Lactoferrin's role in modulating NF-κB pathway to alleviate diabetes-associated inflammation: A novel in-silico study.

Lactoferrin (LF), a multifunctional glycoprotein found in mammalian milk and various exocrine secretions, plays a pivotal role in modulating various responses. Lactoferrin plays a significant role in type-2 diabetes by improving hepatic insulin resistance and pancreatic dysfunction however, the exact mechanism for this improvement is not thoroughly elucidated. To this date, there are no evidence that attributes the direct interaction of lactoferrin with components of NF-κB pathway. Considering this precedent, the current study aimed to investigate the interaction of LF with key components of NF-κB pathway using molecular docking and simulation approaches. Results indicated that LF has shown highly stable interactions with IL-1ß, IL-6, IκBα and NF-κB, and relatively weaker interactions with IKK and TNF-α. All four trajectories, including root mean square of deviations (RMSD), root mean square of fluctuation (RMSF), hydrogen bond interactions, and radius of gyration (RoG), confirmed the stable interactions of LF with NF-κB pathway components. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analysis further supports their stable interactions. To the best of our knowledge, this is the first study to provide convincing evidence that LF can interact with all six major components of the NF-κB pathway. This study provides pioneering in-silico evidence that lactoferrin (LF) can interact with all six major components of the NF-κB pathway, demonstrating highly stable interactions with IL-1ß, IL-6, IκBα, and NF-κB, and relatively weaker interactions with IKK and TNF-α. These findings suggest that LF and its peptides have significant potential for both preventive and therapeutic applications by targeting the NF-κB pathway to inhibit inflammation, thereby improving insulin sensitivity and aiding in the management of diabetes.

Unveiling the therapeutic potential of epigallocatechin gallate in liver cancer: insights from network pharmacology and in vitro assays.

Epigallocatechin gallate (EGCG) is a prominent catechin found in green tea polyphenols and has shown promising anti-tumor properties. However, the exact regulatory mechanism of EGCG on liver cancer is not fully revealed. In this study, we conducted integrative analyses using the SwissTargetPrediction and GeneCards repositories, which identified 98 targets. These targets were used to construct a protein-protein interaction network using STRING and visualised with Cytoscape. Central to this network are hub proteins, notably TNF and PIK3CA, suggesting pivotal roles in the therapeutic landscape. Gene Ontology (GO) enrichment analysis unveiled 1,570 biological terms with a notable preponderance within oxidative stress response processes. Complementary pathway enrichment via the Kyoto Encyclopaedia of Genes and Genomes (KEGG) highlighted 134 pathways, with the PI3K-Akt pathway emerging as prominent. In silico molecular docking supported these findings, revealing binding energies of EGCG-target complexes below -7.0 kcal/mol, indicative of robust interactions. Moreover, cellular assays including CCK-8, wound-healing, and Transwell modalities, established EGCG's inhibitory concentration-dependent effects on HepG2 cell proliferation, migration, and invasion. Apoptotic assays affirmed by FACS, evidenced enhanced apoptosis with escalating EGCG concentrations, underpinned by modulations in caspase activity and apoptotic protein levels. Notably, Western blot analysis demonstrated the attenuation of the PI3K/AKT signalling cascade by EGCG, paralleling the inhibitory profile of LY294002. These multifaceted inhibitory effects underscore EGCG's potential as an anti-tumor agent, deploying a strategic blockade of oncogenic pathways and augmenting apoptotic mechanisms, which provide a strong rationale for its application in liver cancer therapeutics.

Decoding the bitter taste of Idesia polycarpa var. vestita Diels fruit: Bitterness contribution and mechanisms.

To comprehensively explore the contribution and mechanisms of identified low-threshold bitter substances in Idesia polycarpa var. vestita Diels (I. vestita) fruit, we performed quantification and elucidated their interactions with main bitter taste receptors through molecular docking. The established method for quantifying bitter compounds in I. vestita fruit was validated, yielding satisfactory parameters for linearity, stability, and accuracy. Idescarpin (17.71-101.05 mg/g) and idesin (7.88-77.14 mg/g) were the predominant bitter compounds in terms of content. Taste activity values (TAVs) exceeded 10 for the bitter substances, affirming their pivotal role as major contributors to overall bitterness of I. vestita fruit. Notably, idescarpin with the highest TAV, played a crucial role in generating the bitterness of I. vestita fruit. Hydrogen bonds and hydrophobic interactions were the main driving forces. This study holds potential implications for industrial development of I. vestita fruit by providing novel insights into the mechanism underlying its bitterness formation.

