Letters in Drug Design & Discovery - Volume 21, Issue 18, 2024

This study investigates the efficacy of α7-nicotinic acetylcholine receptor (α7nAChR) agonists in mitigating postoperative cognitive dysfunction (POCD) in a rat model. This investigation aimed to elucidate the therapeutic potential of α7nAChR agonists in modulating neuroinflammatory pathways to improve cognitive outcomes post-surgery.

Serum levels of pro-inflammatory cytokines IL-1β and IL-18 were measured as markers of systemic inflammation, while the expression levels of NLRP3 mRNA were quantified to evaluate pyroptosis and NLRP3 inflammasome activation.

Adult male Sprague-Dawley rats were divided into control (no surgery), POCD (surgery-induced), and POCD treated with an α7nAChR agonist. Cognitive function was assessed using the Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests.

The results showed a notable cognitive impairment in the group with POCD, as shown by increased escape latency noted in the MWM test and decreased discrimination index in the NOR test, while controls had no change. However, treatment with the α7nAChR agonist led to a significant improvement in cognitive performance among the POCD rats such that it closely matched those of the controls. Furthermore, the POCD group exhibited elevated serum levels of IL-1β and IL-18 and increased expression of pyroptosis-related markers, indicating enhanced neuroinflammation and inflammasome activation.

These findings highlighted the therapeutic efficacy of α7nAChR agonists in mitigating neuroinflammation and improving cognitive outcomes post-surgery. Our study supports the potential of targeting the cholinergic anti-inflammatory pathway, emphasizing clinical evaluation of α7nAChR agonists in postoperative patients.

Sedum sarmentosu Bunge (SSB), a perennial herb, exhibits notable therapeutic effects on hepatic fibrosis (HF). However, the mechanism of treatment has not been fully determined.

The objective of this study is to explore the active components in SSB and investigate its molecular mechanism of action in the treatment of HF based on network pharmacology, molecular docking, and molecular dynamics simulation (MD).

Databases such as TCMSP, Gene Cards, OMIM, and DAVID, as well as Cytoscape, AutoDock Vina, and Gromacs software, were used for analysis.

A total of 5 active components and 86 HF-related targets were screened for SSB, among which the most prominent components are luteolin and quercetin. The key targets for HF are MMP2, MMP3, MMP9, ABCG2, etc. GO enrichment analysis showed that SSB was closely associated with apoptosis, inflammatory response and cell migration processes. KEGG enrichment analysis showed that the major enrichment pathways for liver fibrosis include EGFR tyrosine kinase inhibitor resistance, PI3K-Akt signaling pathway, and cancer-related pathways. Molecular docking and MD showed that luteolin and quercetin have good affinity and stable binding to MMP2, MMP3, and MMP9.

SSB exerts therapeutic effects on HF through multiple components, targets, and pathways, thereby providing a theoretical foundation for the development of its active compounds and mechanisms of action.

Stroke is one of the most important causes of mortality and disability in the world. Over 80% of strokes are ischemic, resulting from blockages in cerebral arteries. Increasing evidence suggests that enriching the diet with nutritional antioxidants could decrease brain damage and enhance cognitive function. Cornelian cherry has anti-inflammatory and antioxidant properties and is introduced as a potential source of active ingredients, like anthocyanins, vitamin C, phenolic compounds, and minerals.

Our research study aimed to evaluate the neuroprotective impact of Cornus mas L. (cornelian cherry) on a rat model of Cerebral Ischemia/Reperfusion Injury (CIRI).

Middle cerebral artery blockage induced CIRI for 60 minutes. After inducing CIRI, intra-peritoneal injections of Cornus mas Extract (CME) were administered for 14 days in a dose-dependent manner (30, 60, and 120 mg/kg body weight). The effects of CME on learning and memory recovery were evaluated using a shuttle box behavioral test.

Two weeks following CIRI, several factors of oxidative stress, such as nitrite (NO2-), Ferric ion Reducing Antioxidant Power (FRAP), and Malondialdehyde (MDA), were measured in the hippocampal tissues and serum. Anti-inflammatory genes, such as miR-125b, and the target genes (TNF-α and iNOS) were evaluated via real-time PCR assay. Additionally, neural damage in the CA1 and CA3 regions of the hippocampus was assessed using Hematoxylin and Eosin (H&E) staining.

