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bioRxiv2017

Light-dependent decomposition of FICZ, an endogenous ligand of the aryl hydrocarbon receptor

An efficient and scalable synthesis of 6-formylindolo[3,2-b]carbazole (FICZ) has been developed to provide large quantities of this physiologically important ligand of the aryl hydrocarbon receptor. Photo-decomposition of FICZ revealed a new non-enzymatic light-assisted mechanism for its conversion to a biologically less active quinone. The light-dependent synthesis and decomposition of FICZ makes it a candidate hormone to link sun exposure to regulation of biological pathways in peripheral tissues.

pharmacology and toxicology↗

bioRxiv2017

Predicting serious rare adverse reactions of novel chemicals

Adverse drug reactions (ADRs) are one of the main causes of death and a major financial burden on the worlds economy. Due to the limitations of the animal model, computational prediction of serious, rare ADRs is invaluable. However, current state-of-the-art computational methods do not yield significantly better predictions of rare ADRs than random guessing. We present a novel method, based on the theory of \"compressed sensing\", which can accurately predict serious side-effects of candidate and market drugs. Not only is our method able to infer new chemical-ADR associations using existing noisy, biased, and incomplete databases, but our data also demonstrates that the accuracy of our approach in predicting a serious adverse reaction (ADR) for a candidate drug increases with increasing knowledge of other ADRs associated with the drug. In practice, this means that as the candidate drug moves up the different stages of clinical trials, the prediction accuracy of our method will increase accordingly. Thus, the compressed sensing based computational method reported here represents a major advance in predicting severe rare ADRs, and may facilitate reducing the time and cost of drug discovery and development.

pharmacology and toxicology↗

bioRxiv2017

Additive Dose Response Models: Explicit Formulations and the Loewe Additivity Consistency Condition

High-throughput techniques allow for massive screening of drug combinations. To find combinations that exhibit an interaction effect, one filters for promising compound combinations by comparing to a response without interaction. A common principle for no interaction is Loewe Additivity which is based on the assumption that no compound interacts with itself and that doses of both compounds for a given effect are equivalent. For the model to be consistent, the doses of both compounds have to be proportional. We call this restriction the Loewe Additivity Consistency Condition (LACC). We derive explicit and implicit null reference models from the Loewe Additivity principle that are equivalent when the LACC holds. Of these two formulations, the implicit formulation is the known General Isobole Equation [1], whereas the explicit one is the novel contribution. The LACC is violated in a significant number of cases. In this scenario the models make different predictions. We analyze two data sets of drug screening that are non-interactive [2, 3] and show that the LACC is mostly violated and Loewe Additivity not defined. Further, we compare the measurements of the non-interactive cases of both data sets to the theoretical null reference models in terms of bias and mean squared error. We demonstrate that the explicit formulation of the null reference model leads to smaller mean squared errors than the implicit one and is much faster to compute.

pharmacology and toxicology↗

bioRxiv2017

ScreenCube: A 3D Printed System For Rapid and Cost-Effective Chemical Screening in Adult Zebrafish

Phenotype-based small molecule screens in zebrafish embryos and larvae have been successful in accelerating pathway and therapeutic discovery for diverse biological processes. Yet, the application of chemical screens to adult physiologies has been relatively limited due to additional demands on cost, space, and labor associated with screens in adult animals. Here, we present a 3D printed system and methods for intermittent drug dosing that enable rapid and cost-effective chemical administration in adult zebrafish. Using pre-filled screening plates, the system enables dosing of 96 fish in {small tilde}3min, with a tenfold-reduction in drug quantity compared to that used in previous chemical screens in adult zebrafish. We characterize water quality kinetics during immersion in the system, and use these kinetics to rationally design intermittent dosing regimens that result in 100% fish survival. As a demonstration of system fidelity, we show the potential to identify two known chemical inhibitors of adult tail fin regeneration, cyclopamine and dorsomorphin. By developing methods for rapid and cost-effective chemical administration in adult zebrafish, this study expands the potential for small molecule discovery in post-embryonic models of development, disease, and regeneration.

pharmacology and toxicology↗

bioRxiv2017

Two Chinese medicine species constants and the accurate identification of Chinese medicines

