Current Medicinal Chemistry - Volume 32, Issue 13, 2025

Integrated Stress Response Inhibitor (ISRIB) works by inhibiting the integrated stress response, a cellular pathway involved in the regulation of protein synthesis during stress conditions. Conditions that have been studied or suggested as potential candidates for treatment with ISRIB include neurological and metabolic disorders, cognitive impairment, viral infections, and cancer.

The study aimed to discuss the challenges related to specificity, long-term safety, and disease-specific considerations crucial for realizing the full potential of ISRIB.

A narrative review of the literature has been conducted to delve into ISRIB's chemistry, mechanisms of action, disease-specific considerations, and long-term safety implications.

While ISRIB has shown promising results in preclinical studies, more research is needed to determine its safety and effectiveness in human patients. Clinical trials are required to validate its therapeutic potential for various conditions. Despite having been proposed a decade ago, news of its clinical trials has been circulated only recently, without any published information yet and with rumors that its efficacy vs. safety profile may be compromised by side effects.

While ISRIB offers exciting prospects for a range of biomedical applications, addressing challenges related to specificity, disease-specific considerations, and importantly long-term safety, is crucial for realizing its full potential.

Early diagnosis of renal dysfunction in β-thalassemia major (β-TM) may help take specific measures to delay irreversible damage and renal failure. Therefore, the present meta-analysis aimed to compare biochemical markers of premature renal dysfunction between β-TM and healthy subjects and identify renal issues' prevalence in patients with β-TM.

We searched PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Medline, Scopus, Web of Science, ScienceDirect, ProQuest, Google Scholar, and State Inpatient Databases (SIDs) without any language constraints for all relevant articles published up to April 2019.

Out of 1458 articles published up to April 2019, 24 case-control and 22 cross-sectional studies were investigated. The investigated levels of serum phosphorus, uric acid (UA), cystatin C, and ferritin were significantly different between β-TM patients and controls. The albumin/creatinine ratio (ACR), N-acetyl-β-D-glucosaminidase/creatinine (NAG/Cr) ratio, urinary and serum β2 microglobulin (β2MG), and serum ferritin levels were significantly higher in β-TM patients than in healthy individuals. However, glomerular filtration rate, creatinine clearance, and pretransfusion hemoglobin indicated a significantly lower rate. The general prevalence of renal glomerular and/or tubular defects in patients with β-TM was 50.22%.

Urinary NAG, β2MG, ACR, and Scys-C may be early markers of renal dysfunction in patients with β-thalassemia major. An observation of elevated levels of these markers despite normal levels of other markers of renal dysfunction may indicate primary, subclinical injury to the renal tubules and glomeruli.

This study aimed to investigate the antioxidant properties, cytotoxic activity, and apoptotic effects of astaxanthin (ASX) on genes and pathways involved in breast cancer in Balb/c mice models injected with the 4T1 cell line. Background: ASX could inhibit some tumor progression by using in vivo and in vitro models.

The effect of ASX on breast cancer was not fully understood till now.

In an in vivo model, 4T1 cells-injected mice were administered with different concentrations of ASX (100 and 200 mg/kg), and histopathological evaluations were done using an optical microscope and the hematoxylin and eosin (H&E) staining. The real-time PCR investigated the expression levels of B-cell lymphoma 2-associated X (Bax), B-cell lymphoma 2 (Bcl-2), and Caspase 3 genes in mice treated with 100 and 200 mg/kg ASX. Also, the level of superoxide dismutase (SOD) and malondialdehyde (MDA) were examined in ASX-treated cancer mice.

ASX (200 mg/kg) caused a significant reduction in the mitotic cell count of tumor tissues compared to ASX (100 mg/kg). The antiproliferative effects of different concentrations of ASX were shown based on the MTT results. The treatment of breast tumor mice with both concentrations of ASX, especially 200 mg/kg, elevated the expression of Caspase 3, Bax, and SOD enzyme levels and decreased Bcl-2 expression and MDA enzyme levels.

ASX can be considered a promising alternative treatment for breast cancer.

microRNA (miRNA) levels are dysregulated in many cancers, suggesting that miRNA-based therapy may be effective. The molecular pathways of colorectal cancer (CRC) development are unknown.