The avoidance time in the shuttle-box behavior test supported our finding that CME exhibited improved fear memory. Furthermore, it increased the CA1 and CA3 hippocampal post-stroke pyramidal cell layers. Levels of NO2- and MDA were decreased, and FRAP was considerably increased in both the hippocampus and serum by CME. Additionally, CME increased miR-125b expression, while modulating TNF-α and iNOS production in the hippocampal regions.

Based on our findings, we can conclude CME to possess antioxidant and anti-inflammatory properties, which confer neuroprotective potential against CIRI, thereby protecting neurons from ischemic death.

Chronic Renal Failure (CRF) refers to the gradual decline in renal function caused by various chronic kidney diseases, eventually leading to end-stage renal failure. Yangshen Paidu Decoction (YPD) is a Traditional Chinese medicine (TCM) formula utilized in CRF treatment. This work has analyzed the effects of YPD on CRF and the specific mechanism.

Network pharmacology was performed to screen effective components and targets of YPD, from which key targets and signaling pathways contributing the most to the treatment effects on CRF were determined. Subsequently, we validated the therapeutic role of YPD and the underlying pathological mechanisms using the 5/6-nephrectomy rat model.

Network pharmacology analysis showed the mTOR pathway to be a pivotal mechanism underlying the effectiveness of YPD in CRF treatment. YPD significantly suppressed urine protein levels, blood urea nitrogen, and serum creatinine in 5/6 nephrectomized rats. Furthermore, YPD remarkably improved renal pathological injuries. Western blot analysis revealed that YPD enhanced autophagy and upregulated the expression of nephrin, podocin, beclin1, p-AMPK/AMPK, and p-ULK1/ULK1, and attenuated the ratios of p-mTOR/mTOR to its downstream protein phosphorylated eIF4E-binding protein (p-4EBP1). However, these effects were notably reversed by the AMPK inhibitor compound C.

Our findings have demonstrated YPD to suppress the mTOR pathway and stimulate autophagy by modulating AMPK pathways, thereby mitigating podocyte injury and enhancing renal function. Our study has confirmed autophagy and the AMPK/mTOR pathway as potential targets for YPD in CRF treatment.

This study evaluated the effects of Rigosertib (RGS) on the prevention of intra-abdominal adhesions in a mouse model.

Eighteen mice were divided into three groups: Sham (no abrasion or adhesion), Positive Control (surgical abrasion and adhesion), and Rigosertib Treatment (200 mg/kg/day intraperitoneally for 7 days). Adhesions were induced through cecal abrasion and assessed using Nair and Leach adhesion scoring systems. Histological evaluations were performed using Haematoxylin & Eosin (H & E) and Masson's trichrome stains in order to analyze inflammatory cell infiltration and collagen deposition.

Results showed that RGS administration did not have a significant impact on the formation or rigidity of adhesion bands compared to the positive control group. Both Nair and Leach scoring systems confirmed the lack of significant differences. Histological analysis revealed no reduction in inflammatory responses or collagen deposition in RGS-treated mice. H & E staining showed similar inflammatory cell infiltration across all groups, while Masson's trichrome staining indicated no differences in fibrosis levels between treated and untreated mice. In conclusion, Rigosertib did not demonstrate efficacy in down-regulating peritoneal adhesions or associated inflammatory responses and fibrosis in this mouse model.

These findings suggest that Rigosertib may not be suitable for preventing intra-abdominal adhesions, warranting further investigation into alternative therapeutic strategies.

Currently, network pharmacology and molecular docking technology are valuable tools frequently employed to predict the mechanisms and targets of drugs. Wengbu, a Tibetan medicine, is an anti-inflammatory agent commonly used in the Qinghai-Tibet Plateau of China, and it has been demonstrated to have an effect against skin inflammation. However, the network pharmacological mechanisms and targets of Wengbu in relation to skin inflammation have not yet been reported. This paper aims to provide a scientific basis for the anti-skin inflammatory effects of Wengbu through experimental verification based on the predicted targets.

The chemical constituents and targets of Myricaria germanica essential oil were identified through a literature search, as well as databases such as PubChem and Swiss Target Prediction. Targets associated with skin inflammation were obtained from the Gene Cards human gene database, DisGeNET, and the OMIN databases. Subsequently, a Myricaria germanica essential oil-skin inflammation target database and a corresponding target network diagram were constructed. Biological function enrichment analysis and molecular docking verification were then conducted. In vitro cell experiments were performed to validate the role of Myricaria germanica essential oil's key targets in inhibiting skin inflammation.