Since the ancient times, all over the world, the identification of herbal medicines have to be based on empirical knowledge. In this article two species constants of traditional Chinese medicines(TCM) were discovered relying on the maximum information states of Dual index information theory equation, or common heredity and variation information theory. The two species constants, common peak ratios Pg = 61% and Pg = 70%, which corresponding to symmetry and asymmetry variation states, respectively, were used as two absolute quantitative criteria to identify complex biology systems-TCM. Considered the influences of many other factors on components and experiment processes, the practical theoretical identification standards should be established Pg[greater double equals]58~64% and Pg[greater double equals]67~73%, within the relativeerror within -3% and + 3% of information value around the maximum information states. Combining the maximum number of effective sample optimum method with this two theoretical standards, the optimized classification of a TCM sample set can be carried out correctly. 42 samples belonging to four species of combination Chinese medicines were tested. The infrared (IR) fingerprint spectra (FPS) of their powder were measured and analyzed by means of the approach provided above. Among the six pairs of four Chinese medicine species, five of them follow the species constant Pg=61%, one of them obeys the Pg = 70%. The correct recognition ratio of samples was 95.2%, and that of species was 100%.

pharmacology and toxicology↗

bioRxiv2017

Progesterone regulates hypothalamic-pituitary-thyroid axis

Progesterone is a natural steroid hormone excreted by animals and humans, which has been frequently detected in the aquatic ecosystems. The effects of the residual progesterone on fish are unclear. In this study, we aimed to examine the effects of progesterone on the hypothalamic-pituitary-thyroid (HPT) axis by detecting the gene transcriptional expression levels. Zebrafish embryos were treated with different concentrations of progesterone from 12 hours post-fertilization (hpf) to 120 hpf. Total mRNA was extracted and the transcriptional profiles of genes involved in HPT axis were examined using qPCR. The genes related to thyroid hormone metabolism and thyroid hormone synthesis were up-regulated in zebrafish exposed to progesterone. These results indicated that progesterone affected the mRNA expression of genes involved in the HPT axis, which might interrupt the endocrine system in zebrafish. Our data also suggested that zebrafish is a useful tool for evaluating the effects of chemicals on the thyroid endocrine system.

pharmacology and toxicology↗

bioRxiv2017

Identification of Pathways Associated with Chemosensitivity through Network Embedding

Basal gene expression levels have been shown to be predictive of cellular response to cytotoxic treatments. However, such analyses do not fully reveal complex genotype-phenotype relationships, which are partly encoded in highly interconnected molecular networks. Biological pathways provide a complementary way of understanding drug response variation among individuals. In this study, we integrate chemosensitivity data from a recent pharmacogenomics study with basal gene expression data from the CCLE project and prior knowledge of molecular networks to identify specific pathways mediating chemical response. We first develop a computational method called PACER, which ranks pathways for enrichment in a given set of genes using a novel network embedding method. It examines known relationships among genes as encoded in a molecular network along with gene memberships of all pathways to determine a vector representation of each gene and pathway in the same low-dimensional vector space. The relevance of a pathway to the given gene set is then captured by the similarity between the pathway vector and gene vectors. To apply this approach to chemosensitivity data, we identify genes with basal expression levels in a panel of cell lines that are correlated with cytotoxic response to a compound, and then rank pathways for relevance to these response-correlated genes using PACER. Extensive evaluation of this approach on benchmarks constructed from databases of compound target genes, compound chemical structure, as well as large collections of drug response signatures demonstrates its advantages in identifying compound-pathway associations, compared to existing statistical methods of pathway enrichment analysis. The associations identified by PACER can serve as testable hypotheses about chemosensitivity pathways and help further study the mechanism of action of specific cytotoxic drugs. More broadly, PACER represents a novel technique of identifying enriched properties of any gene set of interest while also taking into account networks of known gene-gene relationships and interactions.

pharmacology and toxicology↗

bioRxiv2017

Anti-mutagenic and synergistic cytotoxic effect of cisplatin and Honey Bee venom on 4T1 invasive mammary carcinoma cell line

