Peroxidation Chain Research Articles

Inducible RPE-specific GPX4 knockout causes oxidative stress and retinal degeneration with features of age-related macular degeneration

Age-related macular degeneration (AMD) is one of the leading causes of vision loss in the elderly. This disease involves oxidative stress burden in the retina leading to death of retinal pigment epithelial (RPE) cells and photoreceptors. The retina is susceptible to oxidative stress, in part due to high metabolic activity and high concentration of polyunsaturated fatty acids that undergo lipid peroxidation chain reactions. Antioxidant enzymes exist in the retina to combat this stress, including glutathione peroxidase 4 (GPX4). GPX4 specifically reduces oxidized lipids, protecting against lipid peroxidation-induced oxidative stress, which is noted in dry AMD. We hypothesize that Gpx4 knockout within the RPE will result in an environment of chronic oxidative stress yielding degeneration akin to AMD. C57BL/6J mice with a floxed Gpx4 gene were mated with Rpe65Cre/ER mice. Offspring containing Rpe65Cre ± alleles and either Gpx4 WT or Gpx4 fl/fl alleles were administered tamoxifen to induce Gpx4 knockout in Gpx4 fl/fl mice. At sequential timepoints, retinal phenotypes were assessed via in vivo imaging utilizing confocal scanning laser ophthalmoscopy and optical coherence tomography (OCT), and visual function was probed by electroretinography. Retinas were studied post-mortem by immunohistochemical analyses, electron microscopy, plastic sectioning, and quantitative polymerase chain reaction and Western analyses. The RPE-specific Gpx4 knockout model was validated via Western analysis indicating diminished GPX4 protein only within the RPE and not the neural retina. Following Gpx4 knockout, RPE cells became dysfunctional and died, with significant cell loss occurring 2 weeks post-knockout. Progressive thinning of the photoreceptor layer followed RPE degeneration and was accompanied by loss of visual function. OCT and light microscopy showed hyperreflective foci and enlarged, pigmented cells in and above the RPE layer. Electron microscopy revealed decreased mitochondrial cristae and loss of basal and apical RPE ultrastructure. Finally, there was increased carboxyethylpyrrole staining, indicating oxidation of docosahexaenoic acid, and increased levels of mRNAs encoding oxidative stress-associated genes in the RPE and photoreceptors. Overall, we show that RPE-localized GPX4 is necessary for the health of the RPE and outer retina, and that knockout recapitulates phenotypes of dry AMD.

The biology of ferroptosis in kidney disease.

Ferroptosis is a regulated cell death modality triggered by iron-dependent lipid peroxidation. Ferroptosis plays a causal role in the pathophysiology of various diseases, making it a promising therapeutic target. Unlike all other cell death modalities dependent on distinct signaling cues, ferroptosis occurs when cellular antioxidative defense mechanisms fail to suppress the oxidative destruction of cellular membranes, eventually leading to cell membrane rupture. Physiologically, only two such surveillance systems are known to efficiently prevent the lipid peroxidation chain reaction by reducing (phospho)lipid hydroperoxides to their corresponding alcohols or by reducing radicals in phospholipid bilayers, thus maintaining the integrity of lipid membranes. Mechanistically, these two systems are linked to the reducing capacity of glutathione peroxidase 4 (GPX4) by consuming glutathione (GSH) on one hand and ferroptosis suppressor protein 1 (FSP1, formerly AIFM2) on the other. Notably, the importance of ferroptosis suppression in physiological contexts has been linked to a particular vulnerability of renal tissue. In fact, early work has shown that mice genetically lacking Gpx4 rapidly succumb to acute renal failure with pathohistological features of acute tubular necrosis. Promising research attempting to implicate ferroptosis in various renal disease entities, particularly those with proximal tubular involvement, has generated a wealth of knowledge with widespread potential for clinical translation. Here, we provide a brief overview of the involvement of ferroptosis in nephrology. Our goal is to introduce this expanding field for clinically versed nephrologists in the hope of spurring future efforts to prevent ferroptosis in the pathophysiological processes of the kidney.