Sitagliptin synergizes 5-fluorouracil efficacy in colon cancer cells through MDR1-mediated flux impairment and down regulation of NFκB2 and p-AKT survival proteins.

5-fluorouracil (5-FU) is an inexpensive treatment for colon cancer; however, its efficacy is limited by chemoresistance. This study investigates the combination therapy approach of 5-FU with Sitagliptin (Sita), a diabetic drug with potential cancer-modulating effects. The combination was evaluated in vitro and in silico, focusing on the effects of Sita and 5-FU on colon cancer cells. The results showed that the addition of Sita significantly decreased the IC50 of 5-FU compared to 5-Fu monotherapy. The study also found that Sita and 5-FU interact synergistically, with a combination index below 1. Sita successfully lowered the 5-FU dosage reduction index, decreasing the expression of MDR1 mRNA and p-AKT and NFκB2 subunits p100/p52 protein. Molecular docking analyses confirmed Sita's antagonistic action on MDR1 and thymidylate synthase proteins. The study concludes that sitagliptin can target MDR1, increase apoptosis, and significantly reduce the expression of p-AKT and NFκB2 cell-survival proteins. These effects sensitize colon cancer cells to 5-FU. Repurposing sitagliptin may enhance the anticancer effects of 5-FU at lower dosages.

Assessment of the Aryl Hydrocarbon Receptor-Mediated Effects of Aromatic Sensitizers in Paper Recycling Effluent Employing Zebrafish Embryos and in Silico Docking.

Aromatic sensitizers and related substances (SRCs), which are crucial in the paper industry for facilitating color-forming and color-developing chemical reactions, inadvertently contaminate effluents during paper recycling. Owing to their structural resemblance to endocrine-disrupting aromatic organic compounds, concerns have arisen about potential adverse effects on aquatic organisms. We focused on SRC effects via the aryl hydrocarbon receptor (AHR), employing molecular docking simulations and zebrafish (Danio rerio) embryo exposure assessments. Molecular docking revealed heightened binding affinities between certain SRCs in the paper recycling effluents and zebrafish Ahr2 and human AHR, which are pivotal components in the SRC toxicity mechanism. Fertilized zebrafish eggs were exposed to SRCs for up to 96 h post fertilization; among these substances, benzyl 2-naphthyl ether (BNE) caused morphological abnormalities, such as pericardial edema and shortened body length, at relatively low concentrations (1 µM) during embryogenesis. Gene expression of cytochrome P450 1A (cyp1a) and ahr2 was also significantly increased by BNE. Co-exposure to the AHR antagonist CH-223191 only partially mitigated BNE's phenotypic effects, despite the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin being relatively well restored by CH-223191, indicating BNE's AHR-independent toxic mechanisms. Furthermore, some SRCs, including BNE, exhibited in silico binding affinity to the estrogen receptor and upregulation of cyp19a1b gene expression. Therefore, additional insights into the toxicity of SRCs and their mechanisms are essential. The present results provide important information on SRCs and other papermaking chemicals that could help minimize the environmental impact of the paper industry. Environ Toxicol Chem 2024;00:1-13. © 2024 SETAC.

Anti-oxidant activity of 1-(1H-imidazo[4,5-c]pyridin-4-yl)ethenone, a Maillard reaction product derived from fructose and histidine.

BACKGROUND: The Maillard reaction involves the interaction of various amino acids and reducing sugars, resulting in food browning. It often produces appealing aromas and flavors. The complexities of the reaction are such that it can be challenging to identify the often numerous and frequently volatile products formed by it. In the present study, we sought to identify and evaluate an unusual product with anti-oxidant activity arising from a fructose-histidine Maillard reaction model. The anti-oxidant profile of this product was assessed by computational means. RESULTS: The fructose-histidine Maillard reaction products (FH-MRPs) were generated by heating a 2:1 mixture of the sugar and the amino acid at 140 °C for 2 h. Chromatographically separable fractions, labelled DM-1 to DM-8, were obtained using silica gel as the stationary phase and dichloromethane/methanol (DCM/MeOH) mixtures as the mobile one. Fraction DM-5 exhibited the highest 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, and further bio-assay guided fractionation led to isolation and identification of 1-(1H-imidazo[4,5-c]pyridin-4-yl)ethenone (IMPE) as the active principal, the structure of which was established by nuclear magnetic resonance (NMR) spectroscopic and mass spectral techniques. A mechanism for the formation of IMPE from its precursors is proposed. Density functional theory (DFT) calculations suggest this novel heterocyclic compound exerts its anti-oxidant effects by interacting with DPPH and 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals. Essentially, IMPE was non-toxic below 300 ug mL-1, showing a concentration-dependent free radical clearance capacity and reducing power within the 100-1000 µg mL-1 range, and moreover, exhibiting significant Fe2+ chelating abilities wihin the 50-200 µg mL-1 range. CONCLUSION: This study identified the unique FH-MRP, IMPE, and found that it acts as food antioxidant through the chelation of metal ions. © 2024 Society of Chemical Industry.

