Significance: Acetaminophen overdose is the most common cause of acute liver failure and the leading cause of chronic liver damage requiring liver transplantation in developed countries. There are limited options for early treatment. Acetaminophen liver toxicity leads to the formation of reactive oxygen and nitrogen species which cause an increase in intracellular Ca²⁺and hepatocellular death. We show that acetaminophen-induced liver toxicity depends on Transient Receptor Potential Melanostatine 2 (TRPM2) cation channels in hepatocytes, which are activated in response to oxidative stress and are responsible for Ca²⁺overload. Lack of TRPM2 channels in hepatocytes or their pharmacological inhibition protects liver from acetaminophen toxicity. This provides evidence that TRPM2 may present a potential therapeutic target for treatment of oxidative-stress related liver diseases.

Transient receptor potential vanilloid type 1 (TRPV1) channel responds to a wide spectrum of physical and chemical stimuli. In doing so, it serves as a polymodal cellular sensor for temperature change and pain. Many chemicals are known to strongly potentiate TRPV1 activation, though how this is achieved remains unclear. In this study we investigated the molecular mechanism underlying the gating effects of divalent cations Mg²⁺ and Ba²⁺. Using a combination of fluorescence imaging and patch-clamp analysis, we found that these cations potentiate TRPV1 gating by most likely promoting the heat activation process. Mg²⁺ substantially lowers the activation threshold temperature; as a result, a significant fraction of channels are heat-activated at room temperature. Although Mg²⁺ also potentiates capsaicin- and voltage-dependent activation, these processes were found either to be not required (in the case of capsaicin) or insufficient (in the case of voltage) to mediate the activating effect. In support of a selective effect on heat activation, Mg²⁺ and Ba²⁺ cause a Ca²⁺-independent desensitization that specifically prevents heat-induced channel activation but does not prevent capsaicin-induced activation. These results can be satisfactorily explained within an allosteric gating framework in which divalent cations strongly promote the heat-dependent conformational change or its coupling to channel activation, which is further coupled to the voltage- and capsaicin-dependent processes.

Neoantigen-based cancer vaccines have emerged as a promising immunotherapeutic approach to treat cancer. Nevertheless, the high degree of heterogeneity in tumors poses a significant hurdle for developing a vaccine that targets the therapeutically relevant neoantigens capable of effectively stimulating an immune response as each tumor contains numerous unique putative neoantigens. Understanding the complexities of tumor heterogeneity is crucial for the development of personalized neoantigen-based vaccines, which hold the potential to revolutionize cancer treatment and improve patient outcomes. In this review, we discuss recent advancements in the design of neoantigen-based cancer vaccines emphasizing the identification, validation, formulation, and targeting of neoantigens while addressing the challenges posed by tumor heterogeneity. The review highlights the application of cutting-edge approaches, such as single-cell sequencing and artificial intelligence to identify immunogenic neoantigens, while outlining current limitations and proposing future research directions to develop effective neoantigen-based vaccines.