Current Pharmaceutical Design - Online First

The marine ecosystem, known for its diverse biochemistry and organisms adapted to harsh environments, contains numerous plants with promising anticancer potential. Halodule uninervis, a seagrass, contains a variety of bioactive compounds that provide various pharmacological properties. However, its potential anticancer effects against breast cancer remain largely unexplored.

HRLC-MS analysis was conducted to identify the phytochemicals in the ethanolic extract of H. uninervis leaves. Several publicly available databases, including SEA, STP, MALACARDS, DISGENET, and OMIM, were used to identify target genes. Protein-protein interaction (PPI) networks, gene ontology, and pathway analysis were carried out through the STRING and DAVID databases. Molecular docking was performed by Autodock Vina, while molecular dynamics (MD) simulations and MMPBSA analyses were conducted using GROMACS, demonstrating the stability of the complexes up to 200 ns.

The top five therapeutically active phytochemicals were Quercetin, Arborinine, Methyl 3,4,5-trimethoxycinnamate, Citreorosein, and Scopolin. The five hub genes, AKT1, EGFR, TNF, ESR1, and GAPDH, were found by network analyses. Molecular docking and MD simulation demonstrate that Quercetin and Citreorosein are the best phytochemicals exhibiting the highest affinities to breast cancer targets AKT1, EGFR, and ESR1.

For the first time, this in-silico study investigates the potential of citreorosein and quercetin, two phytochemicals predominantly found in H. uninervis leaves, to inhibit the activity of AKT1, EGFR, and ESR1. However, as these results are based on predictive computational analyses, further experimental validation is necessary to confirm their precise mechanisms of action.

Phytochemicals, namely Quercetin and Citreorosein, may have an impact on the progression of breast cancer by binding to the key targets AKT1, ESR1, and EGFR.

Genetic factors play a significant role in the development of leukemia. The overexpression of MDM2 is associated with the progression of certain leukemias. This meta-analysis investigates the relationship between the MDM2 SNP 309T>G and various forms of leukemia across global populations.

A comprehensive literature search was conducted to retrieve genotyping data from twenty case-control studies related to MDM2 SNP 309T>G polymorphism and leukemia. A random-effects model was used to calculate the pooled odds ratio (OR) and 95% confidence interval (95% CI) for the association analysis. MetaGenyo software was utilized to conduct statistical analyses in this meta-analysis.

The findings indicate a significant association between MDM2 309 SNPT>G polymorphism and leukemia in Asian and Caucasian populations. Additionally, this polymorphism is associated with an increased risk of Acute Myeloid Leukemia (AML) and Chronic Myeloid Leukemia (CML), implying that MDM2 may play a role in the pathogenesis of these specific forms of leukemia.

This meta-analysis suggests that MDM2 may represent a susceptibility gene for leukemia risk.

Glioblastoma Multiforme (GBM) is a highly aggressive and fatal brain malignancy, with Temozolomide (TMZ) serving as the first-line chemotherapeutic treatment. However, over 50% of patients do not respond to TMZ, and the underlying mechanisms remain unclear. This study utilized the GeCKO library to identify novel genes involved in TMZ resistance and to explore their functions.

Loss-of-function genes related to TMZ resistance in GBM cells were identified using the GeCKO library and Next-Generation Sequencing (NGS), validated by qPCR and CCK-8 assays. CD99L2 function was assessed through proliferation, migration, and EdU assays in U251 and U87 cells. Tumor samples from 55 stage IV GBM patients were analyzed to explore the correlation between CD99L2 expression and Progression-Free Survival (PFS).

GeCKO library screening identified seven genes associated with TMZ resistance. After validation, CD99L2 was confirmed as a key contributor to TMZ resistance. Knockdown of CD99L2 increased the IC50 of U251 and U87 cells by 1.39- and 1.54-fold, respectively. Conversely, CD99L2 overexpression reduced the IC50 by 0.52- and 0.58-fold. CD99L2 knockdown also promoted tumor proliferation and aggressiveness. Additionally, higher CD99L2 expression was associated with longer PFS in GBM patients (median PFS: 7.87 months vs. 2.7 months, P=0.0003).

The functions of CD99L2 remain poorly understood. A few studies have reported that CD99L2 may serve as an adhesion molecule modulating inflammatory responses. One study has shown that CD99L2 is highly expressed in the brain and affects neuronal excitability. These findings suggest that CD99L2 may play a positive role in the body’s defense against glioma.

This study demonstrated that CD99L2 knockdown promotes TMZ resistance and tumorigenesis in GBM, suggesting its potential as a novel biomarker for TMZ resistance.

Impaired intestinal immune function is commonly observed in neonates with intrauterine growth retardation (IUGR), yet its underlying mechanisms and regulatory pathways remain poorly understood. Therefore, we aimed to investigate gene regulatory patterns and microbiota alterations in IUGR piglets.

Three newborn IUGR piglets and three normal littermates were selected from the same sow and sacrificed at seven days of age. Ileal digesta was collected for 16S rRNA amplicon sequencing (16S-seq), and ileum segments were dissociated for single-cell RNA sequencing (scRNA-seq).

The scRNA-seq results revealed a reduced proportion of plasma B cells in IUGR piglets, along with alterations in the distribution of various T cell subsets. KEGG pathway analysis further indicated a downregulation of the B cell receptor signaling pathway in B cells from IUGR piglets. In contrast, both the T cell receptor signaling pathway and antigen processing and presentation were attenuated in T cells. Pseudotime trajectory analysis suggested that the differentiation of B cells was impaired in IUGR piglets. SCENIC analysis revealed that GATA3, IRF2, and BCL11A were downregulated in T cells of IUGR piglets. The 16S-seq results revealed that α-diversity was lower in IUGR piglets. At the genus level, the relative abundance of Prevotella was significantly lower in IUGR piglets.

