Genetic variations within the cytochrome P450 (CYP) gene family are significant determinants of type 2 diabetes mellitus (T2DM) susceptibility. This study aimed to investigate the association between CYP2C8 and CYP2D6 gene variants and the risk of T2DM.

We conducted a case-control study involving 512 individuals with T2DM and 515 controls. Genotyping of CYP2C8 and CYP2D6 polymorphisms was performed using the Agena MassARRAY system. Logistic regression analysis was employed to estimate the odds ratios (ORs) and 95% confidence intervals (CIs), thereby assessing the relationship between these genetic variants and T2DM risk. Additionally, multifactor dimensionality reduction (MDR) was utilized to assess the potential interaction effects of SNPs on T2DM risk.

The study found a strong correlation between rs1065852 and increased risk of T2DM in overall (A vs. G: OR = 1.22, 95% CI: 1.03-1.45, p = .024; AA vs. GG: OR = 1.46, 95% CI: 1.04-2.06, p = .031; AA-AG vs. GG: OR = 1.36, 95% CI: 1.04-1.79, p = .026; additive: OR = 1.21, 95% CI: 1.02-1.44, p = .027), males and age < 59 subgroups. However, there is no significant association between the CYP2C8 polymorphisms (rs1934953, rs1934951, rs2275620 and rs17110453) and T2DM risk. MDR analysis results showed that the best model was the one locus model (rs1065852, testing accuracy = 0.534; OR = 1.39; 95% CI: 1.05-1.85; p = .023; CVC = 10/10), indicating that rs1065852 is an independent risk factor for T2DM.

This study suggests that rs1065852 (CYP2D6) is an independent risk factor for T2DM. Further research is warranted to validate these results and explore their clinical implications.

Gut microbiota, which act as a determinant of pharmacokinetics, have long been overlooked. In recent years, a growing body of evidence indicates that the gut microbiota influence drug metabolism and efficacy. Conversely, drugs also exert a substantial influence on the function and composition of the gut microbiota. Pharmacomicrobiomics, an emerging field focusing on the interplay of drugs and gut microbiota, provides a potential foundation for making certain advances in personalized medicine. Understanding the communication between gut microbiota and antiparkinsonian drugs is critical for precise treatment of Parkinson's disease. Here, we provide a historical overview of the interplay between gut microbiota and antiparkinsonian drugs. Moreover, we discuss potential mechanistic insights into the complex associations between gut microbiota and drug metabolism. In addition, we also draw attention to microbiota-based biomarkers for predicting antiparkinsonian drug efficacy and examine current state-of-the-art knowledge of microbiota-based strategies to optimize drug therapy in Parkinson's disease.

Drug overdose is a pressing global public health challenge, with current detoxification treatments often lacking the broad-spectrum efficacy needed for emergency applications. Inspired by the unique advantages of cell membrane-derived nanodiscs (CNDs), including their compact size, rapid distribution, and preservation of native cell membrane functions, we developed endoplasmic reticulum (ER)-derived nanodiscs (ER-NDs) from the ER membranes of mouse hepatic cells for broad-spectrum drug detoxification. ER-NDs retain natural cytochrome P450 (CYP) enzymes, enabling effective detoxification of three model drugs: bupropion, haloperidol, and propranolol. Cell-based assays demonstrated ER-NDs' ability to mitigate drug-induced cytotoxicity, reduce oxidative stress, and restore antioxidant defenses. In mouse models of drug intoxication, ER-ND treatment significantly improved survival rates and alleviated drug-induced oxidative damage. Importantly, ER-NDs showed no evidence of acute toxicity in vivo. These findings underscore the potential of ER-NDs as a versatile platform for broad-spectrum drug detoxification and as a promising tool for managing drug intoxication in emergency and clinical settings.

Cinnamon is one of the oldest known spices used in various food delicacies and herbal formulations. Cinnamaldehyde is a primary active constituent of cinnamon and substantially contributes to the food additive and medicinal properties of cinnamon. This report deals with cinnamaldehyde bioaccessibility, metabolic clearance, and interaction with human xenobiotic receptors (PXR and AhR). Results showed the bioaccessibility of cinnamaldehyde was 100 % in both fasted and fed-state gastric and intestinal fluids. Upon incubation with human liver microsomes (HLMs) and human liver S-9 fraction, cinnamaldehyde (alone or in cinnamon oil) rapidly oxidized into cinnamic acid. Cinnamon oil dose-dependently activated AhR in human AhR-reporter cells, but cinnamaldehyde and cinnamic acid did not affect AhR. In addition, cinnamon oil and cinnamic acid dose-dependently activated PXR in human hepatic (HepG2) and intestinal (LS174T) cells. Both cinnamon oil and cinnamaldehyde inhibited the catalytic activity of CYP2C9 and CYP1A2. Our findings indicated that cinnamaldehyde (alone or in cinnamon oil) possesses high bioaccessibility and adequate metabolic stability. Hence, while controlled ingestion of cinnamon-containing foods or supplements may have beneficial effects but overconsumption could induce PXR or AhR-dependent herb-drug interactions (HDIs) which can bring deleterious effects on human health, particularly in individuals with chronic health conditions.

The use of vegetable residues as a source of bioactive components is a global trend. The production of flours reintroduces these materials into the productive chain and extend their shelf-life. Processing may reduce the diversity of pigments present in the fresh matter. We analysed a beetroot peel flour (BPF) that presented relevant protein and fibre contents and preserved the colour of the in natura beetroot (Beta vulgaris L.) due to the presence of betacyanins and betaxanthins. The bioavailability, pharmacokinetics and mutagenicity of the pigments were predicted using bioinformatics. No mutagenicity was confirmed according to the OECD guidelines. A chemoprotective effect and cancer cell anti-clone activities were observed. BPF processing ensured a good nutritional value and maintained this product as a good source of bioactive compounds and of pigments with antitumor activity, suggesting this vegetable residue as a food industry pigments source for use in the elaboration of functional products.