Understanding miRNAs implicated in CRC formation may reveal new diagnostic and therapeutic targets. Angiogenesis is a key mechanism in tumor growth. CRC treatment may involve inhibiting angiogenesis, but existing drugs can cause negative effects. Tranexamic acid, an FDA-approved medication, may reduce the adverse effects of angiogenesis inhibitors. This work examined miRNAs implicated in CRC angiogenesis and how miR-16 and tranexamic acid may synergistically decrease CRC cell migration and angiogenesis. We identified miRNAs targeting CRC angiogenesis genes using bioinformatic databases. Proteins were docked with tranexamic acid utilizing the PyRx software. Quantitative Real-time PCR was used to analyze the effects of overexpressed miRNA and tranexamic acid on the expression of target genes. Scratch, transwell migration, and Chicken Chorioallantoic Membrane (CAM) assays were used to evaluate the effect of selected miRNA and tranexamic acid on the invasion and angiogenesis of CRC cells. in silico studies identified hsa-miR-16-5p, -101-3p, and 34a-5p as possible CRC angiogenesis modulators.

The study found that miR-16 and tranexamic acid influence the expression of VEGFA, ANGPT2, MMP9, and HIF1A. miR-16 and tranexamic acid influenced CRC cell movement in scratch tests and transwell migration assays. Furthermore, the CAM assay results demonstrated that miR-16 and tranexamic acid can alter angiogenesis in CRC.

These findings highlight the potential of miR-16 and tranexamic acid as combination therapeutic agents for CRC, with the ability to simultaneously target tumorigenesis and angiogenesis.

HCC is a malignant tumor with high morbidity and mortality. Fibroblasts play a key role in the tumor microenvironment (TME). However, the transcriptional regulatory mechanisms of fibroblasts remained unclear in HCC.

The aim of this study was to explore the complex role of fibroblasts in hepatocellular carcinoma (HCC) and to reveal their transcriptional regulatory mechanisms.

The goal of this study was to discover potential prognostic markers for HCC by analyzing the genetic variations and differentiation process of fibroblasts.

Single-cell transcriptome data from the non-tumor liver site and primary tumor site of HCC were acquired from GSE149614, processed, and clustered using the Seurat pipeline. The inferCNV algorithm was applied to infer copy number variations (CNVs) in fibroblasts. Subsequently, the mechanism underlying the interaction between fibroblasts and other cells in the TME of HCC was analyzed using CellChat software. The trajectory of cellular differentiation of fibroblasts from normal state to malignant state was examined using Monocle 2. SCENIC analysis was performed to identify key transcription factors (TFs) in fibroblasts and assess their correlation with HCC prognosis. Finally, qRT-PCR and Transwell assays were carried out to analyze the mRNA expression and cell metastasis.

We identified a total of nine different cell types (B cells, cycling cells, endothelial cells, epithelial cells, fibroblasts, hepatocytes, macrophages, plasma cells, and T cells) based on the single-cell transcriptomic data of HCC. Among them, fibroblasts were highly enriched at the primary tumor site, and their number increased with advanced stages. In addition, significant deletions were detected on chromosome 6p of fibroblasts, and genes in this region were remarkably enriched in pathways associated with antigen processing and presentation. Intercellular communication showed that epithelial cells regulated fibroblasts the most. The differentiation of fibroblasts was mainly accompanied by a transition from normal to malignant state. Importantly, CEBPD and FOSB, the TFs most associated with the putative timing of fibroblasts, were under-expressed in human hepatocytes and showed a significant correlation with HCC prognosis. Overexpressed CEBPD inhibited HCC cell migration and invasion.

In conclusion, our study revealed that fibroblast recruitment and differentiation, as well as copy number loss at chromosome 6p, were associated with a higher degree of malignancy and immune dysfunction in HCC. The current discoveries provided new insights into the clinical treatment and diagnosis of HCC.

Based on comprehensive network-pharmacology and molecular docking analysis, this study was intended to unveil the multiple mechanisms of Si-Ni-San (SNS) in treating anxious insomnia.

The compounds of SNS were meticulously analyzed, selected and standardized with references to their pharmacological attributes. The components included chaihu (Bupleurum chinense DC.), baishao (Paeonia lactiflora Pall.), zhishi (Citrus aurantium L.) and gancao (Glycyrrhiza uralensis Fisch. ex DC.). We used the Traditional Chinese Medicine System Pharmacology (TCMSP) Database, Traditional Chinese Medicines Integrated Database (TCMID), GeneCards database, therapeutic target database (TTD) and comparative toxicogenomic database (CTD) to construct the components-compounds-targets networks and used Cytoscape 3.9.1 software to visualize the outcome. Afterwards, the STRING database and Cytoscape 3.9.1 software were utilized to construct and visualize the protein-protein interaction (PPI) network analysis. In addition, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were also conducted through the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The molecular docking program was carried out using AutoDock 4.2 software to understand interactions between target receptors and compound ligands selected for study.