Antibacterial mechanism and enhancement of antibacterial activity under visible light in Er3+-doped BiOBr

The introduction of oxygen defects in semiconductor electronic structures is considered to be an effective strategy to improve their photocatalytic activity. In this work, rare-earth Er3+−doped BiOBr (Er/BiOBr) with oxygen-rich vacancies (OVs) was prepared via simple hydrothermal method. Compared with pure BiOBr, Er/BiOBr has a narrower band gap and more abundant OVs, which together improve the separation efficiency of photogenerated carriers. The introduction of Er not only creates impurity states between conduction band (CB) and valence band (VB), but also produces more OVs as electron traps. Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus) were used as evaluation systems for these materials with different Er3+ doping contents. The results showed that under the combined action of ·O2− and H2O2, 2.0% EBB samples with Er3+ doping content of BiOBr showed the best broad-spectrum antibacterial activity, and E. coli and S. aureus were completely inactivated at 0.03 mg ml−1 and 0.05 mg ml−1 concentrations. The surface and interfacial structures of Er/BiOBr samples were studied by XRD, brunauer-emmet-teller method, SEM, TEM and EDX. OVs and photogenerated carrier separation in Er/BiOBr were determined by ESR, PL and photochemical detection methods. More importantly, through the detection of lipid peroxidation and bacterial respiratory chain dehydrogenase activities, the internal and external processes of ROS on bacterial inactivation were determined, and the photocatalytic antibacterial mechanism was summarized. This study for the antimicrobial properties of rare earth ions doped improve photocatalytic materials provides a new train of thought.

Bioactive composition and protective properties of Talium triangulare in dextran sodium sulphate-induced ulcerative colitis in rats

BackgroundsThe prevalence of ulcerative colitis (UC) is gradually becoming a global health challenge. Talinum triangulare, commonly called "waterleaf" (Tu ren shen in Chinese) is a plant that is cultivated in Asia, western Africa, and other tropical rainforest regions as a food and medicine plant. Due to its medicinal significance, Talium triangulare has been used in Chinese traditional medicines to treat various human diseases. The purpose of this study was to evaluate the possible protective effect of aqueous leaf extract of Talium triangulare (TT) on dextran sodium sulphate (DSS)-induced colitis. MethodsExposure of rats to 5 % DSS in drinking water induced colitis, and the effect of 200 mg/kg TT was studied over a 10-day period via oral administration. The effect of TT on anti-inflammatory, redox assays, clinical manifestations (disease activity index), and colonic mucosa histological changes was determined. ResultsDSS induced colonic inflammation in rats with a significant increase in NO, MPO, TNF-α, IL-6, and IL-1β levels compared to the untreated group. Oxidative stress was markedly increased in the DSS group with concomitant suppression of antioxidant enzymes activities. Exposure of rats to DSS causes lipid peroxidation with a marked increase in colonic level of malondialdehyde. Nevertheless, the administration of TT significantly suppressed inflammation in the colon by downregulating expression of the inflammatory indicators. TT suppressed the levels of MDA and H2O2 thus mitigating lipid peroxidation chain reaction. Furthermore, TT attenuated DSS-facilitated oxidative damage by improving the enzymatic activities of the protective enzymes (CAT, GST, and SOD) and increasing GSH level. ConclusionTT enhanced the antioxidant enzymes activities, attenuated oxidative stress, suppressed lipid peroxidation, inhibited inflammation, and reduced DAI score. These beneficial activities of TT could be attributed to its phytoconstituents depicted in GCMS results. The results of this research indicated that TT could contain therapeutic agents for the treatment of inflammatory colitis.

Laser-Ignited Lipid Peroxidation Nanoamplifiers for Strengthening Tumor Photodynamic Therapy Through Aggravating Ferroptotic Propagation and Sustainable High Immunogenicity.

Photodynamic therapy (PDT) is extensively investigated for tumor therapy in the clinic. However, the efficacy of PDT is severely limited by the tissue penetrability of light, short effective half-life and radius of reactive oxygen species (ROS), and the weak immunostimulatory effect. In this study, a glutathione (GSH)-activatable nano-photosensitizer is developed to load with arachidonic acid (AA) and camouflage by erythrocyte membrane, which serves as a laser-ignited lipid peroxidation nanoamplifier (MAR). The photosensitive effect of MAR is recovered accompanied by the degradation in the tumor microenvironment and triggers the peroxidation of AA upon laser excitation. Interestingly, it aggravates the propagation of ferroptosis among cancer cells by driving the continuous lipid peroxidation chain reactions with the participation of the degradation products, ferrous ions (Fe2+), and AA. Consequently, even the deep-seated tumor cells without illumination also undergo ferroptosis owing to the propagation of ferroptotic signal. Moreover, the residual tumor cells undergoing ferroptosis still maintain high immunogenicity after PDT, thus continuously triggering sufficient tumor-associated antigens (TAAs) release to remarkably promote the anti-tumor immune response. Therefore, this study will provide a novel "all-in-one" nano-photosensitizer that not only amplifies the damaging effect and expands the effective range of PDT but also improves the immunostimulatory effect after PDT.

