Reactive Quinone Research Articles

Effects of the green cross-linking agent tannic acid and its oxidation on the properties of porcine plasma protein superabsorbent materials.

Tannic acid is a natural polyphenol capable of strongly interacting with proteins, with good antioxidant and antibacterial properties. Thus, tannic acid (TA) or oxidized tannic acid (oxTA) may be used as cross-linking agents in the development of reinforced and fully protein-based superabsorbent materials (SAMs). oxTA was produced so that reactive quinone groups were generated, which are expected to increase its reactivity. In this study, porcine plasma protein (PPP) and glycerol (gly) were used in a 50/50 PPP/gly ratio to obtain SAMs through twin screw mixing and injection molding. The results showed that both TA and oxTA increased the storage modulus and the loss tangent of blends and bioplastics due to the physical interactions established between TA or oxTA and PPP. The mechanical properties, particularly the Young's modulus and tensile strength, were generally enhanced as well. Water absorption was strongly influenced by the addition of TA, resulting in a decrease in the amount of water absorbed. However, samples containing oxTA resulted in a greater water absorption capacity, retaining a higher proportion of the superabsorbent properties of the reference composition. Moreover, systems containing oxTA generally possess better mechanical properties than those of equivalent TA formulations, especially those containing 5 % and 10 % oxTA.

Electrosynthesis of Mussel-inspired Adhesive Polymers as a Novel Class of Transient Enzyme Stabilizers.

Multifunctional ortho-quinones are required for the formation of thiol-catechol-connectivities (TCC) but can be delicate to handle. We present the electrochemical oxidation of the dipeptide DiDOPA, achieving up to 92 % conversion efficiency of the catechols to ortho-quinones. Graphite and stainless steel could be employed as cost-efficient electrodes. The electrochemical activation yields quinone-solutions, which are free of undesired reactive compounds and eliminates the challenging step of isolating the reactive quinones. The DiDOPA quinones were employed in polyaddition reactions with multi-thiols, forming oligomers that functioned as transient enzyme stabilizers (TES). These TCC-TES-additives improved the thermal stability and the activity of tyrosinase in heat stress assays.

Metabolic Activation and Cytotoxicity of Donepezil Induced by CYP3A4.

Donepezil (DNP) is a selective cholinesterase inhibitor widely used for the therapy of Alzheimer's disease. Instances of liver injury correlated with DNP treatment have been reported, yet the underlying hepatotoxic mechanism remains to be elucidated. This study aimed to explore the contribution of metabolic activation to the hepatotoxicity of DNP. The structure of 6-O-desmethyl DNP (M1), the oxidative metabolite of DNP, was characterized by chemical synthesis, LC-MS/MS, and nuclear magnetic resonance. A reactive quinone methide resulting from the metabolism of DNP was captured by glutathione (GSH) fortified in liver microsomal incubations after exposure to DNP, and the resulting GSH conjugate (M2) was detected in the bile of rats receiving DNP. Recombinant human P450 enzyme incubation studies demonstrated that CYP3A4 was the principal enzyme responsible for the production of M1 and M2. The generation of M2 declined in rat primary hepatocytes pretreated with ketoconazole, an inhibitor of CYP3A4, which also decreased the vulnerability of rat primary hepatocytes to DNP-caused cytotoxicity. These findings suggest that the quinone methide metabolite may contribute to the cytotoxicity and hepatotoxicity caused by the DNP.

Polyphenol Oxidase Activity on Guaiacyl and Syringyl Lignin Units.

The natural heterogeneity of guaiacyl (G) and syringyl (S) compounds resulting from lignin processing hampers their direct use as plant-based chemicals and materials. Herein, we explore six short polyphenol oxidases (PPOs) from lignocellulose-degrading ascomycetes for their capacity to react with G-type and S-type phenolic compounds. All six PPOs catalyze the ortho-hydroxylation of G-type compounds (guaiacol, vanillic acid, and ferulic acid), forming the corresponding methoxy-ortho-diphenols. Remarkably, a subset of these PPOs is also active towards S-compounds (syringol, syringic acid, and sinapic acid) resulting in identical methoxy-ortho-diphenols. Assays with 18O2 demonstrate that these PPOs in particular catalyze ortho-hydroxylation and ortho-demethoxylation of S-compounds and generate methanol as a co-product. Notably, oxidative (ortho-)demethoxylation of S-compounds is a novel reaction for PPOs, which we propose occurs via a distinct reaction mechanism compared to aryl-O-demethylases. We further show that addition of a reducing agent can steer the PPO reaction to form methoxy-ortho-diphenols from both G- and S-type substrates rather than reactive quinones that lead to unfavorable polymerization. Application of PPOs opens for new routes to reduce the heterogeneity and methoxylation degree of mixtures of G and S lignin-derived compounds.

