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In breastfeeding mothers, managing medical conditions presents unique challenges, particularly concerning medication use and breastfeeding practices. The transfer of drugs into breast milk and subsequent exposure to nursing infants raises important considerations for drug safety and efficacy. Modeling approaches are increasingly employed to predict infant exposure levels, crucial for assessing drug safety during breastfeeding. Physiologically‐based pharmacokinetic (PBPK) modeling provides a valuable tool for predicting drug exposure in lactating individuals and their infants. This tutorial offers an overview of PBPK modeling in lactation research, covering key concepts, prediction approaches, and best practices for model development and application. We delve into milk composition dynamics and its influence on drug transfer into breast milk, addressing modeling considerations, knowledge gaps, and future research directions. Practical examples and case studies illustrate PBPK modeling application in lactation studies. We demonstrate how prediction algorithms for Milk‐to‐Plasma (M/P) ratios within a PBPK framework can support scenarios lacking clinical lactation data or extend the utility of available lactation clinical data to support further untested clinical scenarios. This tutorial aims to assist researchers and clinicians in understanding and applying PBPK modeling to understand and support clinical scenarios in breastfeeding mothers. Advances in PBPK modeling techniques, along with ongoing research on lactation physiology and drug disposition, promise further insights into drug transfer during lactation. [ABSTRACT FROM AUTHOR]

Natural products are a treasure trove for drug discovery, especially in the areas of infection, inflammation and cancer, due to their diverse bioactivities and complex, and varied structures. Chronic inflammation is closely related to many diseases, including complex diseases such as cancer and neurodegeneration. Improving target identification for natural products contributes to elucidating their mechanism of action and clinical progress. It also facilitates the discovery of novel druggable targets and the elimination of undesirable ones, thereby significantly enhancing the productivity of drug discovery and development. Moreover, the rise of polypharmacological strategies, considered promising for the treatment of complex diseases, will further increase the demand for target deconvolution. This review underscores strategies for identifying natural product targets (NPs) in the context of chronic inflammation over the past 5 years. These strategies encompass computational methodologies for early target discovery and the anticipation of compound binding sites, proteomics‐driven approaches for target delineation and experimental biology techniques for target validation and comprehensive mechanistic exploration. [ABSTRACT FROM AUTHOR]

Neural stem cell (NSC) transplantation is a promising strategy for replacing lost neurons following spinal cord injury. However, the survival and differentiation of transplanted NSCs is limited, possibly owing to the neurotoxic inflammatory microenvironment. Because of the important role of glucose metabolism in M1/M2 polarization of microglia/macrophages, we hypothesized that altering the phenotype of microglia/macrophages by regulating the activity of aldose reductase (AR), a key enzyme in the polyol pathway of glucose metabolism, would provide a more beneficial microenvironment for NSC survival and differentiation. Here, we reveal that inhibition of host AR promoted the polarization of microglia/macrophages toward the M2 phenotype in lesioned spinal cord injuries. M2 macrophages promoted the differentiation of NSCs into neurons in vitro. Transplantation of NSCs into injured spinal cords either deficient in AR or treated with the AR inhibitor sorbinil promoted the survival and neuronal differentiation of NSCs at the injured spinal cord site and contributed to locomotor functional recovery. Our findings suggest that inhibition of host AR activity is beneficial in enhancing the survival and neuronal differentiation of transplanted NSCs and shows potential as a treatment of spinal cord injury.

Modifications at different positions on the aloperine molecule were performed to improve its anticancer activity and develop anticancer drugs. The in vitro anticancer activities of 44 synthesized compounds were evaluated. The effect of modification positions on anticancer activity was discussed and a structure–activity relationship analysis was established. A novel series of compounds with modifications at the N12 position showed much higher cytotoxicity than aloperine. Among them, compound 22 displayed promising in vitro anticancer activity against PC9 cells with a median inhibitory concentration (IC50) of 1.43 μM. The mechanism studies indicated that compound 22 induced cell apoptosis and cell cycle arrest in PC9 cells. These results demonstrate the potential of aloperine thiourea derivatives in anticancer activity. [ABSTRACT FROM AUTHOR]

