Combinatorial Chemistry & High Throughput Screening - Online First

Obesity is a global health issue linked to metabolic disorders and cardiovascular diseases. Guang hawthorn (Malus doumeri) leaves have been traditionally used for medicinal purposes, but their bioactive compounds and anti-obesity potential remain underexplored.

This study extracted compounds from M. doumeri leaves using 70% ethanol and ethyl acetate. The extracts were administered to high-fat diet-induced obese rats. Serum levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured. The chemical composition of the extracts (HML) was analyzed using chromatography, NMR, and mass spectrometry. Network pharmacology and enrichment analyses were conducted using R and Cytoscape to identify compound-target interactions.

Rats treated with high-dose extracts showed significantly reduced TC, TG, and LDL-C levels and increased HDL-C (all p < 0.05). Three major compounds-phlorizin, sieboldin, and kumatakenin β-7-O-glucoside-were identified. A total of 272 overlapping targets and 32 core targets were found between compound-related and obesity-related gene sets. Functional analysis linked these targets to phosphorylation, apoptosis, cell proliferation, and kinase regulation.

The anti-obesity effects of M. doumeri may be mediated by modulation of the PI3K-Akt and FoxO signaling pathways, as well as proteoglycan biosynthesis. These pathways are associated with metabolic regulation and obesity-related changes.

M. doumeri leaf extracts demonstrate anti-obesity potential through multi-target and multi-pathway mechanisms, particularly via sieboldin and kumatakenin β-7-O-glucoside. These findings support their potential as natural therapeutic agents for obesity management.

To develop and characterize a Crocus sativus (saffron)-based solid lipid nanoparticle (SLN) nasal spray for treating depression by enabling direct nose-to-brain delivery and evaluating its antidepressant potential in a Drosophila melanogaster model.

Phytochemical screening, antioxidant assays, and HPLC quantification of picrocrocin were performed on Crocus sativus extract. The SLN-based nasal spray was formulated and characterized for particle size, zeta potential, polydispersity index (PDI), drug entrapment efficiency, in vitro drug release, and stability over 4 weeks. The antidepressant efficacy was assessed via a climbing assay in Drosophila melanogaster.

Phytochemical analysis revealed phenolic content (11–36 μg GAE/mg), flavonoid content (43–56 μg QE/mg), and carotenoid content (1.9–30 μg βC/mg). HPLC analysis quantified picrocrocin at 6.3 mg/g, confirming its presence. The SLNs exhibited a particle size of 110–225 nm, a zeta potential of -1 to -0.8 mV, a PDI of 1, and a drug entrapment efficiency of 99.76%. Drug release reached 37% over 270 minutes, and the nasal spray maintained a pH of 5.8, a viscosity of 23.1 cP, and stability over 4 weeks. In vivo, the climbing assay demonstrated improved locomotor activity, indicating significant antidepressant potential.

The favorable physicochemical characteristics of the nasal spray, along with the observed behavioral improvements in the fly model, suggest that Crocus sativus SLNs effectively cross the nasal-brain barrier and exert antidepressant-like effects. These findings support its potential for non-invasive management of treatment-resistant depression.

ARL6IP1 has been linked to cancer progression, but its precise role in BC, particularly in metabolism and its interaction with an OLFM4, remains unclear.

This study aimed to investigate the role of ADP-ribosylation factor-like 6 interacting protein 1 (ARL6IP1) in breast cancer (BC) cell behavior and metabolism and explore its interaction with an olfactomedin-4 (OLFM4) as a potential therapeutic target.

The objective of this study was to determine the effects of ARL6IP1 knockdown on BC cell proliferation, invasion, migration, apoptosis, oxidative stress, and glycolysis. Additionally, this study also explored the interaction between ARL6IP1 and OLFM4 and their combined role in BC progression and metabolism.

Key gene modules in the GSE73540 dataset were identified through weighted gene co-expression network analysis (WGCNA). Three BC-related datasets (GSE73540, GSE22820, and GSE36295) and The Cancer Genome Atlas (TCGA) were applied for additional examination of differentially expressed genes (DEGs). Intersection analysis selected ARL6IP1 as a hub gene for prognostic analysis. In vitro experiments investigated how ARL6IP1 knockdown influences BC cell proliferation, invasion, migration, apoptosis, epithelial-mesenchymal transition (EMT), oxidative stress, and glycolysis. The connection between ARL6IP1 and an OLFM4 was confirmed using Co-immunoprecipitation (Co-IP), and their roles in BC tumor progression and glycolysis were evaluated.

ARL6IP1 was elevated in BC datasets and linked with poor BC prognosis. Experiments demonstrated that knockdown of ARL6IP1 significantly reduced BC cell growth while promoting apoptosis and oxidative stress. Besides, ARL6IP1 knockdown reduced glycolysis, as manifested by decreased extracellular acidification rate (ECAR), glucose consumption, adenosine triphosphate (ATP) levels, and lactate production while increasing mitochondrial respiration (OCR). Co-IP validated the connection between ARL6IP1 and OLFM4, and OLFM4 overexpression partially counteracted the suppression of glycolysis and cell behavior resulting from ARL6IP1 knockdown.

