Search Results (27)

Background: The candidate therapeutic peptide TnP demonstrates broad, system-level regulatory capacity, revealed through integrated network analysis from transcriptomic data in zebrafish. Our study primarily identifies TnP as a multifaceted modulator of drug metabolism, wound healing, proteolytic activity, and pigmentation pathways. Results: Transcriptomic profiling of TnP-treated larvae following tail fin amputation revealed 558 differentially expressed genes (DEGs), categorized into four functional networks: (1) drug-metabolizing enzymes (cyp3a65, cyp1a) and transporters (SLC/ABC families), where TnP alters xenobiotic processing through Phase I/II modulation; (2) cellular trafficking and immune regulation, with upregulated myosin genes (myhb/mylz3) enhancing wound repair and tlr5-cdc42 signaling fine-tuning inflammation; (3) proteolytic cascades (c6ast4, prss1) coupled to autophagy (ulk1a, atg2a) and metabolic rewiring (g6pca.1-tg axis); and (4) melanogenesis-circadian networks (pmela/dct-fbxl3l) linked to ubiquitin-mediated protein turnover. Key findings highlight TnP’s unique coordination of rapid (protease activation) and sustained (metabolic adaptation) responses, enabled by short network path lengths (1.6–2.1 edges). Hub genes, such as nr1i2 (pxr), ppara, and bcl6aa/b, mediate crosstalk between these systems, while potential risks—including muscle hypercontractility (myhb overexpression) or cardiovascular effects (ace2-ppp3ccb)—underscore the need for targeted delivery. The zebrafish model validated TnP-conserved mechanisms with human relevance, particularly in drug metabolism and tissue repair. TnP’s ability to synchronize extracellular matrix remodeling, immune resolution, and metabolic homeostasis supports its development for the treatment of fibrosis, metabolic disorders, and inflammatory conditions. Conclusions: Future work should focus on optimizing tissue-specific delivery and assessing genetic variability to advance clinical translation. This system-level analysis positions TnP as a model example for next-generation multi-pathway therapeutics. Full article

The present pilot study aimed to investigate whether common single nucleotide polymorphisms (SNPs) in the gene encoding glutathione S-transferase omega 1 (GSTO1), both individually and in combination with variants of the catalytic subunit of the glutamate cysteine ligase (GCLC) gene and environmental risk factors, are associated with the risk of psoriasis. The research included a total of 944 participants, comprising 474 individuals diagnosed with psoriasis and 470 healthy control subjects. Five common SNPs in the GSTO1 gene—specifically, rs11191736, rs34040810, rs2289964, rs11191979, and rs187304410—were genotyped in the study groups using the MassARRAY-4 system. The allele rs187304410-A (OR = 0.19, 95% CI 0.04–0.86, Pperm = 0.02) and the genotype rs187304410-G/A (OR = 0.19, 95% CI 0.04–0.85, Pperm = 0.01) were found to be associated with psoriasis in females. The model-based multifactor dimensionality reduction approach facilitated the identification of higher-order epistatic interactions between the variants of the GSTO1 and GCLC genes (Pperm < 0.0001). These interactions, along with the risk factor of alcohol abuse, collectively contribute to the pathogenesis of psoriasis. This study is the first to demonstrate that polymorphisms in the GSTO1 gene, both individually and in combination with variants of the GCLC gene and alcohol abuse, are associated with an increased risk of psoriasis. Full article

Xenobiotics, including drugs, undergo metabolism to facilitate detoxification and excretion. Predicting a compound’s metabolic fate before clinical trials is crucial for efficacy and safety. The existing methods rely on in vitro systems and in vivo animal testing. In vitro systems do not replicate the complexity of in vivo systems, and differences in biotransformation pathways between humans and nonclinical species may occur; thus, accurate predictions of human-specific drug metabolism are not always achieved. The aim of this study was to evaluate whether a chimeric mouse with a humanized liver, specifically the PXB-mouse, can mimic human metabolic profiles. PXB-mice have livers engrafted with up to 95% human hepatocytes. The biotransformation of 12 different small-molecule drugs were evaluated in PXB-mice (through analysis of blood and urine) and compared with the metabolism by hepatocytes from humans and mice and, when available, literature reports on human in vivo metabolism. The detected metabolites included major Phase I and II transitions, such as hydroxylation, and N- and O-dealkylation and glucuronidation. The metabolic patterns of the PXB-mice closely matched human in vivo data. It is also worth noting that the human hepatocytes formed most of the circulating metabolites, indicating that hepatocytes provide reliable predictions of human metabolic pathways. Thus, for drugs with human biotransformation pathways that are not observed in nonclinical species, the PXB-mouse model can be valuable in predicting human-specific metabolism. Full article

