Targets

Alzheimer’s disease is a neurodegenerative disease that continues to have a rising number of cases. While extensive research has been conducted on Alzheimer’s disease in the last few decades, only a few drugs have been approved by the FDA for its treatment, and even fewer aim to be curative rather than manage symptoms. There remains an urgent need to understand disease pathogenesis, as well as identify new targets for further drug discovery. Alzheimer’s disease (AD) is known to stem from the build-up of amyloid beta (Aβ) plaques, as well as tangles of tau proteins. Furthermore, inflammation in the brain is known to arise from the degeneration of tissue and the build-up of insoluble material. Therefore, there is a potential link between the pathology of AD and inflammation in the brain, especially as the disease progresses to later stages, where neuronal death and degeneration levels are higher. Proteins that are relevant to both brain inflammation and AD, thus, make ideal potential targets for therapeutics; however, the proteins need to be evaluated to determine which targets would be ideal for potential drug therapeutic treatments, or ‘druggable’ targets. Druggability analysis was conducted using two structure-based methods (i.e., drug-like density analysis and SiteMap), as well as a sequence-based approach, SPIDER. The most druggable targets were then evaluated using single-nucleus sequencing data for their clinical relevance to inflammation in AD. For each of the top five targets, small molecule docking was used to evaluate which FDA approved drugs were able to bind with the chosen proteins. The top targets included DRD2 (inhibits adenylyl cyclase activity), C9 (binds with C5B8 to form the membrane attack complex), C4b (binds with C2a to form C3 convertase), C5AR1 (a GPCR that binds C5a), and GABA-A-R (the GPCR involved in inhibiting neurotransmission). Each target had multiple potential inhibitors from the FDA-approved drug list with decent binding infinities. Among these inhibitors, two drugs were found to be top inhibitors for more than one protein target. They were C15H14N2O2 and v316 (paracetamol), originally used to treat pain/inflammation for cataracts and relieve headaches/fever, respectively. These results provide the groundwork for further experimental investigations or clinical trials. Full article

Pulmonary arterial hypertension (PAH) is a progressive and rare condition characterised by the occlusion of pulmonary arterioles, with clinical manifestations resulting from the cross-sectional area reduction of the small pulmonary arteries. The disease is driven by a combination of factors including vasoconstriction, thrombosis, inflammation, proliferation, and the obstructive remodelling of the pulmonary artery walls. Heterozygous mutations in the type II bone morphogenetic protein receptor (BMPR2) underlie the majority of the inherited and familial forms of PAH. Current evidence indicates that in PAH, the BMPR2-mediated-signalling is diminished and the TGFβ signalling is heightened. Even when managed with current therapeutic approaches, the disease eventually results in increased pulmonary vascular resistance, right heart failure, and premature death. Natural products act as vascular disease treatment agents and have been used in clinical practice following compelling clinical trials. The rationale for the selection of natural compounds derives from their multi-targeted approach and synergistic effects. Although novel medicines licenced by the FDA (USA) between 1981 and 2010, constitute approximately 34% natural products or derivatives of natural products, their potentials for the treatment of PAH are not fully explored. The objective of this review is to emphasise the significance of natural products in the therapeutic resolution of PAH. Full article

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

Drug resistance in cancer is a significant contributor to high mortality, and it exists in the complex form of a multi-parameter. Here, we unravel the roles of tumor heterogeneity, intratumoral physiological barriers, and safe havens in the onset and progression of cancer drug resistance, and outline strategies for resolution. We advocate for a “three-step approach” to reverse cancer drug resistance, including the management of cancer evolution and early intervention, the normalization of intratumoral physiological barriers, and the breakage of tumor safe havens. This approach aims to effectively manage the source of drug resistance, dismantle the breeding grounds of drug resistance, and break the sanctuaries where drug resistance hides. Full article

