Current Topics in Medicinal Chemistry - Volume 25, Issue 21, 2025

This review is delving into determining the content and significance of hypericin, a pharmacologically important constituent commonly known as St. John's Wort (SJW). The paper explores the rich history of Hypericin's traditional use in alternative medicine and the recent surge in scientific interest surrounding its bioactive properties.

This review aims to provide a comprehensive analysis the therapeutic potentials of hypericin, focusing on its chemistry, extraction, sources, stability, pharmacokinetics, safety profile, and multifunctional applications in drug and medicinal fields as well as advancements in Bioengineering Approaches for Enhanced Hypericin Delivery.

We performed a non-systematic search of journals. Literature using computerized methods was conducted, utilizing databases such as Medline (PubMed), ChemSciFinder, China National Knowledge Infrastructure (CNKI) and Scirus Library. To effectively identify the most important and relevant research articles, scientific studies, clinical studies and review articles on hypericin were searched using different keywords: “Hypericum”, “traditional use”, “phytochemistry”, “pharmacology”, “drug delivery” and “bioactivity”. Thus, articles available from 1984 to 2024 were analyzed and collected. The selection process for the review primarily considered the originality of the paper and its clinical applications.

Although hypericin is not a novel compound within the research community, it is gaining renewed recognition and showing great effectiveness as a promising agent in the field of medical diagnostics and has promising applications as a therapeutic.

Here, our current comprehensive review of hypericin, its potential and its activities is intended to contribute to this ongoing process actively. Overall, this review provided theoretical direction for future hypericin research. Future studies should, therefore, focus further on the pharmacological processes, pharmacokinetics, and chemistry of hypericin and hypericin-based drug delivery systems. This comprehensive review of hypericin aims to actively contribute to ongoing research and provide a theoretical direction for future studies.

Osteoporosis is a deteriorating skeletal bone disorder that affects in a silent, asymptomatic way. On-demand for new therapeutic strategies, natural products have gained attention as a significant alternative for treating osteoporosis. 7-Hydroxyflavone (7HF) is one of the well-known natural flavones for its anti-inflammatory, anti-oxidant, anti-diabetic, and neuroprotective, which was investigated at the molecular level for restoring bone homeostasis against dexamethasone-induced osteoporosis in vivo with a focus on modulation of oxidative stress (caspase-3), GATA-3, and NF-kB signaling along with in silico ADMET analysis.

Adult male rats were divided into four groups, containing six in each group. I- Control, II- Dexamethasone (Dexa)-treated disease control, III & IV – 7HF treated group (50, 100mg/kg). Animals in all groups, except the control, were injected with dexamethasone sodium phosphate at the dose level of 7mg/kg, intramuscularly, once a week for five weeks. The third and fourth group animals received 7HF-1 and 7HF-2 as a fine suspension with 2% carboxy methyl cellulose at a dose of 50 and 100mg/kg, respectively, by oral route once daily, starting from the second week of dexamethasone treatment. At the end of the 5^th week, blood was collected from the femoral vein after anaesthesia, and the femur bones were dissected. Histopathology, immunohistochemistry of bone, biochemical serum analysis for ALP, TRAP 5b, RANKL, OPG, antioxidants and cytokines, as well as protein expression for RunX2, Bcl2 and Bax were performed. In addition, an analysis of absorption, distribution, metabolism, excretion, and toxicity (ADMET) was conducted for 7HF.

Immunohistochemistry of GATA-3, NF-kB, and caspase-3 on femur bone sections evidenced the suppression of dexamethasone-induced osteoporosis by 7HF. It was found that 7HF lowered the serum levels of cytokines, ALP, TRAP 5b, and RANKL. 7HF elevated the serum level of antioxidants and OPG. In addition, the protein expression of RunX2, and anti-apoptotic Bcl2 was elevated, and the level of pro-apoptotic Bax in rat femur bone tissues was reduced through the use of 7HF. The aforementioned effects of 7HF were more prominent at the dose of 100mg/kg (p<0.001). 7HF exhibited good solubility and efficient absorption in the human intestine, though it showed limited permeability in MDCK cells. It demonstrated positive BBB permeability and Caco-2 permeability values. 7HF interacted with P-glycoprotein, had an optimal VD, high PPB, and was a substrate and inhibitor of CYP450 enzymes. It functioned effectively as a hERG blocker without inducing human hepatotoxicity. Comprehensive toxicity assessments highlight 7HF as a more suitable option for drug development.

The study data confirmed that concurrent treatment of 7HF showed evident effects in the protection against dexamethasone-induced osteoporosis through the modulation of the GATA-3/Caspase-3/NF-KB pathway. Collectively, the ADMET analysis suggests that 7HF possesses promising pharmacokinetic and toxicological attributes, making it a viable candidate for drug development.

Existing research has suggested that the JNK/AP-1/NF-κB/Caspase-1 pathway may account for the activation of HMC-1 mast cells under inflammatory circumstances, and our current study aims to validate whether Tomatidine could act as the candidate to modulate this pathway in Allergic Rhinitis (AR).

This study aimed to characterize the effect of Tomatidine on inflammation in C48/80-activated HMC-1 cells in vitro and to explore the underlying mechanisms involved.