Triazoles are among the most widely used fungicides that were launched in 1980s and are one of the most important pesticide groups used in agriculture as plant growth regulators and stress protectors. Triazoles are also frequently used in the pharmaceutical industry to treat fungal and bacterial infections as well as to treat and prevent some forms of pneumonia. Humans are normally exposed to triazoles through food, water, and medications, which raises concerns about their potential adverse effects on health. Therefore, this review was planned to examine the impact of triazole fungicides on female fertility, as well as their teratogenic and embryotoxic effects. Various search engines such as PubMed, Google Scholar, Elsevier, IEEE were used to search the relevant articles published between 2006 and 2024 using the following keywords: "azoles," "female infertility," "reproductive toxicity," "teratogenicity," "triazoles," and "embryo toxicity." The findings suggest that triazoles might negatively affect female fertility and embryonic development through multiple mechanisms including inhibition or interference with key enzymes such as CYP17A1 and CYP19A1 (aromatase) involved in steroid hormone synthesis, endocrine disruption, oxidative stress, disruption of signaling pathways, and apoptosis. This review consolidates current knowledge on the teratogenic and embryotoxic properties of triazole fungicides, providing a comprehensive understanding of their health implications and addressing critical research gaps.

Fenethylline (street name, captagon) is a synthetic amphetamine-type stimulant that is emerging as a significant public health and security concern, particularly in the Middle East. This systematic review synthesizes original research articles, epidemiological studies, systematic reviews, policy analyses, and case reports to provide a comprehensive analysis of fenethylline's health impacts, addiction potential, and dynamics of illicit trade. Initially developed for therapeutic use, fenethylline illicit production and use have escalated, raising concern about its physiological, psychological, and socio-economic impacts. This stimulant profoundly affects the central nervous system, enhancing wakefulness, concentration, and physical stamina while inducing euphoria. These effects come at the cost of serious adverse health outcomes, particularly with prolonged or heavy use, including cardiovascular complications, neurological damage, and addiction. The dependence-forming nature of captagon contributes to escalating substance use disorders, impacting healthcare systems. Beyond its biomedical implications, fenethylline trafficking has become a global issue, with supply chains deeply intertwined with politically unstable regions where illicit economies thrive. The geopolitical dimensions of captagon's trade amplify its global security threat, influencing international relations and regional stability. This paper underscores the urgent need for systematic data collection and coordinated efforts to regulate illicit fenethylline production and distribution. Strategies such as improved surveillance, public health interventions, and international cooperation are essential to mitigate its escalating risks. Addressing this issue requires a multidisciplinary approach, integrating public health, law enforcement, and policy development to curb its impact on global health and security.

α-Hydroxy acids are naturally occurring organic molecules with various medical and industrial applications. However, some α-hydroxy acids, like D-2-hydroxyglutarate (D2HG), have been implicated in cancers and neurometabolic disorders such as D2HG aciduria. Several studies on the D2HG oxidizing enzyme D-2-hydroxyglutarate dehydrogenase (D2HGDH) from various eukaryotic and prokaryotic sources focus on the use and application of the enzyme as biosensors for detecting D2HG. A recent gene knockout study on the bacterial D2HGDH homologs from Pseudomonas stutzeri and Pseudomonas aeruginosa identified the D2HGDH to be essential for bacterial survival by driving l-serine biosynthesis. Thus, D2HGDH is a good candidate for a therapeutic target against the multidrug-resistant P. aeruginosa. However, there is no consensus on the D2HGDH catalytic mechanism, and several D2HGDH homologs have not been characterized in their structural properties, which are two crucial features for therapeutic design. P. aeruginosa D2HGDH, the most extensively studied D2HGDH homolog, is emerging as a paradigm for D2HGDH and flavoproteins with metal ions in their active site. In this review, we have explored the structures of all published D2HGDH homologs from 12 species using AlphaFold 3 and highlighted the fully conserved structure and active site topologies of all D2HGDH homologs. Additionally, evolutionary and functional studies coupled with analyses of enzymatic activities reveal that prokaryotic and eukaryotic D2HGDH homologs, diverging from two distinct ancestors, may have differentially evolved to specialize in their α-hydroxy acid catalysis. Additionally, this review identifies all D2HGDH homologs as metal and FAD-dependent enzymes that employ a metal-triggered FAD reduction in their catalysis. Elucidation of the D2HGDH mechanism will allow designing antibiotics that target these enzymes as potential therapeutics against pathogenic bacteria like P. aeruginosa in addition to the application of D2HGDH homologs as biosensors.

Drug-metabolizing enzymes (DMEs) and transporters (DTs) play integral roles in drug metabolism and drug-drug interactions (DDIs) which directly impact drug efficacy and safety. It is well-established that inhibition of DMEs and DTs often leads to adverse drug reactions (ADRs) and therapeutic failure. As such, early prediction of such inhibitors is vital in drug development. In this context, the limitations of the traditional in vitro assays and QSAR models methods have been addressed by harnessing artificial intelligence (AI) techniques.

This narrative review presents the insights gained from the application of AI for predicting DME and DT inhibitors over the past decade. Several case studies demonstrate successful AI applications in enzyme-transporter interaction prediction, and the authors discuss workflows for integrating these predictions into drug design and regulatory frameworks.

The application of AI in predicting DME and DT inhibitors has demonstrated significant potential toward enhancing drug safety and effectiveness. However, critical challenges involve the data quality, biases, and model transparency. The availability of diverse, high-quality datasets alongside the integration of pharmacokinetic and genomic data are essential. Lastly, the collaboration among computational scientists, pharmacologists, and regulatory bodies is pyramidal in tailoring AI tools for personalized medicine and safer drug development.

Chronic inflammation (an abnormal state) and autoimmune disease (AD) can both cause multiple organ damage. AD is a heterogeneous group of diseases due to immune dysfunction. Chronic inflammation is closely related to AD and is an important part of AD. With the increasing prevalence of AD, researchers are constantly exploring new drugs with small side effects, considerable curative effects, and lower costs. Kaempferol, a flavonoid, possesses a range of biological functions, including antioxidant, anti-inflammatory, anti-neoplastic, and immunomodulatory capabilities. This compound is prevalent in a variety of plant sources, such as vegetables, fruits, and medicinal herbs traditionally used in Chinese medicine. A plethora of empirical evidence from animal-based research supports the assertion that this particular substance exhibits both anti-inflammatory and immunomodulatory effects, with the curative effect being significant and application prospects. This article mainly summarizes and discusses the pharmacokinetics, drug delivery system, and the mechanism of kaempferol on immune cells, cytokines, signaling pathways, and other aspects. This paper summarizes the existing kaempferol drug delivery system, analyzes the possibility and limitations of kaempferol as a new anti-inflammatory and immunomodulatory drug, and discusses how to apply it in clinical practice. Therefore, kaempferol can more effectively exert its anti-inflammatory and immune-modulating effects, thereby demonstrating therapeutic potential in clinical settings, while reducing patient burden.

