Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity.

The crystallographic structure of the FolB enzyme from Mycobacterium tuberculosis (MtFolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as in vitro inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of MtFolB. These compounds exhibited IC50 values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the M. tuberculosis H37Rv strain were evaluated. Compound 3e exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound 3e showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting MtFolB, an attractive molecular target for TB drug development.

Controlled Pyrazole-Hydrazone Annulation: Regiodivergent Synthesis of 1H- and 2H-Pyrazolo[3,4-d]pyridazinones.

An efficient and controlled site-selective annulation of 3,5-diethoxycarbonyl 4-hydrazonyl pyrazoles is described. The relative proportion of the products is affected by hydrazone intermediate configuration, reaction temperature, and Lewis acid employed. At a temperature of 110-120 °C, the reaction preferentially afforded 1H-pyrazolo[3,4-d]pyridazin-7(6H)-ones, whereas using Yb(OTf)3 in MeCN reflux, 2H-pyrazolo[3,4-d]pyridazin-7(6H)-ones were favored. Computational investigations were performed to clarify the mechanism and the origin of the regiodivergence.

Pesticides analysis in alternative biological matrices.

This review aims to bring together the works on pesticide analysis in alternative biological matrices, such as hair, breast milk, meconium, and placenta. Much is known about the harmful effects of the use and indirect consumption of pesticides; however, the assessment of long-term contamination is still unclear. In this sense, the use of hair as an alternative biological matrix has some advantages, such as segmentation, which makes it possible to assess the presence of xenobiotics to which individuals have been exposed over the years, and possibly relate this exposure to symptoms or diseases that may affect them. Complementarily, the other matrices discussed are able to provide information about the exposure of mothers and newborn children, who may have been indistinctly exposed to pesticides while in the womb. Through the analysis of studies already performed, it can be observed that organochlorine pesticides (OCPs) are the most likely to be found within the biological matrices discussed here, due to the lipophilic characteristics of these compounds. For the other classes, biotransformation products are more easily detected.

Four almost unexplored species of Brazilian Connarus (Connaraceae): Chemical composition by ESI-QTof-MS/MS-GNPS and a pharmacologic potential.

INTRODUCTION: Species of Connaraceae are globally used in traditional medicines. However, several of these have not been studied regarding their chemical composition, and some are even at risk of extinction without proper studies. Therefore, the chemical composition and pharmacological potential of Connarus blanchetii Planch., Connarus nodosus Baker, Connarus regnellii G. Schellenb., and Connarus suberosus Planch., which were previously unknown, were analyzed. OBJECTIVE: This work aims to investigate the pharmacological potential of these four Connarus species. The chemical composition of different extracts was determined by high-resolution mass spectrometry (HRMS), with subsequent analysis by the GNPS platform and competitive fragmentation modeling (CFM). MATERIALS AND METHODS: Leaf extracts (C. blanchetii, C. nodosus, C. regnellii, and C. suberosus) and bark extracts (C. regnellii and C. suberosus) were obtained by decoction, infusion, and maceration. LC/HRMS data were submitted to the GNPS platform and evaluated using CFM in order to confirm the structures. RESULTS: The HRMS-GNPS/CFM analysis indicated the presence of 23 compounds that were mainly identified as phenolic derivatives from quercetin and myricetin, of which 21 are unedited in the Connarus genus. Thus, from the analyses performed, we can identify different compounds with pharmacological potential, as well as the most suitable forms of extraction. CONCLUSION: Using HRMS-GNPS/CFM, 21 unpublished compounds were identified in the studied species. Therefore, our combination of data analysis techniques can be used to determine their chemical composition.

Synthesis of N-phenyl- and N-thiazolyl-1H-indazoles by copper-catalyzed intramolecular N-arylation of ortho-chlorinated arylhydrazones.