Hybrid Biomimetic Membrane Coated Particles-Mediated Bacterial Ferroptosis for Acute MRSA Pneumonia.

Acute methicillin resistant Staphylococcus aureus (MRSA) pneumonia is one of the most frequently seen lung infection diseases with high morbidity and mortality. It is urgent to explore an efficient antibacterial strategy owing to the increase of drug resistance, virulence, and pathogenicity of MRSA. It was found that Fe3O4 can induce ferroptosis in MRSA, but its effect was inhibited by glutathione (GSH) to a certain extent, while cinnamaldehyde (CA) can enhance ferroptosis by consuming GSH. As a bacterial quorum sensing (QS) inhibitor, CA can suppress the QS system and further exert its antibacterial and antibiofilm effects. Here, we developed an Fe3O4-based ferroptosis inducer to promote ferroptosis in MRSA, interrupt the QS, destroy biofilm, and thus effectively treat acute MRSA pneumonia. We used sodium alginate (SA) to wrap Fe3O4 and CA to form particles, and then coated the surface with a hybrid biomimetic membrane composed of an erythrocyte membrane and platelet membrane to obtain lung targeted antibacterial particles (mFe-CA). Under ultrasonic (US) stimulation, mFe-CA can efficiently release Fe3O4 and CA, thereby synergically inducing MRSA death with the characteristics of ferroptosis, including mass ROS production, lipid peroxidation, GSH depletion, and respiratory chain suppression. Furthermore, mFe-CA + US can inhibit the QS system, remove biofilms, and reduce strain virulence. In the mouse model of MRSA pneumonia, mFe-CA + US treatment markedly advanced the survival rate of the mice, reduced the bacterial load in the lungs, and alleviated the inflammatory damage, but there was no obvious toxicity. This study proposes an antibacterial substitute to induce ferroptosis of MRSA, which may provide a foreground for overcoming microbial drug resistance and fighting biofilm-associated infections and also provides a target and theoretical basis for clinical treatment of acute MRSA pneumonia.

OXIDATIVE MECHANISMS UNDERLYING BRAIN CELL DAMAGE IN RATS UNDER CHANGES IN DURATION OF THE LIGHTDARK CYCLES

One of the main mechanisms underlying cell damage is lipid peroxidation, which is characterized by increased levels of free radical, products of lipid peroxidation chain reactions, and alterations in the activity of the antioxidant system in tissues. Therefore, the objective of this study is to investigate the proand antioxidant balance in rat brain homogenate under conditions of disrupted "light-dark" cycles. The study involved 28 white Wistar rats weighing 150-200 gm, divided into two groups: control (15) and the group of animals exposed to acute desynchronosis simulation (13). To simulate desynchronosis, a normal "light-dark" cycle of 12 hours of light and 12 hours of darkness was initially established for three weeks, followed by a shift of the "light-dark" phases backward by six hours over the next three days. The animals were kept in standard conditions with a balanced diet in the vivarium, and the study adhered to the principles of biomedical ethics.
 The results obtained indicate a significant increase in the activity of superoxide anion radical production in the brain tissues of the rats with modelled desynchronosis by 75.8% compared to the control group. This increase is attributed to the NADPH-oxidase mechanism by 20.2% and to xanthine oxidase mechanisms by 28%. The concentration of TBA-active products increased by 36.8%, the growth of TBA-active products elevated by 30%, and the activity of the key antioxidant enzymes, superoxide dismutase and catalase, decreased by 53% and 14%, respectively, in the second group of animals. Furthermore, in the brain tissues of rats with disrupted "light-dark" cycles, there were found elevated levels of nitrites by 23.8%, nitrosothiols by 19%, and peroxynitrites by 69%, along with a reduction in the activity of total NO-synthase by 59.1%, inducible NO-synthase by 61.1%, and constitutive NO-synthase by 9% compared to the control group. The activity of ornithine decarboxylase increased by 26.5% in the brain tissues of the rats with simulated desynchronosis compared to the control group.
 In conclusion, the disruption of "light-dark" cycles leads to the development of oxidative stress in brain tissues of animals and is characterized by increased production of reactive oxygen species and diminished antioxidant protection. Acute desynchronosis decreases nitric oxide production through the NO-synthase pathway, while increasing the accumulation of toxic nitric oxide metabolites in the brain tissues of rats, thereby posing a potential risk of nitrosative stress. Furthermore, alterations in the normal light regimen of the day activate the arginase pathway of L-arginine metabolism and result in increased glutamate production in the brain tissues of rats, potentially leading to oxidative stress.