Ten compounds were selected through a literature review, including linalool, eugenol, and vanillin. A total of 429 essential oil component targets, 889 skin inflammation targets, and 108 intersection targets were identified. MAPK1, PIK3CD, PIK3CA, and MAPK14 could be the principal targets of Myricaria germanica. essential oil to reduce skin inflammation. The principal signaling pathways through which Myricaria germanica essential oil exerts its anti-inflammatory effects include the cancer pathway, coronavirus disease (COVID-19), lipid metabolism, and atherosclerosis. These effects may be attributed to the regulation of the cellular inflammatory response, the cellular response to lipopolysaccharide, and the positive regulation of cytoplasmic calcium concentration. Molecular docking results indicated that the potential components of Myricaria germanica essential oil exhibited strong binding affinity with the core target proteins. In vitro cell experiments demonstrated that Myricaria germanica essential oil effectively reduced the levels of TNF-α, IL-6, and Caspase-3, decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in cells, and enhanced the activity of superoxide dismutase (SOD), thereby inhibiting skin inflammation.

Myricaria germanica essential oil exhibits multi-component, multi-target, and multi-pathway characteristics in the inhibition of skin inflammation. This experiment serves as a reference and foundation for further elucidating its material basis and the mechanisms involved in inhibiting skin inflammation.

Non-ionic surfactant-based vesicles (niosomes) as coherent and self-organization capability structures form organized core/shell nanostructures.

In this academic research, Ni/NiAl2O4 core/shell nanostructures were successfully synthesized with the ultrasound-assisted direct micelle (UADM) method and these structures were used as a delivery system for minoxidil drugs.

The synthesis conditions for producing Ni/NiAl2O4 core/shell structures were optimized using a design of experiments (DOE) approach. Process control was systematically examined through analysis of variance (ANOVA) and response surface methodology (RSM). The Ni/NiAl2O4, core/shell nanostructures, underwent characterization using various techniques such as SEM (scanning electron microscopy), TEM (transmission electron microscopy), AFM (atomic force microscopy), FT-IR (Fourier-transform infrared spectroscopy), TGA (thermogravimetric analysis), BET analysis, differential thermal analysis (DTA), and nitrogen adsorption isotherms. The in vitro release of minoxidil from the Ni/NiAl2O4 core/shell nanostructures was studied using UV-vis spectroscopy at a wavelength of 486 nm.

Results indicated an encapsulation efficiency (EE%) of around 74% after 150 minutes. Furthermore, the loading efficiency of minoxidil in niosomes modified with Ni/NiAl2O4 core/shell nanostructures was calculated to be approximately 99.83% at 486 nm.

Overall, this research lays a foundational framework for developing innovative nanomaterials with tailored properties for advanced delivery systems and other novel applications.

Traditional Chinese medicine rarely applies the herb Safflower (Carthamus tinctorius) to the treatment of tumors and little is known about its mechanisms and the treatment of Safflower for melanoma.

This study aims to analyze the active ingredients and underlying mechanisms of Safflower in treating melanoma using network pharmacology, molecular docking, and in vitro experiments and provide a new direction for the research and development of new drugs for melanoma treatment.

We collected the active chemical ingredients from Safflower and generated a network of “Drug-Active Ingredient-Target” by Cytoscape. From the DrugBank, OMIM, and GeneCard databases, disease-related targets of melanoma were obtained. The intersection target genes between Safflower and melanoma were identified, leading to the construction of a protein-protein interaction (PPI) network via Cytoscape software. Metascape database was used to enrich pathways for relative targets of Safflower. Molecular docking was demonstrated by the software AutoDockTools-1.5.6. Use an online database (https://xenabrowser.net/) and R package IOBR (version 0.99.9) to evaluate the correlation between the core target genes and prognosis or the immune score. CCK8 and PCR were used to detect the toxicity of quercetin on melanoma cells and its effects on mRNA expression of AKT1, JUN, and TP53.

