Amplification of Oxygen-Independent Free Radicals Based on a Glutathione Depletion and Biosynthesis Inhibition Strategy for Photothermal and Thermodynamic Therapy of Hypoxic Tumors.

Thermodynamic therapy (TDT) based on oxygen-independent free radicals exhibits promising potential for the treatment of hypoxic tumors. However, its therapeutic efficacy is seriously limited by the premature release of the drug and the free radical scavenging effect of glutathione (GSH) in tumors. Herein, we report a GSH depletion and biosynthesis inhibition strategy using EGCG/Fe-camouflaged gold nanorod core/ZIF-8 shell nanoparticles embedded with azo initiator 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH) and L-buthionine-sulfoximine (BSO) for tumor-targeting photothermal (PTT) and thermodynamic therapy (TDT). This nanoplatform (GNR@ZIF-8-AIPH/BSO@EGCG/Fe, GZABEF) endows a pH-responsive release performance. With the 67 kDa lamin receptor (67LR)-targeting ability of EGCG, GZABEF could selectively release oxygen-independent free radicals in tumor cells under 1064 nm laser irradiation. More importantly, Fe3+-mediated GSH depletion and BSO-mediated GSH biosynthesis inhibition significantly boosted the accumulation of alkyl radicals. In 4T1 cells, GZABEF induced cancer cell death via intracellular GSH depletion and GSH peroxidase 4 (GPX4) inactivation. In a subcutaneous xenograft model of 4T1, GZABEF demonstrated remarkable tumor growth inhibition (78.2%). In addition, excellent biosafety and biocompatibility of GZABEF were observed both in vitro and in vivo. This study provides inspiration for amplified TDT/PTT-mediated antitumor efficacy.

Application of electron paramagnetic resonance spectroscopy for determining the relative nanoenvironment fluidity of polymeric micelles.

Polymeric micelles are nanocarriers for drug, protein and gene delivery due to their unique core/shell structure, which encapsulates and protects therapeutic cargos with diverse physicochemical properties. However, information regarding the micellar nanoenvironment's fluidity can provide unique insight into their makeup. In this study, we used electron paramagnetic resonance (EPR) spectroscopy to study free radical spin probe (5-doxylstearate methyl ester, 5-MDS, and 16-doxylstearic acid, 16-DS) behaviour in methoxy-poly(ethylene oxide)-poly(α-benzyl carboxylate-ε-caprolactone) (PEO-PBCL) and methoxy-poly(ethylene oxide)-poly(ε-caprolactone) (PEO-PCL) polymeric micelles. Spin probes provided information about the spectroscopic rotational correlation time (τ, s) and the spectroscopic partition parameter F. We hypothesized that spin probes would partition into the polymeric micelles, and these parameters would be calculated. The results showed that both 5-MDS and 16-DS spectra were modulated in the presence of polymeric micelles. Based on τ values, 5-MDS revealed that PEO-PCL (τ = 3.92 ± 0.26 × 10-8 s) was more fluid than PEO-PBCL (τ = 7.15 ± 0.63 × 10-8 s). The F parameter, however, could not be calculated due to the rotational hindrance of the probe within the micelles. With 16-DS, more probe rotation was observed, and although the F parameter could be calculated, it was not helpful to distinguish the micelles' fluidity. Also, doxorubicin-loading interfered with the spin probes, particularly for 16-DS. However, using simulations, we could distinguish the hydrophilic and hydrophobic components of the 16-DS probe. The findings suggest that EPR spectroscopy is a valuable method for determining core fluidity in polymeric micelles.

Alpha-lipoic Acid: An Antioxidant with Anti-Aging Properties for Disease Therapy.