Ninety percent of pregnant patients take at least one medication during pregnancy. Physiological changes during pregnancy can alter drug exposure. Understanding basic physiological principles including absorption, distribution, metabolism and excretion can guide medication management during pregnancy. While physiologic changes related to medications used to treat hypothyroidism, depression and epilepsy are highlighted in this article, the principles of pharmacokinetic changes during pregnancy can be applied to other medical conditions where less data may exist. Given the complexity of pharmacology, physiological changes of pregnancy, and nuances of managing medical conditions, a team approach to managing medications in pregnancy is recommended. Comprehensive care including general and specialized physicians, pharmacists, genetic counselors and more can help provide the most appropriate care to this multifaceted patient population.

Drug-drug interactions associate with concurrent uses of multiple medications. Cytochrome P450 (CYP) 3A4 metabolizes a large portion of marketed drugs. To maintain the efficacy of drugs metabolized by CYP3A4, pan-CYP3A inhibitors such as ritonavir are often co-administered. Although selective CYP3A4 inhibitors have greater therapeutic benefits as they avoid inhibiting unintended CYPs and undesirable clinical consequences, the high homology between CYP3A4 and CYP3A5 has hampered the development of such selective inhibitors. Here, we report a series of selective CYP3A4 inhibitors with scaffolds identified by high-throughput screening. Structural, functional, and computational analyses reveal that the differential C-terminal loop conformations and two distinct ligand binding surfaces disfavor the binding of selective CYP3A4 inhibitors to CYP3A5. Structure-guided design of compounds validates the model and yields analogs that are selective for CYP3A4 versus other major CYPs. These findings demonstrate the feasibility to selectively inhibit CYP3A4 and provide guidance for designing better CYP3A4 selective inhibitors.

Ajuga decumbens, a traditional Chinese medicine, possesses anti-breast cancer effects. Its main component, 8-O-acetylharpagide, exhibits potential anticancer activity; however, the active metabolites and mechanisms underlying its effects remain unclear.

The metabolism and excretion of 8-O-acetylharpagide in rats were investigated using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry analysis of bile, urine, and feces. Active metabolites were identified and evaluated using network pharmacology, molecular docking, and Western blotting assays.

A total of 21 metabolites were identified, with demethylation, hydrolysis, and glucuronidation being the primary metabolic pathways. M3 and M5 were identified as key metabolites, showing strong binding affinity to cancer-related targets, such as AKT1, MMP9, and STAT3. M5 displayed strong pharmacokinetic properties, including better lipid solubility and reduced polarity. Network pharmacology analysis indicated that these metabolites exert anticancer effects by modulating the PI3K/AKT signaling pathway. In vivo experiments demonstrated that oral administration of 8-O-acetylharpagide significantly inhibited the proliferation of 4T1 tumor tissues by suppressing the expression of the AKT/NF-κB/MMP9 signaling axis. This may be related to inhibition of the expression of the AKT/NF-κB/MMP9 signaling axis in 4T1 tumor tissues after metabolism of 8-O-acetylharpagide to M5 and M3.

As a prodrug, 8-O-acetylharpagide is metabolized to M5, which may subsequently exert an anti-breast cancer effect through downregulation of the AKT/NF-κB/MMP9 signaling axis. This study provides a theoretical basis for the clinical application of Ajuga decumbens in breast cancer therapy.

Resistance to cancer therapies is increasingly recognized as being influenced by long non-coding RNAs (lncRNAs), which are pivotal in regulating cellular functions and gene expression. Elucidating the intricate relationship between lncRNAs and the mechanisms underlying drug resistance is critical for advancing effective therapeutic strategies. This study offers an in-depth review of the regulatory roles lncRNAs play in various signaling and immunological pathways implicated in cancer chemoresistance. lncRNA-mediated influence on drug resistance-related signaling pathways will be presented, including immune evasion mechanisms and other essential signaling cascades. Furthermore, the interplay between lncRNAs and the immune landscape will be dissected, illustrating their substantial impact on the development of chemoresistance. Overall, the potential of lncRNA-mediated signaling networks as a therapeutic strategy to combat cancer resistance has been highlighted. This review reiterates the fundamental role of lncRNAs in chemoresistance and proposes promising avenues for future research and the development of targeted therapeutic interventions.

Introduction: Carbonic anhydrase IX (CA IX) is a tumor-associated enzyme involved in cancer progression and survival. Targeting CA IX with selective inhibitors like SLC-0111 has shown therapeutic potential. This study aimed to develop a novel 4-pyridyl analog (Pyr) of SLC-0111 with enhanced anticancer activity. Methods: Pyr was synthesized using a tail-based design and characterized by NMR. Its cytotoxicity was tested against cancer and normal cell lines. CA inhibition, cell cycle effects, apoptosis induction, and protein expression changes were evaluated. Molecular docking and ADMET predictions assessed binding and drug-like properties. Results and Discussion: Pyr showed selective cytotoxicity toward cancer cells and potent CA IX inhibition. It induced G0/G1 arrest, apoptosis, and modulated p53, Bax, and Bcl-2 levels. Docking confirmed strong CA IX binding, and ADMET analysis indicated good oral bioavailability. These results support Pyr as a promising anticancer candidate.

Pregnancy alters the systemic exposure and clearance of many hepatically cleared drugs that are commonly used by obstetric patients. Understanding the molecular mechanisms underlying the changes in factors that affect hepatic drug clearance (blood flow, protein binding, and intrinsic clearance) is essential to more precisely predict systemic drug exposure and dose requirements in obstetric patients.

This review (1) summarizes the anatomic, physiologic, and biochemical changes in maternal hepatic, cardiovascular, endocrine, and renal systems relevant to hepatic drug clearance and (2) reviews the molecular mechanisms underlying the altered hepatic metabolism and intrinsic clearance of drugs during pregnancy via a comprehensive PubMed search. It also identifies knowledge gaps in the molecular mechanisms and factors that modulate hepatic drug clearance during pregnancy.

Pharmacokinetic studies have shown that pregnancy alters systemic exposure, protein binding, and clearance of many drugs during gestation in part due to pregnancy-associated decreases in plasma albumin, increases in organ blood flow, and changes in the activity of drug-metabolizing enzymes (DMEs) and transporters. The changes in the activity of certain DMEs and transporters during pregnancy are likely driven by hormonal-changes that inhibit their activity or alter the expression of these proteins through activation of transcription factors.

