Vol 27, No 11 (2024)
- Year: 2024
- Articles: 10
- URL: https://rjpbr.com/1386-2073/issue/view/9952
Chemistry
A Comprehensive Review on Biotransformation, Interaction, and Health of Gut Microbiota and Bioactive Components
Abstract
Background::The relationship between gut microbiota and bioactive components has become the research focus in the world. We attempted to clarify the relationship between biotransformation and metabolites of gut microbiota and bioactive components, and explore the metabolic pathway and mechanism of bioactive ingredients in vivo, which will provide an important theoretical basis for the clinical research of bioactive ingredients and rationality of drugs, and also provide an important reference for the development of new drugs with high bioavailability.
Methods::The related references of this review on microbiota and bioactive components were collected from both online and offline databases, such as ScienceDirect, PubMed, Elsevier, Willy, SciFinder, Google Scholar, Web of Science, Baidu Scholar, SciHub, Scopus, and CNKI.
Results::This review summarized the biotransformation of bioactive components under the action of gut microbiota, including flavonoids, terpenoids, phenylpropanoids, alkaloids, steroids, and other compounds. The interaction of bioactive components and gut microbiota is a key link for drug efficacy. Relevant research is crucial to clarify bioactive components and their mechanisms, which involve the complex interaction among bioactive components, gut microbiota, and intestinal epithelial cells. This review also summarized the individualized, precise, and targeted intervention of gut microbiota in the field of intestinal microorganisms from the aspects of dietary fiber, microecological agents, fecal microbiota transplantation, and postbiotics. It will provide an important reference for intestinal microecology in the field of nutrition and health for people.
Conclusion::To sum up, the importance of human gut microbiota in the research of bioactive components metabolism and transformation has attracted the attention of scholars all over the world. It is believed that with the deepening of research, human gut microbiota will be more widely used in the pharmacodynamic basis, drug toxicity relationship, new drug discovery, drug absorption mechanism, and drug transport mechanism in the future.
1551-1565
Protective Effects of Liriodendrin on Myocardial Infarction-Induced Fibrosis in Rats via the PI3K/Akt Autophagy Pathway: A Network Pharmacology Study
Abstract
Background:Liriodendrin (LIR) has been reported to improve cardiac function in rats following myocardial infarction. However, its role and mechanism in reparative myocardial fibrosis remain unclear.
Methods:In this study, a rat model of myocardial fibrosis was established via left anterior descending artery ligation and randomly divided into three groups (n = 6 per group): sham-operated, myocardial infarction, and LIR intervention (100 mg/kg/day) groups. The pharmacological effects of LIR were assessed using echocardiography, hematoxylin, and eosin (H&E) staining, and Masson staining. Network pharmacology and bioinformatics were utilized to identify potential mechanisms of LIR, which were further validated via western blot analysis.
Results:Our findings demonstrated that LIR improved cardiac function, histology scores, and col lagen volume fraction. Moreover, LIR downregulated the expression of Beclin-1, LC3-II/LC3-I while upregulating the expression of p62, indicating LIR-inhibited autophagy in the heart after myocardial infarction. Further analysis revealed that the PI3K/Akt signaling pathway was significantly enriched and validated by western blot. This analysis suggested that the ratios of p- PI3K/PI3K, p-Akt/Akt, and p-mTOR/mTOR were significantly increased.
Conclusion:LIR may attenuate myocardial infarction-induced fibrosis in rats by inhibiting excessive myocardial autophagy, with the potential mechanism involving the activation of the PI3K/Akt/mTOR pathway.
1566-1575
A Network Pharmacology Approach and Validation Experiments to Investigate the Mechanism of Wen-Dan Decoction in the Treatment of SINFH
Abstract
Introduction::Steroid-induced necrosis of the femoral head (SINFH) is a femoral head necrotic disease caused by prolonged use of hormones. Wen-Dan decoction is used in Chinese clinical practice for the treatment of steroid-induced necrosis of the femoral head (SINFH). However, the mechanism and active compounds of Wen-Dan decoction used to treat SINFH are not well understood.
