Current Topics in Medicinal Chemistry - Online First

The combinational chemo-herbal therapy effectively suppresses tumors and reduces their chemoresistance.

This study evaluated the anti-cancer and anti-tumor immunity properties of a chemo-herbal therapy combination of Curcumin (Cur), Ginger (Gin), Clove (Clov), Ginger (Gin), and Amygdalin (Amyg) with Doxorubicin (DOX) against the Ehrlich Ascites Carcinoma (EAC) cell line.

The study examined the anti-tumor effects of herbal extracts from Cur, Gin, Clov, and Amyg alone and with DOX against EAC using the MTT assay. It evaluated anti-cancer and anti-tumoral immunity, cell counts, growth rates, and apoptosis of EAC cells, phenotypic expression of T lymphocytes (CD4+T and CD8+T) and natural killer (NK) cells, splenocyte and leucocyte counts, as well as Liver and kidney functions in EAC-challenged mice treated with extracts from Cur, Gin, Clov, and Amyg alone and with DOX.

Chemo-herbal therapy using extracts of Cur, Gin, Clov, and Amyg combined with DOX showed significant anti-proliferative effects on EAC in vitro. In vivo, this combined treatment in tumor-challenged mice reduced EAC cell proliferation by decreasing cell counts and increasing apoptosis rates. Furthermore, it enhanced the expression of CD4+T and CD8+T lymphocytes and NK cells, while slightly increasing total leukocyte counts, neutrophils, and monocytes, but reducing total lymphocytes and eosinophils. Additionally, the combination therapy mitigated EAC-induced liver and kidney damage, restoring normal organ function.

The integration of herbal extracts derived from Cur, Gin, Clov, and Amyg with the chemotherapy drug DOX may improve the effectiveness of chemotherapy in combating tumors and strengthen the immune response of the host against cancer.

Chemo-herbal therapy combining Cur, Gin, Clov, and Amyg with DOX may improve anti-tumor effects, enhance immune response, and reduce chemotherapy side effects, but requires additional in vivo studies for validation.

Postoperative complications are common issues that may arise from anesthetic drugs or surgical procedures. This study aimed to investigate the protective and therapeutic effects of ginsenosides on anesthesia-associated side effects and postoperative complications.

This study was conducted following the PRISMA 2020 guidelines. A comprehensive search was conducted across PubMed/MEDLINE, Scopus, Web of Science, Embase, and the Cochrane Library to identify relevant studies published prior to October 13, 2024. Predefined inclusion and exclusion criteria were applied, and duplicates were removed.

Ginsenosides inhibit oxidative stress and enhance cognitive function by activating pathways such as phosphoinositide 3-kinase (PI3K)/Protein kinase B (PKB) (AKT)/glycogen synthase kinase-3 beta (GSK-3β), promoting neuroplasticity, alleviating oxidative stress, and modulating neuroinflammatory markers, as well as microglia and astrocytes. They help to maintain mitochondrial integrity, thereby reducing apoptosis and neurotoxicity caused by anesthetic agents. Ginsenosides also alleviate postoperative pain by modulating N-methyl-D-aspartate (NMDA) and suppressing inflammatory cytokines. They also improved neuropsychological problems by increasing Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF). The anti-fatigue properties of ginsenosides are attributed to enhanced antioxidant activity, improved skeletal muscle metabolic function, and increased Adenosine Triphosphate (ATP) production.

These results are consistent with prior studies demonstrating the neuroprotective effects of ginsenosides. Despite promising outcomes, the prevalence of animal studies and the absence of clinical data underscore the necessity for clinical validation and safety profiling in future research.

Preclinical evidence shows ginsenosides, particularly Rg1, Rb1, and Rg3, demonstrate promising protective and therapeutic effects against anesthesia-associated adverse effects and postoperative complications.

Transmembrane and immunoglobulin domain-containing 2 (TMIGD2) has been implicated in several malignancies. However, the expression pattern, prognostic significance, and mechanistic role of TMIGD2 in bladder cancer (BLCA) remain largely unexplored. It is still unclear whether TMIGD2 serves as a reliable prognostic biomarker or functions as a druggable mediator of immune evasion and chemoresistance in BLCA.

