Natural products (NPs) have long been used as a rich source of bioactive compounds for drug development. Recent technological advancements have revitalised natural products research as evidenced by increased publications in this field. In this editorial review, we highlight key points from the 2020 British Journal of Pharmacology (BJP) practical guide, which outlines standards for natural products research reports, and provide papers published in BJP between years 2020 to 2023 that demonstrate adherence to these guidelines. Looking ahead, we discuss the potential of chemical proteomics approaches to elucidate natural products mechanisms of action and identify therapeutic targets for future research. By fostering innovation, we aim to advance natural products research and contribute to the development of novel therapeutics that will have a significant impact on healthcare.

Ethanol is a neuroteratogen and neurodegeneration is the most devastating consequence of developmental exposure to ethanol. The mechanisms underlying ethanol-induced neurodegeneration are complex. Ethanol exposure produces reactive oxygen species (ROS) which cause oxidative stress in the brain. We hypothesized that ethanol would activate autophagy to alleviate oxidative stress and neurotoxicity. Our results indicated that ethanol increased the level of the autophagic marker Map1lc3-II (LC3-II) and upregulated LC3 puncta in SH-SY5Y neuroblastoma cells. It also enhanced the levels of LC3-II and BECN1 in the developing brain; meanwhile, ethanol reduced SQSTM1 (p62) levels. Bafilomycin A1, an inhibitor of autophagosome and lysosome fusion, increased p62 levels in the presence of ethanol. Bafilomycin A1 and rapamycin potentiated ethanol-increased LC3 lipidation, whereas wortmannin and a BECN1-specific shRNA inhibited ethanol-promoted LC3 lipidation. Ethanol increased mitophagy, which was also modulated by BECN1 shRNA and rapamycin. The evidence suggested that ethanol promoted autophagic flux. Activation of autophagy by rapamycin reduced ethanol-induced ROS generation and ameliorated ethanol-induced neuronal death in vitro and in the developing brain, whereas inhibition of autophagy by wortmannin and BECN1-specific shRNA potentiated ethanol-induced ROS production and exacerbated ethanol neurotoxicity. Furthermore, ethanol inhibited the MTOR pathway and downregulation of MTOR offered neuroprotection. Taken together, the results suggest that autophagy activation is a neuroprotective response to alleviate ethanol toxicity. Ethanol modulation of autophagic activity may be mediated by the MTOR pathway.

Mitochondrial dysfunction is considered as a crucial contributory factor in cardiac pathology. This has highlighted the therapeutic potential of targeting mitochondria to prevent or treat cardiac disease. Mitochondrial dysfunction is associated with aberrant electron transport chain activity, reduced ATP production, an abnormal shift in metabolic substrates, ROS overproduction and impaired mitochondrial dynamics. This review will cover the mitochondrial functions and how they are altered in various disease conditions. Furthermore, the mechanisms that lead to mitochondrial defects and the protective mechanisms that prevent mitochondrial damage will be discussed. Finally, potential mitochondrial targets for novel therapeutic intervention will be explored. We will highlight the development of small molecules that target mitochondria from different perspectives and their current progress in clinical trials.Linked Articles: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

Background—: Stress-induced hypertrophic remodeling is a critical pathogenetic process leading to heart failure. Although many signal transduction cascades are demonstrated as important regulators to facilitate the induction of cardiac hypertrophy, the signaling pathways for suppressing hypertrophic remodeling remain largely unexplored. In this study, we identified p21-activated kinase 1 (Pak1) as a novel signaling regulator that antagonizes cardiac hypertrophy. Methods and Results—: Hypertrophic stress applied to primary neonatal rat cardiomyocytes (NRCMs) or murine hearts caused the activation of Pak1. Analysis of NRCMs expressing constitutively active Pak1 or in which Pak1 was silenced disclosed that Pak1 played an antihypertrophic role. To investigate the in vivo role of Pak1 in the heart, we generated mice with a cardiomyocyte-specific deletion of Pak1 (Pak1 ^cko ). When subjected to 2 weeks of pressure overload, Pak1 ^cko mice developed greater cardiac hypertrophy with attendant blunting of JNK activation compared with controls, and these knockout mice underwent the transition into heart failure when prolonged stress was applied. Chronic angiotensin II infusion also caused increased cardiac hypertrophy in Pak1 ^cko mice. Moreover, we discovered that the Pak1 activator FTY720, a sphingosine-like analog, was able to prevent pressure overload-induced hypertrophy in wild-type mice without compromising their cardiac functions. Meanwhile, FTY720 failed to exert such an effect on Pak1 ^cko mice, suggesting that the antihypertrophic effect of FTY720 likely acts through Pak1 activation. Conclusions—: These results, for the first time, establish Pak1 as a novel antihypertrophic regulator and suggest that it may be a potential therapeutic target for the treatment of cardiac hypertrophy and heart failure.

Next-generation sequencing has been widely applied to understand the complexity of non-coding RNAs (ncRNAs) in a cost-effective way. In this study, we developed mirTools 2.0, an updated version of mirTools 1.0, which includes the following new features. (1) From miRNA discovery in mirTools 1.0, mirTools 2.0 allows users to detect and profile various types of ncRNAs, such as miRNA, tRNA, snRNA, snoRNA, rRNA, and piRNA. (2) From miRNA profiling in mirTools 1.0, mirTools 2.0 allows users to identify miRNA-targeted genes and performs detailed functional annotation of miRNA targets, including Gene Ontology, KEGG pathway and protein-protein interaction. (3) From comparison of two samples for differentially expressed miRNAs in mirTools 1.0, mirTools 2.0 allows users to detect differentially expressed ncRNAs between two experimental groups or among multiple samples. (4) Other significant improvements include strategies used to detect novel miRNAs and piRNAs, more taxonomy categories to discover more known miRNAs and a stand-alone version of mirTools 2.0. In conclusion, we believe that mirTools 2.0 (122.228.158.106/mr2_dev and centre.bioinformatics.zj.cn/mr2_dev) will provide researchers with more detailed insight into small RNA transcriptomes.