The incidence of multiple-organ cancers has recently increased due to simultaneous exposure to various environmental carcinogens. Houttuynia cordata Thunb. (H. cordata) is recognized for its many health benefits, including its anti-cancer properties. The fermentation of its leaves has been shown to significantly enhance the bioflavonoid content and its bioactivities. This study aimed to evaluate the effectiveness of fermented H.cordata leaf (FHCL) extracts against combined carcinogens and investigate the underlying mechanisms. The crude ethanolic extract of FHCL was partitioned to obtain hexane- (HEX), dichloromethane- (DCM), ethyl acetate- (ETAC), butanol- (nBA), and residue fractions. The crude ethanolic extract (200–250 μg/mL) and the DCM fraction (50 μg/mL) significantly reduced NO production in RAW264.7 macrophages. In addition, the crude extract and the DCM and ETAC fractions showed anti-genotoxicity against aflatoxin B₁ and 2-amino-3,4-dimethylimidazo [4,5-f]quinoline (MeIQ) in Salmonella typhimurium assays (S9+). Despite demonstrating genotoxicity in the Salmonella mutation assay (with and without S9 activation), oral administration of the crude extract at 500 mg/kg of body weight (bw) for 40 days in rats did not induce micronucleated hepatocytes, indicating that the extract is non-genotoxic in vivo. Moreover, the crude extract significantly decreased Phase I but increased Phase II xenobiotic-metabolizing enzyme activities in the rats. Next, the anti-cancer effects of FHCL were evaluated in a dual-organ carcinogenesis model of the colon and liver in rats induced by 1,2-dimethylhydrazine (DMH) and diethylnitrosamine (DEN), respectively. The crude extract significantly reduced not only the number and size of glutathione S-transferase placental form positive foci in the liver (at doses of 100 and 500 mg/kg bw) but also the number of aberrant crypt foci in rat colons (at 500 mg/kg bw). Furthermore, FHCL significantly reduced the expression of proliferating cell nuclear antigen (PCNA) in the colon (at 100 and 500 mg/kg bw) and liver (at 500 mg/kg bw) of the treated rats. In conclusion, FHCL exhibits significant preventive properties against colon and liver cancers in this dual-organ carcinogenesis model. Its mechanisms of action may involve anti-inflammatory effects, the prevention of genotoxicity, the modulation of xenobiotic-metabolizing enzymes, and the inhibition of cancer cell proliferation. These findings support the use of FHCL as a natural supplement for preventing cancer. Full article

Background and Objectives: Phase I and phase II drug-metabolizing enzymes are crucial for the metabolism and elimination of various endogenous and exogenous compounds, such as small-molecule hormones, drugs, and xenobiotic carcinogens. While in vitro and animal studies have suggested a link between genetic mutations in these enzymes and an increased risk of cancer, human in vivo studies have provided limited supportive evidence. Methods: Genome-wide association studies (GWASs) are a powerful tool for identifying genes associated with specific diseases by comparing two large groups of individuals. In the present study, we analyzed a GWAS database to identify key diseases genetically associated with drug-metabolizing enzymes, focusing on UDP-glucuronosyltransferases (UGTs). Results: Our analysis confirmed a strong association between the UGT1 gene and hyperbilirubinemia. Additionally, over ten studies reported a link between the UGT1 gene and increased low-density lipoprotein (LDL) cholesterol levels. UGT2B7 was found to be associated with testosterone levels, total cholesterol levels, and vitamin D levels. Conclusions: Despite the in vitro capability of UGT1 and UGT2 family enzymes to metabolize small-molecule carcinogens, the GWAS data did not indicate their genetic association with cancer, except for one study that linked UGT2B4 to ovarian cancer. Further investigations are necessary to fill the gap between in vitro, animal, and human in vivo data. Full article