Our investigation identified 17 active pharmaceutical ingredients within Safflower alongside 94 potential targets related to melanoma treatment. Gene Ontology (GO) analysis is primarily concerned with extracellular exosomes, positive regulation of transcription from RNA polymerase II promoter, and protein binding. KEGG pathway enrichment analysis mainly involves Pathways in cancer, IL-17 signaling pathway, AGE-RAGE signaling pathway, and other pathways. Using molecular docking, it can be seen that the compounds Quercetin, kaempferol, luteolin, baicalein, and beta-sitosterol in Safflower have strong binding abilities with important targets. The results of survival analysis and immune score analysis suggest that Safflower may regulate the immune cell infiltration of melanoma patients by acting on core target genes and improving the prognosis of patients. In vitro analysis confirmed that Quercetin was cytotoxic toward B16-F10 cells and altered mRNA expression of AKT1, JUN, and TP53 identified through the network pharmacology approach.

This work offered an active pharmaceutical ingredient in Safflower and potential targets for melanoma, and the mechanism of its action on melanoma may be related to the regulation of immune-related pathways in melanoma.

Post-operative adhesion band formation is a serious post-surgery complication with a highly detrimental impact on patient morbidity and health care costs. In this study, we aimed to investigate the repurposed potential of a safe and FDA-approved drug, metformin, in attenuating post-surgical adhesion band formation in Achilles tendon surgeries in an animal model.

Wistar albino rats were divided randomly into three groups: sham, positive control, and metformin-treated groups (n=6). We administered Metformin 100 mg/kg orally for 21 days. Achilles tendon tissue sections were stained with Hematoxylin-Eosin and Masson's trichrome to assess the accumulation of inflammatory cells and collagen deposition. Spectrophotometric analysis was performed on tissue samples to determine oxidative stress markers. According to Tang and Ishiyama scoring systems, Achilles tendon adhesion properties were compared.

Using the Tang and Ishiyama scoring system, we showed that metformin significantly decreased the length, density, grading, and severity of adhesion bands at surgery sites (***p<0.001). Pathologic morphological changes and oxidative stress markers decreased in tendon tissue samples of metformin-treated rats compared to control (**p<0.01, ***p<0.001). Moreover, administration of metformin markedly decreased collagen deposition, fibrosis accumulation, and fibrosis quantity score as visualized by Masson’s trichrome staining in tissue sections (*p<0.05).

These results suggest that metformin, with its potent anti-inflammatory and anti-fibrotic properties, can be repurposed as a potential therapeutic molecule for preventing post-operative adhesion band formation.

Acute myocardial infarction (MI) is a serious emergency disease with high mortality. Hypoxia is associated with unfavorable outcomes in cancer patients. Nevertheless, there remains a shortage of effective hypoxia-related biomarkers to forecast the prognosis of acute MI patients and to identify targeted therapies.

First, data on acute MI patient samples and hypoxia-related genes were obtained based on public databases. Hypoxia-related gene scores were calculated by single sample Gene Set Enrichment Analysis (ssGSEA). Hypoxia-related hub genes in acute MI were screened via weighted correlation network analysis (WGCNA). Acute MI samples were analyzed for differentially expressed genes (DEGs) using the limma package and intersected with hub gene for hypoxia-related DEGs. Then, machine learning methods were used to identify hypoxia-related biomarkers in acute MI. Gene set enrichment analysis (GSEA) and immune infiltration analysis were performed on biomarkers. Targeted drug prediction and molecular docking were conducted based on biomarkers.

The hypoxia-related gene score of the acute MI group was higher than the control group, and 319 hypoxia-related hub genes in acute MI were acquired. A total of 7 hypoxia-related DEGs were obtained by WGCNA and DEGs analysis. Then, 2 hypoxia-related biomarkers in acute MI, HAUS3 and SLC2A3, were identified based on machine learning algorithms. Both HAUS3 and SLC2A3 were enriched in the ribosome and spliceosome pathways. The expression levels of SLC2A3 and HAUS3 were correlated with immune cell infiltration. Furthermore, 8-hydroxyquinoline, perhexiline, and sotalol were selected as the targeted drugs, which could bind to HAUS3 and SLC2A3.

In short, we screened two important hypoxia-related biomarkers and three potential target drugs based on bioinformatics techniques. This provides new ideas and potential drug targets for early diagnosis and targeted therapy of acute MI.