The anti-aging effects of alpha-lipoic acid (αLA), a natural antioxidant synthesized in human tissues, have attracted a growing interest in recent years. αLA is a short- -chain sulfur-containing fatty acid occurring in the mitochondria of all kinds of eukaryotic cells. Both the oxidized disulfide of αLA and its reduced form (dihydrolipoic acid, DHLA) exhibit prominent antioxidant function. The amount of αLA inside the human body gradually decreases with age resulting in various health disorders. Its lack can be compensated by supplying from external sources such as dietary supplements or medicinal dosage forms. The primary objectives of this study were the analysis of updated information on the latest two-decade research regarding the use of αLA from an anti-aging perspective. The information was collected from PubMed, Wiley Online Library, Scopus, ScienceDirect, SpringerLink, Google Scholar, and clinicaltrials.gov. Numerous in silico, in vitro, in vivo, and clinical studies revealed that αLA shows a protective role in biological systems by direct or indirect reactive oxygen/nitrogen species quenching. αLA demonstrated beneficial properties in the prevention and treatment of many age-related disorders such as neurodegeneration, metabolic disorders, different cancers, nephropathy, infertility, and skin senescence. Its preventive effects in case of Alzheimer's and Parkinson's diseases are of particular interest. Further mechanistic and clinical studies are highly recommended to evaluate the wide spectrum of αLA therapeutic potential that could optimize its dietary intake for prevention and alleviation disorders related to aging.

Free Radical Lipid Peroxidation Induced by Reactive Halogen Species.

The review is devoted to the mechanisms of free radical lipid peroxidation (LPO) initiated by reactive halogen species (RHS) produced in mammals, including humans, by heme peroxidase enzymes, primarily myeloperoxidase (MPO). It has been shown that RHS can participate in LPO both in the initiation and branching steps of the LPO chain reactions. The initiation step of RHS-induced LPO mainly involves formation of free radicals in the reactions of RHS with nitrite and/or with amino groups of phosphatidylethanolamine or Lys. The branching step of the oxidative chain is the reaction of RHS with lipid hydroperoxides, in which peroxyl and alkoxyl radicals are formed. The role of RHS-induced LPO in the development of human inflammatory diseases (cardiovascular and neurodegenerative diseases, cancer, diabetes, rheumatoid arthritis) is discussed in detail.

Doxorubicin conjugates: a practical approach for its cardiotoxicity alleviation.

INTRODUCTION: Doxorubicin (DOX) emerges as a cornerstone in the arsenal of potent chemotherapeutic agents. Yet, the clinical deployment of DOX is tarnished by its proclivity to induce severe cardiotoxic effects, culminating in heart failure and other consequential morbidities. In response, a panoply of strategies has undergone rigorous exploration over recent decades, all aimed at attenuating DOX's cardiotoxic impact. The advent of encapsulating DOX within lipidic or polymeric nanocarriers has yielded a dual triumph, augmenting DOX's therapeutic efficacy while mitigating its deleterious side effects. AREAS COVERED: Recent strides have spotlighted the emergence of DOX conjugates as particularly auspicious avenues for ameliorating DOX-induced cardiotoxicity. These conjugates entail the fusion of DOX through physical or chemical bonds with diminutive natural or synthetic moieties, polymers, biomolecules, and nanoparticles. This spectrum encompasses interventions that impinge upon DOX's cardiotoxic mechanism, modulate cellular uptake and localization, confer antioxidative properties, or refine cellular targeting. EXPERT OPINION: The endorsement of DOX conjugates as a compelling stratagem to mitigate DOX-induced cardiotoxicity resounds from this exegesis, amplifying safety margins and the therapeutic profile of this venerated chemotherapeutic agent. Within this ambit, DOX conjugates stand as a beacon of promise in the perpetual pursuit of refining chemotherapy-induced cardiac compromise.

Harmful Free Radicals in Aging: A Narrative Review of Their Detrimental Effects on Health.

The production of harmful free radicals (H-FRs), especially those with oxygen or nitrogen atoms, depends on both internal and environmental causes. The negative effects of H-FRs are greatly alleviated by antioxidant protection. The harmful impact of oxidative stress, or OS, is brought on by a disparity between the defense mechanisms of the body and the creation of H-FRs. Aging is characterized by a slow decline in tissue and organ competence. Age-mediated pathologies start as an aberrant accumulation of H-FRs, which inhibit cells' capacity to divide, repair, and operate, based on the OS theorem of aging. The natural outcome of this situation is apoptosis. These conditions may include skeletal muscle dysfunction, cancer, cardiovascular, chronic hepatitis, chronic renal, and chronic pulmonary disorders. Given the substantial role that OS plays in the progression of many of these illnesses, antioxidant-based therapy may have a favorable impact on how these diseases progress. To ascertain the true efficacy of this therapy strategy, more research is necessary. The aim of this study is to provide an overview of the literature on this challenging issue that is attracting interest.