The broad application of 1H-indazoles has prompted the development of several approaches for the synthesis of such compounds, including metal-free, palladium-, or copper-promoted intramolecular N-arylation of in situ-generated or isolated o-haloarylhydrazones. Such methods mainly start from o-bromo derivatives due to the better yield observed when compared to those obtained from o-chloroarylhydrazones. However, the o-chloroarylaldehydes and o-chloroarylketones used to prepare the arylhydrazones are more commercially available and less expensive than brominated analogs. Seeking to cover a lack in the literature, this work reports a convenient protocol for the synthesis of N-phenyl- and N-thiazolyl-1H-indazoles by copper-catalyzed intramolecular N-arylation of o-chlorinated arylhydrazones. Therefore, a series of seven N-phenyl derivatives and a series of six novel N-thiazolyl derivatives was obtained in 10-70% and 12-35% yield, respectively, after stirring the o-chlorinated arylhydrazones, CuI, KOH, and 1,10-phenantroline for 12-48 hours in DMF at 120 °C. The products were isolated by column chromatography on silica gel. All products were fully characterized by HRMS as well as 1H and 13C NMR spectroscopy. Thus, this approach is valuable for promoting the synthesis of N-phenyl-1H-indazoles in a higher yield than that reported in the literature using copper catalysis and the same substrates. This study also prompted the first reported synthesis of pharmacologically interesting N-thiazolyl derivatives.

1,2-Addition to trifluoromethylated ß-enamino diketones: regioselective synthesis of trifluoromethyl-containing azomethine pyrazoles and isoxazoles.

A simple and efficient methodology for highly regioselective synthesis of azomethine pyrazoles and isoxazoles containing a trifluoromethyl group is reported. The cyclocondensation of trifluoromethylated ß-enamino diketones (TBED) with phenylhydrazine and hydroxylamine hydrochloride, in the presence of BF3, provided 5-aryl-4-[(tert-butyl)iminomethyl]-3-trifluoromethylazoles by aza-Michael-type 1,2-addition. The scope of the reaction was expanded by transimination with arylamines in a one-pot method starting from TBED. Thus, 83 novel 4-[(alkyl/aryl)iminomethyl]-3-trifluoromethylazoles were obtained with high regioselectivity and in yields of 51 to 89%.

Synthesis of novel 3,5,6-trisubstituted 2-pyridone derivatives and evaluation for their anti-inflammatory activity.

The inflammatory response is the reaction of living tissue to an injury of a foreign nature, such as infection and irritants, and occurs as part of the body's natural defence response. Compounds capable of inhibiting cyclooxygenase (COX) enzymes, especially COX-2, have great potential as anti-inflammatory agents. Herein we present the regioselective synthesis of 49 novel compounds based on the 2-pyridone nucleus. The topical anti-inflammatory activity of seventeen compounds was evaluated in mice by croton oil (CO) induced ear edema assay. Most of the compounds exhibited a high level of in vivo anti-inflammatory activity, reducing ear edema and myeloperoxidase (MPO) activity. The most active compounds (2a and 7a) were inhibitors of COX enzymes. Compound 2a selectively inhibited the COX-2, while 7a was nonselective. Further, the compound 2a showed effective binding at the active site of COX-2 co-crystal by docking molecular study.

Chemical Characterization of Lavandula dentata Essential Oil Cultivated in Chile and Its Antibiofilm Effect against Candida albicans.

Candida albicans is the most common human fungal pathogen, and with the increase in resistance rates worldwide, it is necessary to search for new pharmacological alternatives. Lavandula dentata L. essential oil is recognized as having antimicrobial properties. However, its effect against fungal biofilms has been poorly described. C. albicans-related infections involve the development of biofilms, which are highly resistant to conventional antifungals. In this work, we evaluated the antibiofilm effect of L. dentata L. essential oil against C. albicans. First, we characterized the essential oil by gas chromatography-mass spectrometry. The antifungal effect on C. albicans reference strains was evaluated by a disk diffusion assay and the minimal inhibitory concentration was obtained through a microdilution assay. The effect of the essential oil on the adhesion ability of C. albicans was determined through a crystal violet assay, and morphogenesis inhibition was assessed by light microscopy. The effect of the essential oil on the microarchitecture of biofilms was evaluated through scanning electron microscopy. Finally, the antibiofilm effect was evaluated through an adapted biofilm scratch assay and XTT viability assay. The main constituent of the essential oil was the monoterpenoid eucalyptol (60%). The essential oil presented minimal inhibitory concentrations of 156 and 130 µg/mL against two strains assayed. This minimal inhibitory concentration inhibited adhesion, morphogenesis, biofilm formation, altered microarchitecture, and decreased the viability of established biofilms formed on abiotic surfaces for both strains assayed. This study demonstrates that the essential oil from L. dentata could be a promising treatment against C. albicans biofilms.