Honey Bee Venom has various biological activities such as inhibitory effect on several types of cancer. Cisplatin is an old and potent drug to treat the most of cancer. Our aims in this study were determination of the anti-mutagenic and cytotoxic effects of HBV on mammary carcinoma, lonely and in combination with cisplatin. In this study 4T1 cell line were cultured and incubated at 37 C in humidified CO2-incubator. The cell viabilities were examined by MTT assay. Also HBV was screened for its anti-mutagenic activity against sodium azide by Ames test. The result showed that 6g/ml HBV, 20g/ml cisplatin and 6g/ml HBV with 10g/ml cisplatin can induce an approximately 50% 4T1 cell death. 7mg/ml HBV with the inhibition of 62.76% sodium azide showed high potential in decreasing the mutagenic agents. MTT assay demonstrated that HBV and cisplatin can cause cell death in a dose-dependent manner. The cytotoxic effect of cisplatin is also promoted by HBV. Ames test results indicated that HBV can inhibit sodium azide as a mutagenic agent. Anti-mutagenic activity of HBV was increased significantly in presence of S9 mix. Hence, our findings reveal that HBV can enhance the cytotoxic effect of cisplatin drug and it has cancer preventing effects.

pharmacology and toxicology↗

bioRxiv2017

Antidepressant-like effect of losartan involves TRKB transactivation from angiotensin receptor type 2 (AGTR2) and recruitment of FYN

Renin-angiotensin system (RAS) is associated to peripheral fluid homeostasis and cardiovascular function, but recent evidence has also drawn its functional role in the brain. RAS has been described to regulate physiological and behavioral parameters related to stress response, including depressive symptoms. Apparently, RAS can modulate levels of brain derived neurotrophic factor (BDNF) and TRKB, which are important to neurobiology of depression and antidepressant action. However, interaction between BDNF/TRKB system and RAS in models predictive of antidepressant effect has not been investigated before. Accordingly, in the forced swimming test, we observed an antidepressant-like effect of systemic losartan but not with captopril or enalapril treament. Moreover, infusion of losartan into ventral hippocampus (vHC) and prelimbic prefrontal cortex (PL) mimicked the consequences of systemically injected losartan, whereas K252a, a blocker of TRK, infused into these brain areas impaired such effect. PD123319, an antagonist of AT2 receptor (AGTR2), infused into PL but not into vHC, also prevented systemic losartan effect. Cultured cortical cells of rat embryos indicate that angiotensin II (ANG2), possibly through AGTR2, increases the surface levels of TRKB, and favors its coupling to FYN, a SRC family kinase. The higher levels of agtr2 in cortical cells were decreased after insult with glutamate, and under this condition an interaction between losartan and ANG2 was achieved. Occurrence of TRKB/AGTR2 heterodimers was also observed, in MG87 cells GFP-tagged AGTR2 co-immunoprecipitated with TRKB. Therefore, antidepressant-like effect of losartan is proposed to occur through a shift of ANG2 binding towards AGTR2, followed by coupling of TRK/FYN and putative TRKB transactivation. Thus, AGTR1 show therapeutic potential as novel antidepressant therapy.

pharmacology and toxicology↗

bioRxiv2017

Assaying uptake of endocrine disruptor compounds in zebrafish embryos and larvae

To study the effects of environmental endocrine disruptors (EEDs) on aquatic animals, embryos and larvae are typically incubated in water containing defined concentrations of EEDs. However, the amount of EED uptake into the animal is often difficult to determine. Using radiolabeled estradiol ([3H]E2), we previously developed a rapid, straightforward assay to measure estradiol uptake from water into zebrafish embryos and larvae. Here, we extend this approach to measure the uptake of two additional EEDs, bisphenol A (BPA) and ethinyl estradiol (EE2). As with E2, the uptake of each compound by individual larvae was low (< 6%), and increased with increasing concentration, duration, and developmental stage. We found that E2 and EE2 had similar uptake under equivalent exposure conditions, while BPA had comparatively lower uptake. One application of this assay is to test factors that influence EED uptake or efflux. It has been suggested that persistent organic pollutants (POPs) inhibit ABC transporters that may normally efflux EEDs and their metabolites, inducing toxicity in aquatic organisms. We measured [3H]E2 levels in zebrafish in the presence or absence of the POP PDBE-100, and cyclosporine A, a known inhibitor of ABC transporters. Neither chemical significantly affected [3H]E2 levels in zebrafish, suggesting that zebrafish maintain estradiol efflux in the presence of PDBE-100, independently of cyclosporine A-responsive transporters. These uptake results will be a valuable reference for EED exposure studies in developing zebrafish, and provide a rapid assay to screen for chemicals that influence estrogen-like EED levels in vivo.