The microsomal metabolism of phenol (11 °C) over an annual reproductive cycle from June to December was studied using fall spawning adult brook trout (Salvelinus fontinalis). Hepatic microsomes were isolated from three male and three female fish each month. Incubations were optimized for time, cofactor concentration, pH, and microsomal protein concentration. The formation of phase I ring-hydroxylation metabolites, i.e., hydroquinone (HQ) and catechol (CAT), was quantified by HPLC with dual-channel electrochemical detection. Sample preparation and chromatographic conditions were optimized to achieve the separation and sensitivity required for the analysis of these labile products. Biotransformation of phenol over a range of substrate concentrations (1 to 150 mM) was quantified for the calculation of Michaelis–Menten constants (Km and Vmax) for each month. Results indicate a nearly equal production of HQ and CAT among males and females in late June. At the peak of maturity in October, there was an approximate ten-fold greater production of ring-hydroxylation metabolites noted in females in comparison with males on a total liver basis. In vitro phase II biotransformation of phenol glucuronidation was assessed by determining the Michaelis–Menten constants (Km, Vmax) using brook trout hepatic microsomes over a range of substrate concentrations (1 to 60 mM). Initially, there were no significant differences in the glucuronide rate of formation (pmol/min/mg protein) or total capacity (nmol/min/liver) between females and males. At the peak of maturation, the maximum rate of glucuronide formation was 4-fold less in females; however, the total capacity was 2-fold less in females due to the increased liver size in the females. The alterations in biotransformation coincided with increases in the hepatic and gonadal somatic indices and with changes in plasma hormone concentrations. These experiments provide insight into the metabolic deactivation of xenobiotics and to provide data for the prediction of altered hepatic biotransformation rates and pathways during the reproductive cycle. Full article

The in vitro biotransformation of phenol at 11 °C was studied using pre-spawn adult rainbow (Oncorhynchus mykiss) (RBT), brook (Salvelinus fontinalis) (BKT), and lake trout (Salvelinus namaycush) (LKT) hepatic microsomal preparations. The incubations were optimized for time, cofactor concentration, pH, and microsomal protein concentration. Formation of Phase I ring-hydroxylation and Phase II glucuronidation metabolites was quantified using HPLC with dual-channel electrochemical and UV detection. The biotransformation of phenol over a range of substrate concentrations (1 to 180 mM) was quantified, and the Michaelis–Menten kinetics constants, Km and Vmax, for the formation of hydroquinone (HQ), catechol (CAT), and phenylglucuronide (PG) were calculated. Species differences were noted in the Km values for Phase I enzyme production of HQ and CAT, with the following rank order of apparent enzyme affinity for substrate: RBT > BKT = LKT. However, no apparent differences in the Km for Phase II metabolism of phenol to PG were detected. Conversely, while there were no apparent differences in Vmax between species for HQ or CAT formation, the apparent maximum capacity for PG formation was significantly less in LKT than that observed for RBT and BKT. These experiments provide a means to quantify metabolic activation and deactivation of xenobiotics in fish, to compare activation and deactivation reactions across species, and to act as a guide for future predictions of new chemical biotransformation pathways and rates in fish. These experiments provided the necessary rate and capacity (Km and Vmax) inputs that are required to parameterize a fish physiologically based toxicokinetic (PB-TK) model for a reactive chemical that is readily biotransformed, such as phenol. In the future, an extensive database of these rate and capacity parameters on important fish species for selected chemical structures will be needed to allow the effective use of predictive models for reactive, biotransformation chemicals in aquatic toxicology and environmental risk assessment. Full article

Glutathione transferases (GSTs EC 2.5.1.18) are critical components of phase II metabolism, instrumental in xenobiotics’ metabolism. Their primary function involves conjugating glutathione to both endogenous and exogenous toxic compounds, which increases their solubility and enables their ejection from cells. They also play a role in the transport of non-substrate compounds and immunomodulation, aiding in parasite establishment within its host. The cytosolic GST subfamily is the most abundant and diverse in helminths, and sigma-class GST (GSTσ) belongs to it. This review focuses on three key functions of GSTσ: serving as a detoxifying agent that provides drug resistance, functioning as an immune system modulator through its involvement in prostaglandins synthesis, and acting as a vaccine antigen. Full article