Objectives::We studied the mechanism of action of Wen-Dan decoction in treating steroidinduced necrosis of the femoral head (SINFH) via network pharmacology and in vivo experiments.
Methods::The active compounds of Wen-Dan decoction and SINFH-related target genes were identified through public databases. Then, network pharmacological analysis was conducted to explore the potential key active compounds, core targets and biological processes of Wen-Dan decoction in SINFH. The potential mechanisms of Wen-Dan decoction in SINFH obtained by network pharmacology were validated through in vivo experiments.
Results::We identified 608 DEGs (differentially expressed genes) (230 upregulated, 378 downregulated) in SINFH. GO analysis revealed that the SINFH-related genes were mainly involved in neutrophil activation and the immune response. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis showed that the SINFH-related genes were mainly associated with cytokine receptor interactions, lipids, atherosclerosis, and tuberculosis. We identified 147 active ingredients of Wen-Dan decoction; the core ingredient was quercetin, and licorice was an active ingredient. Moreover, 277 target genes in the treatment of SINFH with Wen-Dan decoction were identified, and NCF1, PTGS2, and RUNX2 were selected as core target genes. QRT-PCR of peripheral blood from SINFH patients showed higher levels of PGTS2 and NCF1 and showed lower levels of RUNX2 compared to controls. QRT-PCR analysis of peripheral blood and femoral bone tissue from a mouse model of SINFH showed higher levels of PGTS2 and NCF1 and lower levels of RUNX2 in the experimental animals than the controls, which was consistent with the bioinformatics results. HE, immunohistochemistry, and TUNEL staining confirmed a significant reduction in hormone-induced femoral head necrosis in the quercetintreated mice. HE, immunohistochemistry, and TUNEL staining confirmed significant improvement in hormone-induced femoral head necrosis in the quercetin-treated mice.
Conclusion::We provide new insights into the genes and related pathways involved in SINFH and report that PTGS2, RUNX2, and NCF1 are potential drug targets. Quercetin improved SINFH by promoting osteogenesis and inhibiting apoptosis.
1576-1591
The Different Therapeutic Effects of Traditional Chinese Medicine Shensong Yangxin Capsule and Salubrinal in High-intensity Exercise-induced Heart Failure in Rats with Acute Myocardial Infarction
Abstract
Background:Currently, endoplasmic reticulum stress is studied utilizing a dephosphorylation inhibitor (Sal). The traditional Chinese patent medicine and simple formulation Shensong Yangxin Capsule is a commonly used medication for the treatment of arrhythmia. However, the efficacy and underlying mechanism of the capsule in treating post-ischemic heart failure in myocardial tissue have not yet been investigated.
Objective:The therapeutic effects and the underlying mechanism of the Shensong Yangxin Capsule (SSYX) and the dephosphorylation inhibitor Salubrinal (Sal) on heart failure (HF) induced by high-intensity exercise in rats with acute myocardial infarction (AMI) were investigated.
Methods:Male infants of 8 weeks Spragge-Dawley (SD) rats were randomly assigned to one of four groups: sham surgery group, AMI+placebo group, AMI+Shensong Yangxin Capsule group (AMI+SSYX), and AMI+Sal administration group. Rats' myocardial infarction was induced by left coronary artery ligation. Rats were subjected to a 3-week high-intensity exercise program to simulate heart failure after 7 days of postoperative rest. After the fourth postoperative week, echocardiography was applied to determine the left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and left ventricular systolic volume (LVESV) in each group. HE and TUNEL labeling were employed to examine the morphology of cardiac cells and measure the percentage of apoptosis in each group; Western blotting was applied to detect the cardiomyocyte apoptosis-related proteins p-JNK, p-P38, and NOX2, while ELISA was used to detect glutathione(GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) in serum.
