Current Medicinal Chemistry - Volume 32, Issue 21, 2025

Human Immunodeficiency Virus (HIV) infection is still a major global problem, whose drug treatment consists of prophylactic prevention and antiretroviral combination therapy for better pharmacological efficacy and control of the circulating virus. However, there are still pharmacological problems that need to be overcome, such as low aqueous solubility of drugs, toxicity, and low patient adherence. Drug delivery technologies can be used to overcome these barriers.

This review summarized the latest drug delivery systems for HIV treatment. Initially, an overview of the current therapy was presented, along with the problems it presents. Then, the latest drug delivery systems used to overcome the challenges imposed in conventional HIV therapy were discussed.

This review examines innovative approaches for HIV treatment, where various drug delivery systems have shown significant advantages, such as high drug encapsulation, improved solubility, and enhanced bioavailability both in vitro and in vivo. Strategies like cyclodextrins, solid dispersions, microneedles, and nanoparticles are explored to address challenges in drug solubility, bioavailability, and administration routes. Despite progress, obstacles like limited clinical trials and industrial scalability hinder the widespread adoption of these formulations, emphasizing the need for further research and collaboration to optimize and ensure accessibility of innovative HIV therapies, mainly in regions where access to HIV treatment is scarce and remains a challenge.

Alzheimer’s Disease (AD) is a complicated and advanced neurodegenerative condition accompanied by gradual cholinergic neuronal death and higher levels of monoamine oxidase-B (MAO-B) enzyme. In this study, a series of novel hybrid compounds combining 1,3,4-oxadiazole and quinoline moieties were synthesized and evaluated for their potential as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and MAO enzymes.

The chemical structures of the synthesized compounds were confirmed using various analytical techniques, such as mass spectrometry, infrared spectroscopy (IR), proton nuclear magnetic resonance (1H-NMR), and carbon and nuclear magnetic resonance (13C-NMR). The final products were evaluated for anticholinesterase potential by applying modified Ellman’s spectrometric method, whereas a fluorometric method was used to assess MAO inhibition properties. In-silico studies using molecular docking and molecular dynamics simulation (MDS) methods has been also conducted.

Among the synthesized compounds, 5a, 5c, and 6a demonstrated substantial activity against AChE, with IC50 values of 0.033 µM, 0.096 µM, and 0.177 µM, respectively. A molecular docking study was performed to elucidate the binding modes and establish the structure-activity relationship (SAR) of the most active compounds (5a, 5c, and 6a). Molecular dynamics simulation (MDS) of the most potent compound, 5a, was also conducted to examine the stability of the interactions with the receptor. Moreover, the physicochemical properties of the active products were also studied.

Overall, this research contributes to the development of 1,3,4-oxadiazole-quinoline hybrids as potential AChE inhibitors for the treatment of Alzheimer’s disease.

Gastric cancer (GC) is the fifth most common cancer globally, and the relationship between type 2 diabetes mellitus (T2DM) and cancer risk remains controversial.

We performed Mendelian randomization (MR) analysis using publicly available GWAS data to assess the causal relationship between T2DM and GC, validated by heterogeneity and pleiotropy analyses. Transcriptomic data from TCGA and GEO were analyzed to identify common differentially expressed genes (DEGs). Weighted gene co- expression network analysis (WGCNA) was used to construct a prognostic risk model. Drug sensitivity and immune infiltration were evaluated using GDSC and ImmuCellAI, respectively. Additionally, gene mutation analysis was conducted using TCGA data.

The Mendelian randomization analysis revealed a causal relationship between T2DM and GC at the genetic level. Specifically, the causal effect of T2DM on GC was estimated with an odds ratio (OR) of 1.32 (95% CI: 1.12-1.56), while the reverse causal effect of GC on T2DM was estimated at an OR of 0.78 (95% CI: 0.67-0.91). Sensitivity analyses, including Cochran's Q test and the leave-one-out test, confirmed the robustness of these findings. We constructed a prognostic risk score consisting of three T2DM-related genes (CST2, PSAPL1, and C4orf48) based on transcriptome data analysis. Patients with high-risk scores exhibited significantly worse overall survival (OS) (p < 0.05). Cox regression analysis further confirmed the independent predictive value of the risk score for GC prognosis. Our predictive model demonstrated good performance, with an AUC of 0.786 in the training set and 0.757 in the validation set. Gene enrichment analysis indicated that the genes shared between T2DM and GC were associated with inflammatory response, immune response, and metabolic pathways. Tumor immune microenvironment analysis suggested that immune evasion mechanisms may play a key role in developing GC in patients with coexisting T2DM.