Sulforaphane (SFN) is a naturally occurring compound found in cruciferous vegetables such as broccoli and cauliflower. It has been widely studied for its potential as a neuroprotective and anticancer agent. This review aims to critically evaluate the current evidence supporting the neuroprotective and anticancer effects of SFN and the potential mechanisms through which it exerts these effects. SFN has been shown to exert neuroprotective effects through the activation of the Nrf2 pathway, the modulation of neuroinflammation, and epigenetic mechanisms. In cancer treatment, SFN has demonstrated the ability to selectively induce cell death in cancer cells, inhibit histone deacetylase, and sensitize cancer cells to chemotherapy. SFN has also shown chemoprotective properties through inhibiting phase I metabolizing enzymes, modulating phase II xenobiotic-metabolizing enzymes, and targeting cancer stem cells. In addition to its potential as a therapeutic agent for neurological disorders and cancer treatment, SFN has shown promise as a potential treatment for cerebral ischemic injury and intracranial hemorrhage. Finally, the ongoing and completed clinical trials on SFN suggest potential therapeutic benefits, but more research is needed to establish its effectiveness. Overall, SFN holds significant promise as a natural compound with diverse therapeutic applications. Full article

Oxidative stress is associated with several acute and chronic disorders, including hematological malignancies such as acute myeloid leukemia, the most prevalent acute leukemia in adults. Xenobiotics are usually harmless compounds that may be detrimental, such as pharmaceuticals, environmental pollutants, cosmetics, and even food additives. The storage of xenobiotics can serve as a defense mechanism or a means of bioaccumulation, leading to adverse effects. During the absorption, metabolism, and cellular excretion of xenobiotics, three steps may be distinguished: (i) inflow by transporter enzymes, (ii) phases I and II, and (iii) phase III. Phase I enzymes, such as those in the cytochrome P450 superfamily, catalyze the conversion of xenobiotics into more polar compounds, contributing to an elevated acute myeloid leukemia risk. Furthermore, genetic polymorphism influences the variability and susceptibility of related myeloid neoplasms, infant leukemias associated with mixed-lineage leukemia (MLL) gene rearrangements, and a subset of de novo acute myeloid leukemia. Recent research has shown a sustained interest in determining the regulators of cytochrome P450, family 2, subfamily E, member 1 (CYP2E1) expression and activity as an emerging field that requires further investigation in acute myeloid leukemia evolution. Therefore, this review suggests that CYP2E1 and its mutations can be a therapeutic or diagnostic target in acute myeloid leukemia. Full article

Inflammatory bowel diseases (IBDs) are related to nuclear factor erythroid 2-related factor 2 (Nrf2) dysregulation. In vitro and in vivo studies using phytocompounds as modulators of the Nrf2 signaling in IBD have already been published. However, no existing review emphasizes the whole scenario for the potential of plants and phytocompounds as regulators of Nrf2 in IBD models and colitis-associated colorectal carcinogenesis. For these reasons, this study aimed to build a review that could fill this void. The PubMed, EMBASE, COCHRANE, and Google Scholar databases were searched. The literature review showed that medicinal plants and phytochemicals regulated the Nrf2 on IBD and IBD-associated colorectal cancer by amplifying the expression of the Nrf2-mediated phase II detoxifying enzymes and diminishing NF-κB-related inflammation. These effects improve the bowel environment, mucosal barrier, colon, and crypt disruption, reduce ulceration and microbial translocation, and consequently, reduce the disease activity index (DAI). Moreover, the modulation of Nrf2 can regulate various genes involved in cellular redox, protein degradation, DNA repair, xenobiotic metabolism, and apoptosis, contributing to the prevention of colorectal cancer. Full article