pharmacology and toxicology↗

bioRxiv2017

Harnessing the Cross-talk between Tumor Cells and Tumor-associated Macrophages with a Nano-drug for modulation of Glioblastoma Immune Microenvironment

Glioblastoma (GBM) is the most frequent and malignant brain tumor with a high mortality rate. The presence of a large population of macrophages (M{varphi}) in the tumor microenvironment is a prominent feature of GBM and these so-called tumor-associated M{varphi} (TAM) closely interact with the GBM cells to promote the survival, progression and therapy resistance of the GBM. Various therapeutic strategies have been devised either targeting the GBM cells or the TAM but few have addressed the cross-talks between the two cell populations. The present study was carried out to explore the possibility of exploiting the cross-talks between the GBM cells (GC) and TAM for modulation of the GBM microenvironment through using Nano-DOX, a drug composite based on nanodiamonds bearing doxorubicin. In the in vitro work on human cell models, Nano-DOX-loaded TAM were first shown to be viable and able to infiltrate three-dimensional GC spheroids and release cargo drug therein. GC were then demonstrated to encourage Nano-DOX-loaded TAM to unload Nano-DOX back into GC which consequently emitted damage-associated molecular patterns (DAMPs) that are powerful immunostimulatory agents as well as indicators of cell damage. Nano-DOX was next proven to be a more potent inducer of GC DAMPs emission than doxorubicin. As a result, Nano-DOX-damaged GC exhibited an enhanced ability to attract both TAM and Nano-DOX-loaded TAM. Most remarkably, Nano-DOX-damaged GC reprogrammed the TAM from a pro-GBM phenotype to an anti-GBM phenotype that suppressed GC growth. Finally, the in vivo relevance of the in vitro findings was tested in animal study. Mice bearing orthotopic human GBM xenografts were intravenously injected with Nano-DOX-loaded mouse TAM which were found releasing drug in the GBM xenografts 24 h after injection. GC damage was evidenced by the induction of DAMPs emission within the xenografts and a shift of TAM phenotype was detected as well. Taken together, our results demonstrate a novel way with therapeutic potential to harness the cross-talk between GBM cells and TAM for modulation of the tumor immune microenvironment.\n\nAbbreviationsATP, adenosine triphosphate; BBB, blood-brain barrier; BCA, bicinchoninic acid; BMDM, bone marrow derived macrophages; CD, cluster of differentiation; CFSE, 5(6)-carboxyfluorescein diacetate, succinimidyl ester; CM, conditioned culture medium; CNS, central nervous system; CRT, calreticulin; DAMPs, damage-associated molecular patterns; DAB, diaminobenzidine; DOX, doxorubicin; ECL, enhanced chemiluminescence; ELISA, enzyme-linked immunosorbent assay; HMGB1, high mobility group protein B1; HSP90, heat shock protein 90; FACS, flow cytometry; GBM, glioblastoma; Guanylate Binding Protein 5 (GBP5); GC, glioblastoma cells; IHC, immunohistochemical; IL, interleukin; M{varphi}, macrophages; mBMDM, mouse BMDM; mBMDM2, Type-2 mBMDM; M1, Type-1 Mo; M2, Type-2 Mo; Nano-DOX, ND-PG-RGD-DOX; ND, nanodiamonds; Nano-DOX-mBMDM, Nano-DOX-loaded mouse BMDM; NGCM, Nano-DOX-treated-GC-conditioned medium; PBS, phosphate buffered saline; PG, polyglycerol; PMA, phorbol 12-myristate 13-acetate; PVDF, polyvinylidene fluoride; RGD, tripeptide of L-arginine, glycine and L-aspartic acid; RM, regular culture medium; SD, standard deviation; TAM, tumor-associated M{varphi}; TBST, Tris Buffered Saline with Tween(R) 20.\n\nGraphic abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC=\"FIGDIR/small/170282_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (111K):\norg.highwire.dtl.DTLVardef@180aea2org.highwire.dtl.DTLVardef@14922f7org.highwire.dtl.DTLVardef@96a696org.highwire.dtl.DTLVardef@92f050_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2017

Metabolomic profiling reveals effects of marein on energy metabolism in HepG2 cells

