Current Pharmaceutical Design - Volume 30, Issue 42, 2024

Intestinal dysfunction plays an important role in the clinical progress and prognosis of severe acute pancreatitis (SAP). Qingyi decoction (QYD) has shown beneficial effects on intestinal function recovery, but the prevention actions of the QYD on intestinal paralysis and its mechanism have not been fully explored.

The possible molecular mechanism was unraveled by network pharmacology, including active ingredients and potential target prediction, as well as GO, KEGG, and REATCOME pathway enrichment analyses. The potential interactions between the main active ingredients of the QYD and core genes were explored by molecular docking. A retrospective cohort study on 137 patients with SAP from Tianjin Nankai Hospital was conducted to evaluate the preventive effect of QYD on intestinal paralysis.

A total of 110 active ingredients in QYD were screened out, and 37 key targets were predicted by network pharmacology. GO, KEGG, and REATCOME enrichment analyses showed that bioinformatics annotation of the hub genes was mainly involved in intestinal epithelial functions and inflammatory response pathways. The main components of QYD possessed good affinity with IL-6, TNF, CASP3, CXCL8, and CRP by molecular docking. Patients who used QYD plus usual care seemed to have fewer intestinal paralysis rates, lower risk of renal insufficiency, ARDS and blood purification therapy, and shorter hospital and ICU stays. The multivariable regression analyses indicated that the mode of nasogastric and enemas administration of QYD (P = 0.010) and timely intervention with QYD (P = 0.045) were the independent protective factors for intestinal paralysis prevention in patients with SAP.

In conclusion, QYD can be used as an effective adjuvant procedure to prevent the occurrence and development of intestinal paralysis in patients with SAP. The mechanisms may be involved in the anti-inflammatory response and maintenance of intestinal epithelial function.

Microvascular dysfunction develops in tissues after Ischemia-Reperfusion (IR). The current study aimed to determine the effect of naringin supplementation on kidney caspase-3, IL-1β, and HIF-1α levels and kidney histology in rats undergoing unilateral nephrectomy and kidney-ischemia reperfusion.

The study was conducted on 8-12 weeks old 40 Wistar-type male rats. Experimental renal ischemia-reperfusion and unilateral nephrectomy were performed under general anesthesia in rats. Experimental groups were formed as follows: 1-Control group, 2-Sham control + Vehicle group, 3- Renal ischemia-reperfusion (Renal I+R) + Vehicle group, 4-Renal I+R + Naringin (50 mg/kg/day) group (3 days application) group, 5-Renal I+R + Naringin (100 mg/kg/day) group (3 days supplementation). Nephrectomy in the left kidneys and the ischemia for 45 minutes and reperfusion in the right kidneys followed by 72 hours of reperfusion. Naringin was administered intraperitoneally at the beginning of the reperfusion, 24 hours and 48 hours later. At the end of the experiments, blood was first taken from the heart in animals under general anesthesia. Then, the animals were killed by cervical dislocation, and kidney tissue samples were taken. Tissues were evaluated for caspase-3, IL-1β, and HIF-1α as well as histologically.

As a result of ischemia in kidney tissues, HIF-1α decreased, while caspase-3 and IL-1β increased. IR also caused damage to the kidney tissue. However, naringin supplementation corrected the deterioration to a certain extent.

The results of the study showed that naringin may have protective effects on kidney damage due to anti-inflammatory and antiapoptosis mechanisms caused by unilateral nephrectomy and IR in rats.

We synthetized 10 hydroxylated and methoxylated chalcones and evaluated them targeting MMP-9 inhibition, looking for the rate of adhesion of H. pylori in gastric cells, and then, reduction of the inflammatory response as alternative therapeutic agents for controlling the infection.

Helicobacter pylori is a Gram-negative bacterium that chronically infects the human stomach, a risk factor for the development of inflammatory gastrointestinal diseases, including cancer, and is classified as a group I carcinogen. It is estimated that it infects around 45% of the global population and that the persistence of the infection is related to the adhesion of the bacteria in the gastric epithelium. The progression of gastric lesions to cancer is connected to the activation of the NF-κB and MAPK pathways, especially in cagA+ strains, which are related to increased expression of MMP-9. The activation of these metalloproteinases (MMPs) contributes to the adhesion of the bacterium in gastric cells and the evolving stages of cancer, such as enabling metastasis. Due to the increasing resistance to the current therapy protocols, the search for alternative targets and candidate molecules is necessary. In this way, controlling adhesion seems to be a suitable option since it is a crucial step in the installation of the bacterium in the gastric environment.