Metformin, an oral antihyperglycemic drug that has been in use for over 60 years, remains a first-line therapy for type 2 diabetes (T2D). Numerous studies have suggested that metformin promotes health benefits beyond T2D management, including weight loss, cancer prevention and treatment, and anti-aging, through several proposed mechanistic targets. Here we discuss the established effects of metformin and the progress made in identifying its direct targets. Additionally, we emphasize the importance of elucidating the structural bases of the drug and its direct targets. Ultimately, this review aims to highlight the current state of knowledge regarding metformin and its related emerging discoveries, while also outlining critical future research directions.

This study aimed to profile metabolites from five Trichoderma strains and assess their cytotoxic and pharmacological activities, particularly targeting oral squamous cell carcinoma (OSCC). UHPLC-TOF-MS analysis revealed the presence of 25 compounds, including heptelidic acid, viridiol isomers, and sorbicillinol from the different Trichoderma extracts. Pharmacokinetic analysis showed moderate permeability and low interaction with P-glycoprotein, suggesting good drug absorption with minimal interference in cellular uptake. ADME-Tox analysis indicated limited inhibition of cytochrome P450 enzymes, low renal clearance, which are favorable for maintaining therapeutic levels. Toxicity predictions revealed some compounds with potential mutagenicity, but low hepatotoxicity and skin sensitization risks. Network pharmacology identified MAPK1 as a key target for oral cancer, and molecular docking and induced fit docking studies demonstrated strong binding affinities of Trichoderma metabolites, including stachyose and harzianol, to MAPK1. In addition, molecular dynamics (MD) simulations confirmed stable interactions. In vitro studies on NIH3T3 and YD-10B cells showed significant cytotoxicity, particularly with extracts CNU-05-001 (IC50:10.15 µg/mL) and CNU-02-009 (10.00 µg/mL) against YD-10B cells. These findings underscore the potential of Trichoderma metabolites in drug discovery, particularly for cancer therapies.

Metabolically active compounds can cause toxicity which would otherwise be undetected using traditional in vitro assays with limited proficiency for xenobiotic metabolism. Introduction of liver microsomes to assay systems enables enhanced identification of compounds that require biotransformation to induce toxicity. Previously, metabolically active compounds from the Tox21 10 K compound library were identified using assays probing two targets, p53 and acetylcholinesterase (AChE), in the presence and absence of human or rat liver microsomes, due to the established roles of cytochrome P450 (CYP) enzymes in human drug metabolism. To further explore the role of metabolic activation, the activities of the identified metabolically active compounds were evaluated against five CYP enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. CYP bioactivities were found to be highly predictive (>80 % accuracy) of compounds that required metabolic activation in these assays. Chemical features significantly enriched in metabolically active compounds, as well as chemical features that were specific for each of the five CYPs, were identified. Product use exposures of the metabolically active compounds were examined in this study, with "pesticides" appearing to be the largest category that may produce harmful metabolites. Additionally, the compound interactions with different CYPs were assessed and frequencies for both classes of compounds, drugs and environmental chemicals, were found to be proportionally similar across the five CYP isoforms.

The intestinal barrier constitutes the largest surface of the human body communicating with the external environment. Alterations affecting elements of intestinal wall may lead to increased intestinal permeability and resulting translocation of bacteria or its components to the bloodstream in the form of the "leaky gut syndrome" (LGS). One of the most common causes of LGS is the disruption of tight junctions (TJ) maintained by tight junction proteins (TJP). LGS and associated alterations in TJP are observed in numerous gastrointestinal (GI) diseases, including inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC). Current literature indicates the key role of LGS in many pathological processes, further emphasizing the need for effective pharmacological approaches to treat this syndrome. One of the potential pharmacological targets in LGS treatment are members of the cytochrome P450 (CYP450) superfamily. By affecting intestinal permeability, they may lead to LGS development. It was found that the expression of CYP8B1 synthesizing cholic acid and CYP26 degrading all-trans retinoic acid indirectly influence TJs. CYP2E1 responsible for the metabolism of a wide variety of chemicals, including ethanol, plays a crucial role in the impairment of the intestinal wall. Contrarily, the overexpression of CYP27B1 has a protective effect on the intestinal integrity. CYP1A1, CYP2A6, CYP2J2 and CYP3A were also suggested to influence the GI tract, through their capability to metabolize serotonin, nicotine, endocannabinoids and gemcitabine, respectively. This review summarizes the findings on the role of CYP450 isoforms in intestinal hyperpermeability and their potential involvement in the pathophysiology of LGS.

Oral squamous cell carcinoma (OSCC) is a common form of cancer, with 390,000 new cases estimated for 2022. OSCC has a poor prognosis, largely due to a high recurrence rate and resistance to therapy. Cancer cells develop resistance to standard therapy owing to various factors, such as genetic predispositions, alterations in the apoptotic pathway coupled with DNA repair pathways, drug efflux, and drug detoxification. This review is aimed at exploring the crucial role of paraoxonase 2 (PON2) in conferring resistance to chemotherapy and radiotherapy in OSCC cells. PON2, an antioxidant enzyme, protects cancer cells from the oxidative stress caused by these treatments. By influencing apoptotic pathways and DNA repair mechanisms, PON2 can reduce the effectiveness of therapy. This review is an attempt to explore the complex molecular mechanisms modulated by PON2, such as the mitigation of oxidative stress, enhancement of DNA repair, apoptosis regulation, drug efflux modulation, and drug detoxification, which decrease treatment efficacy.

This study aimed to explore the therapeutic potential of medicinal herbs for chronic periodontitis by examining the molecular interactions between specific herbal compounds and the heme-binding protein of Porphyromonas gingivalis, a key pathogen involved in the disease.

The crystal structure of heme-binding protein was obtained from the Protein Data Bank. Herbal compounds were identified through an extensive literature review. Molecular docking simulations were performed to predict binding affinities, followed by Absorption, Distribution, Metabolism, and Excretion (ADME) parameter prediction. Drug-likeness was assessed based on Lipinski's Rule of Five, and pharmacophore modeling was conducted to identify key molecular interactions.

The molecular docking simulations revealed that chelidonine, rotenone, and myricetin exhibited significant binding affinities to the heme-binding protein, with docking scores of -6.5 kcal/mol, -6.4 kcal/mol, and -6.1 kcal/mol, respectively. These compounds formed stable interactions with key amino acid residues within the binding pocket. ADME analysis indicated that all 3 compounds had favourable pharmacokinetic properties, with no violations of Lipinski's rules and minimal predicted toxicity. Pharmacophore modeling further elucidated the interaction profiles, highlighting specific hydrogen bonds and hydrophobic interactions critical for binding efficacy.