ARL6IP1 is a critical regulator of BC progression, influencing glycolysis, mitochondrial function, and key cellular behaviors. Targeting the ARL6IP1-OLFM4 axis offers a promising therapeutic strategy for managing BC.

Cranberry (Vaccinium macrocarpon) is rich in vitamins, minerals, anthocyanins, flavonoids, and phenolic acids, offering potent antioxidant activity. Polyphenols in cranberries are linked to neuroprotective effects via modulation of oxidative stress, inflammation, and signaling pathways.

This study evaluated the neuroprotective effects of cranberries on behavioral and neurochemical abnormalities induced by intracerebroventricular (ICV) quinolinic acid (QA) in Wistar rats, focusing on ERK and PI3K/AKT pathway modulation.

Thirty Wistar rats were divided into groups: control, QA (240 nM, ICV), QA + cranberry (0.5 g/kg, p.o.), and QA + high-dose cranberry (2 g/kg, p.o.). Treatments continued for 21 days. Behavioral performance was assessed via Novel Object Recognition, Morris Water Maze, rotarod, and footprint analysis. Biochemical assays measured oxidative/nitrosative stress markers, mitochondrial complex activities, and cholinergic function. Histological analysis evaluated neuronal integrity.

QA treatment impaired cognition, motor function, and mitochondrial activity, increased oxidative stress (↑MDA, ↑nitrite, ↓GSH), and induced cholinergic dysfunction. Cranberry supplementation, particularly at 2 g/kg, significantly improved memory, learning, and motor coordination, restored GSH, reduced MDA and nitrite levels, enhanced mitochondrial complexes I, II, and IV activities, and normalized cholinergic markers. Histology confirmed reduced neuronal degeneration and inflammation.

Cranberries exhibit neuroprotective effects likely via antioxidant, anti-inflammatory, and anti-excitotoxic mechanisms, promoting synaptic plasticity and neuronal survival.

Cranberries may serve as a potential natural therapeutic strategy for cognitive deficits and neurodegenerative conditions, warranting further translational studies.

Cancer is a major public health concern, and conventional treatments like surgery, chemotherapy, and radiotherapy are associated with several disadvantages, including chemoresistance, toxicity, and economic burden to the family of cancer patients. Thus, discovery of novel agents of natural agents to reduce these side effects is crucial. A series of studies have shown anthraquinones as a promising adjuvant in enhancing the effectiveness of standard cancer therapies.

This review explores the anticancer potential of anthraquinones and their role in enhancing standard chemotherapy.

Various freely available databases, including PubMed, Scopus, Google Scholar and Web of Science were searched for updated and relevant information on anthraquinones and their use as an adjuvant with standard chemotherapeutic agents.

In this article, we looked at the recent developments in the utilization of anthraquinones as adjuvants in chemotherapy. Further, we have elaborated the mechanism of action that anthraquinones target to chemosensitize the drug-resistant cancer cells.

This review provides updated information on emerging role and their potential to be utilized as adjuvants in augmenting the efficacy of conventional cancer therapies.

Pressure injury (PI) severely affect the quality of life of patients. Infection and inflammation are key factors contributing to the progression of PI; therefore, their inhibition plays a crucial role in preventing the worsening of the condition. Huanglian Jiedu Decoction (HLJDD), as a typical traditional Chinese medicine with heat-clearing and detoxicating effects, has good broad-spectrum antibacterial and anti-inflammatory effects. It is commonly used in the treatment of clinically infected external wounds. However, the therapeutic effects of HLJDD on PI remains unclear.

The extract of HLJDD was prepared using the water extraction and alcohol precipitation method. Sixty male SD rats were randomly divided into five groups (n = 12/group): control group, model group, normal saline group (negative control group), iodophor group (positive control group), and HLJDD group (test group). Except for the control group, magnet clamping and the Staphylococcus aureus inoculation method were used to construct the model of stage 3 PI infection wound in the other groups. After irrigating the wound, the healing rate, bacterial concentration, concentrations of IL-1, IL-6, and TNFα, and the protein expression levels of TLR2, MyD88, and NF-Bp65 were examined. Skin and ocular mucosal irritation tests were conducted to evaluate the safety of the topical application of HLJDD.

Rats treated with HLJDD exhibited an improved wound healing rate, along with reduced bacterial concentration on the wound surface and a significant decrease in the content of inflammatory cytokines (IL-1β, IL-6, and TNF-α). The protein expression levels of TLR2, MyD88, and NF-κBp65 were down-regulated after the administration of HLJDD. The prepared HLJDD did not cause any irritation.

HLJDD can promote the healing of PI wounds and has a protective effect on PI through its anti-inflammatory and anti-bacterial properties.