A Novel Therapeutic Approach of 980 nm Photobiomodulation Delivered with Flattop Beam Profile in Management of Recurrent Aphthous Stomatitis in Paediatrics and Adolescents-A Case Series with 3-Month Follow-Up.

Background/Objectives: Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal lesions and a very debilitating lesion, especially in paediatric and adolescent patients. The current pharmacotherapy offers a pain relief but not without side effects, and therefore photobiomodulation (PBM) can be an alternative therapy. To the authors' best knowledge, no published study has explored the efficacy of λ 980 nm laser PBM in the management of all RAS subtypes in paediatric and adolescent patients, and therefore, this prospective observational clinical study was conducted to bridge this gap by evaluating λ 980 nm laser PBM efficacy in symptomatic RAS management in paediatric and adolescent patients. The objectives were to evaluate (1) pain intensity alleviation; (2) wound healing rate; (3) wound size closure; (4) a complete resolution; (5) evidence of recurrence; and (6) patients' treatment satisfaction. Methods: The study's variables were assessed at the following timepoints: T0: pre-treatment; T1: immediately after first PBM session; T2: 5 hours (h) post first PBM session (via telephone call); T3: immediately after second PBM session (three days post first PBM session); T4: three-day follow-up (after complete PBM treatments); T5: two-week follow-up; and T6: three-month follow-up. The following PBM dosimetry and treatment protocols were employed: λ 980 nm; 300 mW; 60 s; 18 J; CW; flattop beam profile of 1 cm2 spot size; 18 J/cm2; and twice-a-week irradiation (72 h interval). Results: At T1, significant immediate pain intensity relief was reported. 33.33% recorded "4" and 66.67% reported "5" on the quantitative numeric pain intensity scale (NPIS), and this continued to improve significantly (83.33%) at T2. All the subjects reported "0" on the NPIS at T3, T4, T5 and T6. There was a significant reduction in the lesion surface area (>50% complete healing) at T3 compared to T0. Complete healing (100%) with no evidence of scarring and lesion recurrence observed at T4, T5 and T6. Very good patients' satisfaction was reported at all timepoints. Conclusions: This is the first report demonstrating λ980 nm efficacy in all RAS subtype management in paediatric and adolescent patients with a 3-month follow-up, whereby its PBM dosimetry and treatment protocols were effective from scientific and practical standpoints, and hence multicentre RCTs with large data are warranted to validate its reproducibility and to enrich the knowledge of PBM application in all RAS subtypes.

CYTOTOXICITY AND BIOLOGICAL ACTIVITIES OF GEOPOPOLIS EXTRACT FROM THE STINGLESS BEE (Melipona scutellaris) IN CLINICAL ISOLATES OF Staphylococcus aureus.

This work aims to evaluate the biological activities of the EEGP, in order to contribute with a natural therapeutic alternative, to face infections. The EEGP MIC tests showed antibacterial activity against two strains of S. aureus (LPM 63 and LPM 86), both at concentrations of 550 µg/mL. The MBC performed with the inhibition values showed that the EEGP has bacteriostatic activity in both strains. Biofilm inhibition rates exhibited an average value greater than 65% at the highest concentration. The EEGP antioxidant potential test showed good antioxidant activity (IC50) of 11.05 ± 1.55 µg/mL. In the cytotoxicity test against HaCat cells, after 24 hours, EEGP induced cell viability at the three tested concentrations (550 µg/mL: 81.68 ± 3.79%; 1100 µg/mL: 67.10 ± 3.76 % ;2200 µg/mL: 67.40 ± 1.86%). In view of the above, the safe use of EEGP from the brazilian northeast could be proven by the cytotoxicity test, and its use as an antioxidant and antibacterial agent has proven to be effective, as an alternative in combating oxidative stress and microorganisms such as S. aureus, which, through the spread and ongoing evolution of drug resistance, generates an active search for effective solutions.

Influence of microplastics and environmentally persistent free radicals on the ability of biochar components to promote degradation of antibiotics by activated peroxymonosulfate.