The vast majority of advanced NSCLC cases are histologically represented by adenocarcinomas. EGFR activating mutations (exon 19 deletions, exon 21 L858R substitutions, exon 20 insertions) represent one of the most common druggable alterations. Since erlotinib’s FDA approval in 2013, EGFR-TKIs have represented a staple of EGFR+ advanced NSCLC treatment, with osimertinib representing the latest major FDA-approved third-generation EGFR-TKI. In recent years, however, several preclinical data have highlighted promising results regarding combination therapies involving EGFR-TKIs plus chemotherapy, and various recent clinical trials have confirmed these results. In addition, in 2021, amivantamab was the first FDA-approved mAb for the treatment of EGFR+ advanced NSCLC patients; according to some extremely up-to-date clinical trials, the combination of amivantamab plus chemotherapy is also associated with superior results. Therefore, this paper aims to provide a comprehensive review of both the bases and the latest evidence of the combination therapies involving EGFR+ advanced NSCLC patients. Full article

Epigenetic modulation of DNA and histones facilitated by and histone deacetylases (HDAC) is associated with the development and progression of many cancers, although less is known about DNA methyltransferase (DNMT) in oral cancers and the regulation of these targets. Using commercially available cell lines, oral squamous cell carcinomas (SCC4, SCC9, SCC15, SCC25, and CAL27), and normal gingival fibroblasts (HGF-1), growth assays and mRNA expression were evaluated using ANOVA. These results revealed homeostasis enzyme DNMT1 expression was significantly higher among slow-growing HGF-1 cells than among fast-growing oral cancers, p < 0.05. In contrast, DNMT3A and DNMT3B expression was significantly higher among oral cancers compared with HGF-1 cells, p < 0.05. However, differential expression of HDAC1 and HDAC2 was observed among SCC4, SCC25, and CAL27 cells. Further analysis of miR-152 (regulation and control of DNMT expression) and miR-21, miR-221, and miR-145 (regulation of HDAC expression) revealed all oral cancers produced miR-21, but none produced miR-221. However, differential expression of miR-145 (SCC15) and miR-152 (SCC25) suggested alternative epigenetic pathways and mechanisms of DNMT and HDAC regulation may be responsible for some of the observations revealed in this study. Full article

The significance of hydrogen sulfide (H₂S) in biological research is covered in detail in this work. H₂S is a crucial gas-signaling molecule that is involved in a wide range of illnesses and biological processes. Whether H₂S has a beneficial therapeutic effect or negative pathological toxicity in an organism depends on changes in its concentration. A novel approach to treatment is the regulation of H₂S production by medications or other measures. Furthermore, H₂S is a useful marker for disease assessment because of its dual nature and sensitivity. We can better understand the onset and progression of disease by developing probes to track changes in H₂S concentration based on the nucleophilicity, reducing properties, and metal coordination properties of H₂S. This will aid in diagnosis and treatment. These results demonstrate the enormous potential of H₂S in the detection and management of disease. Future studies should concentrate on clarifying the relationship between diseases and the mechanism of action of H₂S in organisms. Ultimately, this work opens new possibilities for disease diagnosis and treatment while highlighting the significance of H₂S in biological research. Future clinical practice and medical advancements will benefit greatly from our thorough understanding of the mechanism of action and therapeutic applications of H₂S. Full article

The landscape of cancer therapy has gained major impetus through the development of materials capable of selectively targeting cancer cells while sparing normal cells. Synthetic peptides are appealing as scaffolds for the creation of such materials. They are small in size, amenable to chemical synthesis and functionalization, and possess diverse chemical and structural space for modulating targeting properties. Here, we review some fundamental insights into the design, discovery, and evolution of peptide-based targeting agents, with a particular focus on two types of cancer cell targets: unique/overexpressed surface receptors and abnormal physiological properties. We highlight the cutting-edge strategies from the literature of the last two decades that demonstrate innovative approaches to constructing receptor-specific cyclic binders and stimulus-responsive targeting materials. Additionally, we discuss potential future directions for advancing this field, with the aim of pushing the frontiers of targeted cancer therapy forward. Full article