The expression levels of TMIGD2 were assessed in BLCA cell lines using quantitative real-time PCR (qRT-PCR). Data from The Cancer Genome Atlas (TCGA) were used to analyze the correlation between TMIGD2 expression and clinical characteristics and to assess its prognostic value in BLCA patients. Potential regulatory mechanisms involving TMIGD2 were explored, including its interactions with immune infiltration, immune checkpoint genes, and drug responsiveness. A ceRNA network centered on TMIGD2 was established. The expression of TMIGD2 at both mRNA and protein levels was validated using data from the Gene Expression Omnibus (GEO) and the Human Protein Atlas (HPA).

TMIGD2 was found to be downregulated in BLCA cell lines and tissues compared to normal urothelial cells. Lower TMIGD2 expression was significantly associated with poorer overall survival (OS) (HR = 0.66, 95% CI = 0.49-0.89, p = 0.006), progression-free survival (PFS) (HR = 0.61, 95% CI = 0.46-0.83, p = 0.001), and disease-specific survival (DSS) (HR = 0.53, 95% CI = 0.37-0.76, p < 0.001) among BLCA patients. Multivariate analysis identified TMIGD2 as an independent prognostic factor (p = 0.046). Gene Set Enrichment Analysis (GSEA) indicated that TMIGD2 expression was connected to several pathways, including cell adhesion molecules and T cell receptor signaling. Immune-infiltration analysis showed a previously unrecognized positive association between TMIGD2 expression and intratumoral T-cell/cytotoxic cell abundance as well as PD-L1, CTLA-4, LAG-3, and TIGIT levels, indicating that TMIGD2 may refine patient stratification beyond PD-L1 status. Low TMIGD2 expression correlated with greater resistance to afatinib, sorafenib, and paclitaxel. Finally, we constructed the TCGA-derived ceRNA network (AC009245.1/miR-1304-3p/TMIGD2), which provides a new post-transcriptional mechanism governing TMIGD2 expression in BLCA.

The findings highlight the potential of TMIGD2 as both a prognostic biomarker and a therapeutic target in BLCA. The downregulation of TMIGD2 in BLCA and its correlation with adverse prognosis and immune modulation suggest its involvement in tumor progression and immune response. The ceRNA network provides insights into the regulatory mechanisms of TMIGD2. However, the study's reliance on publicly available datasets, coupled with the lack of direct experimental validation of TMIGD2's functional role in BLCA, limits the immediate clinical application of these findings. Future research should focus on validating these results in larger cohorts and elucidating the specific mechanisms through which TMIGD2 influences BLCA progression and immune response.

This study demonstrates that TMIGD2 is downregulated in BLCA and correlates with adverse prognosis and immune regulation. Its potential as a prognostic biomarker and therapeutic target is underscored by its involvement in key pathways, immune infiltration, and drug sensitivity. Further research is essential to fully realize the clinical potential of TMIGD2 in the management of BLCA.

Fungi are ubiquitous and play crucial ecological roles, but fungal infections pose serious threats to human, animal, and environmental health, with a significant economic and social burden. Current antifungal therapies face challenges, such as limited drugs, toxicity, and resistance, highlighting the urgent need for drugs with new mechanisms of action. The enzyme acetohydroxyacid synthase (AHAS) is a promising target, as it is involved in branched-chain amino acid biosynthesis, a pathway lacking in animals and already explored in herbicide development.

We conducted an integrative review covering the antifungal potential of known AHAS inhibitors and the development of novel inhibitors with antifungal activity within the PubMed, ScienceDirect, and Web of Science databases.

A total of 590 articles were obtained, and after applying the inclusion and exclusion criteria, 17 articles were selected. The review identified commercial herbicides as potent AHAS inhibitors of plant and animal pathogenic fungi and to have a broad spectrum of antifungal activity against many species, such as Candida albicans, C. auris, Cryptococcus neoformans, Aspergillus fumigatus, and Saccharomyces cerevisiae.

Based on these results, several compounds were designed, synthesized, and evaluated as antifungal agents, showing promising inhibitory properties against fungal AHAS and growth. Structural features of AHAS from different organisms were also investigated to guide drug development.

Considering structural insights and experimental data, AHAS inhibitors showed promising profile as broad-spectrum antifungals, with low toxicity to humans and the environment, supporting a One Health approach to control fungal infections across human, animal, and environmental health.

