Targets

Colorectal cancer (CRC) is one of the major reasons for cancer-related deaths around the world. Constitutive activation of WNT pathway, due to APC gene mutation, is the characteristic feature of most human colon tumors. Familial adenomatous polyposis (FAP) patients inherit APC mutations and pose an absolute risk of developing CRC in their lifetime. The genetically modified APC mouse models have paved the way to study various aspects of the hereditary human CRC, including biochemical, molecular, and histological aspects. Preclinical and clinical data suggest that certain dietary supplements, NSAIDs, natural products, and chemically synthesized compounds, can help in intercepting CRC incidence and progression by modulating various hallmarks of cancer. In this review, we have provided a summary of promising natural and synthetic agents that demonstrated chemopreventive efficacy against CRC in the FAP-mimicking APC^Min/+ mouse model. Full article

We recently found that myometrial distension stimulates maternal uterine vascular remodeling, and hypothesized that this may be a previously unrecognized mechanism for inducing arterial growth during pregnancy. The aim of this study was to further characterize a recently developed surgical model in which medical-grade silicone was infused into one uterine horn of a non-gravid rat to induce acute myometrial stretch, followed by an additional, gradual distension due to the secretion of an exudate into the uterine lumen. Our objectives were to better understand the effects of stretch on the myometrium and to look for the expression of proangiogenic and proinflammatory factors that may stimulate uterine vascular remodeling. Morphometric analysis showed hypertrophy of the uterine corpus that was primarily due to axial growth since the myometrial cross-sectional area was unchanged due to a thinning of the uterine wall secondary to stretch. This finding was supported by significantly increased myometrial smooth muscle cell mitosis. There was also an increase in the concentration of myometrial elastin but not collagen. The analysis showed modest increases in neutrophils, activated and unactivated macrophages, and the proinflammatory cytokines RANTES, MIP-3α, GRO-KC, and TNFα. The most dramatic change was the extremely high level of VEGF in the exudate, which was increased >900× above circulating levels. Full article

In recent years, machine learning algorithms have seen extensive application in chemical science, especially in cell detection technologies. Machine learning, a branch of artificial intelligence, is designed to automatically discover patterns in data. This review provides an overview of cell detection methods such as bright-field microscopy (BL), dark-field microscopy (DL), surface-enhanced Raman scattering (SERS), and fluorescence detection (FL). We highlight key computational models like support vector machines and convolutional neural networks that significantly enhance the precision and efficiency of automated cell detection. Relevant research applications are discussed, along with future prospects for machine learning in cell analysis. Full article

Aromatic properties of two series of quinoline derivatives were studied theoretically using the Density Functional Theory (DFT) approach. One series of compounds possesses antimalarial activity while the other does not have such properties. The B3LYP functional and the 6-311++G** basis set were employed in the study. The optimized geometries of the studied compounds were used for aromaticity level determination using several aromaticity indices, like HOMA, NICS, PDI, I₆, FLU, and PLR. It was shown that the level of aromaticity seems to be a feature that differentiates these two series of compounds. This is reasonable because it has been presented, previously in the literature, that this type of drug acts as an antimalarial drug through the formation of the π-π complex with ferriprotoporphyrin. There are two types of rings in the quinoline system, a benzene type, and a pyridine type. The aromaticity of the benzene-type ring in both series of studied compounds is similar while the aromaticity of the pyridine-type ring is lower for compounds that have antimalarial properties. It is derived on the basis of performed research that the properties of the pyridine-type ring are more important for the drug activity of studied compounds. Full article

Head and neck cancer (HNC) is the seventh most commonly diagnosed malignancy worldwide, and its incidence is expected to increase in coming years. Current diagnostic methods for HNC are often limited by suboptimal accuracy and speed, which can negatively impact therapeutic decision-making and patient outcomes. To address the shortcomings of conventional diagnostics, biomarker detection has attracted increasing clinical interest as a promising alternative. However, a major challenge is the identification of biomarkers with sufficient accuracy and sensitivity for HNC. The integration of bioinformatics tools with omics data analysis has proven to be a robust approach for biomarker discovery. In this study, we outline a bioinformatics protocol aimed at identifying differentially expressed genes (DEGs) in HNC and evaluating the diagnostic and prognostic relevance of specific genes, including FN1, LGALS3, MMP9, TIMP1, MMP2, and TIMP2, in this pathology. In addition, we performed an enrichment analysis for the genes of interest. The prognostic significance of the selected genes was evaluated in relation to patient survival. This study contributes to the growing body of knowledge by identifying potential biomarkers with diagnostic and prognostic utility in this malignancy. Full article

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