Polyphenol Oxidase Activity on Guaiacyl and Syringyl Lignin Units

AbstractThe natural heterogeneity of guaiacyl (G) and syringyl (S) compounds resulting from lignin processing hampers their direct use as plant‐based chemicals and materials. Herein, we explore six short polyphenol oxidases (PPOs) from lignocellulose‐degrading ascomycetes for their capacity to react with G‐type and S‐type phenolic compounds. All six PPOs catalyze the ortho‐hydroxylation of G‐type compounds (guaiacol, vanillic acid, and ferulic acid), forming the corresponding methoxy‐ortho‐diphenols. Remarkably, a subset of these PPOs is also active towards S‐compounds (syringol, syringic acid, and sinapic acid) resulting in identical methoxy‐ortho‐diphenols. Assays with 18O2 demonstrate that these PPOs in particular catalyze ortho‐hydroxylation and ortho‐demethoxylation of S‐compounds and generate methanol as a co‐product. Oxidative (ortho−) demethoxylation of S‐compounds is a novel reaction for PPOs, which we propose occurs by a distinct reaction mechanism as compared to aryl‐O‐demethylases. We further show that addition of a reducing agent can steer the PPO reaction to form methoxy‐ortho‐diphenols from both G‐ and S‐type substrates rather than reactive quinones that lead to unfavorable polymerization. Application of PPOs opens for new routes to reduce the heterogeneity and methoxylation degree of mixtures of G and S lignin‐derived compounds.

A Self-Immobilizing Photosensitizer with Long-Term Retention for Hypoxia Imaging and Enhanced Photodynamic Therapy.

The precise theranostic strategy of fluorescence imaging-guided photodynamic therapy (PDT) can effectively mitigate the adverse effect of photosensitizers in normal cells and tissues. However, low tumor enrichment and high diffusivity of photosensitizers significantly compromise the imaging accuracy and PDT effect. In this study, we have developed a nitroreductase (NTR)-activated and self-immobilizing photosensitizer CyNT-F, which showed enhanced enrichment in tumor tissues and facilitated precise and sustained imaging as well as PDT for hypoxia tumors. mPEG-b-PDPA nanomicelles encapsulating photosensitizers underwent dissociation and released CyNT-F in tumor cells. CyNT-F and NTR enzymatically reacted in situ to generate highly reactive quinone methide, subsequently covalently binding to adjacent proteins for fluorescence and PDT activation. CyNT-F exhibited longer intracellular retention (7 days) and effectively inhibited the tumor growth of solid hypoxia tumor. We believe the activatable and self-immobilizing strategy of PDT presents a novel methodology for minimizing the adverse effect and enabling spatiotemporally accurate ablation of diseased cells and tissues.

Catalytic pyrolysis mechanism of lignin moieties driven by aldehyde, hydroxyl, methoxy, and allyl functionalization: the role of reactive quinone methide and ketene intermediates.

The catalytic pyrolysis of guaiacol-based lignin monomers, vanillin, syringol, and eugenol over commercial HZSM-5 has been investigated using operando Photoelectron Photoion Coincidence (PEPICO) spectroscopy to unveil the reaction mechanism by detecting reactive intermediates, such as quinone methides and ketenes, and products. Vanillin shares the decomposition mechanism with guaiacol due to prompt and efficient decarbonylation, which allows us to control this reaction leading to a phenol selectivity increase by switching to a faujasite catalyst and decreasing the Si/Al ratio. Syringol first demethylates to 3-methoxycatechol, which mainly dehydroxylates to o- and m-guaiacol. Ketene formation channels over HZSM-5 are less important here than for guaiacol or vanillin, but product distributionremains similar. C3 addition to guaiacol yields eugenol, which shows a more complex product distribution upon catalytic pyrolysis. By analogies to monomers with simplified functionalization, namely allylbenzene, 4-allylcatechol, and 4-methylcatechol, the eugenol chemistry could be fully resolved. Previously postulated reactive semi-quinone intermediates are detected spectroscopically, and their involvement opens alternative pathways to condensation and phenol formation. Allyl groups, produced by dehydroxylation of the β-O-4 bond, may not only decompose via C1/C2/C3 loss, but also cyclize to indene and its derivatives over HZSM-5. This comparably high reactivity leads to an unselective branching of the chemistry and to a complex product distribution, which is difficult to control. Indenes and naphthalenes are also prototypical coke precursors efficiently deactivating the catalyst. We rely on these mechanistic insights to discuss strategies to fine-tune process conditions to increase the selectivities of desired products by enhancing either vanillin and guaiacol or supressing eugenol yields from native lignin.