To investigate the causal relationship between 1-palmitoyl-GPG (16:0) and serous ovarian cancer (SOC), and explore the underlying mechanisms.

Two-sample Mendelian randomization (MR) and mediation effect analyses were employed to determine the causal effects of 1-palmitoyl-GPG (16:0) on serous ovarian cancer (SOC), focusing particularly on naive CD4+ T cell proportions as potential mediators. Single-cell RNA sequencing, immune infiltration analysis, and bulk machine learning algorithms were also integrated to examine the expression and impact of palmitoyl-CoA synthesis genes in CD4+ T cells. Lasso regression was utilized to refine the set of marker genes, and CatBoost machine learning algorithm was applied for predictive modeling. SHAP analysis was performed to interpret the model results.

MR and mediation analyses indicated that 1-palmitoyl-GPG (16:0) has a causal effect on SOC, partly mediated by the proportion of naive CD4+ T cells, and partly through direct effects potentially involving metabolic gene expression (e.g., PIGB) in CD4+ T cells. Single-cell and immune infiltration analyses confirmed that key palmitoyl-CoA synthesis genes, including PIGB, were highly expressed in CD4+ T cells and may contribute to SOC both indirectly, by influencing naive CD4+ T cell proportions, and directly through metabolic modulation within CD4+ subsets. The bulk RNA-seq machine learning model showed good predictive performance on an independent validation dataset. SHAP analysis was used to interpret feature contributions, with PIGB having the greatest impact on model predictions. The immune-related genes, including upregulated PIGB, GZMA, PRF1, S100A4, and CCL5, while downregulated AHNAK and LGALS1 (except in fibroblasts). Furthermore, different patterns of gene expression were observed in different CD4+ T cell clusters, which corresponded to various developmental statuses and functional roles. We identified a causal relationship between 1-palmitoyl-GPG (16:0) and SOC, which is mediated by naive CD4+ T cells and key synthesis genes.

Our findings provide new insights into the metabolic and immunological mechanisms underlying SOC, and highlight potential targets for therapeutic interventions.

The objective of this study was to synthesize and characterize the Formononetin-Celecoxib Conjugate, evaluate its efficacy both in vitro and in vivo, and ascertain its potential as a medicinal agent for osteoarthritis (OA).

Phytoconstituents from Glycine max and FDA-approved drugs were meticulously curated and subjected to computational analyses for target identification and molecular docking. The Formononetin-Celecoxib Conjugate was subsequently synthesized and characterized using spectroscopic techniques. In vitro assessments included MTT viability assays and ELISA analyses. In vivo efficacy was evaluated using an MIA-induced OA mouse model.

Molecular Formononetin-Celecoxib Conjugate has high binding affinity towards MMP-9. In vitro, the conjugate was non-toxic and significantly reduced MMP-9 expression. In vivo, it attenuated paw volume (p < 0.05) and prevented body weight loss in OA-induced mice, especially at 200 mg/kg. Statistical analysis (Mean ± SD; two-way ANOVA with Tukey’s test) confirmed significant therapeutic benefits.

The study validates the conjugate's anti-inflammatory and disease-modifying potential through both computational and experimental approaches. Its effects on MMP-9 inhibition suggest translational relevance for human OA. However, small sample size and lack of blinding remain limitations requiring further investigation.

Our study demonstrates the promising potential of the Formononetin-Celecoxib Conjugate as a novel therapeutic intervention for OA. By integrating computational predictions with experimental validations, this approach represents a step toward precision medicine in managing OA.

This study aimed to investigate the effects of the extract and purified protein from the microalga Chlorella vulgaris against T. gondii in infected Vero cells.

The extract was obtained through magnetic stirring with Tris-HCl buffer and evaluated for cytotoxicity and anti-Toxoplasma activity. The purified protein was isolated using Sephadex G-75 chromatography and assessed in light microscopy assays.

Results indicated that the CC50 of the C. vulgaris extract was > 2000 μg/mL. Both the extract and the purified protein effectively inhibited parasite multiplication, with IC50 values of 132.6 and 8.6 μg/mL, respectively, and selectivity indices of 11.5 and > 20, respectively.

Microscopic analysis showed that the purified protein, even at higher concentrations, did not exhibit toxicity to the cells and reduced the number of intracellular tachyzoites.

