Annual review of pharmacology and toxicology最新文献

RNA splicing is a nuclear enzymatic process that catalyzes excision of segments of premature messenger RNA (mRNA) and ligation to give rise to mature coding mRNA. Genomic and transcriptomic studies of cancer have revealed that RNA splicing is often dysregulated in cancer due to mutations in genes affecting their splicing in cis, alterations in the components of the splicing machinery in trans, and transcriptional as well as epigenetic alterations that impact cotranscriptional splicing. These observations have motivated a number of efforts to pharmacologically modulate splicing using small molecules that bind, degrade, or modify the RNA splicing machinery as well as oligonucleotides and small molecules that bind mRNA transcripts to modulate their processing. These therapeutic modalities are reviewed here along with early findings from clinical trials evaluating these agents in patients. The vast number of opportunities to alter splicing continues to highlight splicing as an exciting therapeutic target in cancer.

The global population breathes unsafe levels of pollutants. In recent years, electronic cigarettes (e-cigs) have become a significant source of particulate matter (PM), which causes injurious effects across organ systems. E-cig users and bystanders are exposed to concentrated aerosols, commonly called vapor, that we now know can have harmful long-term consequences due to PM and chemicals contained within. E-cigs are diverse in design, and e-liquids vary dramatically, making it difficult to draw broad conclusions from studies of different devices, brands, and flavors. With the rise in popularity of e-cigs, it is important to define the health effects across the body. In this comprehensive review, we dissect and summarize the known organ-specific effects of e-cigs, including underlying molecular mechanisms. Notably, e-cig aerosols broadly cause increased cytokine release and oxidative stress, which are associated with a heightened risk of organ dysfunction. We also highlight ways to minimize harmful e-cig constituents to develop safer products.

In light of the success of blockbuster drugs for type 2 diabetes and obesity based on the GLP-1 hormone, drugmakers have concentrated their efforts on developing new and improved variations that address the route of administration, dosing, pathway selectivity, or polypharmacology. While some of these modifications have demonstrated improved efficacy in clinical studies and offered exciting opportunities for treating other diseases, drug-induced shifts to the conformational landscape of target receptors may have consequences for side effects. Our review summarizes advances in the understanding of the biochemistry, pharmacogenomics, and molecular pharmacology of incretins and their cognate receptors. We further highlight the current landscape of incretin mimetics and discuss how differences in compartmentalized pathway selectivity affect drug action and outcomes.

When I was young and pictured my future, it wasn't a path that could be determined a priori. The world was full of interesting things. Obtaining the qualifications to become a professor and a researcher was the easy part. The rest relied on being in the right place at the right moment and having the intuition to feel the importance of events we were witnessing. This is how I met my mentors and how my scientific partner and I came upon the paradox that caused us to propose the principle of biological inertia. This is also how we discovered that estrogens leached from plasticware were ruining our experiments, and thus we became "toxicologists by accident." Indeed, we were never formally trained in pharmacology or toxicology; however, our discovery that the estrogen nonylphenol leached from plastics made us pioneers of the new field of endocrine disruptors that encompasses endocrinology and toxicology.

Although HIV treatment and prevention efforts in recent decades have significantly reduced new infections and mortality worldwide, progress has been uneven. Regions with the highest prevalence are those where HIV control programs fail to reach key populations, such as people who inject drugs, men who have sex with men, transgender people, and certain ethnic minorities. More specifically, the rollout of proven HIV prevention tools in these populations, such as antiretroviral therapy and pre-exposure prophylaxis, still presents a challenge. Community-based organizations play a key role in facilitating access to testing and treatment, particularly through rapid testing programs and peer support. These initiatives are crucial for overcoming social and cultural barriers, reducing stigma, and ensuring treatment adherence, especially among key populations.