We thoroughly sorted and filtered 31 pharmacologically active compounds from SNS. Subsequently, several potential target genes were predicted, of which there were 59 target genes distinctly associated with anxious insomnia. The PPI analysis indicated that the core target proteins included AKT1, IL6, TNF, SLC6A4, MAOA and GABRA2. The results of our study indicated that SNS potentially remediates anxious insomnia by reducing inflammation, neurodegeneration, and cell apoptosis of neurons. In addition, GO and KEGG enrichment analysis results indicated that SNS could modulate multiple aspects of anxious insomnia through mechanisms related to pathways of neuroactive ligand-receptor interaction. These pathways include various kinds of synaptic transmission pathways, and anti-inflammatory activity associated with response pathways. When we compared the components-compounds-targets networks and the compounds-targets-synaptic pathways networks, the five active compounds, including beta-Sitosterol, Kaempferol, Tetramethoxyluteolin, Isorhamnetin and Shinpterocarpin, were selected to conduct molecular docking experiments. Eleven target proteins, (AKT1, SLC6A4, ADRB2, MAOA, ACHE, ESR1, CYP3A4, CHRNA7, GABRA2, HTR2A and NOS3), which also play significant roles in regulating serotonergic, cholinergic, dopaminergic and GABAergic systems in the PPI network, were selected to act as receptors in molecular docking trials. The results showed that docking pairs isorhamnetin-AKT1, isorhamnetin-SLC6A4, β-sitosterol-MAOA, β-sitosterol-ACHE, isorhamnetin-CHRNA7 and shinpterocarpin-GABRA2 provided the most stable conformations of ligand-receptor binding between key compounds and core target proteins in the SNS.

In the study, we offer a computational result, revealing that SNS may alleviate sleep disorders associated with anxiety through a “multi-compounds, multi-targets, and multi-pathways” mechanism. The network-pharmacology and molecular docking outcomes could theoretically confirm the anti-anxiety and anti-insomnia effects of SNS. Although this research is purely statistical and systematic without empirical validation, it serves as a stepping stone and cornerstone for subsequent experimental investigations.

Clinical endocrinology has observed emerging endocrine complications following COVID-19 vaccination, amidst successful reductions in COVID-19 hospitalizations and deaths. The Pfizer-BioNTech and Moderna mRNA vaccines have demonstrated efficacy. Reports indicate a potential association between SARS-CoV-2 vaccination and diabetes, exploring interactions with ACE-2 receptors and molecular mimicry. Additionally, altered liver and kidney function tests post-vaccination prompt investigation into their role in predicting type 2 diabetes. This study aims to explore these biochemical abnormalities in a case-control, single-centre prospective study.

This prospective study aimed to evaluate a total of five hundred healthy donors, out of which 203 qualified for final analysis. Participants were selected based on their vaccination status with a COVID-19 vaccine and prior exposure to the SARS-CoV-2 virus. Donors without prior SARS-CoV-2 infection were excluded from the study. Included participants were adults who had received three doses of the COVID-19 vaccine.

A total of 203 individuals were included in the study, comprising 104 with type 2 diabetes mellitus (T2DM) and 99 without. Demographic characteristics including age, sex, nationality, Rh factors, ABO blood groups, liver function tests (LFT), kidney function tests (KFT), lactate dehydrogenase (LDH), and mineral ion levels were analysed. Among the participants, the distribution based on HbA1c levels showed 47.8% with HbA1c <7% classified as normal, 38.48% with HbA1c 8-10% classified as high, and 16.64% with HbA1c >10% classified as uncontrolled diabetes. Significant findings included a decrease in magnesium levels to 0.77±0.82 mmol/L (p<0.04*), an increase in LDH levels to 420.70±356.26 µL (p<0.01*), and elevated levels of alkaline phosphatase (143.22 ± 142.62 µL, p<0.001), gamma-glutamyl transferase (GGT) (55.70 ± 32.20 µL, p<0.001), and serum bilirubin (9.23 ± 4.87 µmol/L, p<0.001). Creatinine levels were significantly lower at 116.75 ± 101.94 µmol/L (p<0.001), while uric acid levels were significantly elevated at 305.92 ± 145.04 µmol/L (p<0.001) in individuals with uncontrolled HbA1c >10%. A majority of these individuals belonged to the O+ blood group.

This study underscores significant shifts in serum biomarkers and their complex interplay with mRNA-based SARS-CoV-2 vaccination and diabetes, particularly in uncontrolled cases. The findings suggest potential autoimmune reactions triggered by the self-adjuvant properties of mRNA and polyethylene glycol lipid conjugates. Variations observed among different blood groups may correspond to racial disparities influencing molecular mimicry mechanisms. Despite these insights, the underlying pathophysiological mechanisms remain unclear, highlighting the critical need for further research to validate and expand upon these findings.