These findings suggest that both the extract and purified protein of C. vulgaris possess the ability to inhibit T. gondii tachyzoites without causing toxicity to healthy cells, indicating their potential as bioactive compounds for pharmacological applications against toxoplasmosis.

Dihydromyricetin (DMY) presents itself as a promising therapeutic candidate due to its inhibitory effects on various receptor tyrosine kinases, prompting an investigation of its structural characteristics, molecular interactions, and biological activity across the FGFR, HER, PDGFR, and VEGFR families.

Protein sequences and structures for FGFR1/2, HER2/3, PDGFRA/B, and VEGFR1/2 were retrieved from UniProt/PDB. DMY and reference inhibitors were docked to each kinase using AutoDock Vina. Anti-angiogenic activity was measured by HET-CAM assay with vessel metrics quantified via IKOSA CAM. MTT determined cytotoxicity (IC50) and tumor-selectivity index in 4T1 and L929 cells; data (mean ± SEM) were analyzed by one-way ANOVA with Tukey’s test (p < 0.005).

DMY exhibited docking scores comparable to established inhibitors, achieved over 45 % inhibition of neovascularization in the HET-CAM assay at nanomolar concentrations, displayed a tumor-selectivity index of less than one in 4T1 versus L929 cells (mirroring many clinical chemotherapeutics), and, notably, coadministration with doxorubicin reduced in vitro cardiotoxicity markers.

The high-affinity, multi-kinase binding profile and significant anti-angiogenic efficacy underscore DMY’s multifunctional potential, while its tumor-selectivity index aligns with accepted therapeutic risk–benefit balances and its cardioprotective effect suggests a way to mitigate anthracycline toxicity.

These findings indicate that DMY is a multifunctional agent exhibiting both anti-angiogenic and cytotoxic properties, warranting further preclinical and clinical investigation.

Glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) are distributed in the brain, and they are particularly dense in the hippocampus. The two receptors are implicated in stress-related psychiatric diseases, such as anxiety, autism spectrum disorders (ASD) and depression. This study aims to investigate the alterations in neurological behaviour and the expression of GRs and MRs in male offspring from prenatal stress-exposed dams that were subjected to chronic stress.

In our study, we conducted the elevated plus maze (EPM) test on adult offspring of pregnant mice exposed to chronic stress, as well as on mice in the control group, to examine their neurological behaviors. Expression levels of GRs, MRs, and interleukin 6 (IL-6) were detected by Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction (qRT PCR). After euthanizing the adult mice from both groups, we dissected their cortex and hippocampus for immunofluorescence staining.

We observed an increase in the IL-6 mRNA content in the cerebral cortex of male offspring from the stress group, which was accompanied by the activation of microglial cells. Additionally, the relative mRNA expression levels of GRs and MRs in the hippocampus of male offspring from the stress group were found to be decreased. As a result, adult offspring from the stress group exhibited anxiety-like behavior.

The observed reduction in hippocampal GR and MR expression, alongside increased cortical IL-6 and anxiety-like behavior in male offspring, suggests that prenatal stress disrupts neuroendocrine and inflammatory pathways, supporting previous findings on stress-induced neurodevelopmental vulnerability, although further studies are needed to address sex differences, long-term behavioral outcomes, and causal mechanisms.

Our study indicates that chronic prenatal stress induces anxiety like behaviour in offspring and decreases the expression levels of GRs and MRs.

Prostate cancer is among the most prominent malignant tumors in the male population, characterized by growing morbidity, a high fatality rate, and currently limited therapeutic options, necessitating the urgent development of novel clinical medications. The objective of the current study was to examine the therapeutic potential of zingerone in prostate cancer cells.

In this study, we investigated the underlying mechanism by which zingerone exerts its anticancer effects in prostate cancer cells. We conducted various in vitro and in silico experiments to determine the therapeutic efficacy and mechanism of action of zingerone.

Cytotoxicity analysis of zingerone revealed its substantial cytotoxic impact and ability to elevate lactose dehydrogenase levels in DU145 cells. Using the MTT assay, we determined that a concentration of 24.84 μM zingerone in DU145 cells grown for 24 h resulted in an IC50 value. Zingerone effectively induced apoptosis by increasing the levels of cytochrome c and caspase in DU145 cells. Regarding the identification of signs of ferroptosis, evidence has been shown for the presence of heightened mitochondrial ROS, disrupted mitochondrial membrane potential, increased levels of glutathione (GSH) and malondialdehyde (MDA), and reduced expression of SCL7A11 and GPX4.

