Oxidative stress (OS) is a key feature of a wide range of human disorders, including aging and cancer. The nuclear factor erythroid 2-related factor 2 (Nrf2; NFE2L2) is the master regulator of antioxidant responses via antioxidant response element (ARE)-driven gene expression. Its activity is regulated by Keap1. Under basal conditions, Keap1 binds Nrf2, promoting its degradation; OS disrupts this interaction, enabling Nrf2 stabilization, nuclear translocation, and activation of NRF2 regulated. While protecting in normal cells, persistent activation of Nrf2 in cancer promotes chemoresistance and tumor progression. microRNAs (miRNAs) are key post-transcriptional regulators of Nrf2, via binding to its 3′untranslated region. Databases such as miRBase and Human MiRNA Disease Database, which catalogue thousands of miRNA-disease associations, highlight the complexity and biological relevance of this regulatory network. Several tumor-suppressive miRNAs downregulate Nrf2 and attenuate ARE activity, thereby increasing OS sensitivity, apoptosis, and responsiveness to chemotherapy. Conversely, Nrf2 modulates miRNA networks, forming feedback loops that fine-tune redox homeostasis. While transient Nrf2 activation is generally cytoprotective, sustained Nrf2 hyperactivation in cancer promotes chemoresistance, radioresistance, metabolic reprogramming, metastasis, and poor prognosis, underscoring the need for strategies aimed at limiting Nrf2 signaling and its downstream effects. Given its multifaceted role, Nrf2 has emerged as a promising therapeutic target. Natural Nrf2 modulators and miRNA-based therapeutics (mimics/inhibitors) represent promising strategies to restore redox balance, suppress tumor progression, and overcome multidrug resistance. This review highlights the bidirectional crosstalk between Nrf2 and miRNAs and discusses its therapeutic potential in cancer.
In vitro drug metabolism assays are essential in early drug development to evaluate drug disposition. These assays often use hepatic subcellular fractions and recombinant enzymes originating from both human and nonclinical species. Within this domain, cytochrome P450 (CYP) 3A enzymes are considered key players for drug metabolism. Although recombinant CYP3A enzymes are available for several nonclinical species, isoform-specific enzymes from Göttingen Minipigs remain unavailable. Therefore, recombinant Göttingen Minipig CYP3A22 and CYP3A29 enzymes were developed in Escherichia coli. Their catalytic functionalities were examined using probe substrates (i.e., benzyl-oxy-methyl-resorufin and Luciferin-IPA), and clinically relevant human CYP3A4 substrates (i.e., midazolam and testosterone) along with known inhibitors (i.e., ketoconazole and troleandomycin). Gene sequence comparison to domestic pig revealed sequence variations for both r-CYP3A22 and r-CYP3A29. BOMR metabolism was detected in both constructs, but only r-CYP3A22 metabolized Luciferin-IPA. r-CYP3A22 exhibited a higher apparent affinity for midazolam, with a lower Km and comparable Vmax to r-CYP3A29, whereas r-CYP3A29 showed a greater maximal metabolic capacity toward testosterone, with a higher Vmax and similar Km as compared to r-CYP3A22. Ketoconazole exhibited potent reversible inhibitory effects on testosterone and midazolam metabolism in both enzymes. Troleandomycin strongly inhibited both constructs in a time-dependent manner; however, an IC50 shift was only measurable for r-CYP3A22. These results provide important insights into Göttingen Minipig CYP3A isoform-specific functionality which are relevant for species selection in future nonclinical studies.
Botanical and herbal supplements offer a natural approach to replace antibiotics and are applied for a wide range of purposes. Oregano essential oil (OEO) and its biological active components have attracted attention due to their numerous useful biological activities. As a natural extract, OEO exhibits significant antimicrobial and antioxidant properties, as well as other bioactivities. These potent pharmacological properties enable OEO gradually apply in the fields of food preservation by inhibiting foodborne pathogens and spoilage microbes, thereby extending shelf life while reducing reliance on synthetic additives. Furthermore, OEO is widely used in livestock farming as a natural feed additive that enhance growth performance and rumen health, offering a sustainable alternative to chemical growth promoters. This review summarizes the chemical composition and bioactivity profiles of OEO, with particular emphasis on its application in food preservation and livestock farming as a potential alternative to antibiotics and growth promoters.
Targeted protein degradation (TPD) offersa way to remove disease-associated proteins rather than only inhibit their activity. Its modalities include heterobifunctional degraders, molecular glues, and lysosome-directed strategies, which differ in their mechanisms and accessible substrates. This review examines how disease pathology can guide TPD selection across cancer, neurodegenerative diseases, metabolic syndrome, autoimmune diseases, and infectious diseases. We compare these approaches according to target localization, protein conformation or aggregation state, and the availability of cellular degradation machinery. Representative preclinical studies and clinical programs illustrate both their potential and the limits of current evidence. Clinical translation remains constrained by tissue delivery, pharmacokinetic properties, target and effector selectivity, acquired resistance, and long-term safety. Molecular design and delivery strategies may help address these barriers, but target degradation must be distinguished from demonstrated therapeutic benefit. A pathology-guided framework can therefore support candidate selection and experimental design, while its clinical utility requires validation in specific disease settings.