Selection of low nitrogen demand yeast strains and their impact on the physicochemical and volatile composition of mead.

Mead is an ancient alcoholic beverage produced through the fermentation of a diluted solution of honey. Due to the peculiar and varied composition of honey, mead production faces several problems, such as slow or stuck fermentations mainly due to the low nitrogen concentration, lack of uniformity of the final product and the production of unpleasant aromas. In this context, this work aimed to select low nitrogen-demand yeast strains and evaluate their potential for the production of mead. Therefore, among 21 commercial wine yeast strains, 5 were selected based on their fermentative behavior at low assimilable nitrogen concentrations. The selected strains were further evaluated for their contributions in meads produced with limited nitrogen availability, and the results showed significant differences on some physicochemical parameters like biomass production, residual sugars, glycerol concentration, and fermentative rate. Moreover, meads obtained with selected strains differed in the concentration of several volatile compounds. The volatile compounds concentration and the principal component analysis based on odor activity values allowed separating strains into three groups. In general, S. cerevisiae var bayanus strains (QA23, Spark, and AWRI-R2) were the largest producers of aromatic compounds, particularly those with floral and fruity descriptors. The selection of yeast strains with low nitrogen-demand and different volatile compounds production can be explored by mead makers to limit fermentation problems and obtain characteristic products.

Bio-guided search of active indole alkaloids from Tabernaemontana catharinensis: Antitumour activity, toxicity in silico and molecular modelling studies.

Active plant metabolites have been used as prototype drugs. In this context, Tabernaemontana catharinensis (Apocynaceae) has been highlighted because of the presence of active indole alkaloids. Thus, this study aims the bio-guided search of T. catharinensis cytotoxic alkaloids. The chemical composition was identified by high-resolution mass spectrometry, and fractionation was performed by open column and preparative thin-layer chromatography, from plant stems. The enriched fractions were tested in vitro in tumour cells A375 (melanoma cell line) and A549 (adenocarcinomic human alveolar basal epithelial cells), and non-tumour Vero cells (African green monkey kidney epithelial cells). The alkaloids identified as active were submitted to in silico toxicity prediction by ADME-Tox and OSIRIS programs and, also, to molecular docking, using topoisomerase I (PDB ID: 1SC7) by iGEMDOCK. As a result, six sub-fractions were obtained, which were identified as containing 16-epi-affinine, 12-methoxy-n-methyl-voachalotine, affinisine, voachalotine, coronaridine hydroxyindoline and ibogamine, respectively. The affinisine-containing sub-fraction showed selective toxicity against A375, with an IC50 of 11.73 µg mL-1, and no cytotoxicity against normal cells (Vero). From the in silico toxicity test results, all indole alkaloid compounds had a low toxicity risk. The molecular docking data provided structural models and binding affinities of the plant's indole alkaloids and topoisomerase I. In summary, this bio-guided search revealed that the indole alkaloids from T. catharinensis display selective cytotoxicity in A375 tumour cells and toxicity in silico. Particularly, affinisine might be a chemotherapeutic for A375 melanoma cells.

Extraction, isolation and in vitro evaluation of affinisine from Tabernaemontana catharinensis in human melanoma cells.

