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Purpose of Review: Dietary phytochemicals, bioactive compounds derived from plants, have gained increasing attention for their potential role in cancer prevention. Among these, NRF2 (nuclear factor erythroid 2-related factor 2) activating dietary phytochemicals such as curcumin, sulforaphane, ursolic acid, and cyanidin have demonstrated significant antioxidant and anti-inflammatory properties, making them promising agents in chemoprevention. This review examines the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of these dietary phytochemicals, with a focus on their NRF2-mediated effects in cancer prevention., Recent Findings: Preclinical studies have highlighted the potential of these dietary phytochemicals to modulate oxidative stress and inflammation, key drivers of carcinogenesis. We explore the complexity of their PK/PD properties, influenced by factors such as bioavailability, metabolism, and drug interactions. While most of these phytochemicals follow two compartmental PK, their anti-oxidant and anti-inflammatory effects follow the indirect response (IDR) model. Furthermore, we discuss the application of physiologically based pharmacokinetic (PBPK) modeling to simulate the behavior of these compounds in humans, providing insights for clinical translation., Summary: The integration of PK-PD analysis into the development of dietary phytochemical-based therapies offers a pathway to optimize dosing strategies, enhance therapeutic efficacy, and improve safety. This review underscores the importance of these compounds as part of cancer interception strategies, particularly in the early stages of cancer development, where they may offer a natural, less toxic alternative to conventional therapies., Competing Interests: Competing InterestsThe corresponding author, Ah-Ng Tony Kong, is a member of the editorial board of Current Pharmacology Reports., (© The Author(s) 2024.)

Background: Non-small cell lung cancer (NSCLC) accounts for 81% of lung cancer cases, among which over 47% presented with distant metastasis at the time of diagnosis. Despite the introduction of targeted therapy and immunotherapy, enhancing the survival rate and overcoming the development of resistance remain a big challenge. Thus, it is crucial to find potential new therapeutics and targets that can mitigate lung metastasis and investigate its effects on biomarkers, such as cellular metabolomics. In the current study, we investigated the role of cyproheptadine (CPH), an FDA-approved anti-histamine drug in lung metastasis in vitro and in vivo., Methods and Results: CPH showed potent cytotoxicity on different lung cancer cell lines in vitro. Moreover, CPH decreased invasion and migration of LLC1 and A549 cells in Matrigel invasion transwell and plate scratch assays. The in vivo LLC1 syngeneic lung cancer model found decreased number of metastatic nodules on the surface of lungs of Setd7 KO mice compared to SETD7 WT. CPH treatment resulted in decreased growth of LLC1 subcutaneous tumors compared to untreated SETD7 WT. Finally, metabolomic study of tumor tissues showed rewiring of metabolomic pathways and downregulation of amino acids, such as arginine, serine, and glycine) in Setd7 KO and WT treated with CPH compared to untreated Setd7 WT mice., Conclusion: These findings identify CPH as a potential therapeutic agent to block metastasis in advanced NSCLC and suggest SETD7 as a potential target for the prevention of lung metastasis., (© 2024. The Author(s).)

