Targets, Volume 2, Issue 4 (December 2024) – 8 articles

This review article explores the current landscape of acute myeloid leukemia treatment, including novel target molecules and recent advancements in cell therapy and immunotherapy focused on T cell activity. Advances in treatment have been promising in recent years, driven by the development of therapies targeting new molecular and genetic therapeutic targets. These findings allowed for the approval of several target therapies by the European and American drug agencies in the last 5 years. However, mortality remains very high, particularly in relapsed or refractory (R/R) patients. In recent years, the development of immunotherapy has expanded this field, leading to the introduction of new drugs and treatments. Full article

Interleukin 19 (IL-19) is an anti-inflammatory cytokine that belongs to the IL-10 family, where IL-20 and IL-24 also exist. While IL-19 and IL-20 share some comparable structural folds, there are certain structural divergences in their N-terminal ends. To date, there are no reported IL-19 receptors; although, it has been suggested in the literature that IL-19 would bind to lL-20 receptor (IL-20R) and trigger the JAK-STAT signaling pathways. The present report examines the structure of the IL-19 cytokine and its receptor complex using a computational approach. Specifically, the postulated modes of interactions for IL-20R as an IL-19 receptor are examined on the basis of a set of computational findings. The author has used molecular docking and molecular dynamics simulation to generate a 3D model for the IL-19 complex with IL-20R. When a protein’s crystal structure is not available in the literature, predictive modeling is often employed to determine the protein’s 3D structure. The model assessment can be based on various factors, which include stability analysis using RMSD calculations, tracking changes in time-based secondary structures and the associated Gibbs energies, ΔG. Since one model complex (referred to as model A throughout this paper) can be used as a working hypothesis for future experiments, this structure has been explored here in detail to check its stability, subunit interfaces, and binding residues. The information gathered in this approach can potentially help to design specific experiments to test the validity of the model protein structure. Additionally, the results of this research should be relevant for understanding anti-inflammatory mechanisms and, eventually, could contribute to the efforts for therapeutic developments and targeted therapy. Full article

Molecular cages have promising host–guest properties for drug delivery applications. Specifically, guest⊂cage complexes can be used for the on-command release of encapsulated guest molecules in response to specific stimuli. This research explores both the dynamic and constrictive binding guest⊂cage systems for drug encapsulation and release in biological environments. In dynamic systems, the guest rapidly passes in-and-out through the portals of the cage, enabling drug delivery in vitro but facing limitations in vivo due to dilution effects that result in guest release. These challenges are addressed by constrictive binding systems, where the guest is trapped in a “gate-closed” state within the cage. In these systems, the on-command release is triggered by a “gate opening” event, which lowers the guest–out energy barrier. A full guest release is achieved when the gate opening reduces the cage–guest affinity, making constrictive binding systems more effective for controlled drug delivery. As a result, this study shows that guest⊂cage complexes have suitable properties for drug delivery in biological contexts. Full article

RAPTOR (regulatory-associated protein of mTOR) is a pivotal component of the mammalian target of rapamycin complex 1 (mTORC1), playing a central role in regulating cell growth, metabolism and stress responses. As a scaffold protein, RAPTOR recruits key substrates such as eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) and ribosomal protein S6 kinase (S6K), facilitating their phosphorylation by mTORC1, which in turn drives protein synthesis, lipid metabolism and cellular proliferation. Its regulatory function becomes especially crucial under conditions of nutrient deprivation or stress, where it enhances the stability of the mTORC1 complex, allowing cells to adapt to fluctuating environmental cues. The hyperactivation of mTORC1, largely mediated by RAPTOR, is frequently observed in various cancers, contributing to uncontrolled cell proliferation and tumorigenesis. Moreover, RAPTOR’s modulation of immune responses and metabolic pathways extends its influence beyond oncogenesis, impacting inflammatory diseases and metabolic disorders. This review meticulously elucidates RAPTOR’s structure, post-translational modifications as well as its indispensable role within the mTORC1 complex, emphasizing its regulatory functions in cellular growth, metabolic adaptation, immune response and disease pathology including oncogenesis. Furthermore, it explores emergent therapeutic avenues targeting RAPTOR-mediated mTORC1 signaling, underscoring their potential to revolutionize cancer treatment and the management of related pathophysiological conditions. Full article