Plant compounds have been identified as new drug prototypes. In this line, this work aimed to isolate the indole alkaloid affinisine from Tabernaemontana catharinensis and test its antitumor activity. The alkaloid was isolated by silica gel open column chromatography from the ethanolic extract of the stem of T. catharinensis. Afterwards, this molecule was characterized by high-resolution mass spectrometry and nuclear magnetic resonance. In the next step, the cytotoxicity of the compound was tested against human melanoma cell lines (A375, WM1366 and SK-MEL-28) and a normal skin cell line (CCD-1059Sk) using a MTT (3-4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cells treated with affinisine were evaluated by flow cytometry to analyze apoptosis and the induction of cell cycle arrest, to evaluate the dead mechanism. The metabolite was isolated in a 0.2% yield relative to the extract. Cytotoxic activity of the molecule was observed at 48 h, resulting in considerable growth inhibition rates in melanoma cells, especially in WM1366, which had the lowest IC50 (32.86 ± 2.54 µg/mL). The apoptosis rate was lower in A375 (56.66 and 86.71% with 57 and 65 µg/mL, respectively). Moreover, affinisine was able to significantly induce cell cycle arrest in different phases in the A375 and WM1366 cell lines. However, in SK-MEL-28 cells, cycle arrest was not observed. In summary, this compound significantly decreased the viability of tumor cells in a dose- and time-dependent manner for all evaluated lineages, reduced cell viability by the apoptosis mechanism and presented prominent activities of cell cycle arrest. In this way, the use of antineoplastic agents is among the most widely used therapeutic measures for the control and treatment of cancer. Affinisine is a promising prototype in the search for new drugs to treat cancer.

Sida tuberculata extract reduces the nociceptive response by chemical noxious stimuli in mice: Implications for mechanism of action, relation to chemical composition and molecular docking.

Sida tuberculata R.E.Fr. (Malvaceae) is a medicinal plant widely found in Southern Brazil, and popularly used for inflammatory disorders and to pain relief. A phytochemical analysis followed by an investigation about antinociceptive potential and mechanism of action were performed with leaves and roots extracts. Methanolic extracts, designated as S. tuberculata leaves extract (STLE) and S. tuberculata roots extract, were analyzed both by UHPLC­MS. The in vivo antinociceptive potential of STLE (10­300 mg kg−1) was assessed in mice subjected to the acetic acid­induced abdominal writhes and formalin model. Agonist/antagonist tests and computational docking suggest the involvement of opioid and adenosinergic systems. The main chemical class detected on extracts was the ecdysteroids, and 20­hydoxyecdysone (20HE) was confirmed as the major phytoconstituent. The pretreatment with STLE (100 mg kg−1) reduced more than 70% abdominal contortions induced by acetic acid model and produced significant inhibition on formalin­induced licking response. The mechanism of action study revealed STLE might act through opioid and adenosine systems. Molecular docking suggested kaempferol derivative and 20HE might interacting with µ­opioid receptor. Thus, the results suggest the existence of antinociceptive potential from S. tuberculata extracts being in accordance to the traditional use.

Unconventional Method for Synthesis of 3-Carboxyethyl-4-formyl(hydroxy)-5-aryl-N-arylpyrazoles.

An alternative highly regioselective synthetic method for the preparation of 3,5-disubstituted 4-formyl-N-arylpyrazoles in a one-pot procedure is reported. The methodology developed was based on the regiochemical control of the cyclocondensation reaction of ß-enamino diketones with arylhydrazines. Structural modifications in the ß-enamino diketone system allied to the Lewis acid carbonyl activator BF3 were strategically employed for this control. Also a one-pot method for the preparation of 3,5-disubstituted 4-hydroxymethyl-N-arylpyrazole derivatives from the ß-enamino diketone and arylhydrazine substrates is described.

Biological Activity of Piper aduncum extracts on Anticarsia gemmatalis (Hübner) (Lepidoptera: Erebidae) and Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae).

Piper aduncum found naturally in the Amazon and southeastern Brazil, is known for its secondary metabolites that have activity on insects. Anticarsia gemmatalis and Spodoptera frugiperda are among the major insect pests associated with agricultural production. This research evaluated the biological activity of hexane, ethyl acetate, and ethanol extracts of P. aduncum leaves on mortality and duration of larval and pupal periods, as well as weight, width, and length of A. gemmatalis and S. frugiperda pupae. The mortality of A. gemmatalis larvae in trials with P. aduncum extracts were 93.3% (hexane) and 90% (ethyl acetate), estimating LC50 of 6.35 and 5.79 mg/mL, respectively. Mortality in S. frugiperda submitted to the hexane extract ranged from 3.33% to 96.66% (LC50 of 8.22 mg/mL). The ethanol extract induced low mortality (3.33% to 23.33%). The P. aduncum extracts did not affect the development of S. frugiperda pupae. In A. gemmatalis differences in weight and length occurred. The chemical characterization was by GC-MS, which revealed that the major constituent in the hexane extract of P. aduncum was apiol (90.7%). P. aduncum extracts are important and promising components to manage A. gemmatalis and S. frugiperda, which cause extensive production losses.