Unsaturated phospholipid modified FeOCl nanosheets for enhancing tumor ferroptosis.

Iron-dependent accumulation of reactive oxygen species (ROS) and lipid peroxidation play key roles in ferroptosis, which has been an attractive strategy to kill tumor cells. However, the rapid annihilation of hydroxyl radicals (˙OH) produced from the Fenton reaction has become a major obstacle in inducing lipid peroxidation in cells. In this study, we develop a nano-delivery system of unsaturated phospholipid (Lip) and polyacrylic acid (PAA) functionalized FeOCl nanosheets (FeOCl@PAA-Lip). In this system, the ˙OH radicals produced from the Fenton reaction between FeOCl nanosheets and endogenous H2O2 of tumor cells attack Lip on the nanosheets in situ to initiate the lipid peroxidation chain reaction, which not only realizes free radical conversion but also leads to the amplification of ROS and lipid peroxides, thus enhancing tumor ferroptosis. The in vitro and in vivo results confirmed that FeOCl@PAA-Lip nanosheets exhibited specific tumor cell-killing effects, good biocompatibility, long circulation time, low side effects, high tumor targeting and an excellent tumor inhibition rate (73%). The Lip functionalization strategy offers a paradigm of enhancing ferroptosis treatment by conversion of ˙OH/phospholipid radicals/lipid peroxyl radicals and strengthening lipid peroxidation.

Influence of Water on Noncatalytic Oxidative Desulfurization of High-Sulfur Straight-Run Oil Fractions.

The noncatalytic oxidative desulfurization process of straight-run kerosene and diesel fractions with high sulfur contents due to their treatment with air without using expensive catalysts and strong oxidants is considered. The research was carried out in a periodic mode in a bubble-type reactor with a volume of 1 × 10–3 m3 under the following conditions: 180–200 °C; 2.5–3.0 MPa; the process lasted for 20–30 min; the air/raw material ratio was 1.6–2.2 m3/min per 1 m3 of raw material. The process can be used to obtain industrial jet fuels and diesel fuel components with good lubricating properties. The possibility and expediency of carrying out the process in the presence of water have been studied. The ratio of water/raw materials (vol.) varied from 0:1 to 2:1. It was proven that the water presence in the reaction medium has a positive effect on the studied process and decreases the oxidation intensity of hydrocarbon medium by 2–4 times. This is due to both the slowing of oxidation reactions by water during peroxide decomposition and chain growth and branching and the partial change in chemical oxidation with the formation of phenols and/or tertiary alcohols, which are inhibitors of oxidation reactions. On the other hand, water has almost no effect on the removal degree of sulfur compounds.

Assessment of lipid peroxidation in irradiated cells.

Lipid peroxidation occurs under conditions where reactive oxygen species (ROS) readily react with vulnerable lipids on cell membranes. Polyunsaturated fatty acids (PUFAs) are highly susceptible to lipid peroxidation because of their unstable double bonds. Because the cell membrane is particularly rich in PUFAs, it is often the site at which many lipid peroxidation chain reactions occur. Lipid peroxidation is considered the ultimate trigger of ferroptosis, an iron-dependent form of non-apoptotic cell death. Radiotherapy is a common cancer treatment that uses high-energy ionizing radiation to kill cancer cells, and radiation-induced cell death is partially attributed to lipid peroxidation-driven ferroptosis. Here, we describe methods to assess lipid peroxidation in irradiated cells. The same techniques can be applied to a variety of lipid peroxidation measurements under different treatment conditions.

Antiradical Activity of Dopamine, L-DOPA, Adrenaline, and Noradrenaline in Water/Methanol and in Liposomal Systems.