Chelidonine, rotenone, and myricetin emerged as promising therapeutic candidates for chronic periodontitis due to their strong binding affinities, favorable ADME profiles, and lack of significant toxicity. The detailed pharmacophore modeling provided insights into the molecular mechanisms underpinning their inhibitory effects on the heme-binding protein of P. gingivalis. These findings suggest that these compounds have the potential for further development as effective treatments for chronic periodontitis. Future research should focus on in vitro and in vivo validation of these findings to confirm the efficacy and safety of these compounds in biological systems.

Cytochrome P450 (CYP) enzymes play an important role in the biotransformation of drugs and endogenous substances. Clinical medications and herbal remedies can either enhance or inhibit the activity of CYP enzymes, leading to potential drug interactions between herbal supplements and prescribed medications. Such interactions can lead to serious consequences, especially for drugs with a narrow therapeutic index, such as digoxin, warfarin, and cyclosporine A. In this review article, we provide an updated review of the impact of saffron, and its active constituents, safranal and crocin, on the 12 major human CYP enzymes and possible drug interactions between saffron and prescription drugs. The available evidence indicates that saffron and its active constituents affect the expression or activity of some CYP isoforms, including the CYP1A1/2, CYP3A4, and CYP2E1 subfamily. Considering the important role of these CYPs in the biotransformation of frequently prescribed medications and the activation of procarcinogen into carcinogenic metabolites, it can be expected that the consumption of saffron and its active constituents may influence the pharmacokinetics and toxicity of several substances. In particular, given the critical role of CYP3A4 in drug metabolism, and saffron's inhibitory impact on this CYP enzyme, it appears that saffron's most significant interaction is linked to its inhibition of CYP3A4. In addition, the inhibitory effect of saffron on CYP1A1/2, and CYP2E1 expression can play a role in the chemopreventive effect of this herbal medicine. Additional research is crucial for evaluating the clinical significance of these interactions in patients who consume saffron along with prescription drugs and determining the dose that can lead to drug interactions.

In all organisms, the biotransformation of xenobiotics to less toxic and more hydrophilic compounds represents an effective defense strategy. In pathogens, the biotransformation of drugs (used for their elimination from the host) may provide undesirable protective effects that could potentially compromise the drug's efficacy. Accordingly, increased drug deactivation via accelerated biotransformation is now considered as one of the mechanisms of drug resistance. The present study summarizes the current knowledge regarding the biotransformation of anthelmintics, specifically drugs used to treat mainly nematodes, a group of parasites that are a significant health concern for humans and animals. The main biotransformation enzymes are introduced and their roles in anthelmintics metabolism in nematodes are discussed with a particular focus on their potential participation in drug resistance. Similarly, the inducibility of biotransformation enzymes with sublethal doses of anthelmintics is presented in view of its potential contribution to drug resistance development. In the conclusion, the main tasks awaiting scientists in this area are outlined.

With the development of science and technology and the acceleration of industrialization, environmental pollution is becoming more and more serious, and the global fertility rate is decreasing every year, which makes people pay more attention to reproductive health. Nitrosamines are a kind of easy to contact food pollutants, widely exist in pickled food (10.2-14.8 mg/kg) and contaminated water sources (10-150 ng/L), etc. They have been confirmed to be carcinogenic, but the reproductive and developmental toxic effects of nitrosamines have not been systematically reported. Based on relevant researches, the classification, distribution and metabolism kinetics of nitrosamines were summarized in this review. In addition, nitrosamines can inhibit testosterone synthesis (Leydig cells) and spermatogenesis (spermatogenic cells) in F0 male, and reduce ovary functions in F0 female, finally induce parental reproductive toxic effects. Meanwhile, the effects of parental (including maternal pregnancy, paternal) nitrosamine exposure on offspring development (such as cancer susceptibility) and related research deficiencies were summarized. To sum up, this paper systematically reviewed the reproductive and developmental toxic effects caused by exposure to nitrosamines, enabling people to fully understand the negative effects of nitrosamines on the body, so as to effectively avoid and reduce intake in daily life, and at the same time provide a theoretical and literature basis for guiding the healthy life and maintaining fertility.

Arthritis is an autoimmune disorder that predominantly causes inflammation and impacts peripheral joints. Even though immunosuppressive and NSAIDs or non-steroidal anti-inflammatory medicines are implemented for the management of this disorder, sbut they carry some severe side effects along with them. Therefore, society requires treatment with fewer side effects and powerful anti-arthritic properties, such as flavonoids. These are the most prevalent phenolic compounds found in nature that have potent antioxidant, and immunomodulatory activity and there are several bioactive flavonoids that carry potent anti-inflammatory properties. Nevertheless, only a handful has reached their clinical use. Still, in both clinical and preclinical models of arthritis, flavonoids found in the diet have been shown to reduce swelling in joints and arthritis symptoms. There are only a few scientific studies regarding their mechanisms of action in arthritis. However, the arthritic potential of dietary flavonoids is insufficient because of their limited solubility, absorption, and fast metabolism. Nanocarriers may enhance the bioavailability of flavonoids. This review examines the therapeutic effects of the most prevalent and abundant flavonoid groups on arthritis. Specifically, the modes of action of the most important flavonoids on the chemical messengers in the body that contribute to the signalling of joint inflammation-related indicators of arthritis are discussed in more detail.

This work focuses on the synthesis and characterization of a new series of coumarin-hydrazone derivatives, as well as the evaluation of their inhibitory effects on platelet aggregation induced by adenosine diphosphate (ADP), arachidonic acid (AA), and collagen. Compounds 10 and 11 exhibit a significant inhibition of ADP-induced platelet aggregation. The AA-induced aggregation pathway was inhibited by compound 11 (45%), while none showed an inhibitory effect against collagen-induced aggregation. In addition, both compounds inhibited platelet binding to fibrinogen, CD62-P expression, and glycoprotein IIb/IIIa activation. The interaction of these compounds with their potential targets, P2Y12 and COX-1, was studied using a molecular docking approach. Furthermore, the ADMET properties of the compounds selected were evaluated in silico using Swiss ADME and ProTox-II tools. Selected active compounds demonstrated interesting pharmacokinetic and drug properties, indicating a favorable ADMET profile. In vitro and in silico results are in accordance. Toxicity on lymphocytes, erythrocytes, and platelets was evaluated for the two selected molecules and found to be safe. In summary, this study proposes two novel coumarin-hydrazone derivatives as new potential treatments to prevent cardiovascular events by acting on platelet adhesion, activation, and aggregation.