The bioavailability of a monoclonal antibody (mAb) or another therapeutic protein after subcutaneous (SC) dosing is challenging to predict from first principles, even if the impact of injection site physiology and drug properties on mAb bioavailability is generally understood. We used a physiologically based pharmacokinetic model to predict pre-systemic clearance after SC administration mechanistically by incorporating the FcRn salvage pathway in antigen-presenting cells (APCs) in peripheral lymph nodes, draining the injection site. Clinically observed data of the removal rate of IgG from the arm as well as its plasma concentration after SC dosing were mostly predicted within the 95% confidence interval. The bioavailability of IgG was predicted to be 70%, which mechanistically relates to macropinocytosis in the draining lymph nodes and transient local dose-dependent partial saturation of the FcRn receptor in the APCs, resulting in higher catabolism and consequently less drug reaching the systemic circulation. The predicted free FcRn concentration was reduced to 40–45%, reaching the minimum 1–2 days after the SC administration of IgG, and returned to baseline after 8–12 days, depending on the site of injection. The model predicted the uptake into APCs, the binding affinity to FcRn, and the dose to be important factors impacting the bioavailability of a mAb. [ABSTRACT FROM AUTHOR]

Substrates of a major drug-metabolizing enzyme CYP2D6 display increased elimination during pregnancy, but the underlying mechanisms are unknown in part due to a lack of experimental models. Here, we introduce CYP2D6-humanized (Tg-CYP2D6) mice as an animal model where hepatic CYP2D6 expression is increased during pregnancy. In the mouse livers, expression of a known positive regulator of CYP2D6, hepatocyte nuclear factor 4α (HNF4α), did not change during pregnancy. However, HNF4α recruitment to CYP2D6 promoter increased at term pregnancy, accompanied by repressed expression of small heterodimer partner (SHP). In HepG2 cells, SHP repressed HNF4α transactivation of CYP2D6 promoter. In transgenic (Tg)-CYP2D6 mice, SHP knockdown led to a significant increase in CYP2D6 expression. Retinoic acid, an endogenous compound that induces SHP, exhibited decreased hepatic levels during pregnancy in Tg-CYP2D6 mice. Administration of all-trans-retinoic acid led to a significant decrease in the expression and activity of hepatic CYP2D6 in Tg-CYP2D6 mice. This study provides key insights into mechanisms underlying altered CYP2D6-mediated drug metabolism during pregnancy, laying a foundation for improved drug therapy in pregnant women.

SUMMARY: Prunella vulgaris is one of the bestselling and widely used medicinal herbs. It is recorded as an ace medicine for cleansing and protecting the liver in Chinese Pharmacopoeia and has been used as the main constitutions of many herbal tea formulas in China for centuries. It is also a traditional folk medicine in Europe and other countries of Asia. Pentacyclic triterpenoids are a major class of bioactive compounds produced in P. vulgaris. However, their biosynthetic mechanism remains to be elucidated. Here, we report a chromosome‐level reference genome of P. vulgaris using an approach combining Illumina, ONT, and Hi‐C technologies. It is 671.95 Mb in size with a scaffold N50 of 49.10 Mb and a complete BUSCO of 98.45%. About 98.31% of the sequence was anchored into 14 pseudochromosomes. Comparative genome analysis revealed a recent WGD in P. vulgaris. Genome‐wide analysis identified 35 932 protein‐coding genes (PCGs), of which 59 encode enzymes involved in 2,3‐oxidosqualene biosynthesis. In addition, 10 PvOSC, 358 PvCYP, and 177 PvUGT genes were identified, of which five PvOSCs, 25 PvCYPs, and 9 PvUGTs were predicted to be involved in the biosynthesis of pentacyclic triterpenoids. Biochemical activity assay of PvOSC2, PvOSC4, and PvOSC6 recombinant proteins showed that they were mixed amyrin synthase (MAS), lupeol synthase (LUS), and β‐amyrin synthase (BAS), respectively. The results provide a solid foundation for further elucidating the biosynthetic mechanism of pentacyclic triterpenoids in P. vulgaris. Significance Statement: The first chromosome‐level reference genome of Prunella vulgaris and the Prunella genus was reported. Fifty‐nine 2,3‐oxidosqualene biosynthesis‐related genes and 39 pentacyclic triterpenoid biosynthesis‐related PvOSCs, PvCYPs, and PvUGTs genes were systematically analyzed. PvOSC2, PvOSC4, and PvOSC6 were experimentally verified to be mixed amyrin synthase, lupeol synthase, and β‐amyrin synthase, respectively. The results provide a solid foundation for further elucidating the biosynthetic mechanism of bioactive compounds in the widely used medicinal plant, P. vulgaris. [ABSTRACT FROM AUTHOR]