Microplastics (MPs) in sludge can affect the ability of biochar-activated peroxymonosulfate (PMS) to degrade antibiotics. In this work, biochar was prepared by mixing sludge and polystyrene (PS) through hydrothermal carbonization (HTC) and high-temperature pyrolysis processes. The resulting biochar was used to activate PMS to degrade ofloxacin (OFX), levofloxacin (LEV), and pefloxacin (PFX). The addition of PS significantly enhanced the ability of biochar/PMS to degrade antibiotics and the levels of environmentally persistent free radicals (EPFRs, 4.59 × 1020 spin/g) due to the decomposition of PS. The addition of PS resulted in a slight decrease in the specific surface area of biochar (2-3 m2/g on average), but a significant increase in the concentration of EPFRs increased the removal efficiency. The activation of PMS by biochar is dominated by free radicals, accounting for about 70%, in which SO4•- and •OH contribute the most and O2•- the least. However, 1O2 contributes 15-20% to the degradation of antibiotics in non-free radical processes. Overall, the process of biochar/PMS degradation of antibiotics is mainly dominated by free radicals, and the effect of non-free radicals is not obvious. Both hydrochar and pyrocarbon samples showed good hydrophilicity, and this property should improve the ability of active sites on biochar to degrade antibiotics. In the HTC process, PS can decompose during hydrochar preparation, with a maximum reduction value of 40.09%. The three-dimension excitation emission matrix fluorescence spectroscopy (3D-EEM) and total organic carbon (TOC) results show that the protein content in sludge plays a major role in reducing PS, with little effect of polysaccharide and SiO2. There are six to seven degradation intermediates of quinolone antibiotics, which are eventually degraded into CO2, H2O, and inorganic substances. The regeneration experiment showed good reusability of hydrochar and pyrocarbon, further demonstrating the suitability of biochar for the degradation of antibiotics.

Serum testosterone levels and oxidative stress in type 1 diabetes, type 2 diabetes, and obesity.

INTRODUCTION: Obesity, type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM) are metabolic diseases that continue to be a global problem. Testosterone levels in men are affected by several factors, including obesity and DM. Although the relationship between diabetes and testosterone is not fully understood, oxidative stress is thought to play a major role. The aim of this study was to compare serum testosterone levels and oxidative stress markers [total antioxidant status (TAS), total oxidant capacity (TOS), oxidative stress index (OSI), and ischaemic modified albumin (IMA)] among the control group and experimentally induced obese, T1DM, and T2DM rats. MATERIAL AND METHODS: The study included 28 male Sprague-Dawley rats divided into 4 groups: the obesity group were fed a high-fat diet (HFD), the T2DM group received a HFD plus a single dose of streptozocin (STZ), the T1DM group received only STZ, and there was a control group. Serum testosterone, TAS, TOS, OSI, and IMA were analysed. RESULTS: Serum testosterone levels were lower in the T1DM and T2DM groups compared to the control and obesity groups. The TOS levels were highest in the T2DM group, followed by the T1DM group, the obesity group, and finally the control group. No significant difference was found between the obesity group and the control group in terms of TOS levels. Regarding TAS levels, the order observed was control group > obesity group > T2DM > T1DM. Testosterone was positively correlated with TAS and negatively correlated with TOS and OSI. CONCLUSIONS: Increased oxidative stress in diabetes may be an important factor that decreases serum testosterone levels.

Investigating environmentally persistent free radicals (EPFRs) emissions of 3D printing process.

In recent years, the emission of particles and gaseous pollutants from 3D printing has attracted much attention due to potential health risks. This study investigated the generation of environmentally persistent free radicals (EPFRs, organic free radicals stabilized on or inside particles) in total particulate matter (TPM) released during the 3D printing process. Commercially available 3D printer filaments, made of acrylonitrile-butadiene-styrene (ABS) in two different colors and metal content, ABS-blue (19.66 µg/g Cu) and ABS-black (3.69 µg/g Fe), were used for printing. We hypothesized that the metal content/composition of the filaments contributes not only to the type and number of EPFRs in TPM emissions, but also impacts the overall yield of TPM emissions. TPM emissions during printing with ABS-blue (11.28 µg/g of printed material) were higher than with ABS-black (7.29 µg/g). Electron paramagnetic resonance (EPR) spectroscopy, employed to measure EPFRs in TPM emissions of both filaments, revealed higher EPFR concentrations in ABS-blue TPM (6.23 × 1017 spins/g) than in ABS-black TPM (9.72 × 1016 spins/g). The presence of copper in the ABS-blue contributed to the formation of mostly oxygen-centered EPFR species with a g-factor of ~2.0041 and a lifetime of 98 days. The ABS-black EPFR signal had a lower g-factor of ~2.0011, reflecting the formation of superoxide radicals during the printing process, which were shown to have an "estimated tentative" lifetime of 26 days. Both radical species (EPFRs and superoxides) translate to a potential health risk through inhalation of emitted particles.