Microplastics are emerging as mediators in the interaction between environmental pollutants and cardiovascular health. Micro- and nanoplastics (MNPs) can enter the human body through ingestion, inhalation, or skin exposure, disrupting biological processes such as autophagy, inflammation, oxidative stress, immune activation, and vascular dysfunction. Therefore, MNPs might promote the development of cardiovascular diseases. The link between MNPs and cardiovascular diseases remains unclear, with no consistent data confirming a correlation between their concentration in tissues and disease onset. Continuously evolving analytical techniques to detect MNPs within human organs and tissues will help the design of prospective studies detailing the possible harm provided by different microplastics as well as their effects according to their physical properties and associated chemicals. In this review, we provide an update on the existing techniques for MNP detection and characterization to summarize the mechanisms linking these pollutants to human health, focusing on their effects on the cardiovascular system.

Sensing specific temperature ranges as noxious is crucial for protecting organisms from tissue damage. While the molecular detectors for noxious heat are well-characterized, those responsible for noxious cold detection remain elusive. The transient receptor potential vanilloid 1 (TRPV1) is a polymodal channel activated by heat, acid, and various animal and plant toxins. Due to its association with inflammatory pain, TRPV1 has become a promising target for analgesic development. A recent study reported on an individual carrying a homozygous TRPV1 mutation (N331K) that led to pronounced functional loss. Examination of the affected individual revealed an expected decrease in sensitivity to noxious heat and an unexpected increase in sensitivity to noxious cold. Furthermore, extensive neurogenic inflammatory, flare, and pain responses were observed following the application of a TRPA1 channel activator. These findings suggest that the combined activity of TRPV1 and TRPA1 is essential for controlling noxious cold sensitivity and should be considered when assessing TRPV1 pharmacology.

In conventional drug discovery, particularly for small molecules, investigating a small compound that matches the structure of the target molecule and alters its activity has been a crucial process. On the other hand, artificially regulating the activity of a target molecule that is inherently present in cells or organisms and involved in a physiological function can cause various side effects. One possible approach to overcoming this side effect problem is to explore molecules that affect the behavior or motility of molecules related to diseases. If a screening method is developed to search for drugs that target only specific motions of the target molecules, a new concept of motility-targeted drug discovery will be created. In this review article, single-molecule live imaging-a core technology for analyzing the motility of molecules in living cells and organisms-is introduced by describing examples of single-molecule imaging, such as membrane receptors and RNAs. The potential of single-molecule imaging to contribute to drug discovery is also discussed.

Phosphoinositide 3-kinase alpha (PI3Kα) is a pivotal regulator of cell growth, proliferation, and survival. Dysregulation of the PI3K/AKT/mTOR pathway, driven predominantly by PIK3CA mutations (e.g., H1047R, E542K, and E545K), is a hallmark of many cancers. Advances in structural, biochemical, and computational studies have elucidated mutation-specific conformational changes of PI3Kα. While early pan- and isoform-selective PI3K inhibitors (alpelisib) show clinical utility, their intrinsic toxicity and resistance to treatment persist. Recent breakthroughs include the emergence of allosteric inhibitors (RLY-2608 and STX-478) that exploit mutation-induced cryptic pockets to achieve mutant selectivity as well as covalent inhibitors and degraders (inavolisib) that enhance specificity, aiming at decoupling antitumor activity from metabolic dysfunction. This review synthesizes current progress in PI3Kα inhibitor development, emphasizing structural characteristics, clinical challenges, and emerging strategies. Addressing challenges to increase mutant selectivity, exploring conformational modulation, uncovering new mechanisms of action, and implementing personalized therapies are key future directions for PI3Kα-targeted drug discovery.

Toluene intoxication constitutes a persistent public health problem worldwide. While most organs can be damaged, the brain is a primary target whether exposure is accidental, occupational, or recreational. Interventions to prevent/revert brain damage by toluene are curtailed by the scarce information on the molecular targets and mechanisms mediating toluene's brain toxicity and the common exposure to other neurotoxins and/or coexistence of neurological/psychiatric disorders. We examine (a) the physicochemical properties of toluene that allow this inhalant to primarily target the lipid-rich brain; (b) the cell types targeted by toluene (neurons, different types of glia), while considering a cerebrovascular component; and (c) putative molecular mechanisms by which toluene may modify receptor function while analyzing structural features that allow toluene to directly interact with membrane lipids or specific proteins. This information constitutes a stepping stone to design pharmacotherapies that counteract toluene brain intoxication.