Synthetize ten hydroxylated and methoxylated chalcones. Assess their anti-H. pylori potential, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC). Evaluate their cytotoxicity in AGS cells and selectivity with L-929 cells. Analyze the results and correlate them with in silico predictions to evaluate potential anti-adhesive properties for the chalcones against H. pylori.

The chalcones were synthetized by Claisen-Schmidt condensation using Ba(OH)2 or LiOH as catalysts. Predictive in silico assays in PASS Online, tanimoto similarity, ADME properties and molecular docking in MMP-9 (PDB code: 6ESM) were performed. The in vitro assays carried out were the cell viability in gastric adenocarcinoma cells (AGS) and fibroblasts (L-929) by the MMT method and anti-H. pylori, by the broth microdilution method, through the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC).

Ten chalcones were synthesized through Claisen-Schimdt condensation with yields of 10 to 52% and characterized by ¹H and ¹³C nuclear magnetic resonance (NMR) and mass spectrometry (MS). In silico data revealed the possibility of anti-H. pylori, anti-inflammatory, and MMP-9 inhibition for the chalcones. Chalcone 9 showed the best growth inhibition values for MIC and MBC, at 1 μg/mL and 2 μg/mL, respectively. Chalcones 14 and 15 likewise demonstrated excellent inhibitory results, being 2 μg/mL for both MIC and MBC. Additionally, 15 had the best MMP-9 inhibition score. Despite not corroborating the in silico findings, chalcones 10, 13, and 18 showed good cytotoxicity and the best selectivity indices.

All compounds exhibited strong activity against H. pylori, specially 15. The predicted MMP-9 inhibition by molecular docking added to the reasonable SI and CI50 values for 15 and the satisfactory reduction in the rate of survival of the bacteria, reveals that it may be acting synergically to reduce the inflammatory response and the possibilities for developing a tumor by inhibiting both bacteria and malignant cells.

To uncover the potential hub targets of Kunkui Baoshen decoction (KKBS) in alleviating diabetic kidney disease (DKD).

Targets associated with KKBS and DKD were curated from TCMSP, GeneCards, OMIM, and DisGeNET databases. Common targets were identified through intersection analysis using a Venn diagram. Employing the “Drug-component-target” approach and constructing a Protein-protein Interaction (PPI) network, pivotal components and hub targets involved in KKBS's therapeutic action against DKD were identified. Functional enrichment and Gene Set Enrichment Analysis (GSEA) elucidated the potential mechanisms of these hub targets. Molecular docking simulations validated binding interactions. Subsequently, hub targets were validated using independent cohorts and clinical datasets. Immune cell infiltration in DKD samples was assessed using ESTIMATE, CIBERSORT, and IPS algorithms. A nomogram was developed to predict DKD prevalence. Finally, causal relationships between hub targets and DKD were explored through Mendelian randomization (MR) analysis at the genetic level.

Jaranol, isorhamnetin, nobiletin, calycosin, and quercetin emerged as principal effective components in KKBS, with predicted modulation of the PI3K/Akt, MAPK, HIF-1, NF-kB, and IL-17 signaling pathways. The hub targets in the PPI network include proteins involved in regulating podocyte autophagy and apoptosis, managing antioxidant stress, contributing to insulin resistance, and participating in extracellular matrix deposition in DKD. Molecular docking affirmed favorable binding interactions between principal components and hub targets. Validation efforts across cohorts and databases underscored the potential of hub targets as DKD biomarkers. Among 20 model algorithms, the Extra Tree model yielded the largest Area Under the Curve (AUC) in receiver operating characteristic (ROC) analysis. MR analysis elucidated that the targets related to antioxidant stress had a positive impact on DKD, while the target associated with renal tubular basement membrane degradation had a negative impact.

Integration of Network Pharmacology, Bioinformatics, and MR analysis unveiled the capacity of KKBS to modulate pivotal targets in the treatment of DKD.