Stimuli-Responsive mRNA Vaccines to Induce Robust CD8+ T Cell Response via ROS-Mediated Innate Immunity Boosting.

The messenger RNA (mRNA) vaccines hold great significance in contagion prevention and cancer immunotherapy. However, safely and effectively harnessing innate immunity to stimulate robust and durable adaptive immune protection is crucial, yet challenging. In this study, we synthesized a library of stimuli-responsive bivalent ionizable lipids (srBiv iLPs) with smart molecular blocks responsive to esterase, H2O2, cytochrome P450, alkaline phosphatase, nitroreductase, or glutathione (GSH), aiming to leverage physiological cues to trigger fast lipid degradation, promote mRNA translation, and induce robust antitumor immunity via reactive oxygen species (ROS)-mediated boosting. After subcutaneous immunization, esterase-responsive vaccine (eBiv-mVac) was rapidly internalized and transported into the draining lymph nodes. It then underwent fast decaging and self-immolative degradation in esterase-rich antigen-presenting cells, releasing sufficient mRNA for antigen translation and massive reactive quinone methides to elevate ROS levels. This resulted in broad activation of innate immunity to boost T cell response, prompting a large number of primed antigen-specific CD8+ T cells to circulate and infiltrate into tumors (>1000-fold versus unvaccinated control), thereby orchestrating innate and adaptive immunity to control tumor growth. Moreover, by further combining our vaccination strategy with immune checkpoint blockade, we demonstrated a synergism that significantly amplified the magnitude and function of antigen-specific CD8+ T cells. This, in turn, caused potent systemic antitumor efficacy and prolonged survival with high complete response rate in xenograft and metastasis models. Overall, our generalized stimuli-responsive mRNA delivery platform promises a paradigm shift in the design of potent vaccines for cancer immunotherapy, as well as effective and precise carriers for gene editing, protein replacement, and cell engineering.

Oxidative Stress and Dopaminergic Metabolism: A Major PD Pathogenic Mechanism and Basis of Potential Antioxidant Therapies

Reactive oxygen species (ROS)-induced oxidative stress triggers the vicious cycle leading to the degeneration of dopaminergic neurons in the nigra pars compacta. ROS produced during the metabolism of dopamine is immediately neutralized by the endogenous antioxidant defense system (EADS) under physiological conditions. Aging decreases the vigilance of EADS and makes the dopaminergic neurons more vulnerable to oxidative stress. As a result, ROS left over by EADS oxidize the dopamine-derived catechols and produces a number of reactive dopamine quinones, which are precursors to endogenous neurotoxins. In addition, ROS causes lipid peroxidation, uncoupling of the electron transport chain, and DNA damage, which lead to mitochondrial dysfunction, lysosomal dysfunction, and synaptic dysfunction. The mutations in genes such as DNAJC6, SYNJ1, SH3GL2, LRRK2, PRKN, and VPS35 caused by ROS have been associated with synaptic dysfunction and the pathogenesis of Parkinson’s disease (PD). The available drugs that are used against PD can only delay the progression of the disease, but they produce various side effects. Through their antioxidant activity, flavonoids can substantiate the EADS of dopaminergic neurons and disrupt the vicious cycle incepted by oxidative stress. In this review, we show how the oxidative metabolism of dopamine generates ROS and dopamine-quinones, which then exert unrestrained OS, causing mutations in several genes involved in the proper functioning of mitochondrion, synapse, and lysosome. Besides, we also present some examples of approved drugs used for the treatment of PD, therapies in the clinical trial phase, and an update on the flavonoids that have been tested to boost the EADS of dopaminergic neurons.

Glutathione-Responsive Polymersome with Continuous Glutathione Depletion for Enhanced Photodynamic Therapy and Hypoxia-Activated Chemotherapy.