Previous studies have suggested that Coreopsis tinctoria improves insulin resistance in rats fed with high-fat diet. But little is known about the antidiabetic effects of marein which is the main component of C. tinctoria. This study investigated the effects of ethyl acetate extract of C. tinctoria (AC) on insulin resistance (IR) in rats fed a high-fat diet. High glucose and fat conditions cause a significant increase in blood glucose, insulin, serum TC,TG and LDL-C, leading to an abnormal IR in rats. However, treatment with AC protects against HFD-induced IR by improving fasting serum glucose and lipid homeostasis. High glucose conditions cause a significant decrease in glycogen synthesis and increases PEPCK and G6Pase protein levels and Krebs-cycle-related enzymes levels, leading to an abnormal metabolic state in HepG2 Cells. However, treatment with Marein improves IR by increasing glucose uptake and glycogen synthesis and by downregulating PEPCK and G6Pase protein levels. The statistical analysis of HPLC/MS data demonstrates that Marein restores the normal metabolic state. The results show that AC ameliorates IR in rats and Marein has the potential effect in improving IR by ameliorating glucose metabolic disorders.\n\nAbbreviations

pharmacology and toxicology↗

bioRxiv2017

Impairment of zebrafish reproduction upon exposure to TDCPP

TDCPP is one of the most common organophosphate flame retardant, which has been widely used in many products. It has been detected in the environment and biota; however, its potential affect to the wildlife and human health remains largely unknown. In this study, we aimed to investigate the effect of long-term exposure to TDCPP on fish reproduction. Zebrafish eggs were treated with various concentration of TDCPP (0, 1, 10 and 100 g/L) from 1 day post-fertilization (hpf) to 6 months. The fecundity of female fish was significantly decreased as indicated by reduced embryos production. The egg quality was decreased and the malformation rates were increased in the F1 generation. Taken together, long-term exposure to TDCPP affects the reproduction of zebrafish.

pharmacology and toxicology↗

bioRxiv2017

Case report: intermittent fasting and probiotic yogurt consumption are associated with reduction of serum alpha-N-acetylgalactosaminidase and increased urinary excretion of lipophilic toxicants

In this study, we describe the changes associated with three months of intermittent fasting and probiotic yogurt consumption in a 72-year-old marathon runner with chronic lymphocytic leukemia for a number of years. Serum alpha-N-acetylgalactosaminidase (nagalase), a marker of inflammation and cancer cell proliferation, was significantly decreased at the end of a three-month observation. These results are consistent with immune modulating properties of certain probiotics based on the fermentation of milk and colostrum. Urinary excretion of non-metal toxicants that accumulate in adipose tissue such as Perchlorate, N-acetyl(2-hydroxypropyl)cysteine (NAHP), 2,4-Dichlorophenoxyacetic acid, 3-Phenoxybenzoic acid (3PBA), N-acetyl phenyl cysteine (NAP), Phenylglycoxylic acid (PGO), Monoethylphthalate (MEP) and 2-Hydroxyisobutyric Acid (2HIB) was significantly increased. These results are consistent with the weight loss (5 Kg) associated with intermittent fasting and with the known features of probiotics as detoxification tools. Consistent with certain toxicants acting as endocrine disruptors, we observed an increased elimination of toxicants and a 33% decrease of serum Thyroid Stimulating Hormone (TSH), suggesting a trend toward normalization of thyroid function. These results support the hypothesis that a combination of intermittent fasting with the consumption of specific probiotic yogurts may lead to immune modulation, detoxification and other improvements.\n\nAbbreviations

pharmacology and toxicology↗

bioRxiv2017

Propofol induces metabolic reprogramming and cell death in a mitochondrial electron transport chain-dependent manner

The intravenous anesthetic propofol (2,6-diisopropylphenol) has been used for the induction and maintenance of anesthesia in operating rooms and for sedation in intensive care units. Although there is no widely accepted definition of propofol infusion syndrome (PRIS), PRIS is defined as the development of metabolic acidosis, rhabdomyolysis, hyperkalemia, hepatomegaly, renal failure, arrhythmia, and progressive cardiac failure. In vitro evidence suggests that PRIS is related to the impaired mitochondrial function. There are indications that preexisting mitochondrial disorders predispose to PRIS. However, the precise molecular mechanisms, including mitochondrial defects and a metabolic conversion by propofol, are largely unknown as yet. To elucidate the underlying cellular and molecular mechanisms of PRIS, we investigated the effects of propofol on the cellular metabolic mode and cell death. We demonstrated that clinically relevant concentrations of propofol, used within a clinically relevant exposure time, suppressed the mitochondrial function, caused the generation of reactive oxygen species, and induced a metabolic switch, from oxidative phosphorylation to glycolysis, by targeting complexes I and III of mitochondria. The data also indicated that a predisposition to mitochondrial dysfunction, caused by a genetic mutation or pharmacological suppression of the electron transport chain by biguanides such as metformin and phenformin, promoted the cell death and caspase activation induced by propofol.