The immunotherapy mechanism of Hedyotis Diffusae Herba in treating liver cancer: a study based on network pharmacology, bioinformatics, and experimental validation.

Liver cancer is a malignant tumor that develops on or inside the liver. Hedyotis diffusa Willd (HDW) plays a significant role in anti-tumor activities; however, its mechanism against liver cancer remains unclear. This study aims to evaluate the immunotherapeutic mechanism of HDW in treating liver cancer through network pharmacology, bioinformatics analysis, and experimental validation. Network pharmacology was utilized to identify the active components and potential targets of HDW from the TCMSP database. A potential target protein-protein interaction (PPI) network was constructed using the STRING database, followed by function and pathway enrichment analysis of the targets using GO and KEGG methods. In addition, the key targets for HDW against liver cancer were identified using five different algorithms in Cytoscape. The TCGA and HPA databases were used to assess the mRNA and protein expression of core target genes in normal liver and liver cancer tissues and their relationship with overall survival in liver cancer, as well as their role in immune infiltration. Molecular docking between the core components of HDW and the core targets was performed using PyMOL software. The effects of HDW on the proliferation and apoptosis of liver cancer cells were examined using MTT and flow cytometry. The regulatory effects of the core component quercetin on core targets were validated using RT-qPCR and Western blot. A total of 163 potential targets were identified by searching for intersections among 7 types of active components and all potential and liver cancer targets. PPI network analysis revealed the core targets IL6 and TNF. GO enrichment analysis involved 2089 biological processes, 76 cellular components, and 196 molecular functions. KEGG enrichment analysis suggested that the anti-cancer effects of HDW might be mediated by the AGE-RAGE signaling pathway, IL-17 signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway, and NF-κB signaling pathway. Database validation of key targets showed that mRNA and protein expression results for the IL6 gene were contradictory, while those for the TNF gene were consistent, both being underexpressed in liver cancer. Importantly, the expression of IL6 and TNF was related to the infiltration of 24 types of immune cells, with the highest correlation with macrophages. Molecular docking showed that IL6 and TNF had high binding stability with quercetin, with binding energies of - 7.4 and - 6.0 kJ∙mol-1, respectively. Experimental validation showed that quercetin inhibited liver cancer cell proliferation and promoted apoptosis in a dose-dependent manner, with protein results indicating that quercetin downregulated the mRNA and protein expression of IL6 and TNF, and upregulated key proteins in the AGE-RAGE signaling pathway, AGEs, and RAGE. This study comprehensively elucidates the activity, potential targets, and molecular mechanisms of HDW against liver cancer, providing a promising strategy for the scientific basis and treatment mechanism of traditional Chinese medicine in treating liver cancer.

Exploring essential oil-based bio-composites: molecular docking and in vitro analysis for oral bacterial biofilm inhibition.

Oral bacterial biofilms are the main reason for the progression of resistance to antimicrobial agents that may lead to severe conditions, including periodontitis and gingivitis. Essential oil-based nanocomposites can be a promising treatment option. We investigated cardamom, cinnamon, and clove essential oils for their potential in the treatment of oral bacterial infections using in vitro and computational tools. A detailed analysis of the drug-likeness and physicochemical properties of all constituents was performed. Molecular docking studies revealed that the binding free energy of a Carbopol 940 and eugenol complex was -2.0 kcal/mol, of a Carbopol 940-anisaldehyde complex was -1.9 kcal/mol, and a Carbapol 940-eugenol-anisaldehyde complex was -3.4 kcal/mol. Molecular docking was performed against transcriptional regulator genes 2XCT, 1JIJ, 2Q0P, 4M81, and 3QPI. Eugenol cinnamaldehyde and cineol presented strong interaction with targets. The essential oils were analyzed against Staphylococcus aureus and Staphylococcus epidermidis isolated from the oral cavity of diabetic patients. The cinnamon and clove essential oil combination presented significant minimum inhibitory concentrations (MICs) (0.0625/0.0312 mg/mL) against S. epidermidis and S. aureus (0.0156/0.0078 mg/mL). In the anti-quorum sensing activity, the cinnamon and clove oil combination presented moderate inhibition (8 mm) against Chromobacterium voilaceum with substantial violacein inhibition (58% ± 1.2%). Likewise, a significant biofilm inhibition was recorded in the case of S. aureus (82.1% ± 0.21%) and S. epidermidis (84.2% ± 1.3%) in combination. It was concluded that a clove and cinnamon essential oil-based formulation could be employed to prepare a stable nanocomposite, and Carbapol 940 could be used as a compatible biopolymer.

