Current Medicinal Chemistry - Volume 31, Issue 42, 2024

Although radiotherapy is one of the main cancer treatment modalities, exposing healthy organs/tissues to ionizing radiation during treatment and tumor resistance to ionizing radiation are the chief challenges of radiotherapy that can lead to different adverse effects. It was shown that the combined treatment of radiotherapy and natural bioactive compounds (such as silymarin/silibinin) can alleviate the ionizing radiation-induced adverse side effects and induce synergies between these therapeutic modalities. In the present review, the potential radiosensitization effects of silymarin/silibinin during cancer radiation exposure/radiotherapy were studied.

According to the PRISMA guideline, a systematic search was performed for the identification of relevant studies in different electronic databases of Google Scholar, PubMed, Web of Science, and Scopus up to October 2022. We screened 843 articles in accordance with a pre-defined set of inclusion and exclusion criteria. Seven studies were finally included in this systematic review.

Compared to the control group, the cell survival/proliferation of cancer cells treated with ionizing radiation was considerably less, and silymarin/silibinin administration synergistically increased ionizing radiation-induced cytotoxicity. Furthermore, there was a decrease in the tumor volume, weight, and growth of ionizing radiation-treated mice as compared to the untreated groups, and these diminutions were predominant in those treated with radiotherapy plus silymarin/silibinin. Furthermore, the irradiation led to a set of biochemical and histopathological changes in tumoral cells/tissues, and the ionizing radiation-induced alterations were synergized following silymarin/silibinin administration (in most cases).

In most cases, silymarin/silibinin administration could sensitize the cancer cells to ionizing radiation through an increase of free radical formation, induction of DNA damage, increase of apoptosis, inhibition of angiogenesis and metastasis, etc.  However, suggesting the use of silymarin/silibinin during radiotherapeutic treatment of cancer patients requires further clinical studies.

Mechanism of fibroblasts in skin melanoma (SKME) revealed by single-cell RNA sequencing data.

SKME is responsible for more than 80% of skin-related cancer deaths. Cancer-associated fibroblasts (CAFs) generate inflammatory factors, growth factors and extracellular matrix proteins to facilitate cancer cell growth, metastasis, drug resistance and immune exclusion. However, molecular mechanisms of CAFs in SKME are still lacking.

Our goal was to reveal the role of CAFs in SKME.

We downloaded the single-cell RNA sequencing (scRNA-seq) dataset from the Gene Expression Omnibus (GSE215120) database. Then, the Seurat package was applied to analyze the single-cell atlas of SKME data, and cell subsets were annotated with the CellMarker database. The molecular mechanisms of CAFs in SKME were disclosed via differential gene expression and enrichment analysis, Cellchat and SCENIC methods.

Using scRNA-seq data, three SKME cases were used and downscaled and clustered to identify 11 cell subgroups and 5 CAF subsets. The enrichment of highly expressed genes among the 5 CAF subsets suggests that cell migration-inducing hyaluronan-binding protein (CEMIP) ⁺ fibroblasts and naked cuticle homolog 1 (NKD1)⁺ fibroblasts were closely associated with epithelial to mesenchymal transition. Cellchat analysis revealed that CAF subpopulations promoted melanocyte proliferation through Jagged1 (JAG1)-Notch homolog 1 (NOTCH1), JAG1-NOTCH3 and migration through pleiotrophin (PTN)-syndecan-3 (SDC3) receptor-ligand pairs. The SCENIC analysis identified that most of the transcription factors in each CAF subpopulation played a certain role in the metastasis of melanoma and were highly expressed in metastatic SKME samples. Specifically, we observed that CEMIP⁺ fibroblasts and NKD1⁺ fibroblasts had potential roles in participating in immune therapy resistance. Collectively, we uncovered a single-cell atlas of SKME and revealed the molecular mechanisms of CAFs in SKME development, providing a base for immune therapy and prognosis assessment.

Our study reveals that 5 CAFs in SKME have a promoting effect on melanocyte proliferation and metastasis. More importantly, CEMIP⁺ fibroblasts and NKD1⁺ fibroblasts displayed close connections with immune therapy resistance. These findings help provide a good basis for future immune therapy and prognosis assessment targeting CAFs in SKME.

Metastasis is a major cause of death in UM, highlighting the need to use highly specific and sensitive prognostic markers to identify patients with a risk of developing metastasis.

The aim of this study was to improve the current precision treatment for patients with metastatic uveal melanoma (UM).

The objective of this work was to investigate the heterogeneity between primary human UM and metastatic UM at the single-cell level and to discover potential molecules regulating UM metastasis.

Seurat R toolkit was employed to analyze single-cell sequencing data of UM and to identify differentially expressed genes (DEGs) between primary and metastatic UM. Least absolute shrinkage and selection operator (LASSO) and Cox regression analyses were performed on the DEGs from the bulk RNA-seq cohort to develop a prognostic model. Based on the model, patients were divided into high and low groups. The correlations among the risk score, immune indicators, immune checkpoint blockade (ICB) therapy, and anti-tumor drug therapy were analyzed.