Chromatography coupled with mass spectrometry (MS) has emerged as a cornerstone analytical technique in drug research. Over the years, advancements in chromatography-MS have significantly enhanced its capabilities, leading to improved sensitivity, specificity, and throughput. This review explores the innovative applications of chromatography-MS in drug research, particularly focusing on its role in drug absorption, distribution, metabolism, excretion (ADME), toxicity evaluation, and personalized medicine. It also addresses the future perspectives of this powerful technique, including challenges and potential solutions, and highlights how emerging trends such as high spatial resolution imaging and multimodal integration could revolutionize drug discovery and development. Through these innovations, chromatography-MS promises to contribute substantially to the development of more effective, safer, and personalized therapeutic interventions.

Pharmacological research has traditionally been skewed toward male subjects, leading to uniform treatment guidelines for both men and women that assume similar drug pharmacokinetics across sexes. This oversight contributes to women experiencing adverse drug reactions on average twice as often as men. More recent studies have revealed significant pharmacokinetic differences between the sexes, partly due to different sex hormone levels. Additionally, intraindividual differences in women have been observed due to fluctuating estrogen levels, impacting important aspects of drug pharmacokinetics.

This review highlights key sex differences in drug pharmacokinetics, focusing on absorption, distribution, metabolism, and excretion. A particular emphasis is placed on the role of cytochrome P450 (CYP) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes in drug metabolism, and on the role of P-glycoprotein (P-gp). The impact of estrogens is reviewed by exploring how drug pharmacokinetics change over the menstrual cycle, before and after menopause, and with estrogen-containing medications.

Personalized dosing based on sex and estrogen levels is important for improving treatment outcomes in female drug users. Clinical trials of drugs likely affected by these factors should incorporate pharmacokinetic studies that distinguish between sexes and evaluate the impact of estrogens, aiming to develop optimized dosing regimens.

The global incidence and prevalence of cardiometabolic disorders have risen significantly in recent years. Although lifestyle choices in adulthood play a crucial role in the development of these conditions, it is well established that events occurring early in life can have an important effect. Recent research on cardiometabolic diseases has highlighted the influence of sexual dimorphism on risk factors, underlying mechanisms, and response to therapies. In this narrative review, we summarize the current understanding of sexual dimorphism in cardiovascular and metabolic diseases in the general population and within the framework of the Developmental Origins of Health and Disease (DOHaD) concept. We explore key risk factors and mechanisms, including the influence of genetic and epigenetic factors, placental and embryonic development, maternal nutrition, sex hormones, energy metabolism, microbiota, oxidative stress, cell death, inflammation, endothelial dysfunction, circadian rhythm, and lifestyle factors. Finally, we discuss some of the main therapeutic approaches, responses to which may be influenced by sexual dimorphism, such as antihypertensive and cardiovascular treatments, oxidative stress management, nutrition, cell therapies, and hormone replacement therapy.

Chronic pain significantly impacts quality of life and is often accompanied by inflammation, a natural bodily response that can become harmful when excessive. The orofacial region is commonly affected, making effective treatment crucial. However, current drugs often cause undesirable side effects, highlighting the need for new pharmacological alternatives. 4-hydroxycoumarin (4-HC), a natural compound, has shown promising antinociceptive and anti-inflammatory effects, but studies confirming its specific properties are limited. In silico analyses suggest that 4-HC exhibits favorable pharmacokinetic characteristics, not interacting with P-glycoprotein and successfully crossing the blood-brain barrier. Molecular docking studies indicate that its effects may be mediated through NMDAR or by inhibiting iNOS. Our study assessed the antinociceptive and anti-inflammatory effects of 4-HC in animal models at doses of 25, 50, and 75 mg/kg. 4-HC significantly reduced abdominal contortions induced by acetic acid and decreased nociceptive rubbing in orofacial pain models induced by formalin, glutamate, and capsaicin. Interactions with opioid receptors were not observed, suggesting that 4-HC's antinociceptive effect does not involve this pathway. Additionally, 4-HC reduced paw edema induced by carrageenan and significantly decreased leukocyte migration and TNF-α levels. These findings highlight the therapeutic potential of 4-HC and warrant further investigation into its mechanisms.

Therapeutic proteins play a crucial role in modern healthcare. However, the rapid clearance of proteins in the circulation system poses a significant threat to their therapeutic efficacy. The generation of anti-drug antibodies expedites drug clearance, resulting in another challenge to overcome in protein delivery. Several methods to increase the circulation half-lives of these proteins and to minimize their immunogenicity have been developed. This Review discusses the causes of protein clearance in the body, evaluates the FDA-approved strategies to prolong protein circulation, and highlights recent progress in the field. Additionally, the strengths and drawbacks of these methods and our perspectives for advancing protein delivery are provided.

Human cytochrome P450 (CYP) enzymes in the brain represent a crucial frontier in neuroscience, with far-reaching implications for drug detoxification, cellular metabolism, and the progression of neurodegenerative diseases. The brain's complex architecture, composed of interconnected cell types and receptors, drives unique neuronal signaling pathways, modulates enzyme functions, and leads to distinct CYP gene expression and regulation patterns compared to the liver. Despite their relatively low levels of expression, brain CYPs exert significant influence on drug responses, neurotoxin susceptibility, behavior, and neurological disease risk. These enzymes are essential for maintaining brain homeostasis, mediating cholesterol turnover, and synthesizing and metabolizing neurochemicals, neurosteroids, and neurotransmitters. Moreover, they are key participants in oxidative stress responses, neuroprotection, and the regulation of inflammation. In addition to their roles in metabolizing psychotropic drugs, substances of abuse, and endogenous compounds, brain CYPs impact drug efficacy, safety, and resistance, underscoring their importance beyond traditional drug metabolism. Their involvement in critical physiological processes also links them to neuroprotection, with significant implications for the onset and progression of neurodegenerative diseases. Understanding the roles of cerebral CYP enzymes is vital for advancing neuroprotective strategies, personalizing treatments for brain disorders, and developing CNS-targeting therapeutics. This review explores the emerging roles of CYP enzymes, particularly those within the CYP1-3 and CYP46 families, highlighting their functional diversity and the pathological consequences of their dysregulation on neurological health. It also examines the potential of cerebral CYP-based biomarkers to improve the diagnosis and treatment of neurodegenerative disorders, offering new avenues for therapeutic innovation.

