Microtubule-destabilizing agents enhance STING-mediated innate immune response via biased mechanism in human monocyte cells.

The stimulator of the interferon gene (STING) signaling pathway acts as a primary defense system against DNA pathogens. Because of the crucial role of STING in type I interferon (IFN) response and innate immunity, extensive research has been conducted to elucidate the roles of various effector molecules involved in STING-mediated signal transduction. However, despite the substantial contribution of microtubules to the immune system, the association between the STING signaling pathway and microtubules remains unclear. In this study, we revealed that the modulation of STING via microtubule-destabilizing agents (MDAs) specifically induced type I IFN responses rather than inflammatory responses in human monocytes. Co-treatment of MDAs with STING agonists induced the elevation of phospho-TANK-binding kinase 1 (TBK1), amplifying the innate immune response. However, during the deficiency of TBK1, the non-canonical signaling pathway through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) contributed to MDA-induced STING activation in type I IFN response which suggested the versatile regulation of MDA in STING-mediated immunity.

Autonomic Dysfunction in Sleep Disorders: From Neurobiological Basis to Potential Therapeutic Approaches.

Sleep disorder has been portrayed as merely a common dissatisfaction with sleep quality and quantity. However, sleep disorder is actually a medical condition characterized by inconsistent sleep patterns that interfere with emotional dynamics, cognitive functioning, and even physical performance. This is consistent with sleep abnormalities being more common in patients with autonomic dysfunction than in the general population. The autonomic nervous system coordinates various visceral functions ranging from respiration to neuroendocrine secretion in order to maintain homeostasis of the body. Because the cell population and efferent signals involved in autonomic regulation are spatially adjacent to those that regulate the sleep-wake system, sleep architecture and autonomic coordination exert effects on each other, suggesting the presence of a bidirectional relationship in addition to shared pathology. The primary goal of this review is to highlight the bidirectional and shared relationship between sleep and autonomic regulation. It also introduces the effects of autonomic dysfunction on insomnia, breathing disorders, central disorders of hypersomnolence, parasomnias, and movement disorders. This information will assist clinicians in determining how neuromodulation can have the greatest therapeutic effects in patients with sleep disorders.

Development of Potent Immune Modulators Targeting Stimulator of Interferon Genes Receptor.

Stimulator of interferon genes (STING) is an endoplasmic reticulum-membrane protein that plays important roles in cancer immunotherapy by activating innate immune responses. We designed and synthesized STING modulators and characterized compounds 4a and 4c that share a crucial amidobenzimidazole moiety. In vitro STING binding and cell-based activity assays demonstrated the potency and efficacy of the compounds that function as direct STING agonists by stimulating STING downstream signaling and promoting type I interferon immune responses. In vitro metabolic studies and the pharmacokinetic properties of the compounds led us to investigate their anticancer activity in an in vivo syngeneic model. Intravenous injection of compounds 4a and 4c significantly decreased tumor volume in a CT26 murine colorectal carcinoma model, and the immunological memory-derived cancer inhibition was observed in 4c-treated mouse models. The present results suggest the therapeutic potential of the compounds for cancer immunotherapy via STING-mediated immune activation.

Development of Small-Molecule STING Activators for Cancer Immunotherapy.

In cancer immunotherapy, the cyclic GMP-AMP synthase-stimulator of interferon genes (STING) pathway is an attractive target for switching the tumor immunophenotype from 'cold' to 'hot' through the activation of the type I interferon response. To develop a new chemical entity for STING activator to improve cyclic GMP-AMP (cGAMP)-induced innate immune response, we identified KAS-08 via the structural modification of DW2282, which was previously reported as an anti-cancer agent with an unknown mechanism. Further investigation revealed that direct STING binding or the enhanced phosphorylation of STING and downstream effectors were responsible for DW2282-or KAS-08-mediated STING activity. Furthermore, KAS-08 was validated as an effective STING pathway activator in vitro and in vivo. The synergistic effect of cGAMP-mediated immunity and efficient anti-cancer effects successfully demonstrated the therapeutic potential of KAS-08 for combination therapy in cancer treatment.