The high glutathione (GSH) level of the tumor microenvironment severely affects the efficacy of photodynamic therapy (PDT). The current GSH depletion strategies have difficulty meeting the dual needs of security and efficiency. In this study, we report a photosensitizer Chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) coloaded cross-linked multifunctional polymersome (TPZ/Ce6@SSPS) with GSH-triggered continuous GSH depletion for enhanced photodynamic therapy and hypoxia-activated chemotherapy. At tumor sites, the disulfide bonds of TPZ/Ce6@SSPS react with GSH to realize decross-linking for on-demand drug release. Meanwhile, the generated highly reactive quinone methide (QM) can further deplete GSH. This continuous GSH depletion will amplify tumor oxidative stress, enhancing the PDT effect of Ce6. Aggravated tumor hypoxia induced by PDT activates the prodrug TPZ, resulting in an enhanced combination of PDT and hypoxia-activated chemotherapy. Both in vitro and in vivo results demonstrate the efficient GSH depletion and potent antitumor activities by TPZ/Ce6@SSPS. This work provides a strategy for the design of a continuous GSH depletion platform, which holds great promise for enhanced combination tumor therapy.

Parkinson's Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges.

The core pathological event in Parkinson's disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The reasons why SNc DA neurons are especially vulnerable and why idiopathic PD has only been found in humans are still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca2+ oscillations in the absence of the Ca2+-buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca2+ concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite the fact that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca2+ oscillations, and (3) providing bioenergetic support.

Synthesis of Benzoxazines by Heterogeneous Multicomponent Biochemo Multienzymes Cascade Reaction.

This work describes the possibility to combine multicomponent chemistry and multienzymes cascade transformations in a unique reactive framework to yield highly functionalized 1,4-benzoxazines under favorable heterogeneous conditions. The synthetic scheme involved the generation in situ of electrophilic reactive quinone intermediates of tyrosol esters catalyzed by lipase M and tyrosinase followed by nucleophilic 1,6-Michael addition of selected α-amino acid methyl esters, and successive intramolecular lactonization and aromatization processes. The immobilization of the multienzymes cascade on electroactive lignin nanoparticles improved the sustainability and recyclability of the overall system.

O-Semiquinone Radical and o-Benzoquinone Selectively Degrade Aniline Contaminants in the Periodate-Mediated Advanced Oxidation Process.

Advanced oxidation processes (AOPs) often employ strong oxidizing inorganic radicals (e.g., hydroxyl and sulfate radicals) to oxidize contaminants in water treatment. However, the water matrix could scavenge the strong oxidizing radicals, significantly deteriorating the treatment efficiency. Here, we report a periodate/catechol process in which reactive quinone species (RQS) including the o-semiquinone radical (o-SQ•-) and o-benzoquinone (o-Q) were dominant to effectively degrade anilines within 60 s. The second-order reaction rate constants of o-SQ•- and o-Q with aniline were determined to be 1.0 × 108 and 4.0 × 103 M-1 s-1, respectively, at pH 7.0, which accounted for 21% and 79% of the degradation of aniline with a periodate-to-catechol molar ratio of 1:1. The major byproducts were generated via addition or polymerization. The RQS-based process exhibited excellent anti-interference performance in the degradation of aniline-containing contaminants in real water samples in the presence of diverse inorganic ions and organics. Subsequently, we extended the RQS-based process by employing tea extract and dissolved organic matter as catechol replacements as well as metal ions [e.g., Fe(III) or Cu(II)] as periodate replacements, which also exhibited good performance in aniline degradation. This study provides a novel strategy to develop RQS-based AOPs for the highly selective degradation of aniline-containing emerging contaminants.

A versatile nano-transformer for efficient localization-specific imaging and synergistic therapy of bladder cancer

A versatile nano-transformer for efficient localization-specific imaging and synergistic therapy of bladder cancer

Sustained pigmentation causes DNA damage and invokes translesion polymerase Polκ for repair in melanocytes.

Melanin protects skin cells from ultraviolet radiation-induced DNA damage. However, intermediates of eumelanin are highly reactive quinones that are potentially genotoxic. In this study, we systematically investigate the effect of sustained elevation of melanogenesis and map the consequent cellular repair response of melanocytes. Pigmentation increases γH2AX foci, DNA abasic sites, causes replication stress and invokes translesion polymerase Polκ in primary human melanocytes, as well as mouse melanoma cells. Confirming the causal link, CRISPR-based genetic ablation of tyrosinase results in depigmented cells with low Polκ levels. During pigmentation, Polκ activates replication stress response and keeps a check on uncontrolled proliferation of cells harboring melanin-damaged DNA. The mutational landscape observed in human melanoma could in part explain the error-prone bypass of DNA lesions by Polκ, whose absence would lead to genome instability. Thereby, translesion polymerase Polκ is a critical response of pigmenting melanocytes to combat melanin-induced DNA alterations. Our study illuminates the dark side of melanin and identifies (eu)melanogenesis as a key missing link between tanning response and mutagenesis, mediated via the necessary evil translesion polymerase, Polκ.