Cell types in primary UM and metastatic UM tumors include B/plasma cells, endothelial cells, melanocytes, monocytes/macrophages, photoreceptor cells, and T cells. Among 157 DEGs between the two tumor types, S100A4, PDE4B, CHCHD10, NSG1, and C4orf48 were selected to construct a prognostic model. The model could accurately and independently predict response to ICB treatment and sensitivity to antineoplastic drugs for UM patients as well as their immune infiltration levels, risk of death, and metastasis possibility.

This study analyzed the tumor ecosystem of primary and metastatic UM, providing a metastasis-related model that could be used to evaluate the prognosis, risk of metastasis, immunotherapy, and efficacy of antineoplastic drug treatment of UM.

Gastric cancer is one of the most common malignant tumours of the gastrointestinal tract, which has a significant negative impact on human health.

CCL chemokines play important roles in a variety of tumor microenvironments; nevertheless, gastric cancer has surprisingly limited associations with CCL chemokines.

In our study, we comprehensively utilized bioinformatics analysis tools and databases such as cBioPortal, UALCAN, GEPIA, GeneMANIA, STRING, and TRRUST to clarify the clinical significance and biology function of CCL chemokines in gastric cancer.

The mRNA expression levels of CCL1/3/4/5/7/8/14/15/18/20/21/22/26 were up-regulated, while the mRNA expression levels of CCL2/11/13/16/17/19/23/24/25/28 were down-regulated. The chemokine significantly associated with the pathological stage of gastric cancer is CCL2/11/19/21. In gastric cancer, the expression level of CCL chemokines was not associated with disease-free survival, but low expression of CCL14 was significantly associated with longer overall survival. Therein, associated with the regulation of CCL chemokines are only 10 transcription factors (RELA, NFKB1, STAT6, IRF3, REL, SPI1, STAT1, STAT3, JUN and SP1). The major biological process and functional enrichment of CCL chemokines are to induce cell-directed migration.

These results may indicate that CCL chemokines may be immunotherapeutic targets and promising prognostic biomarkers for gastric cancer.

The aims of this study were to determine hub genes in glaucoma through multiple machine learning algorithms.

Glaucoma has afflicted many patients for many years, with excessive pressure in the eye continuously damaging the nervous system and leading to severe blindness. An effective molecular diagnostic method is currently lacking.

The present study attempted to reveal the molecular mechanism and gene regulatory network of hub genes in glaucoma, followed by an attempt to reveal the drug-gene-disease network regulated by hub genes.

A microarray sequencing dataset (GSE9944) was obtained through the Gene Expression Omnibus database. The differentially expressed genes in Glaucoma were identified. Based on these genes, we constructed three machine learning models for feature training, Random Forest model (RF), Least absolute shrinkage and selection operator regression model (LASSO), and Support Vector Machines model (SVM). Meanwhile, Weighted Gene Co-Expression Network Analysis (WGCNA) was performed for GSE9944 expression profiles to identify Glaucoma-related genes. The overlapping genes in the four groups were considered as hub genes of Glaucoma. Based on these genes, we also constructed a molecular diagnostic model of Glaucoma. In this study, we also performed molecular docking analysis to explore the gene-drug network targeting hub genes. In addition, we evaluated the immune cell infiltration landscape in Glaucoma samples and normal samples by applying CIBERSORT method.

8 hub genes were determined: ATP6V0D1, PLEC, SLC25A1, HRSP12, PKN1, RHOD, TMEM158 and GSN. The diagnostic model showed excellent diagnostic performance (area under the curve=1). GSN might positively regulate T cell CD4 naïve as well as negatively regulate T cell regulation (Tregs). In addition, we constructed gene-drug networks in an attempt to explore novel therapeutic agents for Glaucoma.

Our results systematically determined 8 hub genes and established a molecular diagnostic model that allowed the diagnosis of Glaucoma. Our study provided a basis for future systematic studies of Glaucoma pathogenesis.

Perillyl alcohol (POH) is a monoterpenoid found in plant essential oils and has been shown to relax murine vessels, but its effect on human vessels remains poorly studied.

The study aimed to characterize the effect of POH on human umbilical arteries (HUA).

Rings of HUA were obtained from uncomplicated patients and suspended in an organ bath for isometric recording. The vasorelaxant effect of POH in HUA was evaluated on basal tone and electromechanical or pharmacomechanical contractions, and possible mechanisms of action were also investigated.

POH (1-1000 µM) altered the basal tone of HUA and completely relaxed HUA rings precontracted with KCl (60 mM) or 5-HT (10 µM), obtaining greater potency in the pharmacomechanical pathway (EC50 110.1 µM), suggesting a complex interference in the mobilization of extra- and intracellular Ca²⁺. POH (1000 µM) inhibited contractions induced by BaCl2 (0.1-30 mM) in a similar way to nifedipine (10 µM), indicating a possible blockade of L-type VOCC. In the presence of potassium channel blockers, tetraethylammonium (1 mM), 4-aminopyridine (1 mM), or glibenclamide (10 µM), an increase in the EC50 value of the POH was observed, suggesting a modulation of the activity of BKCa, KV, and KATP channels.

The data from this study suggest that POH modulates Ca²⁺ and K⁺ ion channels to induce a relaxant response in HUA.