Residue profiles of peptides with cholesterol esterase and pancreatic lipase inhibitory activities through virtual screening and sequence analysis.

The detailed characterization of the structural features of peptides targeting cholesterol esterase (CEase) or pancreatic lipase (PPL) will benefit the management of hyperlipidemia and obesity. This study employed the Glide SP (standard precision)-peptide method to predict the binding modes of 202 dipeptides and 203 tripeptides to these targets, correlating residue composition and position with binding energy. Strong preferences for Trp, Phe, and Tyr were observed at all positions of potential inhibitory peptides, whereas negatively charged residues Glu and Asp were disfavored. Notably, Arg and aromatic rings significantly influenced the peptide conformation at the active site. Tripeptide IWR demonstrated the high efficacy, with IC50 values of 0.214 mg/mL for CEase and 0.230 mg/mL for PPL. Five novel IWR scaffold-tetrapeptides exhibited promising inhibitory activity. Non-covalent interactions and energy contributions dominated the formation of stable complexes. Our results provide insights for the development of new sequences or peptide-like molecules with enhanced inhibitory activity.

Modulation of energetic and lipid pathways by curcumin as a potential chemopreventive strategy in human prostate cancer cells.

In Western industrialized countries, prostate cancer (PCa) is the second most common malignant disease and prevalent cause of death for men. Epidemiological studies have shown that curcumin (CUR) either prevents PCa initiation or delays its progression to a more aggressive and treatment-refractory form, thus reducing related mortality. Our previous studies have proven the anticancer, antioxidant, and anti-inflammatory properties of CUR on PCa cells. However, there are few reports of the effect of CUR on energy and lipid pathways in PCa. Herein, we show that CUR can modulate the two metabolic energy pathways, increasing glycolytic reserve and reducing oxidative phosphorylation. Moreover, through the regulation of key enzymes and proteins, CUR affected the lipid pathway in PC-3 to a greater extent compared to the healthy PNT-2 cells. According to molecular docking investigations, the CUR activity in PCa may be mediated by the direct binding to the pyruvate dehydrogenase (PDHA1) enzyme, which is essential for regulating the appropriate mitochondrial activity. Taken together, our results shed light on the mechanism of action of CUR in the PCa cell metabolism and provide evidence of its potential value as an anticancer metabolic modulator, paving opportunities for novel therapeutic strategies.

Preparation, characterization, and mechanism of DPP-IV inhibitory peptides derived from Bactrian camel milk.

In this study, double enzyme hydrolysis significantly enhanced the DPP-IV inhibition rate compared to single enzyme. The α + K enzymes exhibited the highest inhibition rate. Ultrasonic pretreatment for 30 min improved the hydrolysis efficiency and DPP-IV inhibition rate, potentially due to the structural changes in hydrolysates, such as the increased surface hydrophobicity, and reduced particle size, α-helix and ß-turn. Six peptides were screened and verified in vitro. QPY, WPEYL, and YPPQVM displayed competitive inhibition, while LPAAP and IPAPSFPRL displayed mixed competitive/non-competitive inhibition. The interactions between these six peptides and DPP-IV primarily occurred through hydrogen bonds, electrostatic and hydrophobic interactions. Network pharmacological analysis indicated that LPAAP might inhibit DPP-IV activity trough interactions with diabetes-related targets such as CASP3, HSP90AA1, MMP9, and MMP9. These results uncover the potential mechanism of regulating blood glucose by camel milk hydrolysates, establishing camel milk peptide as a source of DPP-IV inhibitory peptide.