Catecholamines play a crucial role in signal transduction and are also expected to act as endogeneous antioxidants, but the mechanism of their antioxidant action is not fully understood. Here, we describe the impact of pH on the kinetics of reaction of four catecholamines (L-DOPA, dopamine, adrenaline, and noradrenaline) with model 2,2-diphenyl-1-picrylhydrazyl radical (dpph•) in methanol/water. The increase in pH from 5.5 to 7.4 is followed by a 2 order of magnitude increase in the rate constant, e.g., for dopamine (DA) kpH5.5 = 1,200 M–1 s–1 versus kpH7.4 = 170,000 M–1 s–1, and such rate acceleration is attributed to a fast electron transfer from the DA anion to dpph•. We also proved that at pH 7.0 DA breaks the peroxidation chain of methyl linoleate in liposomes assembled from neutral and negatively charged phospholipids. In contrast to no inhibitory effect during peroxidation in non-ionic emulsions, in bilayers one molecule of DA traps approximately four peroxyl radicals, with a rate constant kinh >103 M–1 s–1. Our results from a homogeneous system and bilayers prove that catecholamines act as effective, radical trapping antioxidants with activity depending on the ionization status of the catechol moiety, as well as microenvironment: organization of the lipid system (emulsions vs bilayers) and interactions of catecholamines with the biomembrane.

Intermembrane Translocation of Photodynamically Generated Lipid Hydroperoxides: Broadcasting of Redox Damage.

Lipid hydroperoxides (LOOHs), including cholesterol- and phospholipid-derived species, are reactive intermediates that arise during photosensitized peroxidation of unsaturated lipids in biological membranes. These intermediates may appear in cancer cell membranes during anti-tumor photodynamic therapy (PDT). Photodynamically generated LOOHs have several different fates, including (a) iron-catalyzed one-electron reduction to free radical species which trigger damaging chain peroxidation reactions, (b) selenoperoxidase-catalyzed two-electron reduction to redox-inert alcohols (LOHs), and (c) spontaneous or protein-mediated translocation to other lipid membrane compartments where (a) or (b) may take place. These different LOOH fates will be described in this review, but with special attention to category (c), which the authors were the first to describe and characterize. Seminal early findings on cholesterol hydroperoxide (ChOOH) translocation and its potential negative consequences will be discussed. In reviewing this work, we wish to congratulate Jean Cadet, for his many outstanding accomplishments as a photobiologist and P&P editor.

Self-assembled Co-doped β-Bi2O3 flower-like structure for enhanced photocatalytic antibacterial effect under visible light

A series of β-Bi2O3 with different Co doping amounts were prepared by a co-precipitation and pyrolysis process. A flower-like self-assembly of β-Bi2O3 sheets was realized by the doping of Co. Simulation results showed that an impurity state was introduced into the band gap of doped β-Bi2O3, mainly due to the Co 3d orbital. Co doping enhanced the visible light utilization rate by reducing the band gap and improving electrons holes separation efficiency. E. coli was used to evaluate the photocatalytic antibacterial ability of undoped and Co-doped β-Bi2O3 under visible light. β-Bi2O3 exhibited optimal efficiency for both electron-hole separation and antibacterial effect when doped with 0.4% Co (0.4%-CBO). Gradient experiments were performed to determine that reactive oxygen species (ROS) were the main factor behind the antibacterial effect of β-Bi2O3. The enhanced antibacterial properties of 0.4%-CBO were due to its increased production of O2–, OH, and H2O2, with scavenger experiments finding that O2– was the main contributor to its antibacterial effect. Through the detection of lipid peroxidation and bacterial respiratory chain dehydrogenase activity, it was determined that the antibacterial effect of ROS simultaneously occurred in the interior and exterior of E. coli and that this activity was enhanced by Co doping.

Telfairia occidentalis mitigates dextran sodium sulfate-induced ulcerative colitis in rats via suppression of oxidative stress, lipid peroxidation, and inflammation.