Catecholamine Derivatives as Novel Crosslinkers for the Synthesis of Versatile Biopolymers.

Catecholamine metabolites are not only involved in primary metabolism, but also in secondary metabolism, serving a diverse array of physiologically and biochemically important functions. Melanin, which originates from dopa and dopamine, found in the hair, eye, and skin of all animals, is an important biopolymeric pigment. It provides protection against damaging solar radiation to animals. N-Acetyldopamine and N-β-alanyldopamine play a crucial role in the hardening of the exoskeletons of all insects. In addition, insects and other arthropods utilize the melanogenic process as a key component of their defense systems. Many marine organisms utilize dopyl peptides and proteins as bonding materials to adhere to various substrata. Moreover, the complex dopa derivatives that are precursors to the formation of the exoskeletons of numerous marine organisms also exhibit antibiotic properties. The biochemistry and mechanistic transformations of different catecholamine derivatives to produce various biomaterials with antioxidant, antibiotic, crosslinking, and gluing capabilities are highlighted. These reactivities are exhibited through the transient and highly reactive quinones, quinone methides, and quinone methide imine amide intermediates, as well as chelation to metal ions. A careful consideration of the reactivities summarized in this review will inspire numerous strategies for synthesizing novel biomaterials for future medical and industrial use.

Polydopamine-coated hexagonal boron nitride-based electrochemical immunosensing of T-Tau as a marker of Alzheimer's disease

Alzheimer's disease (AD) is a complex pathological process that is one of the leading causes of dementia globally. The demand for diagnostic tools that are minimally invasive, timely, and accurate is on the rise. Total tau (T-Tau) protein in blood serum is a promising biomarker for predicting early-stage AD diagnosis. In this study, the hexagonal boron nitride (HBN) based immunosensor platform was developed to detect T-Tau in artificial blood serum. After the exfoliation of HBN, its surface was coated with polydopamine (PDA) in alkaline conditions. The Anti-T-Tau was immobilized on a hydrophilic nanocomposite surface using PDA's reactive catechol and quinone groups, eliminating the need for extra crosslinkers. The working electrode surface of the screen-printed carbon electrode (SPCE) was coated with HBN-PDA nanocomposite using the drop-casting method. The biofunctional surface was created by directly immobilizing Anti-T-Tau on the HBN-PDA nanocomposite-modified SPCE. The analytical performance of the HBN-PDA/Anti-T-Tau/T-Tau immunosensor in the presence of T-Tau isoforms was determined through electrochemical measurements. The linear detection range was 1-30pg/mL with a detection limit of 0.42pg/mL for T-Tau, which is suitable for detecting T-Tau in the blood serum.

In Vitro Characterization of CYP3A4 Inhibition and Induction of Nevirapine Analogs as Substitutes in HIV Treatment