Analysis of the prognostic value of mitochondria-related genes in patients with acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) is a leading cause of death worldwide. Mitochondrial dysfunction is a key determinant of cell death post-AMI. Preventing mitochondrial dysfunction is thus a key therapeutic strategy. This study aimed to explore key genes and target compounds related to mitochondrial dysfunction in AMI patients and their association with major adverse cardiovascular events (MACE). METHODS: Differentially expressed genes in AMI were identified from the Gene Expression Omnibus (GEO) datasets (GSE166780 and GSE24519), and mitochondria-related genes were obtained from MitoCarta3.0 database. By intersection of the two gene groups, mitochondria-related genes in AMI were identified. Next, the identified genes related to mitochondria were subject to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. Protein-protein interaction (PPI) network was constructed, and key genes were screened. Then, targeted drug screening and molecular docking were performed. Blood samples from AMI patients and healthy volunteers were analyzed for the key genes expressions using quantitative real time polymerase chain reaction (qRT-PCR). Later, receiver operating characteristic (ROC) curves assessed the diagnostic value of key genes, and univariate and multivariate COX analyses identified risk factors and protective factors for MACE in AMI patients. RESULTS: After screening and identification, 138 mitochondria-related genes were identified, mainly enriched in the processes and pathways of cellular respiration, redox, mitochondrial metabolism, apoptosis, amino acid and fatty acid metabolism. According to the PPI network, 5 key mitochondria-related genes in AMI were obtained: translational activator of cytochrome c oxidase I (TACO1), cytochrome c oxidase subunit Va (COX5A), PTEN-induced putative kinase 1 (PINK1), SURF1, and NDUFA11. Molecular docking showed that Cholic Acid, N-Formylmethionine interacted with COX5A, nicotinamide adenine dinucleotide + hydrogen (NADH) and NDUFA11. Subsequent basic experiments revealed that COX5A and NDUFA11 expressions were significantly lower in the blood of patients with AMI than those in the corresponding healthy volunteers; also, AMI patients with MACE had lower COX5A and NDUFA11 expressions in the blood than those without MACE (P < 0.01). ROC analysis also showed high diagnostic value for COX5A and NDUFA11 [area under the curve (AUC) > 0.85]. In terms of COX results, COX5A, NDUFA11 and left ventricular ejection fraction (LVEF) were protective factors for MACE in AMI, while C-reactive protein (CRP) was a risk factor. CONCLUSION: COX5A and NDUFA11, key mitochondria-related genes in AMI, may be used as biomarkers to diagnose AMI and predict MACE.

In silico and ADMET molecular analysis targeted to discover novel anti-inflammatory drug candidates as COX-2 inhibitors from specific metabolites of Diospyros batokana (Ebenaceae).

Diospyros batokana (Ebenaceae) is a valuable medicinal plant that grows in the wild in Zambia. The aqua crude plant extract is valuable in treating oxidative stress and microbes-related diseases. In this study, bioactive metabolites from the leaf of the plant were tentatively identified using ultra-high-pressure liquid chromatography tandem high-resolution mass spectrometry (UHPLC-HRMS). Raw LCMS data were processed using MZmine3.6. Pyrenophorol, N-[1-(diethylamino)-3-morpholin-4-ylpropan-2-yl]-2,2-diphenylacetamide, losartan, and isoarthonin, (2E,4E)-N-[2-(4-hydroxyphenyl)ethyl]dodeca-2,4-dienamide were among the many metabolites identified from the plant studied using LCMS-MZmine 3.6. Furthermore, in silico anti-inflammatory molecular docking was applied to the five (5) metabolites with the aim of predicting the ability of the metabolites to inhibit the COX-2 enzyme. The docking simulation for the five metabolites was executed using the Auto-dock tools. The lowest binding energy of the complexes was visualized using Discovery Studio, 2021 Client l molecular viewer. Pyrenophorol, (N-[1-(diethylamino)-3-morpholin-4-ylpropan-2-yl] -2,2-diphenylacetamide) and losartan were found to provide the lowest binding energy to COX-2 compared to the standard anti-inflammatory drug, diclofenac. Furthermore, binding affinities, inhibition constants, and ligand efficiencies demonstrated that pyrenophorol, N-[1-(diethylamino)-3-morpholin-4-ylpropan-2-yl]-2,2-diphenylacetamide, losartan, isoarthonin and (2E,4E)-N-[2-(4-hydroxyphenyl)ethyl]dodeca-2,4-dienamide could be useful as anti-inflammatory drug candidates supporting the traditional uses of D. batokana. However, the bioavailability radar and physicochemical properties only predict losartan, pyrenophorol, and (2E,4E)-N-[2-(4-hydroxyphenyl)ethyl]dodeca-2,4-dienamide to be bioavailable and suitable drug candidates. In silico and ADMET analysis, shows that the five metabolites could be used as anti-inflammatory drugs comparable to the standard drugs, diclofenac and ibuprofen. However, in vitro and in vivo studies are needed to further support our findings.