Exploring the Mechanism of Acupuncture's Influence on the Protease Activity and Free Radical Damage in Synovial Fluid of Rheumatoid Arthritis Rats Induced by Type II Collagen from the Release of Active Oxygen.

Acupuncture was studied to investigate the mechanism of its effect on protease vitality and free radical damage in Type I CIA rats induced by type II collagen. The study divided rats into a control group (injected with physiological saline, n = 10), a model group (injected with type II collagen, n = 10), and an intervention group (injected with type II collagen + acupuncture ST36 and GB39, 3 times a week, for a total of 4 weeks, n = 10) based on the different injected drugs. Then, various indicators of the mice were experimentally tested using joint index scoring, H&E histological staining, protein blotting, and immunohistochemistry staining methods. Acupuncture ST36 and GB39 can reduce arthritis scores, histological staining scores, and increase MVD in CIA rats. And reduce protease levels, alleviate inflammation, synovial hyperplasia, and angiogenesis. In addition, the intervention group TNF-α, IL-1ß and IL-6 mRNA were reduced, and the clearance rates of hydrogen peroxide free radicals and nitric oxide free radicals were increased. The expression levels of ROS and MDA decrease, while the expression levels of SOD increase It has been proved that acupuncture at ST36 and GB39 can inhibit the release of ROS, reduce protease activity, inflammation, synovial hyperplasia, angiogenesis and free radical damage, thus reducing the severity of CIA (Collagen-Induced Arthritis) in rats.

Antioxidant Activity, Inhibition of Intestinal Cancer Cell Growth and Polyphenolic Compounds of the Seagrass Posidonia oceanica's Extracts from Living Plants and Beach Casts.

The aim of the present study was to investigate the use of Posidonia oceanica for making products beneficial for human health. Firstly, we demonstrated that the antioxidant defense (i.e., SOD and APX activity) of P. oceanica's living leaves (LP) has low efficacy, as they partly neutralize the produced H2O2. However, high H2O2 levels led LP to produce, as a response to oxidative stress, high phenolic content, including chicoric acid, p-coumaric acid, caftaric acid, trans-cinnamic and rutin hydrate, as shown by UHPLC-DAD analysis. In addition, LP extracts inhibited intestinal cancer cell proliferation. Moreover, P. oceanica's beach casts consisting of either Wet 'Necromass' (WNP) or Dry 'Necromass' (DNP) were used for preparing extracts. Both DNP and WNP exhibited antioxidant and antiproliferative activities, although lower as compared to those of LP extracts. Although both P. oceanica's meadows and beach casts are considered priority habitats in the Mediterranean Sea due to their high ecological value, legislation framework for beach casts forbidding their removal is still missing. Our results suggested that both LP and DNP could be utilized for the production of high-added value products promoting human health, provided that a sustainability management strategy would be applied for P. oceanica's meadows and beach casts.

Implications of COVID-19 in Parkinson's disease: the purinergic system in a therapeutic-target perspective to diminish neurodegeneration.

The pathophysiology of Parkinson's disease (PD) is marked by degeneration of dopaminergic neurons in the substantia nigra. With advent of COVID-19, which is closely associated with generalized inflammation and multiple organ dysfunctions, the PD patients may develop severe conditions of disease leading to exacerbated degeneration. This condition is caused by the excessive release of pro-inflammatory markers, called cytokine storm, that is capable of triggering neurodegenerative conditions by affecting the blood-brain barrier (BBB). A possible SARS-CoV-2 infection, in serious cases, may compromise the immune system by triggering a hyperstimulation of the neuroimmune response, similar to the pathological processes found in PD. From this perspective, the inflammatory scenario triggers oxidative stress and, consequently, cellular dysfunction in the nervous tissue. The P2X7R seems to be the key mediator of the neuroinflammatory process, as it acts by increasing the concentration of ATP, allowing the influx of Ca2+ and the occurrence of mutations in the α-synuclein protein, causing activation of this receptor. Thus, modulation of the purinergic system may have therapeutic potential on the effects of PD, as well as on the damage caused by inflammation of the BBB, which may be able to mitigate the neurodegeneration caused by diseases. Considering all the processes of neuroinflammation, oxidative stress, and mitochondrial dysfunction that PD propose, we can conclude that the P2X7 antagonist acts in the prevention of viral diseases, and it also controls purinergic receptors formed by multi-target compounds directed to self-amplification circuits and, therefore, may be a viable strategy to obtain the desired disease-modifying effect. Thus, purinergic system receptor modulations have a high therapeutic potential for neurodegenerative diseases such as PD.