In vitro antifungal activity of four chemotypes of Lippia alba (Verbenaceae) essential oils against Alternaria solani (Pleosporeaceae) isolates.

Several volatile natural compounds produced by plant secondary metabolism have been proven to present antimicrobial action, enabling their use in phytopathogen control. They also present low environmental impact when compared to conventional pesticides. Essential oils contain these compounds and can be found in several plant species, such as Lippia alba (Mill.) N.E. Brown (Verbenaceae). Essential oils of four chemotypes of L. alba, characterized by their major compounds, namely camphor, citral, linalool and camphor/1,8-cineole, were tested against the phytopathogen Alternaria solani Sorauer (Pleosporaceae), which causes early blight on tomatoes and is responsible for great economic losses regarding production. Essential oils antifungal action was tested in vitro using potato dextrose agar medium with essential oil concentrations at 0.1, 0.5, 1.0, 1.5 and 2.0 µL mL-1. The chemotype that had the best performance was citral, showing significant inhibition compared to the others, starting at the 0.5 µL mL-1 concentration. The essential oil belonging to the linalool chemotype was efficient starting at the 1.5 µL mL-1 concentration. Conversely, the camphor chemotype did not show any action against the phytopathogen. Moreover, the essential oils had no remarkable effect on tomato germination and growth. In conclusion, these essential oils presented fungicidal action against A. solani.

Pharmacological perspectives from Brazilian Salvia officinalis (Lamiaceae): antioxidant, and antitumor in mammalian cells.

Salvia officinalis (Lamiaceae) has been used in south of Brazil as a diary homemade, in food condiment and tea-beverage used for the treatment of several disorders. The objective of this study was to characterize chemical compounds in the hydroalcoholic (ExtHS) and aqueous (ExtAS) extract from Salvia officinalis (L.) by gas chromatography-mass spectrometry (GC-MS) and by high-resolution electrospray ionization mass spectrometry (ESI-QTOF MS/MS), evaluate in vitro ability to scavenge the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH•) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS•+), catalase (CAT-like) and superoxide dismutase (SOD-like) activity, moreover cytotoxic by MTT assay, alterations on cell morphology by giemsa and apoptotic-induced mechanism for annexin V/propidium iodide. Chemical identification sage extracts revealed the presence of acids and phenolic compounds. In vitro antioxidant analysis for both extracts indicated promising activities. The cytotoxic assays using tumor (Hep-2, HeLa, A-549, HT-29 and A-375) and in non-tumor (HEK-293 and MRC-5), showed selectivity for tumor cell lines. Immunocytochemistry presenting a majority of tumor cells at late stages of the apoptotic process and necrosis. Given the results presented here, Brazilian Salvia officinalis (L.) used as condiment and tea, may protect the body against some disease, in particularly those where oxidative stress is involved, like neurodegenerative disorders, inflammation and cancer.

Hydroalcoholic extract of red propolis promotes functional recovery and axon repair after sciatic nerve injury in rats.