pharmacology and toxicology↗

bioRxiv2017

Evaluating Antioxidant Capacity of Different Propolis Samples from Konya, Turkey and Their Inhibitory Effect on Head and Neck Cancer Cells

Propolis is a resinous mixture collected and used by the honey bees to construct and repair their hives. The component of propolis varies depend on the type of the plants collected. Propolis and its constituents have been subjected to many studies and are known for their antioxidant, antimicrobial and anticarcinogenic properties. In our study, antioxidant and antitumor capacity of propolis from Konya Sakyatan and Kiziloren regions were investigated. According to our result, Kzloren propolis sample possesses higher antioxidant component and antioxidant capacity than Sakyatan sample. Accordingly, Kiziloren sample showed antiproliferative effect at much lower doses compared to the Sakyatan sample. Both samples effectively inhibited the migration of cancer cells at their determined IC50 dosages. Obtained data indicates that constituents of propolis can greatly vary from one sample to another even in the same region and propolis selections for cancer prevention and treatment studies should be carefully considered.

pharmacology and toxicology↗

bioRxiv2017

Ahr and Cyp1a2 genotypes both affect susceptibility to motor deficits following gestational and lactational exposure to polychlorinated biphenyls

Polychlorinated biphenyls (PCBs) are persistent organic pollutants known to cause adverse health effects and linked to neurological deficits in both human and animal studies. Children born to exposed mothers are at highest risk of learning and memory and motor deficits. We developed a mouse model that mimics human variation in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) to determine if genetic variation increases susceptibility to developmental PCB exposure. In our previous studies, we found that high-affinity AhrbCyp1a2(-/-) and poor-affinity AhrdCyp1a2(-/-) knockout mice were most susceptible to learning and memory deficits following developmental PCB exposure compared with AhrbCyp1a2(+/+) wild type mice (C57BL/6J strain). Our follow-up studies focused on motor deficits, because human studies have identified PCBs as a potential risk factor for Parkinsons disease. Dams were treated with an environmentally relevant PCB mixture at gestational day 10 and postnatal day 5. We used a motor battery that included tests of nigrostriatal function as well as cerebellar function, because PCBs deplete thyroid hormone, which is essential to normal cerebellar development. There was a significant effect of PCB treatment in the rotarod test with impaired performance in all three genotypes, but decreased motor learning as well in the two Cyp1a2(-/-) knockout lines. Interestingly, we found a main effect of genotype with corn oil-treated control Cyp1a2(-/-) mice performing significantly worse than Cyp1a2(+/+) wild type mice. In contrast, we found that PCB-treated high-affinity Ahrb mice were most susceptible to disruption of nigrostriatal function with the greatest deficits in AhrbCyp1a2(-/-) mice. We conclude that differences in both genes affect susceptibility to motor deficits following developmental PCB exposure.

pharmacology and toxicology↗

bioRxiv2017

Characterization of antioxidant properties and metabolite profile of Agave atrovirens extracts

Agave spp. is widely analyzed because several functional properties have been described. Some minor bioactive compounds such as polyphenols, saponins and Maillard compounds produced during extraction procedures have been reported to exert antioxidant properties. The objective of this study was to elucidate the antioxidant properties of three different Agave atrovirens extracts in a HepG2 cell culture assay. The three extracts analyzed mostly showed antioxidant properties with an increase in NRF2 content in nuclear extracts. However, a differential response was observed in the reduction of protein oxidative damage in the three extracts analyzed, the crude extract being the one that mainly induced a reduction in oxidative damage. Metabolomic analysis was performed to elucidate the potential molecules responsible for the antioxidant properties, where 2-amino-4-methylphenol could be the main candidate responsible for inducing the transcription of cellular antioxidant response elements. It could be concluded that crude extract of Agave atrovirens may increase the cellular antioxidant defense system, with a reduction in oxidative damage

pharmacology and toxicology↗