Oxidative Stress: The Role of Antioxidant Phytochemicals in the Prevention and Treatment of Diseases.

Oxidative stress, characterized by an imbalance favouring oxidants over antioxidants, is a key contributor to the development of various common diseases. Counteracting these oxidants is considered an effective strategy to mitigate the levels of oxidative stress in organisms. Numerous studies have indicated an inverse correlation between the consumption of vegetables and fruits and the risk of chronic diseases, attributing these health benefits to the presence of antioxidant phytochemicals in these foods. Phytochemicals, present in a wide range of foods and medicinal plants, play a pivotal role in preventing and treating chronic diseases induced by oxidative stress by working as antioxidants. These compounds exhibit potent antioxidant, anti-inflammatory, anti-aging, anticancer, and protective properties against cardiovascular diseases, diabetes mellitus, obesity, and neurodegenerative conditions. This comprehensive review delves into the significance of these compounds in averting and managing chronic diseases, elucidating the key sources of these invaluable elements. Additionally, it provides a summary of recent advancements in understanding the health benefits associated with antioxidant phytochemicals.

Oxidative Stress and Bio-Regulation.

Reactive oxygen species (ROS) and free radicals work to maintain homeostasis in the body, but their excessive production causes damage to the organism. The human body is composed of a variety of cells totaling over 60 trillion cells. Each cell performs different functions and has a unique lifespan. The lifespan of cells is preprogrammed in their genes, and the death of cells that have reached the end of their lifespan is called apoptosis. This is contrary to necrosis, which is the premature death of cells brought about by physical or scientific forces. Each species has its own unique lifespan, which in humans is estimated to be up to 120 years. Elucidating the mechanism of the death of a single cell will lead to a better understanding of human death, and, conversely, the death of a single cell will lead to exploring the mechanisms of life. In this sense, research on active oxygen and free radicals, which are implicated in biological disorders and homeostasis, requires an understanding of both the physicochemical as well as the biochemical aspects. Based on the discussion above, it is clear to see that active oxygen and free radicals have dual functions of both injuring and facilitating homeostasis in living organisms.

Upregulation of NADPH-oxidase, inducible nitric oxide synthase and apoptosis in the hippocampus following impaired insulin signaling in the rats: Development of sporadic Alzheimer's disease.

NADPH-oxidase (NOX) is a multi-subunit enzyme complex. The upregulation of NOX causes massive production of superoxide (O2¯), which avidly reacts with nitric oxide (NO) and increases cellular reactive oxygen/nitrogen species (ROS/RNS). Increased ROS/RNS plays pivotal role in the sporadic Alzheimer's disease (sAD) development and brain damage following impaired insulin signaling. Hence, this study aimed to examine early-time course of changes in NOX and NOS expression, and apoptotic proteins in the rats hippocampi following insulin signaling impairment [induced by STZ injection; intraperitoneal (IP) or in cerebral ventricles (ICV)]. Early effects (1, 3, or 6 weeks) on the NOX activity, translocation of NOX subunits from cytosol to the membrane, NO-synthases [neuronal-, inducible- and endothelial-NOS; nNOS, iNOS and eNOS], The Rac-1 protein expression, levels of NO and O2¯, cytochrome c release, caspase-3 and 9 activations (cleavage) were studied. STZ injection (in both models) increased NOX activity, O2¯ production, and enhanced cytosolic subunits translocation into membrane. The iNOS but not nNOS and eNOS expression and NO levels were increased in STZ treated rats. Finally, STZ injection increased cytochrome c release, caspase-3 and 9 activations in a manner that was significantly associated with levels of O2¯ and NO in the hippocampus. ICV-STZ administration resulted in significant profound changes over the IP route. In conclusion, impairment in insulin function induces early changes in ROS/RNS contents through NOX and iNOS upregulation and neuronal apoptosis in the hippocampus. Our results could mechanistically explain the role of impaired insulin function in the development of sAD.