Ulcerative colitis (UC), a subcategory of inflammatory bowel diseases, affects more than 2 million people globally. This study sought to investigate the curative ability of aqueous leaf extract of Telfairia occidentalis (ATO) on dextran sodium sulfate (DSS)-mediated colitis in rats. UC was induced by 5% of DSS in drinking water, and the curative ability of ATO was assessed at 200mg/kg by oral administration for 10days. The effect of ATO was deduced on anti-inflammatory, preclinical features [disease activity index (DAI)], redox assays, and alterations both microscopic and macroscopic of the colonic mucosa. DSS mediated inflammation in colons of rats with a significant increase in nitric oxide, myeloperoxidase, IL-1β, IL-6, and TNF-α levels compared with a control group. Lipid peroxidation was also induced following exposure of rats to DSS. There is a marked decrease in antioxidant enzymes activities in DSS group. However, treatment with ATO markedly inhibited the colonic inflammation by reversing the elevated levels of inflammatory markers. Furthermore, ATO suppressed the lipid peroxidation chain reaction by reducing the level of malondialdehyde and hydrogen peroxide. ATO attenuates DSS-induced oxidative stress by increase the level of GSH and enhancing the activities of the cytoprotective enzymes (catalase, glutathione-S-transferase, and superoxide dismutase). Taken together, ATO reduced DAI score, inhibited inflammation, suppressed lipid peroxidation, attenuated oxidative stress, and enhanced the antioxidant enzymes activities. These therapeutic effects of ATO might be due to its phytochemicals as showed in gas chromatography-mass spectroscopy results. The findings of this study indicate that aqueous leaf extract of T. occidentalis has could be a drug candidate for the treatment of UC. PRACTICAL APPLICATIONS: The study focused on the curative ability of aqueous leaf extract of Telfairia occidentalis on dextran sodium sulfate (DSS) mediated colitis in rats. The extract elicits beneficial effects against colitis via its ability to reduce mucosal inflammation, suppress lipid peroxidation, attenuate oxidative stress, enhance the antioxidant enzymes activities, and reduce both infiltration of inflammatory cells and mucosal damage in colon. This study provides scientific evidence to the therapeutic ability of aqueous leaf extract of T. occidentalis in the treatment of DSS-induced ulcerative colitis and could be a drug candidate for the treatment of inflammatory bowel diseases in humans.

Nitric oxide protects against ferroptosis by aborting the lipid peroxidation chain reaction

Ferroptosis is a type of iron-dependent necrotic cell death, which is typically triggered by the depletion of intracellular glutathione (GSH), which is associated with increased lipid peroxidation. Nitric oxide (NO) is a highly reactive gaseous radical mediator with anti-oxidation properties that terminates lipid peroxidation reactions. In the current study, we report the anti-ferroptotic action of NOC18, an NO donor that spontaneously releases NO, in cells under various ferroptotic conditions in vitro. Our results indicate that, when mouse hepatoma Hepa 1–6 cells are incubated with NOC18, cell death induced by various ferroptotic stimuli such as cysteine (Cys) starvation, the inhibition of glutathione peroxidase 4 (GPX4) and treatment with tertiary-butyl hydroperoxide (TBHP) is significantly reduced. Treatment with NOC18 failed to improve the decrease in the levels of Cys or GSH and the accumulation of ferrous iron upon ferroptotic stimuli. The fluorescent intensity of C11-BODIPY581/591, a probe that is used to detect lipid peroxidation products, was increased somewhat by treatment with NOC18 under conditions of Cys starvation, and the accumulation of lipid peroxidation end-products, as evidenced by the levels of 4-hydroxynonenal, were effectively suppressed. The pre-incubation of TBHP with NOC7, a short-lived NO donor completely eliminated its ability to trigger ferroptosis. These collective results indicate that NO exerts a cytoprotective action against various ferroptotic stimuli by aborting the lipid peroxidation chain reaction.

Tumor-killing nanoreactors fueled by tumor debris can enhance radiofrequency ablation therapy and boost antitumor immune responses

Radiofrequency ablation (RFA) is clinically adopted to destruct solid tumors, but is often incapable of completely ablating large tumors and those with multiple metastatic sites. Here we develop a CaCO3-assisted double emulsion method to encapsulate lipoxidase and hemin with poly(lactic-co-glycolic acid) (PLGA) to enhance RFA. We show the HLCaP nanoreactors (NRs) with pH-dependent catalytic capacity can continuously produce cytotoxic lipid radicals via the lipid peroxidation chain reaction using cancer cell debris as the fuel. Upon being fixed inside the residual tumors post RFA, HLCaP NRs exhibit a suppression effect on residual tumors in mice and rabbits by triggering ferroptosis. Moreover, treatment with HLCaP NRs post RFA can prime antitumor immunity to effectively suppress the growth of both residual and metastatic tumors, also in combination with immune checkpoint blockade. This work highlights that tumor-debris-fueled nanoreactors can benefit RFA by inhibiting tumor recurrence and preventing tumor metastasis.