Understanding the Molecular Landscape of Endometriosis: A Bioinformatics Approach to Uncover Signaling Pathways and Hub Genes.

Background: Endometriosis is a chronic gynecological disorder characterized by the ectopic growth of endometrial tissue outside the uterus, leading to debilitating pain and infertility in affected women. Despite its prevalence and clinical significance, the molecular mechanisms underlying the progression of endometriosis remain poorly understood. This study employs bioinformatics tools and molecular docking simulations to unravel the intricate genetic and molecular networks associated with endometriosis progression. Objectives: The primary objectives of this research are to identify differentially expressed genes (DEGs) linked to endometriosis, elucidate associated biological pathways using the Database for Annotation, Visualization, and Integrated Discovery (DAVID), construct a Protein-Protein Interaction (PPI) network to identify hub genes, and perform molecular docking simulations to explore potential ligand-protein interactions associated with endometriosis. Methods: Microarray data from Homo sapiens, specifically Accession: GDS3092 Series = GSE5108 (Platform: GPL2895), were retrieved from the NCBI Gene Expression Omnibus (GEO). The data underwent rigorous preprocessing and DEG analysis using NCBI GEO2. Database for Annotation, Visualization, and Integrated Discovery analysis was employed for functional annotation, and a PPI network was constructed using the STITCH database and Cytoscape 3.8.2. Molecular docking simulations against target proteins associated with endometriosis were conducted using MVD 7.0. Results: A total of 1 911 unique elements were identified as DEGs associated with endometriosis from the microarray data. Database for Annotation, Visualization, and Integrated Discovery analysis revealed pathways and biological characteristics positively and negatively correlated with endometriosis. Hub genes, including BCL2, CCNA2, CDK7, EGF, GAS6, MAP3K7, and TAB2, were identified through PPI network analysis. Molecular docking simulations highlighted potential ligands, such as Quercetin-3-o-galactopyranoside and Kushenol E, exhibiting favorable interactions with target proteins associated with endometriosis. Conclusions: This study provides insights into the molecular signatures, pathways, and hub genes associated with endometriosis. Utilizing DAVID in this study clarifies biological pathways associated with endometriosis, revealing insights into intricate genetic networks. Molecular docking simulations identified ligands for further exploration in therapeutic interventions. The consistent efficacy of these ligands across diverse targets suggests broad-spectrum effectiveness, encouraging further exploration for potential therapeutic interventions. The study contributes to a deeper understanding of endometriosis pathogenesis, paving the way for targeted therapies and precision medicine approaches to improve patient outcomes. These findings advance our understanding of the molecular mechanisms in endometriosis (EMS), offering promising avenues for future research and therapeutic development in addressing this complex condition.

Causal relationship between complement C1QB and colorectal cancer: a drug target Mendelian randomization study.

Background: Colorectal cancer is influenced by several factors such as unhealthy habits and genetic factors. C1QB has been linked to a number of malignancies. However, uncertainty surrounds the connection between C1QB and CRC. Therefore, this study aimed to explore a bidirectional causal relationship of C1QB as a drug target in CRC through Mendelian randomization (MR) analysis. Methods: The GWASs for C1QB and CRC were obtained from the Integrative Epidemiology Unit Open GWAS database. There were five strategies to investigate MR. Sensitivity analysis was carried out via tests for heterogeneity, horizontal pleiotropy and leave-one-out effects to evaluate the dependability of the MR analysis results. Furthermore, colocalization analysis of C1QB and CRC, protein-protein interaction network and drug prediction according to exposure factors as well as phenotype scanning were performed. Results: The results of forward MR analysis demonstrated that C1QB was a risk factor for CRC (OR = 1.104, p = 0.033). However, we did not find a causal relationship between CRC and C1QB (reverse MR). Rs294180 and rs291985 corresponded to the same linkage interval and had the potential to influence C1QB and CRC, respectively. The PPI results demonstrated that C1QB interacted with 10 genes (C1QA, C1QC, C1R, C1S, C2, C4A, C4B, CALR, SERPING1, and VSIG4). Additionally, 21 medications were predicted to match C1QB. Molecular docking data, including for benzo(a)pyrene, 1-naphthylisothiocyanate, calcitriol and medroxyprogesterone acetate, revealed excellent binding for drugs and proteins. Moreover, we identified 29 diseases that were associated with C1QB and related medicines via disease prediction and intersection methods. As a therapeutic target for CRC, phenotypic scanning revealed that C1QB does not significantly affect weight loss, liver cirrhosis, or nonalcoholic fatty liver disease, but might have protective impacts on ovarian cancer and melanoma. Conclusion: The results highlight a causal relationship between C1QB and CRC and imply an oncogenic role for C1QB in CRC, as potential drug targets. Drugs designed to target C1QB have a greater chance of success in clinical trials and are expected to help prioritize CRC drug development and reduce drug development costs. That provided a theoretical foundation and reference for research on CRC and C1QB in MR.