Afterglow imaging plays a crucial role in the cancer treatment field. In contrast to inorganic afterglow imaging agents, organic afterglow imaging agents possess easily modifiable structures and exhibit excellent biocompatibility, thereby presenting significant prospects for application in tumor diagnosis and management. In this review, we summarize the design principles and applications of afterglow probes in tumor imaging and therapy. Finally, we discuss the future challenges and prospects of organic afterglow probes in cancer diagnosis and therapy. Full article

Resveratrol, a naturally occurring polyphenol found in grapes, berries, and peanuts, has garnered significant attention for its potential anti-cancer properties. This review provides a comprehensive analysis of its role in cancer therapy, both as a standalone treatment and in combination with other therapeutic approaches. This review explores the molecular mechanisms underlying resveratrol’s anti-cancer effects, including its antioxidant activity, modulation of cellular signaling pathways, antiproliferative properties, anti-inflammatory effects, and epigenetic influences. This review also examines in vitro and in vivo studies that highlight resveratrol’s efficacy against various cancer types. Furthermore, the synergistic effects of resveratrol when used in conjunction with conventional treatments like chemotherapy and radiotherapy, as well as targeted therapies and immunotherapies, are discussed. Despite promising preclinical results, this review addresses the challenges and limitations faced in translating these findings into clinical practice, including issues of bioavailability and toxicity. Finally, it outlines future research directions and the potential for resveratrol to enhance existing cancer treatment regimens. This review aims to provide a thorough understanding of resveratrol’s therapeutic potential and to identify areas for further investigation in the quest for effective cancer treatments. Full article

Immunological risk factors in recurrent pregnancy loss include autoantibodies, alterations in NK cell number and function, regulatory T cells, the human leukocyte antigen system (HLA), etc., where the treatment options aim to regulate immune dysfunction. Intralipid is a synthetic product traditionally used as a dietary supplement consisting of soybean oil combined with refined egg phospholipids. It has been shown that intralipid exerts physiologic activities, including altering immunological functions, that may benefit patients with certain types of infertility. In this review, we summarize the current state of the art of targeting NK cells and NK cell activity in women with implantation failure or/and recurrent pregnancy loss. We focus on intralipid mechanisms of action and outcomes of clinical trials regarding the efficacy and safety of intralipid infusions in women with reproductive failure. More studies are needed to reveal all the aspects of the safety and effectiveness of intralipid administration in reproductive failure treatment. Full article

Glucocorticoids are the mainstay treatments for diverse pathologies. Ultraviolet (UV) radiation is a risk factor for alterations in the skin, including cell viability (skin thickness), mediators of angiogenesis (blood flow/inflammation), and remodeling of the extracellular matrix (skin integrity). We examined the effects of hydrocortisone on cell viability, p53 promoter activity, and expression of interleukin-8 (IL-8), matrixmetalloproteinase-1 (MMP-1), and tissue inhibitor of matrixmetalloproteinase-1 (TIMP-1) in non-irradiated, UVA-radiated, and UVB-irradiated dermal fibroblasts and melanoma cells. Hydrocortisone inhibited cell viability by stimulating p53 promoter activity in fibroblasts, but not in melanoma cells, which instead showed a decrease in p53 promoter activity in non-irradiated and UVA-irradiated cells. Hydrocortisone inhibited the IL-8 protein levels in non-irradiated and UV-irradiated fibroblasts, and in the non-irradiated melanoma cells, by post-transcriptional mechanisms. Hydrocortisone increased the MMP-1 to TIMP-1 ratio in non-irradiated and UVB-irradiated fibroblasts by inhibiting TIMP-1, and in melanoma cells by inhibiting TIMP-1 in non-irradiated cells and stimulating MMP-1 in UV-irradiated cells. It may be inferred that hydrocortisone has the potential to cause skin thinning by inhibiting cell viability, angiogenesis, and deposition of structural ECM by fibroblasts, regardless of UV exposure, and facilitating UV-exposed melanoma cells by increasing MMP-1 expression. Full article