Importantly, our study confirms that zingerone triggered both apoptosis and ferroptosis in DU145 cells by downregulating SLC7A11 and GPX4 expression.

This study provides evidence that makes zingerone a potent therapeutic agent for prostate cancer.

Cancer is a prevalent public health issue and a significant global problem. Patients receive different treatments, including Western Medicine (WM) and Traditional Chinese Medicine (TCM). This review article aims to discuss a Traditional Chinese Medicine (TCM), “Celastrol,” its traditional design, modification, and nano-drug delivery systems for the treatment of cancer.

Nine electronic databases, such as WanFang Data, PubMed, ScienceDirect, Scopus, Web of Science, SpringerLink, SciFinder, and China National Knowledge Infrastructure (CNKI), were used to find relevant information from the past twenty years, with searched keywords including “celastrol,” “cancer,” and “nano-drug delivery system,” etc., without language restrictions.

Celastrol is a therapeutic agent with anticancer properties against liver and breast cancers, ovarian cancer, multiple myeloma, and glioma. PI3K/Akt/mTOR, Bcl-2/Bax-caspases, EGFR, ROS/JNK, NF-κB, STAT3, JNK/Nrf2/HO-1, VEGF, AR/miR-101, HSF1-LKB1-AMPKα-YAP, Wnt/β-catenin, and CIP2A/c-MYC signaling pathways are the possible mechanisms by which celastrol acts against cancer.

A naturally occurring bioactive substance, “celastrol,” is extracted from the root of Tripterygium wilfordii Hook F. Its effectiveness can be enhanced with the support of nanotechnology to overcome its limitations in cancer treatment. However, the toxicity, dosage, and safety assessments of celastrol and nanocelastrol in cancer applications must be further investigated.

This study aimed to explore the mechanisms by which interleukin-10 (IL-10) influences tumorigenesis through T regulatory cells (Treg) regulation.

Environmental factors, such as IL-10, significantly shape the immune microenvironment and tumor progression, yet the regulatory pathways remain unclear.

1) To elucidate the regulatory mechanism of IL-10 on Treg cells through in vitro assays; 2) To elaborate whether Nrp-1/PDX1 knockout affects tumorigenesis via in vivo assays.

CD4+ T cells were isolated from the healthy mice's spleen and induced to differentiate into Treg cells. Then, after being treated with IL-10 and mouse melanoma cell supernatant (CM), the expression levels of Nrp-1 and FoxP3 in Treg cells were examined via qRT-PCR and Western blotting. The ratio of Treg cells was measured by flow cytometry. The interaction between Nrp-1 and PDX1 proteins was detected through GST pull-down assay, Co-IP, Western blotting and immunofluorescence staining. STAT3 luciferase activity was detected, and the expression levels of JAK1 and STAT1 proteins were detected by Western blotting. Furthermore, the B16-bearing melanoma mice and Nrp-1/PDX1 knockout mice model were established to verify the effects of Nrp-1 and PDX1 on Treg formation and tumor development.

The results demonstrated that IL-10 promoted Nrp-1 expression in Treg cells via the JAK-STAT3 signaling pathway. Nrp-1 could combine with PDX1 to form a complex, facilitating PDX1-mediated activation of FoxP3 and Treg production. In melanoma xenograft models, targeting Nrp-1 and PDX1 using shRNAs or antibodies significantly reduced Treg levels and inhibited tumor growth. Collectively, IL-10 promotes Treg formation and tumorigenesis via regulating Nrp-1/PDX1/FoxP3 axis.

This study was the first to identify the interaction between Nrp-1 and PDX1, leading to PDX1 ubiquitination, which enhanced FoxP3 expression and Treg function in the tumor microenvironment. These novel insights highlighted the Nrp-1/PDX1/FoxP3 axis as a critical regulator of Treg-mediated tumorigenesis, offering potential targets for cancer therapy.

These findings highlight the interplay between environmental influences and immune regulation, providing novel insights into Treg-mediated tumorigenesis and suggesting potential strategies for targeted therapy.