Synthesis, characterization, and mechanistic insights into the enhanced anti-inflammatory activity of baicalin butyl ester via the PI3K-AKT pathway.

Objective: To investigate the anti-inflammatory activity and mechanism of Baicalin derivative (Baicalin butyl ester, BE). Methods: BE was synthesized and identified using UV-Vis spectroscopy, FT-IR spectroscopy, mass spectrometry (MS) and high-performance liquid chromatography (HPLC) methods. Its anti-inflammatory potential was explored by an in vitro inflammation model. Network pharmacology was employed to predict the anti-inflammatory targets of BE, construct protein-protein interaction (PPI) networks, and analysis topological features and KEGG pathway enrichment. Additionally, molecular docking was conducted to evaluate the binding affinity between BE and its core targets. qRT-PCR analysis was conducted to validate the network pharmacology results. The organizational efficiency was further evaluated through octanol-water partition coefficient and transmembrane activity analysis. Results: UV-Vis, FT-IR, MS, and HPLC analyses confirmed the successfully synthesis of BE with a high purity of 93.75%. In vitro anti-inflammatory research showed that BE could more effectively suppress the expression of NO, COX-2, IL-6, IL-1ß, and iNOS. Network pharmacology and in vitro experiments validated that BE's anti-inflammatory effects was mediated through the suppression of SRC, HSP90AA1, PIK3CA, JAK2, AKT1, and NF-κB via PI3K-AKT pathway. Molecular docking results revealed that the binding affinities of BA to the core targets were lower than those of BE. The Log p-value of BE (1.7) was markedly higher than that of BA (-0.5). Furthermore, BE accumulated in cells at a level approximately 200 times greater than BA. Conclusion: BE exhibits stronger anti-inflammatory activity relative to BA, possibly attributed to its better lipid solubility and cellular penetration capabilities. The anti-inflammatory mechanism of BE may be mediated through the PI3K-AKT pathway.

Thiazolo-pyridopyrimidines: An in silico evaluation as a lead for CDK4/6 inhibition, synthesis and cytotoxicity screening against breast cancer cell lines.

Introduction: Pyridopyrimidines belong to a class of compounds characterized by the presence of nitrogen as heteroatoms. These compounds exhibit diverse biological effects, particularly showing promise as anticancer agents, including actions that inhibit CDK4/6. Methods: We designed and synthesized a range of substituted thiazolo-pyridopyrimidines (4a-p). Computational ADME/T analysis and molecular docking were performed using the crystal structure of CDK4/6. Subsequently, we synthesized the top-scoring compounds, characterized them using IR, NMR, and Mass spectroscopy, and assessed their impact on MCF-7 and MDAMB-231 cell lines using the SRB assay. To further evaluate stability, molecular dynamics simulations were conducted for the two most promising compounds within the binding site. Results: The docking scores indicated stronger interactions for compounds 4a, 4c, 4d, and 4g. As a result, these specific compounds (4a, 4c, 4d, and 4g) were chosen for synthesis and subsequent screening to assess their cytotoxic effects. Remarkably, compounds 4c and 4a exhibited the most promising activity in terms of their IC50 values across both tested cell lines. Furthermore, molecular dynamics simulation studies uncovered an elevated level of stability within the 4c-6OQO complex. Conclusion: By integrating insights from computational, in vitro, and molecular dynamics simulation findings, compound 4c emerges as a leading candidate for future investigations. The presence of a polar hydroxyl group at the C2 position of the 8-phenyl substitution on the pyridopyrimidine rings appears to contribute to the heightened activity of the compound. Further enhancements to cytotoxic potential could be achieved through structural refinements.