Significant changes were identified in the proportions of B and T cells, their associated signaling pathways, and intestinal microbiota composition in IUGR piglets, suggesting underlying immune dysfunction and dysbiosis.

We identified novel immune-related transcription factors and key microbes as potential therapeutic targets, shedding light on strategies for preventing and treating IUGR.

Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons within the substantia nigra, leading to progressive motor dysfunction. There are still limited disease-modifying options that counteract the process of disease progression. This study aimed to evaluate the neuroprotective effects of thymol, both in its free form and when loaded onto selenium nanoparticles (SeNPs), in a 6-hydroxydopamine (6-OHDA)-induced PD model using SH-SY5Y cells.

SeNPs were synthesized using a chemical reduction method with ascorbic acid, achieving a 68% entrapment efficiency for thymol. FTIR analysis suggested an interaction between thymol and selenium, which was confirmed by EDX analysis. Nano-Se-thymol particles were observed to be spherical, with a mean size of 135.7 nm and a negative surface charge.

Nano-Se-thymol exhibited low toxicity in normal fibroblast cells and demonstrated greater neuroprotective effects against 6-OHDA-induced cytotoxicity compared to thymol. Nano-Se-thymol significantly reduced ROS generation and increased cell viability compared to 6-OHDA. Furthermore, Nano-Se-thymol decreased the expression of NF-κB inflammatory markers and caspase-3 apoptotic proteins, which were elevated by 6-OHDA, compared to thymol alone.

Nano-Se-Thymol significantly attenuates 6-OHDA-induced cytotoxicity in an established in vitro model of PD. The neuroprotective efficacy of Nano-Se-Thymol is attributed to its enhanced antioxidant capacity, as evidenced by a significant reduction in ROS levels, along with its ability to inhibit apoptosis and modulate cell cycle progression.

Nano-Se-thymol is a potential disease-modifying agent for the treatment of PD; however, further studies and long-term safety assessments are essential to confirm these benefits and understand the underlying mechanisms.

The aim of the study was to prepare polyelectrolyte complex stabilized piperine adjuvant simvastatin nanoformulations and evaluate the antimicrobial effect. Simvastatin has antimicrobial properties but low therapeutic efficacy due to rapid metabolism, with only 12% oral bioavailability. Piperine, a CYP3A4 inhibitor, enhances bioavailability by inhibiting drug-metabolizing enzymes. This study developed chitosan-neem gum polyelectrolyte complex (Ch-NG PEC) nanoparticles combining piperine and simvastatin and evaluated their antimicrobial efficacy compared to simvastatin alone.

A flower-shaped nanoparticles of piperine adjuvant simvastatin were prepared by using chitosan (Ch)-neem gum (NG) as a polyelectrolyte complex (PEC) forming agent, and the anti-microbial effect of nanoformulations with and without piperine was evaluated. A solvent-anti-solvent method was used to form the nanoparticles, and a 3²-factorial design was employed to analyze the impact of chitosan and neem gum concentration on the size of the nanoparticles and entrapment efficiency of simvastatin and piperine followed by their release profile and kinetics.

Nanoparticles showed high drug entrapment efficiency (simvastatin: 96.4-99.7%, piperine: 64.8-99.4%) with sizes ranging from 341.3-629.1 nm. Drug release exceeded 50% in 3 hours and 99% in 8 hours, following Hixon-Crowell and Baker’s Lonsdale models. Antimicrobial assays revealed activity against Staphylococcus aureus but not Candida albicans. The results of the anti-microbial assay indicated that the PEC-based NPs stabilized piperine adjuvant simvastatin showed anti-microbial activity against Staphylococcus aureus but did not exhibit anti-fungal activity against Candida albicans.

Piperine-adjuvant simvastatin Ch-NG-PEC nanoparticles demonstrate potential as a dual-treatment agent for hypercholesterolemia and bacterial infections.

Rheumatoid arthritis (RA) is a chronic inflammatory condition of the joints and a leading cause of global disability. However, the use of current anti-inflammatory treatments is often limited by serious side effects and multi-organ toxicity, necessitating the exploration of safer alternatives.

This study aims to investigate the anti-rheumatic potential of natural compounds of Cassia angustifolia as small-molecule inhibitors of PTGS2.

The therapeutic potential of C. angustifolia was evaluated through antioxidant and anti-inflammatory assays. Gas chromatography-mass spectrometry (GC-MS) was used to identify its constituents. ADMET profiling (absorption, distribution, metabolism, excretion, and toxicity), network pharmacology, and molecular dynamics simulation were employed to uncover the active compounds against PTGS2 for RA treatment.

C. angustifolia extract contained significant phenolic (18.2 ± 0.008 mg GAE/g DW) and flavonoid (27.57 ± 0.03 mg RE/g DW) content. GC-MS yielded 288 compounds of which four passed the toxicity parameters. Protein-protein interaction analysis revealed 10 RA-related targets, with PTGS2 emerging as the most prominent one. Molecular docking and simulations revealed that compound-2 [2-Benzo [1,3] dioxol-5-yl-8-methoxy-3-nitro-2H-chromene] and compound-4 [alpha-hydroxy-N-[2-methoxyphenyl]-benzene propanamide] binds strongly with PTGS2 (-7.7 kcal/mol and -7.9 kcal/mol, respectively) predicting its stable interaction.

C. angustifolia compounds present a significant potential as PTGS2 inhibitors, warranting further in vitro and in vivo investigations to confirm their therapeutic efficacy against RA.