ABCA family proteins regulate cholesterol transport, which affects cancer-related processes such as membrane dynamics and tumor progression. However, their roles in gastric cancer (GC) remain unclear.

This study systematically investigated the expression profiles, prognostic significance, and immune-related roles of ABCA family genes in GC using data from The Cancer Genome Atlas (TCGA). Kaplan-Meier and Cox regression analyses assessed survival relevance, while logistic regression and ROC curves evaluated clinical associations and diagnostic value. Immune infiltration and gene correlation were analyzed via ssGSEA and Pearson correlation. TIDE and “oncoPredict” were used to estimate immunotherapy response and chemotherapy resistance. Gene Set Enrichment Analysis (GSEA) identified related signaling pathways. Quantitative PCR validated ABCA expression in cell lines.

Several ABCA genes (e.g., ABCA1, ABCA2, ABCA7, ABCA13) were upregulated, while others (e.g., ABCA8, ABCA9) were downregulated in GC tissues. Expression levels correlated with pathological stage, grade, and lymph node metastasis. ABCA1, ABCA3, ABCA4, ABCA6, ABCA8, and ABCA9 were identified as independent prognostic factors. Nomogram models showed good predictive performance. High ABCA expression was associated with increased infiltration of multiple immune cells and co-expression with immune checkpoint genes. TIDE analysis indicated lower predicted ICI response, and ABCA levels correlated with resistance to cisplatin, 5-FU, and paclitaxel. GSEA revealed enrichment in ECM-receptor interaction, cell adhesion, autophagy, and PI3K-Akt pathways.

ABCA genes exhibit distinct expression and prognostic patterns in GC and are closely linked to tumor immunity and drug resistance, supporting their potential as biomarkers and therapeutic targets.

This study aimed to explore the mechanism of moxibustion in the knee by combining osteoarthritis metabolomics and network pharmacology.

A rat knee osteoarthritis (KOA) model was established by intra-articular injection of papain. The efficacy of moxibustion in KOA rats was evaluated by swelling degree, pathological progress, and mobility loss of knee joint. On this basis, the metabolic mechanism of moxibustion in relieving knee osteoarthritis was analyzed by metabolomics analysis.

Moxibustion significantly reduced joint swelling and inflammation in the knee joint of KOA rats. Sixteen metabolites and nine metabolic pathways were found to be associated with the mechanism of action of moxibustion in metabolomics analysis results. According to network pharmacology, 3186 KOA disease targets, 158 drug targets, and 89 intersecting targets were obtained. The key targets included MAPK-3, AKT-1, RELA, MAPK-8, MAPK-14, etc. Signal pathways were found to be involved in mechanisms of moxibustion in knee osteoarthritis, such as alanine, aspartate, and glutamate metabolism, cysteine and methionine metabolism, and arginine and proline metabolism.

At present, the mechanism of moxibustion for KOA is not completely clear, but it is certain that its effect is related to the effect produced by heat and radiation. In addition, the aromatic substances produced during the combustion of moxa leaves have anti-inflammatory, antioxidant, and immune-enhancing effects on KOA.

The mechanism of moxibustion in knee osteoarthritis may involve alanine, aspartate, and glutamate metabolism, cysteine and methionine metabolism, arginine and proline metabolism, amino tRNA biosynthesis, and D-glutamine and D-glutamate metabolism signaling pathways with MAPK-3, AKT-1, RELA, MAPK-8, and MAPK-14 as core targets. More precise mechanisms need to be verified by further systematic molecular biology experiments.

For clarifying the “multi genes and multi targets” characteristic of the treatment of Erxia Decoction (EXD), the aim of this study was to employ network pharmacology technology to perform cluster analysis on selected EXD targets.

EXD, a famous Chinese herbal prescription, consisting of Pinelliae Rhizoma (PR) and Prunellae Spica (PS), was mainly used to treat sleep disorder (SLD).

Using network pharmacology combined with proteomics to find out the main active components and core targets of EXD in the treatment of SLD.

By constructing the network of drug–component–target, the key protein targets of EXD for the treatment of SLD were screened. Then the interaction of the main active components of EXD and predicted candidate targets were verified. Then the proteomic analysis was used to screen the core targets in BV2 cells treated with EXD or the chemical ingredients, and the expression level was validated by Western blotting. Finally, molecular docking was used to further evaluate the mechanism of the action of the main ingredients and the core targets.

The 24 components of EXD mainly participate in the SLD treatment process by acting on 15 important key genes, and the core signal pathways were identified in the process of the action of EXD in treating SLD. Four key ingredients and five core targets were revealed from the results of network pharmacological analysis combination with proteomics, and then the AKT1 protein as a key target was validated by PCR and Western blotting.

This study preliminarily revealed EXD, morin (MOR) and quercetin (QUE) mainly inhibited the AKT1 core targets for the treatment of SLD using the network pharmacological analysis, proteomics, Western blotting and molecular docking.

The results elucidated partly the molecular mechanism and provided clues and a basis for further research.