T2DM is associated with reduced GC risk. The risk score and model may help guide GC prognosis and management.

Diffuse midline gliomas (DMG) pose a grave threat as a malignant tumor primarily affecting children in the pons region. These tumors exhibit a distinct and heightened resistance to therapeutic interventions, coupled with exceptionally aggressive behavior.

In this study, we accessed DMG data from the Gene Expression Omnibus (GEO) database. Subsequently, we performed functional annotation and conducted pathway enrichment analysis as well as gene set enrichment analysis (GSEA). Constructing a protein-protein interaction (PPI) network, we identified pivotal hub genes. To evaluate the impact of these hub genes on immune infiltration, we employed the CIBERSORT algorithm. Furthermore, to bolster our findings, we conducted a single-cell analysis.

Our findings indicate the involvement of CD8A, IL7R, and ICAM1 in immune responses targeting diverse immune cell types, such as T cells, neutrophils, NK cells, dendritic cells, γδ T cells, and Macrophages M1. Additionally, the presence of immune checkpoints, including IDO1 and TIGIT, likely contributes to intratumoral immunosuppression, thereby fostering the development of an aggressive phenotype and resistance in pediatric DMG.

In conclusion, the collective findings of our study suggest the potential role of CD8A, IL7R, and ICAM1 as innovative biomarkers for diagnosing and prognosticating pediatric DMG. Moreover, these molecules hold promise as therapeutic targets in the management of this disease. The implications of our research underscore the importance of exploring these novel avenues for improved patient outcomes.

This study aimed to examine the role of ferroptosis on the pathogenesis and progression of COVID-19.

A total of 127 patients who were hospitalized for COVID-19 were categorized into two groups according to the intensity of oxygen therapy (high-flow or low-flow). Clinical characteristics, laboratory parameters, plasma markers, and peripheral blood mononuclear cell (PBMC) markers were measured at baseline and one or two weeks after treatment. Telephone follow-up was performed 3 months after discharge to assess long COVID.

Patients receiving high-flow oxygen therapy had greater levels of neutrophils, D-dimer, C reactive protein, procalcitonin, plasma protein levels of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), IL-17, acyl-CoA synthetase long-chain family member 4 (ACSL4), and PBMC mRNA level of TNF-α but had lower levels of lymphocytes and plasma glutathione peroxidase 4 (GPX4). There were negative correlations of plasma GPX4 and cystine/glutamate transporter-11 (SLC7A11) with TNF-α, IL-6, and IL-17 and positive correlations of ACSL4 with inflammatory markers in plasma and PBMCs. The plasma levels of TNF-α, IL-6, IL-17, and ACSL4 were significantly lower after treatment than at baseline, but there were higher post-treatment levels of lymphocytes, GPX4, and SLC7A11. Patients with long COVID had a lower baseline level of plasma SLC7A11.

Ferroptosis is activated during the progression of COVID-19, and a low baseline level of a ferroptosis marker (SLC7A11) may indicate an increased risk for long COVID-19. Ferroptosis has potential as a clinical indicator of long COVID and as a therapeutic target.

Commercial Minoxidil (MXD) is commonly used as a vasodilator agent of hair follicles for providing direct dermal papilla cell proliferation and consequently enhancing the rate of hair growth.

The current study attempted to improve the bioactivity and water solubility of MXD by producing nanocrystal structures and investigating the obtained hair growth-stimulating activity on C57BL/6 mice.

The MXD nanoparticles (MXD-NPs) were prepared through a bead mill and ultrasonic process and characterized by DLS, XRD, UV-Vis, FTIR, FESEM, TEM, and Zeta-potential techniques.

The cytotoxicity of MXD-NPs was studied on human dermal fibroblast (HDF) by MTT assay. Lastly, we analyzed the comparative hair growth inductive activity of certain MXD-NPs concentrations on C57BL/6 mice. The stabled MXD-NPs (-46 mV, 21.9 nm) caused a significant increase in the hair growth rate of C57BL/6 mice by running a safe site-specific delivery mechanism on the targeted pilosebaceous follicles when compared to MXD.

The MXD-NPs-receiving mice exhibited a greater rate of anagen/telogen follicular when compared with MXD-treated types, which verified the improvement of their hair re-growing and follicular-stimulative activities. Therefore, these outcomes confirmed the potential of MXD-NPs for substituting its commercial solution format as a safe and efficient iso-formulation structure.