Mitochondrial functionality and cellular iron homeostasis are closely intertwined. Mitochondria are biosynthetic hubs for essential iron cofactors such as iron-sulfur (Fe-S) clusters and heme. These cofactors, in turn, enable key mitochondrial pathways, such as energy and metabolite production. Mishandling of mitochondrial iron is associated with a spectrum of human pathologies ranging from rare genetic disorders to common conditions. Here, we review mitochondrial iron utilization and its intersection with disease.

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are known as major sources of reactive oxygen species (ROS), yet their role in regulating cellular antioxidative metabolism and ferroptosis is unclear. This study assessed the expression and clinical relevance of NOXs across pan-cancer and investigated the role of NOX4 in colorectal cancer progression METHODS: We analyzed transcriptomic and survival data from The Cancer Genome Atlas (TCGA) for NOXs across 22 types of solid tumors. A CRISPR library targeting NOXs was developed for potential therapeutic target screening in colorectal cancer cells (CRCs). Techniques such as CRISPR-knockout cell lines, 1,2-13C-glucose tracing, PI staining, BrdU assays, and coimmunoprecipitation were employed to elucidate the function of NOX4 in CRCs.

NOX4 emerged as a key therapeutic target for colorectal cancer from TCGA data. CRISPR screening highlighted its essential role in CRC survival, with functional experiments confirming that NOX4 upregulation promotes cell survival and proliferation. The interaction of NOX4 with glucose‑6‑phosphate dehydrogenase (G6PD) was found to enhance the pentose phosphate pathway (PPP), facilitating ROS clearance and protecting CRCs against ferroptosis.

This study identified NOX4 as a novel ferroptosis suppressor and a therapeutic target for the treatment of colorectal cancer. The findings suggest that a coupling between NADPH oxidase enzyme NOX4 and the PPP regulates ferroptosis and reveal an accompanying metabolic vulnerability for therapeutic targeting in colorectal cancer.

Pharmacogenetics-predicted drug metabolism may not match clinically observed metabolism due to a phenomenon known as phenoconversion. Phenoconversion can occur when an inhibitor or inducer of a drug-metabolizing enzyme is present. Although estimates of phenoconversion in adult populations are available, prevalence estimates in youth populations are limited. To address this gap, we estimated the prevalence of phenoconversion in 1281 youth (6-24 years) receiving pharmacotherapy for mental health conditions and who had pharmacogenetics testing completed for four genes (CYP2B6, CYP2C19, CYP2D6, CYP3A4). Self-reported medication and cannabidiol/cannabis use were collected at the time of pharmacogenetics testing. Nearly, half (46%) of the cohort was estimated to be phenoconverted for one of the four genes examined. Comparison of metabolizer phenotype frequencies before and after adjustment for phenoconversion showed significantly more youth had actionable phenotypes for CYP2C19 (60.3% vs. 69.1%; P =< 0.001), CYP2D6 (49.3% vs. 63.0%; P =< 0.001), and CYP3A4 (8.5% vs.12.2%; P = 0.003) after phenoconversion adjustment. Of youth who were phenoconverted, 24% had a change in their metabolizer phenotype that would lead to current pharmacogenetics-based prescribing guidelines recommending a change to standard prescribing (dose adjustment, alternative medication). Our findings indicate a high prevalence of cytochrome P450 phenoconversion among youth receiving pharmacotherapy for mental health conditions. Adjustment for phenoconversion should be considered when implementing pharmacogenetics testing in youth populations to improve the clinical utility of this testing in practice.

Ascorbic acid, the reduced form of vitamin C, is a ubiquitous small carbohydrate. Despite decades of focused research, new metabolic functions of this universal electron donor are still being discovered and add to the complexity of our view of vitamin C in human health. Although praised as an unsurpassed water-soluble antioxidant in plasma and cells, the most interesting functions of vitamin C seem to be its roles as specific electron donor in numerous biological reactions ranging from the well-known hydroxylation of proline to cofactor for the epigenetic master regulators ten-eleven translocation enzymes and Jumonji domain-containing histone-lysine demethylases. Some of these functions may have important implications for disease prevention and treatment and have spiked renewed interest in, eg, vitamin C's potential in cancer therapy. Moreover, some fundamental pharmacokinetic properties of vitamin C remain to be established including if other mechanisms than passive diffusion governs the efflux of ascorbate anions from the cell. Taken together, there still seems to be much to learn about the pharmacology of vitamin C and its role in health and disease. This review explores new avenues of vitamin C and integrates our present knowledge of its pharmacology. SIGNIFICANCE STATEMENT: Vitamin C is involved in multiple biological reactions of which most are essential to human health. Hundreds of millions of people are considered deficient in vitamin C according to accepted guidelines, but little is known about the long-term consequences. Although the complexity of vitamin C's physiology and pharmacology has been widely disregarded in clinical studies for decades, it seems clear that a deeper understanding of particularly its pharmacology holds the key to unravel and possibly exploit the potential of vitamin C in disease prevention and therapy.

This study used 24 male rats to determine the protective effects of a new selenium molecule (glucose selenol) on cadmium (Cd) induced hepatic toxicity. The rats were randomly divided into four groups: control group, Cd group, Cd + 0.15 Se group, and Cd + 0.4 Se group. The results showed that glucose selenol supplementation alleviated the adverse impact of Cd on lipid metabolism, including decreased serum triacylglycerol and cholesterol levels. Transcriptome analysis revealed that, compared to the control group, Cd changed the expression of 1379 genes - discernibly affecting lipid metabolism pathways. Proteomic analysis primarily indicated alterations in lipid metabolism-related pathways. In conclusion, glucose selenol restored lipid metabolism disorders induced by Cd, thus rescuing hepatic damage. This integrated analysis identified the influence of glucose selenol on Cd-induced hepatic toxicity and provided its potential application prospects in alleviating the impact of heavy metal pollution, such as Cd, on human health.

Neurotoxicity investigations of inhaled organophosphorus pesticide (OP), ethyl-parathion (EP), were conducted in Sprague Dawley rats comparing exposures to EP volatilized at 0, 1, 10, and 20 mg/m3 versus EP incorporated into soil dust (5 mg/m3) at 0, 0.0095, 0.09, and 0.185 mg/mg3. All exposures were sublethal, caused no respiratory effects, and no effects on balance and coordination behavior. Both volatilized and dust-incorporated EP exposures significantly decreased acetylcholinesterase (AChE) activity in plasma and hippocampus tissue. Correspondingly, plasma and hippocampal dopamine levels spiked in these exposures suggesting compensatory cholinergic / dopaminergic signal balancing. The EP exposures significantly increased expression of pro-inflammatory genes, including MAPK-14, IL6, IL1β, and TNF-α, while global RNA-seq results identified significant enrichment of inflammation, oxidative stress, and apoptosis pathways. Remarkably, dust-incorporated EP impacted similar molecular endpoints as volatilized EP but at concentrations two orders of magnitude lower highlighting potentially increased potency of EP incorporated into soil dust.

