplasmic reticulum stress, autophagy, and microcirculation dysfunction. Mitochondrial oxidative stress and dysfunction are the major cellular events associated with APAP-induced liver injury. Many biomolecules involved in these biological processes are potential therapeutic targets for AIH. Therefore, there is an urgent need to comprehensively clarify the molecular mechanisms underlying AIH and to explore novel therapeutic strategies. This review summarizes the various cellular events involved in AIH and discusses their potential therapeutic targets, with the aim of providing new ideas for the treatment of AIH.

Phenolic organochalcogen chain-breaking antioxidants, i.e. 6-bromo-8 (hexadecyltellanyl)-3,3-dimethyl-1,5-dihydro-[1,3]dioxepino[5,6-c]pyridin-9-ol and 2-methyl-2,3-dihydrobenzo[b]selenophene-5-ol, have been investigated in a two-phase (chlorobenzene/water) lipid peroxidation model system as potent inhibitors of lipid peroxyl radicals with various co-antioxidants at various pH values. The pH has a significant effect on the chain-breaking antioxidant activities of phenolic organochalcogens. The key chain-breaking mechanism profile was attributed to the first oxygen atom transfer from the lipid peroxyl radicals to the Se/Te atom, followed by hydrogen atom transfer in a solvent cage from the nearby phenolic group to the resulting alkoxyl radical. Finally, regeneration of organochalcogen antioxidants could take place in the presence of aqueous-soluble co-antioxidants. Also, in the presence of aqueous soluble N-acetylcysteine at pH 1-7, both antioxidants behaved as very good inhibitors of lipid peroxyl radicals. The role of aqueous soluble mild co-antioxidants in the regeneration studies of organochalcogen antioxidants has been investigated in a two-phase lipid peroxidation model system. The importance of the phase transfer catalyst has been explored in the inhibition studies of selenium containing antioxidants using an Fe(II) source. The overall pH-dependent antioxidant activities of organochalcogens depend on their hydrogen atom transfer ability, relative stability, and distribution in the aqueous/lipid phase.