Unravelling the Role of Free Radicals in Photocatalysis.

Free radicals are increasingly recognized as active intermediate reactive species that can participate in various redox processes, significantly influencing the mechanistic pathways of reactions. Numerous researchers have investigated the generation of one or more distinct photogenerated radicals, proposing various hypotheses to explain the reaction mechanisms. Notably, recent research has demonstrated the emergence of photogenerated radicals in innovative processes, including organic chemical reactions and the photocatalytic dissolution of precious metals. To harness the potential of these free radicals more effectively, it is imperative to consolidate and analyze the processes and action modes of these photogenerated radicals. This conceptual paper delves into the latest advancements in understanding the mechanics of photogenerated radicals.

The white rot basidiomycete Gelatoporia subvermispora produces fatty aldehydes that enable fungal manganese peroxidases to degrade recalcitrant lignin structures.

The ability of some white rot basidiomycetes to remove lignin selectively from wood indicates that low molecular weight oxidants have a role in ligninolysis. These oxidants are likely free radicals generated by fungal peroxidases from compounds in the biodegrading wood. Past work supports a role for manganese peroxidases (MnPs) in the production of ligninolytic oxidants from fungal membrane lipids. However, the fatty acid alkylperoxyl radicals initially formed during this process are not reactive enough to attack the major structures in lignin. Here, we evaluate the hypothesis that the peroxidation of fatty aldehydes might provide a source of more reactive acylperoxyl radicals. We found that Gelatoporia subvermispora produced trans-2-nonenal, trans-2-octenal, and n-hexanal (a likely metabolite of trans-2,4-decadienal) during the incipient decay of aspen wood. Fungal fatty aldehydes supported the in vitro oxidation by MnPs of a nonphenolic lignin model dimer, and also of the monomeric model veratryl alcohol. Experiments with the latter compound showed that the reactions were partially inhibited by oxalate, the chelator that white rot fungi employ to detach Mn3+ from the MnP active site, but nevertheless proceeded at its physiological concentration of 1 mM. The addition of catalase was inhibitory, which suggests that the standard MnP catalytic cycle is involved in the oxidation of aldehydes. MnP oxidized trans-2-nonenal quantitatively to trans-2-nonenoic acid with the consumption of one O2 equivalent. The data suggest that when Mn3+ remains associated with MnP, it can oxidize aldehydes to their acyl radicals, and the latter subsequently add O2 to become ligninolytic acylperoxyl radicals.IMPORTANCEThe biodegradation of lignin by white rot fungi is essential for the natural recycling of plant biomass and has useful applications in lignocellulose bioprocessing. Although fungal peroxidases have a key role in ligninolysis, past work indicates that biodegradation is initiated by smaller, as yet unidentified oxidants that can infiltrate the substrate. Here, we present evidence that the peroxidase-catalyzed oxidation of naturally occurring fungal aldehydes may provide a source of ligninolytic free radical oxidants.

3-bromopyruvate induces morphological alteration and may initiate programmed cell death in Cryptococcus neoformans cells.

3-Bromopyruvate (3BP), known for its potent anticancer properties, also exhibits remarkable efficacy against the pathogenic fungus Cryptococcus neoformans. So far it has been proven that the main fungicidal activity of 3BP is based on ATP depletion and a reduction of intracellular level of glutathione. The presented study includes a broad range of methods to further investigate the mechanistic effects of 3BP on C. neoformans cells. The use of flow cytometry allowed a thorough examination of their survival during 3BP treatment, while observations using electron microscopy made it possible to note the changes in cellular morphology. Utilizing ruthenium red, the study suggests a mitochondrial pathway may initiate programmed cell death in response to 3BP. Analysis of free radical generation and gene expression changes supports this hypothesis. These findings enhance comprehension of 3BP's mechanisms in fungal cells, paving the way for its potential application as a therapeutic agent against cryptococcosis.