Metabolic switching has been raised as an important phenomenon to be studied in relation to xenobiotic metabolites, since the dose of the exposure determines the formation of metabolites and their bioactivity. Limonene is a monoterpene mostly found in citrus fruits with health activity, and its phase II metabolites and activity are still not clear. The aim of this work was to evaluate the effects of D-limonene in the development of diet-induced obesity in mice and to investigate metabolites that could be generated in a study assessing different doses of supplementation. Animals were induced to obesity and supplemented with 0.1% or 0.8% D-limonene added to the feed. Limonene phase I and II metabolites were identified in liver and urine by LC-ESI-qToF-MS/MS. To the best of our knowledge, in this study three new phase I metabolites and ten different phase II metabolites were first attributed to D-limonene. Supplementation with 0.1% D-limonene was associated with lower weight gain and a trend to lower accumulation of adipose tissue deposits. The metabolites limonene-8,9-diol, perillic acid and perillic acid-8,9-diol should be explored in future research as anti-obesogenic agents as they were the metabolites most abundant in the urine of mice that received 0.1% D-limonene in their feed. Full article

UDP-glucuronosyltransferases (UGTs) are one of the most important enzymes for xenobiotic metabolism or detoxification. Through duplication and loss of genes, mammals evolved the species-specific variety of UGT isoforms. Among mammals, Carnivora is one of the orders that includes various carnivorous species, yet there is huge variation of food habitat. Recently, lower activity of UGT1A and 2B were shown in Felidae and pinnipeds, suggesting evolutional loss of these isoforms. However, comprehensive analysis for genetic or evolutional features are still missing. This study was conducted to reveal evolutional history of UGTs in Carnivoran species. We found specific gene expansion of UGT1As in Canidae, brown bear and black bear. We also found similar genetic duplication in UGT2Bs in Canidae, and some Mustelidae and Ursidae. In addition, we discovered contraction or complete loss of UGT1A7–12 in phocids, some otariids, felids, and some Mustelids. These studies indicate that even closely related species have completely different evolution of UGTs and further imply the difficulty of extrapolation of the pharmacokinetics and toxicokinetic result of experimental animals into wildlife carnivorans. Full article

Hyperglycemia is reported to be associated with oxidative stress. It can result in changes in the activities of drug-metabolizing enzymes and membrane-integrated transporters, which can modify the fate of drugs and other xenobiotics; furthermore, it can result in the formation of non-enzyme catalyzed oxidative metabolites. The present work aimed to investigate how experimental hyperglycemia affects the intestinal and biliary appearance of the oxidative and Phase II metabolites of ibuprofen in rats. In vivo studies were performed by luminal perfusion of 250 μM racemic ibuprofen solution in control and streptozotocin-treated (hyperglycemic) rats. Analysis of the collected intestinal perfusate and bile samples was performed by HPLC-UV and HPLC-MS. No oxidative metabolites could be detected in the perfusate samples. The biliary appearance of ibuprofen, 2-hydroxyibuprofen, ibuprofen glucuronide, hydroxylated ibuprofen glucuronide, and ibuprofen taurate was depressed in the hyperglycemic animals. However, no specific non-enzymatic (hydroxyl radical initiated) hydroxylation product could be detected. Instead, the depression of biliary excretion of ibuprofen and ibuprofen metabolites turned out to be the indicative marker of hyperglycemia. The observed changes impact the pharmacokinetics of drugs administered in hyperglycemic individuals. Full article

In cattle, phenobarbital (PB) upregulates target drug-metabolizing enzyme (DME) mRNA levels. However, few data about PB’s post-transcriptional effects are actually available. This work provides the first, and an almost complete, characterization of PB-dependent changes in DME catalytic activities in bovine liver using common probe substrates and confirmatory immunoblotting investigations. As expected, PB increased the total cytochrome P450 (CYP) content and the extent of metyrapone binding; moreover, an augmentation of protein amounts and related enzyme activities was observed for known PB targets such as CYP2B, 2C, and 3A, but also CYP2E1. However, contradictory results were obtained for CYP1A, while a decreased catalytic activity was observed for flavin-containing monooxygenases 1 and 3. The barbiturate had no effect on the chosen hydrolytic and conjugative DMEs. For the first time, we also measured the 26S proteasome activity, and the increase observed in PB-treated cattle would suggest this post-translational event might contribute to cattle DME regulation. Overall, this study increased the knowledge of cattle hepatic drug metabolism, and further confirmed the presence of species differences in DME expression and activity between cattle, humans, and rodents. This reinforced the need for an extensive characterization and understanding of comparative molecular mechanisms involved in expression, regulation, and function of DMEs. Full article