Abstract: Cancer development takes 10 to 50 years, and epigenetics plays an important role. Recent evidence suggests that ~80% of human cancers are linked to environmental factors impinging upon genetics/epigenetics. Because advanced metastasized cancers are resistant to radiation/chemotherapeutic drugs, cancer prevention by relatively nontoxic "epigenetic modifiers" will be logical. Many dietary phytochemicals possess powerful antioxidant and anti-inflammatory properties that are hallmarks of cancer prevention. Dietary phytochemicals can regulate gene expression of the cellular genome via epigenetic mechanisms. In this review, we will summarize preclinical studies that demonstrate epigenetic mechanisms of dietary phytochemicals in skin, colorectal, and prostate cancer prevention. Key examples of the importance of epigenetic regulation in carcinogenesis include hypermethylation of the NRF2 promoter region in cancer cells, resulting in inhibition of NRF2-ARE signaling. Many dietary phytochemicals demethylate NRF2 promoter region and restore NRF2 signaling. Phytochemicals can also inhibit inflammatory responses via hypermethylation of inflammation-relevant genes to block gene expression. Altogether, dietary phytochemicals are excellent candidates for cancer prevention due to their low toxicity, potent antioxidant and anti-inflammatory properties, and powerful epigenetic effects in reversing procarcinogenic events., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. This work was supported in part by institutional funds and by R01 AT009152 from the National Center for Complementary and Integrative Health, R01 CA200129 from the National Cancer Institute, and P30 ES005022 from the National Institute of Environmental Health., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Since ancient times, dietary phytochemicals are known for their medicinal properties. They are broadly classified into polyphenols, terpenoids, alkaloids, phytosterols, and organosulfur compounds. Currently, there is considerable interest in their potential health effects against various diseases, including lung cancer. Lung cancer is the leading cause of cancer deaths with an average of five-year survival rate of lung cancer patients limited to just 14%. Identifying potential early molecular biomarkers of pre-malignant lung cancer cells may provide a strong basis to develop early cancer detection and interception methods. In this review, we will discuss molecular changes, including genetic alterations, inflammation, signal transduction pathways, redox imbalance, epigenetic and proteomic signatures associated with initiation and progression of lung carcinoma. We will also highlight molecular targets of phytochemicals during lung cancer development. These targets mainly consist of cellular signaling pathways, epigenetic regulators and metabolic reprogramming. With growing interest in natural products research, translation of these compounds into new cancer prevention approaches to medical care will be urgently needed. In this context, we will also discuss the overall pharmacokinetic challenges of phytochemicals in translating to humans. Lastly, we will discuss clinical trials of phytochemicals in lung cancer patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Achievement of the elimination target for mother-to-child transmission (MTCT) of HIV in selected countries has increased hope to end the HIV epidemic in children across the world. However, MTCT rates remain well above the 5% elimination target in most sub-Saharan Africa countries. These countries require innovative strategies to scale-up their interventions to end paediatric HIV. We describe how the Elizabeth Glaser Paediatric AIDS Foundation (EGPAF) consortium and the Children's Investment Fund Foundation (CIFF) used the critical path method to facilitate rapid expansion and optimization of 2010 and 2013 WHO PMTCT guidelines to reduce Zimbabwe's MTCT rate from 22% in 2010 to 6.4% in 2015., Methods: We analysed activities implemented and PMTCT programme data for the period before and during the EGPAF-CIFF project. The critical path method involved a cycle of collecting and analysing quarterly PMTCT indicator data and planning and implementing targeted activities to improve the PMTCT indicators. We performed a graphical trend analysis of data that measured availability of PMTCT services. Using Pearson's Chi2 test, we compared results of PMTCT uptake indicators at the start and end of the EGPAF-CIFF project and used regression discontinuity analysis to assess effectiveness of activities implemented to improve the PMTCT service uptake indicators., Results: Zimbabwe rolled out WHO 2010 and 2013 PMTCT guidelines in less than 1 year during the EGPAF-CIFF project, yet it took more than 4 years to roll-out previous guidelines. All PMTCT indicators increased significantly (p < 0.001) comparing the five-year periods before and during the EGPAF-CIFF project. Critical path activities implemented increased five of the seven PMTCT uptake indicators., Conclusion: Zimbabwe rapidly rolled-out and optimised new WHO PMTCT guidelines and drastically reduced its MTCT rate using the critical path method. We recommend wider use of the critical path method in public health programmes.

Previous epidemiological studies of risk factors for classical scrapie at flock level have identified a variety of management and purchase related variables, along with increased flock size and, in some cases, breed effects. Although known as a risk factor at the individual animal level, PrP genotype frequencies at flock level have not yet been studied. In an unmatched case-control study, three measures of flock-level prion protein (PrP) frequency estimates were investigated with respect to the scrapie status of the flock in 293 British sheep flocks (195 control flocks and 98 case flocks). Flocks with positive frequencies (more than 0 per cent) of two genotypes (VRQ/VRQ and AHQ/VRQ), large frequencies (more than 10 per cent) of the ARR/VRQ genotype, and large frequencies (more than 5.2 per cent) of the VRQ allele were at increased odds of being affected with clinical classical scrapie. When adjusted for flock size, breed and sampling strategy the genotype and allele effects remained, except that for flocks with positive frequencies of VRQ/VRQ. The known effect of increased risk with increased flock size was confirmed. A measure of the flock PrP genotype frequency profile should thus be included in studies of risk factors for scrapie. It could also be integrated into risk-based surveillance strategies for identification of "at-risk-of scrapie" flocks.