Nitric Oxide-elicited Resistance to Antitumor Photodynamic Therapy via Inhibition of Membrane Free Radical-mediated Lipid Peroxidation.

This review focuses on the ability of nitric oxide (NO) to antagonize antitumor photodynamic therapy (PDT). NO's anti-PDT effects were recognized relatively recently and require a better mechanistic understanding for developing new strategies to improve PDT efficacy. Many PDT sensitizers (PSs) are amphiphilic and tend to localize in membrane compartments of tumor cells. Unsaturated lipids in these compartments can undergo peroxidative degradation after PS photoactivation. Primary Type I (free radical) vs. Type II (singlet oxygen) photochemistry of lipid peroxidation is discussed, along with light-independent turnover of primary lipid hydroperoxides to free radical species. Chain lipid peroxidation mediated by the latter exacerbates membrane damage and cytotoxicity after a PDT challenge. Our studies have shown that NO from chemical donors can suppress chain peroxidation by intercepting lipid-derived free radical intermediates, thereby protecting cancer cells against photokilling. More recent evidence has revealed that inducible NO synthase (iNOS) is dramatically upregulated in several cancer cell types after a photodynamic challenge, and that iNOS-derived NO enhances resistance as well as growth and migratory aggressiveness of surviving cells. Chain breaking by NO and other possible NO-based resistance mechanisms are discussed, along with novel pharmacologic approaches for overcoming these negative effects.

Use of meglumine sodium succinate in the postoperative period in obese patients

Since the intensity of membrane-destructive phenomena largely depends on disorders of lipid metabolism, which occur in people even with a normal body mass index, for obese patients it is even more reasonable to use drugs that are able to regulate lipid metabolism in the early postoperative period. The effect of sodium succinate megluminate on the postoperative period was studied in 20 patients (7 men and 13 women) with a body mass index over 30 kg/m2 who underwent laparoscopic cholecystectomy. The age of the subjects ranged from 40 to 60 years, the body weight was from 95 to 103 kg. The patients were divided into two groups: I group consists of 10 patients who received meglumine sodium succinate in the postoperative period; II group consists of 10 patients who did not receive meglumine sodium succinate in the postoperative period. It has been shown that the use of the antioxidant meglumine sodium succinate in the treatment of patients (group I) with acute cholecystitis with obesity in the early postoperative period leads to positive clinical and laboratory dynamics (after the first dose of the drug), one of the indicators of which is a reduction in hospital stay by 2.29 bed-days. Against the background of the use of meglumine sodium succinate, the indicators of the antioxidant system increase almost several times, and the indicators of the peroxide chain reaction decrease already on the first day and have values close to normal. The use of the antioxidant meglumine sodium succinate in the complex treatment of obese patients who underwent cholecystectomy makes it possible to optimize the early postoperative period.

Method for Structural Determination of Lipid-Derived Radicals.

Diversified oxidized-lipid molecules are responsible for inflammation and cell death, including ferroptosis. Lipid radicals are the source of these oxidized lipids, which are the initial key molecules in the lipid peroxidation chain reaction. However, owing to their extremely high reactivity and short half-life, an established detection technique is not available. Here, we propose a high-performance liquid chromatography fluorometry and high-resolution tandem mass spectrometry system combined with a fluorescent probe as a structural analysis method for lipid-derived radicals. We detected 132 lipid-derived radicals, including 111 new species, from five polyunsaturated fatty acids. In addition, a database was constructed for which the initial fatty acid could be determined using the radical structure. Further, 12 endogenous lipid-derived radicals were identified in carcinogen-induced liver cancer mouse models. Therefore, this method and its corresponding database will provide novel insights into mechanisms underlying the lipid peroxidation, including the associated inflammation and ferroptosis.

Antimicrobial and antidiabetic evaluation of local flora of medicinal plants of Pakistan: A review

Pakistan has variety of medicinal herbs, shrubs, and other plants, useful to treat wide range of diseases. Medicines obtained from plants have fewer side effects and are inexpensive. Natural products obtained from the biologically active plants extract are being used to explore new antibiotics to treat infectious diseases. Plants extracts are comprised of herbal antioxidants which help to boost immunity against diabetes by inhibiting peroxidation chain reaction. Alkaloids, flavonoids, and other biologically active compounds extracted from the different parts of medicinal plants have great potential to inhibit α-glucosidase.