<b>Abstract ID 21354</b> <b>Poster Board 379</b> Nevirapine (NVP) is an HIV non-nucleoside reverse transcriptase inhibitor used both in the US and developing countries to treat and prevent HIV transmission in women and infants. NVP is generally well tolerated, but idiosyncratic drug reactions such as hepatotoxicity have been reported. NVP can cause drug-drug interactions (DDI) through both inhibition and induction of the cytochrome P450 (CYP) enzymes. NVP is metabolized by several CYPs, such as CYP3A4 and CYP2B6 and it also induces their expression. NVP is a mechanism-based inactivator (MBI) of CYP3A4, although the exact mechanism is still debated in the literature. One prominent hypothesis is that NVP forms a reactive quinone methide metabolite, through the 12-OH-NVP oxidation pathway, which can form adducts to CYP3A4. Previous data from our lab has demonstrated several NVP analogs have similar efficacy against the target HIV-1 reverse transcriptase compared to NVP. Our hypothesis is that a structural analog of NVP with similar efficacy but reduced toxicity could be a candidate to replace NVP by decreasing the formation of the reactive quinone methide species through the 12-OH pathway, thereby reducing DDI resulting from MBI of CYP3A4. <b>Methods:</b> We analyzed three NVP analogs and NVP for their CYP induction of mRNA and activity in primary human hepatocytes. mRNA induction was analyzed via qPCR and activity was determined using probe substrate reactions and analyzed via LC-MS. We characterized the inactivation of CYP3A4 by the top candidate NVP-d3 versus NVP. IC₅₀ shift assays, K_I/k_inact assays, and GSH incubations were performed with recombinant CYP3A4 and analyzed via LC-MS. <b>Results:</b> NVP and NVP-d3 demonstrated similar mRNA induction of CYP3A4 and CYP2B6. CYP3A4 activity was reduced from 25 μM to 100 μM for NVP, despite the increased mRNA levels. NVP-d3 demonstrated increased activity at 100 μM compared to 25 μM. The CYP3A4 IC₅₀ values with a 30 minute pre-incubation were 30.0 ± 2.8 μM (- NADPH) and 5.3 ± 1.0 μM (+NAPDH) for NVP, and 9.4 ± 1.6 μM (- NADPH) and 2.9 ± 0.4μM (+NAPDH) for NVP-d3, resulting in a shift of 5.7x for NVP and 3.2x for NVP-d3. The MBI assay resulted in a K_I of 142.4 ± 10.9 μM and k_inact of 0.103 ± 0.003 min^-1 for NVP, and a K_I of 128.0 ± 18.1 μM and k_inact of 0.079 ± 0.004 min^-1 for NVP-d3. No GSH adducts were found for NVP or NVP-d3 at the 12 position, but one likely adduct was identified at the 3 position. There was a significant difference in the metabolites produced by CYP3A4. With NVP-d3, the fold change of 12-OH metabolite formation was 0.16, while 2-OH and GSH metabolites increased by about 2 fold each. <b>Discussion and Conclusions:</b> These results demonstrate that both NVP and NVP-d3 are MBIs of CYP3A4 with important differences in metabolite profiles. NVP-d3 demonstrated lower CYP3A4 IC₅₀ and K_I values, although the difference may not be significant. Deuteration decreased the 12-OH metabolite from being formed and increased the GSH adduct formation at the 3 position, indicating reduced formation of the quinone methide reactive species at the 12 position. In rats, it was previously reported that NVP-d3 is cleared faster than NVP, indicating the induction effect may overcome inhibition, as supported by our data here. NVP-d3 may still be a candidate to replace NVP in the future, but pharmacokinetics need to be evaluated if decreasing the MBI of CYP3A4 is leading to increased clearance. This work was supported by the NIH, NIAID Award Number R01 AI150494 (JNL).

Toward anthelmintic drug candidates for toxocariasis: Challenges and recent developments.

Infections caused by parasitic helminths rank among the most prevalent infections of humans and animals. Toxocariasis, caused by nematodes of the genus Toxocara, is one of the most widespread and economically important zoonotic parasitic infections that humans share with dogs and cats. Despite the completion of the Toxocara canis draft genome project, which has been an important step towards advancing the understanding of this parasite and the search for drug targets, the treatment of toxocariasis has been dependent on a limited set of drugs, necessitating the search for novel anthelmintic agents, specially against Toxocara larvae in tissues. Given that research, development, and innovation are crucial to finding appropriate solutions in the fight against helminthiasis, this paper reviews the progress made in the discovery of anthelmintic drug candidates for toxocariasis. The main compounds reported in the recent years regards on analogues of albendazole, reactive quinone derivatives and natural produts and its analogues. Nanoparticles and formulations were also reviewed. The in vitro and/or in vivo anthelmintic properties of such alternatives are herein discussed as well as the opportunities and challenges for treatment of human toxocariasis. The performed review clarify that the scarcity of validated molecular targets and limited chemical space explored are the main bottlenecks for advancing in the field of anti-Toxocara agents.

Oxidative Stress and Neuroinflammation in Parkinson's Disease: The Role of Dopamine Oxidation Products.

Parkinson's disease (PD) is a chronic neurodegenerative condition affecting more than 1% of people over 65 years old. It is characterized by the preferential degeneration of nigrostriatal dopaminergic neurons, which is responsible for the motor symptoms of PD patients. The pathogenesis of this multifactorial disorder is still elusive, hampering the discovery of therapeutic strategies able to suppress the disease's progression. While redox alterations, mitochondrial dysfunctions, and neuroinflammation are clearly involved in PD pathology, how these processes lead to the preferential degeneration of dopaminergic neurons is still an unanswered question. In this context, the presence of dopamine itself within this neuronal population could represent a crucial determinant. In the present review, an attempt is made to link the aforementioned pathways to the oxidation chemistry of dopamine, leading to the formation of free radical species, reactive quinones and toxic metabolites, and sustaining a pathological vicious cycle.