CONTEXT: Peripheral axon injury and degeneration are often mediated by oxidative stress and inflammation. The hydroalcoholic extract of the red propolis (HERP) has attracted great attention because of its antioxidant and anti-inflammatory activities. OBJECTIVE: The objective of this work is to study the effect of HERP on nerve repair and functional recovery after sciatic nerve injury (SNI) in rats. MATERIALS AND METHODS: The chemical markers in HERP were identified using high-resolution mass spectroscopy. After axonotmesis of sciatic nerve, ibuprofen (IBP) and HERP treatments were orally administered for 28 d. Behavioural tests were performed weekly after SNI. The myelinated axon number was counted using morphometric analysis. RESULTS: The compounds found in HERP were pinocembrin, formononetin, vestitol, and biochanin A. The animals that underwent SNI showed a significant decrease in motor function based on the Basso, Beattie and Bresnahan scale and sciatic functional index compared with sham animals until 7 d after the surgery (p < 0.05). After 14 and 21 d, the SNI groups treated with either HERP or IBP showed significant improvement (p < 0.01), and the SNI group treated with HERP 10 mg/kg showed accelerated motor recovery compared with the other groups (p < 0.01). SNI caused also a reduction in the myelinated axon counts, and treatment with HERP 10 mg/kg induced a significant increase in the number of myelinated fibres compared with all other groups. CONCLUSION: HERP promoted regenerative responses and accelerated functional recovery after sciatic nerve crush. Thus, it can be considered to be a new strategy or complementary therapy for treating nerve injuries.

Biflorin: an o-naphthoquinone of clinical significance.

Biflorin is an o-naphthoquinone with proven cytotoxic effects on tumor cells showing antimicrobial, antitumor and antimutagenic activities. Biflorin is an isolated compound taken from the roots of the plant Capraria biflora L. (Schrophulariaceae), indigenous of the West Indies and South America, which is located in temperate or tropical areas. This compound has shown to be strongly active against grampositive and alcohol-acid-resistant bacteria. It has been efficient in inhibiting the proliferation tumor cell lines CEM, HL-60, B16, HCT-8 and MCF-7. Recently, SK-Br3 cell line was treated with biflorin showing important cytotoxic effects. In this article, information related to the first structural characterization studies are presented, as well as the latest reports concerning the biological activity of this molecule.

What's in drugs freely used by Brazilian truck drivers - "Rebites"? Determination of target and nontarget compounds by high-resolution mass spectrometry and nuclear magnetic resonance.

Highways, the lifeline of the Brazilian economy, transport approximately 75% of the country's economic activity, highlighting its importance. However, professional drivers, accustomed to long daily journeys, make use of tablets widely available in Gas Station, which are known as "Rebites," which could contain a mixture of legal and illegal compounds. Thus, this study aims at the chemical characterization of these through different analytical methods. Initially, we performed a comprehensive screening of compounds present in seven samples collected across the country using high-resolution mass spectrometry (HRMS). The findings revealed caffeine as the main compound, alongside theophylline, lidocaine, and clobenzorex, among others. In the next step, we employ quantitative nuclear magnetic resonance (qNMR) to quantify the caffeine content in the tablets. The results indicated a caffeine concentration ranging between 14% and 31% (m/m), which may imply a daily overdose of this compound from around four tablets. In summary, this investigation provides a chemical characterization of real samples of "Rebites" freely obtained along Brazilian highways. Caffeine emerged as the predominant active compound, with its concentration determined by qNMR analysis. The notable presence of caffeine, combined with other stimulants, depressants, and hallucinogens, underscores the need for strict quality control measures regarding "Rebites" to safeguard public health.

Neurotoxic and behavioral deficit in Drosophila melanogaster exposed to photocatalytic products of Paraquat.

The Advanced Oxidative Processes have demonstrated potential for application in the degradation of organic pollutants, such as Paraquat (PQ) from water and wastewater, due to their low price, high efficiency, and non-toxic properties. In this study, we investigated whether the photodegradation of PQ with TiO2 nanotubes reduced its toxicity in Drosophila melanogaster. However, dietary ingestion of degradation products PQ for larvae resulted in a low axial ratio (pupal volume). In the adults, products of photodegradation of PQ exposure markedly diminished climbing ability in a time-dependent manner after 10 days of feeding. In addition, exposure of D. melanogaster to photodegradation of PQ reduced acetylcholinesterase and citrate synthase activities but improved oxidative stress, as evidenced by oxide nitric, protein carbonyl, and lactate production. These results suggest that the photodegradation of PQ with TiO2 nanotubes produced PQ fragments with higher toxicity than PQ, while the precise mechanism of its action needs further investigation.