The inflammation in HMC-1 cells was triggered via C48/80 induction to mimic the AR, and the effects of Tomatidine on the viability of HMC-1 cells were tested using the Cell Counting Kit-8 assay. Thereafter, the concentrations of inflammation-related cytokines, Interleukin-1β, tumor necrosis factor-α, as well as the histamine and β-hexosaminidase, were quantified by enzyme-linked immunosorbent assay. The activation status of the JNK/AP-1/NF-κB/Caspase-1 pathway in HMC-1 cells following C48/80 and/or Tomatidine intervention was determined based on immunoblotting assay.

The viability was elevated in HMC-1 cells following C48/80-induced activation, and the concentration of inflammation-related cytokines and mediators was increased as well. Meanwhile, the protein levels of active Caspase-1 and the phosphorylation of JNK/AP-1/NF-κB/Caspase-1 pathway-related proteins were also observed in HMC-1 cells after the treatment of C48/80. On the contrary, Tomatidine intervention suppressed the viability and the concentration of inflammation-related cytokines and mediators of modeled HMC-1 cells and led to the inactivation of the JNK/AP-1/NF-κB/Caspase-1 pathway in modeled HMC-1 cells.

Our study demonstrates that Tomatidine can attenuate C48/80-induced inflammatory responses in HMC-1 cells in vitro, potentially through modulation of the JNK/AP-1/NF-κB/Caspase-1 signaling pathway. These findings provide preliminary evidence supporting Tomatidine as a candidate for further investigation in allergic inflammation.

Gefitinib is associated with various adverse reactions, with diarrhea being prevalent. It is mainly managed through lifestyle changes and symptomatic pharmacological interventions, but these approaches have limited effectiveness and frequent recurrence. Qi Yin San Liang San Decoction (QYSLS) shows promise in relieving gefitinib-induced diarrhea, but its mechanisms are unclear.

This study aims to explore the pathological mechanisms underlying gefitinib-induced diarrhea and to elucidate the molecular pathways through which QYSLS mediates its therapeutic effects.

RNA-seq identified differentially expressed genes (DEGs) in colon samples from control and gefitinib-induced diarrhea rats. Network pharmacology was employed to predict the bioactive components and potential targets of QYSLS. A protein-protein interaction (PPI) network was utilized to explore the interactions among these targets, while GO, KEGG, and GSEA enrichment analyses were conducted to reveal the signaling pathways associated with these targets. RNA-seq was used to detect DEGs in QYSLS-mediated relieving of gefitinib-induced diarrhea; the intersection with potential targets was further analyzed to identify key genes. The expression of hub genes was validated through immunohistochemistry and RT-qPCR.

RNA-seq and network pharmacology identified 103 bioactive components of QYSLS, with 84 potential targets in QYSLS relieving gefitinib-induced diarrhea. The DEGs in QYSLS relieving gefitinib-induced diarrhea and 84 potential targets were intersected, resulting in the identification of 26 key genes. Further analysis highlighted three central hub genes (CCL20, CCL25, NOS2), which were enriched in pathways related to innate immune response. Furthermore, immunohistochemistry and RT-qPCR confirmed that the expression of CCL25 was reduced by QYSLS in gefitinib-induced diarrhea rats.

These results indicate that QYSLS may exert its therapeutic effect on gefitinib-induced diarrhea via the modulation of chemokines and innate immune responses.

The programmed cell death (PCD) is crucial in inhibiting cancer cell proliferation and enhancing anti-tumor immune responses. Mining targeted therapeutics for liver hepatocellular carcinoma (LIHC) based on PCD genes and revealing their molecular mechanisms are essential for the development of effective clinical treatments for LIHC.

Key genes associated with PCD characteristics of LIHC were identified in cancer genome mapping by the weighted gene co-expression network analysis (WGCNA). In this study, the performance and clinical value of key genes were evaluated by the receiver operating characteristic curve (ROC). The relative expressions of genes related to PCD in LIHC cells were measured employing QRT-PCR. The practical regulation of PCD-correlated key genes on the migration and invasion levels of LIHC cells was assessed by transwell and wound healing assays. Functional and pathway characterization of gene sets was performed by Gene Set Enrichment Analysis (GSEA). CIBERSORT was used to assess immune cell infiltration in the samples. DSigDB and AutoDock tools were used for molecular docking of key genes and downstream targeted drugs. Impact omics characterization of the samples was determined by the nomogram.

Three genes, CAMK4, CD200R1, and KCNA3, were screened as key PCD-related genes in LIHC. Cellular experiments verified that CD200R1 knockdown repressed the migration and invasion in LIHC cells. GSEA showed that these three genes were enriched for cytokine release, apoptosis, and other pathways. In immune profiling, we revealed that the three genes were related to the infiltration of immune cells such as CD4+ memory T cells and CD8+ T cells. Molecular docking predicted potential drugs for the three biomarkers, among which CAMK4 was tightly bound to GSK1838705A and had the highest AUC value in the ROC curve. In addition, we constructed a nomogram to accurately assess the imaging features of LIHC.

This study provided a new strategy for precision treatment of LIHC by screening key genes associated with PCD in LIHC (CAMK4, CD200R1, and KCNA3), revealing their roles in the regulation of the tumor immune microenvironment and predicting potential target drugs, as well as constructing a diagnostic model based on imaging histology; however, the study did not delve deeper into the long-range drug-target interaction mechanism and lacked molecular dynamics simulation validation, which limited the comprehensiveness of the results.

This study identified key genes associated with PCD in LIHC, revealed its immunoregulatory mechanism, and predicted potential target drugs, providing new ideas for precision treatment and diagnosis of LIHC.