From waste to wonder: exploring the hypoglycemic and anti-oxidant properties of corn processing by-products.

Introduction: The industrial processing of corn (Zeamays L.) generates by-products such as corn silk, straw peels, and straw core, which contribute to adverse environmental impacts. Our study aimed to investigate sustainable approaches for mitigating these effects by evaluating the hypoglycemic potential and mechanisms of ethyl acetate fractions derived from these corn derivatives. Methods: We employed glucose consumption assays, high glucose stress tests, UPLC-QE-Orbitrap-MS analysis, molecular docking, and simulations to assess their components and efficacy. Antioxidant capacities were evaluated using DPPH, FRAP, ABTS, and •OH scavenging assays. Results: Notably, the ethyl acetate fraction extracted from straw peels (SPE) exhibited a high concentration of flavonoids and phenolic compounds along with pronounced hypoglycemic activity and antioxidant capacity. SPE significantly enhanced glucose consumption in insulin-resistant HepG2 cells while protecting HUVECs against damage caused by high glucose levels. Molecular docking analyses confirmed the interaction between active compounds and α-glucosidase as well as α-amylase, while molecular dynamic simulations indicated stability at their binding sites. Discussion: In conclusion, the hypoglycemic and antioxidative properties observed in corn by-products such as straw peels, corn silk, and straw core can be attributed to the inhibition of α-glucosidase and α-amylase activities, coupled with their rich phenolic and flavonoid content. These findings highlight the potential of these by-products for applications in healthcare management and their sustainable utilization, demonstrating significant value in the use of agricultural residues.

A novel ACE inhibitory peptide from Douchi hydrolysate: Stability, inhibition mechanism, and antihypertensive potential in spontaneously hypertensive rats.

Angiotensin I-converting enzyme (ACE) regulates blood pressure through the renin-angiotensin system. Douchi, a traditional fermented soybean condiment, may have antihypertensive effects, but research on ACE inhibitory peptides from Douchi hydrolysates is limited. We hypothesized that enzymatic treatment could enhance ACE inhibitory peptide diversity and efficacy. We tested ten single enzymes and four combinations, finding pepsin-trypsin-chymotrypsin most effective. Hydrolysates were purified using Sephadex G-15 and reversed-phase HPLC, and peptides were identified via LC-MS/MS. Five peptides (LF, VVF, VGAW, GLFG, NGK) were identified, with VGAW as the most potent ACE inhibitor (IC50 46.6 ± 5.2 µM) showing excellent thermal and pH stability. Lineweaver-Burk plots confirmed competitive inhibition, and molecular docking revealed eight hydrogen bonds between VGAW and ACE. In hypertensive rats, VGAW significantly reduced blood pressure at 12.5, 25, and 50 mg/kg. These findings highlight Douchi as a source of ACE inhibitory peptides and suggest VGAW as a promising functional food ingredient.

Investigating the anticancer properties of six benzothiazolopyrimidine derivatives on colon carcinoma cells, in vitro and in vivo.

Colorectal cancer (CRC) is the third most common cancer in the world. Despite considerable improvements in the treatment of this cancer, further research to discover novel and more effective agents is ongoing. In this study, possible cytotoxic and apoptotic properties of six benzothiazolopyrimidine derivatives were studied. To assess the IC50 values of these agents, MTT assay was performed on HCT 116, CT26, and NIH/3T3 cells. Moreover, cell death mechanism induced by studied compounds was evaluated by PI/annexin V staining. Then, based on molecular docking results and in vitro experiments, the compounds with the highest anticancer properties were further analyzed in vivo in a mouse model of CRC. MTT results indicated that BTP(1) and BTP(4) had the highest selective cytotoxicity on colorectal cancer cells. Furthermore, flow cytometry results demonstrated a considerable increase in the percentage of the early apoptotic cells in BTP(1)- and BTP(4)-treated groups. In vivo studies confirmed the antitumor properties of the two compounds by a significant regression in tumor size of BTP(1)- and BTP(4)-treated mice compared to control groups. Histopathological examination of tumor tissues showed an increased number of apoptotic cells in these two groups compared to the control animals. Additionally, hematoxylin and eosin staining of the spleen and liver of treated mice did not exhibit considerable tissue damage. Thus, BTP(1) and BTP(4) can be considered promising agents in the treatment of colorectal cancer, although further experiments are required to assess their mechanism of action before their application in clinical studies.