Farzaneh Motafeghi

The gut–liver axis is a complex, bidirectional communication network in which metabolites produced by the gut microbiota play an important role in regulating liver function and xenobiotic metabolism. At the center of this interaction is a group of molecular sensors called xenosensors, which include ligand-activated nuclear transcription factors, such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), aryl hydrocarbon receptor (AhR), and farnesoid X receptor (FXR), as well as membrane receptors such as TGR5. By recognizing and responding to endogenous and exogenous chemical compounds, these receptors regulate the expression of enzymes and transporters involved in the metabolism of drugs and other xenobiotics, thereby influencing the body’s detoxification capacity and susceptibility to chemical toxicity. Evidence suggests that gut microbiota-derived metabolites, including short-chain fatty acids, secondary bile acids, and tryptophan derivatives, can directly or indirectly modulate the activity of xenosensors. These findings suggest an important mechanistic link between gut microbiota composition and host toxicological responses. Furthermore, individual differences in the expression and signaling pathways of xenosensors, influenced by factors such as genetic polymorphisms, diet, environmental exposures, and microbiome diversity, can contribute to differences in individual responses to drugs and toxicants. This review aims to summarize current findings on the role of gut microbiota-derived metabolites in the regulation of xenosensors in the gut–liver axis and to investigate the impact of these interactions on xenobiotic metabolism and toxicity. In addition, the mechanistic aspects of this process, its potential applications in clinical and translational fields, including the identification of biomarkers and the development of personalized medicine strategies, as well as gaps in current knowledge that could determine the direction of future research, are discussed. A better understanding of the integrated network of microbiome-derived signals and the activation of hepatic xenosensors is of fundamental importance for predicting individual differences in drug response and sensitivity to environmental pollutants and chemicals, and could help design safer therapeutic strategies and improve risk assessment frameworks.

Advanced prostate cancer, particularly metastatic castration-resistant disease (mCRPC), represents a major clinical challenge due to its evasion of classical apoptotic pathways. Exploiting alternative regulated cell death modalities, specifically ferroptosis and cuproptosis, has emerged as a critical therapeutic goal. This review evaluates the complex biochemical structure of these metal-dependent vulnerabilities, emphasizing their intersection with mitochondrial bioenergetics, lipid remodeling, and the inflammatory tumor microenvironment. We review the role of the NRF2/GPX4 antioxidant axis and the modulatory influence of pro-inflammatory signaling on metal ion homeostasis. By synthesizing current multi-omics data and pharmacological strategies, including nanotherapies and theranostic radiopharmaceuticals, this manuscript emphasizes the necessity for predictive biomarkers and combinatorial rationales. Bridging these mechanistic discoveries with precision oncology is essential for overcoming therapeutic resistance and improving clinical outcomes in advanced prostate cancer.

Since the mid-20th century, pesticides have become widely considered essential components in current conventional agricultural systems through the management and control of weeds, insect pests, and...

This study aimed to provide integrative mechanistic insights into benzalkonium chloride (BAK)-induced cytotoxicity in human corneal epithelial (HCE-T) cells, with a particular focus on the crosstalk between oxidative stress, DNA damage, ferroptosis-related events, apoptosis, and inflammatory signaling. HCE-T cells were exposed to increasing concentrations of BAK. Cell viability and membrane integrity were evaluated using MTT and lactate dehydrogenase assays, respectively. Oxidative stress was assessed by measuring intracellular reactive oxygen species (ROS) and antioxidant defense markers, including superoxide dismutase, catalase, glutathione peroxidase, and total antioxidant capacity. Genotoxic effects were analyzed using the comet assay, while lipid peroxidation was quantified by malondialdehyde levels. To distinguish cell death mechanisms, ferroptosis-related events (iron accumulation) and apoptotic markers (caspase-3/7 activity and DNA fragmentation via TUNEL assay) were examined. Additionally, inflammatory responses were evaluated by measuring the expression of interleukin-1β, interleukin-6, and tumor necrosis factor-α. The results demonstrate that BAK induces dose-dependent cytotoxicity in HCE-T cells, characterized by excessive ROS generation, impaired antioxidant defenses, significant DNA damage, and enhanced lipid peroxidation. Iron accumulation and oxidative lipid damage suggested a prominent role for ferroptosis-related events, occurring alongside apoptosis. Moreover, BAK exposure markedly activated inflammatory signaling pathways. Collectively, these findings highlight a complex, interconnected network of oxidative stress, DNA damage, ferroptosis-related events, and inflammation underlying BAK-induced corneal epithelial toxicity. This study provides mechanistic evidence relevant to ocular safety and preservative formulation strategies.

Background: Population studies elucidating the genetic architecture of endometriosis have predominantly focused on individuals of European ancestry, thereby leaving a gap in understanding the genetic influences within non-European populations. This present study aims to identify potential genetic variants associated with endometriosis in Iranian women. Research design and methods: We conducted a genome-wide association study on endometriosis involving a discovery group of 1978 women, comprising 305 women with endometriosis and 1673 unaffected individuals. An independent confirmation cohort comprising 829 women (101 cases and 728 controls) was selected from the TCGS cohort. Over 9 million genetic variants were analyzed using the Genome-wide Complex Trait Analysis framework, followed by integrative bioinformatics and functional annotation analyses. Results: In the discovery phase, we identified rs12886544 at the GNPNAT1 locus as genome-wide significant for endometriosis susceptibility (OR = 1.66, p -value = 5.89 × 10⁻⁸). In the confirmation cohort, the direction of effect was consistent with the discovery phase, although the association did not remain statistically significant after correction for multiple testing (OR = 1.4, 95% [CI 0.89–2.11], p = 0.14). A pooled analysis of the discovery and confirmation cohorts demonstrated a statistically significant association between rs12886544 and endometriosis risk (combined p -value = 0.001, OR = 1.59, 95% CI 1.19–1.89). Epigenomics results suggest that rs12886544 may affect a regulatory motif associated with the Bobby Sox homolog (BBX) transcription factor in women, implicating a potential role in modulating gene expression. Conclusions: Our findings provide supportive evidence that rs12886544 at the GNPNAT1 locus is associated with endometriosis susceptibility in Iranian women. The association was supported by a consistent direction of effect in an independent cohort and a significant pooled analysis, although further validation in larger independent populations is required. Additionally, observed differences in allele frequencies between Iranian and European populations highlight the importance of trans-ethnic studies for understanding population-specific genetic architecture in endometriosis. Graphical

The convergence of immunogenetics and reproductive endocrinology highlights Tumor Necrosis Factor-alpha (TNF-α) as a central mediator of ovarian physi

Endometriosis, a chronic gynecological disorder, is clinically associated with an increased risk of osteoporosis. While this link has been primarily attrib