Facing the increasingly global crisis of antibiotic resistance, it is urgent to develop new antibacterial agents and methods. Simultaneously, as research progresses, the occurrence, development, and treatment of diseases, especially some malignant cancers, are found to be closely associated with the bacterial microenvironment, prompting us to reconsider the efficiency of existing antibacterial strategies for disease treatments. Bacteriophages have been employed as antibacterial agents for an extended period owing to their high biocompatibility and particular targetability toward the host bacterial strains. Nonetheless, they are almost neglected due to their slow and limited efficacy in antibacterial practice, especially in acute and severe infectious cases. In recent years, fantastic advancements in various biochemical technologies, such as bacteriophage display technology, genetic engineering, and chemical molecular engineering, have enabled scientists to conduct a broader range of modifications and transformations on the existing bacteriophages with inherited unique characteristics of themselves. As a result, a series of novel bacteriophage platforms are designed and fabricated with significantly enhanced properties and multiplied functionalities. These offer new avenues for combating infections caused by drug-resistant bacteria and treatment of malignancies that are associated with bacterial infections, holding great significance and potential in the innovative theranostic applications. Full article

Cancer remains a significant global health challenge despite advancements in diagnosis and treatment. Traditional cancer therapies often face limitations such as toxicity and drug resistance. Drug repurposing has emerged as a promising strategy to overcome these challenges by identifying new therapeutic uses for existing drugs. This review explores the potential of repurposing positive inotropic agents, which are traditionally used in cardiovascular medicine, for cancer therapy. Positive inotropic agents, including cardiac glycosides, β-agonists, phosphodiesterase inhibitors, and calcium sensitizers have shown preclinical evidence of anti-tumor activity through various mechanisms, such as modulation of the intracellular signaling pathways, increasing cyclic adenosine monophosphate (cAMP) levels, the production of nitric oxide, and decreasing reactive oxygen species levels. Despite the absence of specific clinical trials in this area, these findings suggest a promising avenue for further research and development of combination therapies to improve cancer treatment outcomes. However, challenges such as elucidating specific anti-tumor mechanisms, identifying predictive biomarkers, and optimizing safety profiles need to be addressed to fully realize the therapeutic potential of positive inotropic agents in oncology. Full article

The interactions between carbon dots (C-dots) and cells and the corresponding subcellular organelle localization are both significant for bio-sensing and bio-imaging. In this study, we explore cellular uptake and internalization behaviors of two kinds of lipophilic unit-emitting C-dots for three different kinds of cells. It is found that both C-dots can localize in lipid droplets with high efficiency. Compared with commercial dyes, the imaged lipid droplets by the proposed C-dots possess well-defined outlines. Based on such superior imaging performances, the quantification of lipid droplets for cells pretreated by oleic acid stimulation and starvation is well achieved. Full article

Fibrosarcoma represents a significant challenge in oncology, characterized by high invasiveness and a poor prognosis. Gelatinases, particularly matrix metalloproteinases MMP-2 and MMP-9, play a pivotal role in the degradation of the extracellular matrix, facilitating tumor invasion and metastasis. Inhibiting these enzymes has emerged as a promising therapeutic strategy. This review evaluates the progress in the development and therapeutic potential of gelatinase inhibitors as treatments for fibrosarcoma over the last decade, highlighting molecular mechanisms and future directions. A comprehensive literature review was conducted, focusing on studies published from 2013 to 2023. Research articles and review papers relevant to gelatinase inhibition and fibrosarcoma were examined to assess the efficacy and mechanisms of gelatinase inhibitors. Gelatinase inhibitors have shown the potential to reduce tumor progression, invasion, and metastasis in fibrosarcoma. Clinical trials, although limited, have indicated that these inhibitors can be effectively integrated into existing therapeutic regimens, offering a reduction in metastatic spread and potentially improving patient survival rates. Mechanistic studies suggest that the inhibition of MMP-2 and MMP-9 disrupts critical pathways involved in tumor growth and cell invasion. Gelatinase inhibition represents a viable and promising approach to fibrosarcoma treatment. Future research should focus on developing more specific inhibitors, understanding long-term outcomes, and integrating gelatinase inhibition into multimodal treatment strategies to enhance efficacy. Full article