Phosphodiesterase-5 (PDE5) is an enzyme that promotes the degradation of cGMP in the blood, leading to a restriction in regulating blood flow in the penis, thereby reducing cGMP causing difficulties for men in achieving hardness (erectile dysfunction). Natural products with fewer side effects are being developed in many different treatment strategies and are necessary today. The current study aims to evaluate this enzyme's in silico inhibitory potential and marine xanthones through computational models.

The database of marine xanthones was collected from previously published literature. Protein structures were downloaded from the RCSB protein data bank (PDB ID: 1UDT). Molecular docking studies were performed using the AutoDock Vina v1.2.3 program to conduct screening. Molecular dynamics simulations were carried out with the GROMACS program to assess structural stability, and gmx_MMPBSA was used to make free-binding energy calculations for each PDE5 protein complex with potential compounds. Furthermore, Density Functional Theory (DFT) was applied in this study to calculate the atomic properties of the molecules based on quantum mechanics using the Gaussian 09 program.

Molecular docking revealed that 21 compounds (staprexanthone A (69), emerixanthone E (89), emerixanthone A (90), emerixanthone C (91), varixanthone (92), aspergixanthone H (95), austocystin L (98), austocystin M (99), emerixanthone D (109), 15-acetyl tajixanthone hydrate (117), tajixanthone hydrate (118), 16-chlorotajixanthone (119), citreamicin ε A (131), citreamicin ε B (132), engyodontochone A (146), citreamicin θ B (151), citreaglycon A (152), dehydrocitreaglycon A (153), neocitreamicin I (159), citreamicin α (161), ukixanthomycin A (165) had superior binding affinities (ΔG < -11 kcal/mol) compared to the control inhibitor. Molecular dynamics confirmed the stability of the protein-ligand complexes. MM/GBSA analysis showed nine compounds (91, 98, 109, 118, 119, 151, 159, 161, 131) had binding energies comparable to or better than sildenafil. Quantum mechanical estimates indicated their potential as electron donors and acceptors, highlighting their antagonistic potential.

These promising marine xanthones warrant further research to assess their PDE5 inhibitory activity in vitro and in vivo. This could provide valuable insights for developing new natural resource-based drugs to prevent or treat erectile dysfunction.

To address the issues of liposomal instability and enhance the delivery of docetaxel (DTX) to breast cancer cells, the development of polyethylene glycol (PEG)-coated proliposomes was proposed, utilizing a thin film hydration technique followed by lyophilization with an appropriate cryoprotectant. Various compositions of phospholipid, cholesterol, and docetaxel were optimized, and the PEG was used in a 1.3:1 ratio of the phospholipid.

The liposomes were converted to proliposomes using a lyophilizer. The optimized formulation possesses a particle size of 117.0 ± 9.78 nm, with a polydispersity index (PDI) of 0.265 ± 0.094, drug entrapment (DE) of 96.0± 6.14%, and drug loading (DL) of 9.20 ± 3.17%. In-vitro study demonstrated a controlled release pattern consistent with the Higuchi model, alongside significantly lower protein binding relative to free DTX, indicating a potential reduction in side effects.

Cell viability study demonstrated increased cytotoxicity of PEG-DTX proliposomes (PEG-DTX PL) against MDA-MB-231 cells, evidenced by a lower IC50 (4.677 μg/mL) relative to free DTX, underscoring the promise of this nanocarrier for targeted therapy.

The findings are promising as a simple and scalable carrier comprising general and biocompatible materials that can provide a safe surfactant free nanosystem with improved efficacy and performance.

Breast cancer is a common and deadly disease that affects women worldwide. Despite advancements in research and treatment, breast cancer continues to be a significant health issue.

This study examined the potential of black soybean, commonly known as Sojae Semen Nigrum (SSN), in the prevention and therapy of breast cancer using a mix of data mining, network pharmacology, and docking analysis.

Molecular dynamic simulation studies and docking analysis supported the findings by confirming the bioactive compounds' efficient activity against potential target genes.

The study discovered the top three significant compounds Pramoxine, Sapogenol C, and beta-sitosterol, that may change target genes involved in the etiology of breast cancer as well as proteins like AKT1, MAPK1, and MAPK3. The study's conclusions point to SSN as having potential multi-target pharmacological defenses against breast cancer, laying the groundwork for more experimental exploration.

The study's conclusion suggests that SSN may help certain people with breast cancer and might transform cancer treatment.