The abundance of drug metabolic enzymes (DMEs) and transporters (DTs) in the human gastrointestinal tract significantly affects xenobiotic exposure in the circulating system, the basis of these compounds acting on humans. However, accurately predicting individual exposure in healthy subjects remains challenging due to limited data on protein levels throughout the gastrointestinal tract within the same individuals and inadequate assessment of factors influencing these levels. Therefore, we conducted a clinical study to obtain biopsy samples from 8 different gastrointestinal segments in 24 healthy Chinese volunteers. Concurrently, blood and fecal samples were collected for genotypic analysis and fecal microbiota metagenomic sequencing. Using an optimized LC-MS/MS method, we quantified the absolute protein abundance of CYP2C9, CYP2C19, CYP2D6, CYP3A4, P-gp, and BCRP from the stomach to the colon. Our results revealed significant regional differences in protein expression: CYP3A4 was the most abundant in the small intestine, whereas CYP2C9 was predominantly found in the colon. CYP2D6 was primarily located in the ileum, while other DMEs/DTs showed higher concentrations in the jejunum. Meanwhile, the enzyme abundance in the small intestine and colon and the relative ratio of transporters in different regions to the jejunum were accurately calculated, providing valuable data for refining the physiological parameters in the virtual gastrointestinal tract of Chinese healthy population in PBBMs. Additionally, BMI, IBW, sex, age, genotype, and fecal microbiota were identified as critical factors influencing the protein levels of these DMEs/DTs throughout the gastrointestinal tract, with notable regional differences. Consequently, this study provides a unique foundation for understanding xenobiotic absorption in humans.

Emilia sonchifolia is a very widely used traditional Chinese medicine, with the efficacy of heat-clearing, detoxicating, dissipating blood stasis, reducing swelling and relieving pain. As a widely used traditional miao herb, Emilia sonchifolia is often used to treat upper respiratory tract infections, oral ulcer, pneumonia, mastitis, enteritis, bacillum, urinary tract infection, sores, eczema, falls and injuries, etc. In fact, many cases of liver injury caused by Emilia sonchifolia have been reported clinically. However, the mechanisms underlying hepatotoxicity induced by Emilia sonchifolia remain poorly understood.

This study aimed to systematically evaluate the acute and chronic hepatotoxicity of water extract from Emilia sonchifolia, identify its hepatotoxic metabolites, and elucidate the potential mechanisms underlying Emilia sonchifolia-induced hepatotoxicity.

The chemical components in the water extract of Emilia sonchifolia were identified using mass spectrometry. The acute toxicity study was conducted by orally administering a gradient dose of water extract of Emilia sonchifolia ranging from 0 to 37.6 g/kg. Mice were orally administered a water extract of Emilia sonchifolia at a dose of 13.72 g/kg/d for 14 days to induce liver injury. The hepatotoxicity was evaluated using hematoxylin and eosin staining as well as enzyme-linked immunosorbent assay (ELISA). The mechanisms of hepatotoxicity were explored through transcriptomics, proteomics, and metabolomics analysis. Meanwhile, the core pathways related to the hepatotoxicity of Emilia sonchifolia were analyzed and validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and ELISA.

The present study demonstrates that the water extract of Emilia sonchifolia can induce hepatotoxicity in mice. We found that the water extract of Emilia sonchifolia contained hepatotoxic pyrrolizidine alkaloids, such as seneciphyllin, senecionine, rinderine, echimidine, retrorsine and echimidine N-oxide. A dose of 19.20 g/kg or higher of the water extract of Emilia sonchifolia caused acute liver failure and death in mice. A dose of 13.72 g/kg or lower of the water extract of Emilia sonchifolia produced dose-dependent acute hepatotoxicity. Meanwhile, a dose of 13.72 g/kg of the water extract from Emilia sonchifolia induced chronic hepatotoxicity in mice. Furthermore, the results of liver transcriptomics, proteomics, and metabolomics indicate that the mechanism of hepatotoxicity induced by the water extract of Emilia sonchifolia is associated with ferroptosis caused by abnormalities in bile acid accumulation, lipid and bilirubin accumulation, and glutathione metabolism. The validation experiment results demonstrate that in mice treated with the water extract of Emilia sonchifolia, the gene levels of Cyp2c29, Cyp3a41a and Ugt2b1 decreased while the gene level of Hsd3b3 increased. In mice treated with a water extract of Emilia sonchifolia, the levels of total bilirubin, direct bilirubin, total bile acids, alkaline phosphatase, and γ-glutamyl transferase were significantly elevated. Additionally, in mice treated with a water extract of Emilia sonchifolia, the levels of malondialdehyde increased while the levels of catalase and superoxide dismutase decreased.

In conclusion, our results suggest that the water extract of Emilia sonchifolia can cause hepatotoxicity in mice. The chronic hepatotoxicity of Emilia sonchifolia is associated with Cyp2c29, Cyp3a41a, Ugt2b1, and Hsd3b3-mediated cholestasis, oxidative stress, and ferroptosis.

Atrazine is a chlorotriazine herbicide that is one of the most widely used herbicides in the USA and the world. For over 60 years atrazine has been used on major crops including corn, sorghum, and sugarcane to control broadleaf and grassy weed emergence and growth. Atrazine has exerted a major economic and environmental impact over that time, resulting in reduced production costs and increased conservation tillage practices. However, widespread use and a long half-life led to a high prevalence of atrazine in the environment. Indeed, atrazine is the most frequent herbicide contaminant detected in water sources in the USA. Due to its almost ubiquitous presence and questions regarding its safety, atrazine has been well-studied. First reported to affect reproduction with potential disruptive effects which were later linked to the immune system, cancer, stress response, neurological disorders, and cardiovascular ailments in experimental models. Atrazine impact on multiple interwoven systems broadens the significance of atrazine exposure. The endeavor to uncover the mechanisms underlying atrazine-induced dysfunction in mammals is ongoing, with new genetic and pharmacological targets being reported. This review aims to summarize the prominent effects of atrazine on mammalian physiology, primarily focusing on empirical studies conducted in lab animal models and establish correlations with epidemiological human studies when relevant. In addition, current common patterns of toxicity and potential underlying mechanisms of atrazine action will be examined.