Results:Following a 4-week drug intervention:(1)LVFS and LVEF in the AMI+placebo group were statistically significantly reduced, while LVESV were significantly higher, compared to those in the sham surgery group (P(<0.05); The AMI+SSYX group performed statistically significantly better than the AMI+placebo group(P(<0.05). (2) The myocardial cells in the AMI+placebo group exhibited significant swelling and inflammatory cell infiltration; the myocardial cells in the AMI+SSYX group and AMI+Sal group displayed mild swelling and minimal inflammatory cell infiltration; the AMI+SSYX group's myocardial cell morphology was superior to that of the AMI+Sal group; (3) The apoptosis rate of the AMI+placebo group was around 95%, greater than that of the sham surgery group (2.55%). The apoptosis rate of the AMI+SSYX group is approximately 21%, while the apoptosis rate of the AMI+Sal group is about 43%. (4) In the AMI+placebo group, p-JNK, p-P38, and NOX2 protein expression dramatically increased compared to the sham surgery group. The expression of p-P38, NOX2, and p-JNK/t-JNK was considerably reduced in the AMI+Shensong group and AMI+Sal group， compared to the AMI+placebo group. (P(<0.01)The AMI+SSYX group's result is superior to that of the AMI+Sal group. (5) Compared to the sham surgery group, the serum levels of SOD and GSH were significantly lower, and MDA was significantly higher in the AMI+placebo group. Compared to the AMI+placebo group, the serum levels of SOD and GSH were significantly higher, and MDA was significantly lower in the AMI+SSYX group and the AMI+Sal group. (P(<0.05)
Conclusion:In rats with acute myocardial infarction in high-intensity exercise-induced heart failure, Shensong Yangxin Capsule dramatically reduces myocardial cell death and cardiac dysfunction. SSYX has a shorter course of treatment and a better therapeutic effect than Sal.
1592-1601
Mitigating Effect of Matricin Against Benzo(a)pyrene-induced Lung Carcinogenesis in Experimental Mice Model
Abstract
Background:Lung cancer is a life-threatening disease that is still prevalent worldwide. This study aims to evaluate the effects of matricin, a sesquiterpene, on the carcinogenic agent benzo(a)pyrene [B(a)P]-induced lung cancer in Swiss albino mice.
Methods:Lung cancer was induced by oral administration of B(a)P at 50 mg/kg b. wt. in model Swiss-albino mice (group II) as well in experimental group III, and treated with matricin (100 mg/kg b. wt.) in group III. Upon completion of treatment for 18 weeks, the changes in body weight, tumor formation, enzymatic and non-enzymatic antioxidant levels (GSH, SOD, GPx, GR, QR, CAT), lipid peroxidation (LPO) level, pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), immunoglobulin levels (IgG, IgM), apoptosis markers (Bax, Bcl-xL), tumor markers (carcinoembryogenic antigen (CEA), neuron-specific enolase (NSE)), and histopathological (H&E) alterations were determined.
Results:The results indicate that B(a)P caused a significant increase of tumor formation in the lungs, increased tumor markers and inflammatory cytokines in serum, and depletion of enzymatic/ non-enzymatic antioxidants and immunoglobulins, compared to the untreated control group. Matricin treatment significantly reversed the changes caused by B(a)P as evidenced by the biochemical and histopathological assays.
Conclusion:The changes caused by matricin clearly indicate the cancer-preventive effects of matricin against B(a)P-induced lung cancer in animal models, which can be attributed to the antioxidant activity, immunomodulation, and mitigation of the NF-kβ pathway.
1602-1610
Disulfidptosis-related Protein RPN1 may be a Novel Anti-osteoporosis Target of Kaempferol
Abstract
Background:Osteoporosis (OP) is an age-related skeletal disease. Kaempferol can regulate bone mesenchymal stem cells (BMSCs) osteogenesis to improve OP, but its mechanism related to disulfidptosis, a newly discovered cell death mechanism, remains unclear.
Objective:The study aimed to investigate the biological function and immune mechanism of disulfidptosis- related ribophorin I (RPN1) in OP and to experimentally confirm that RPN1 is the target for the treatment of OP with kaempferol.
Methods:Differential expression analysis was conducted on disulfide-related genes extracted from the GSE56815 and GSE7158 datasets. Four machine learning algorithms identified disease signature genes, with RPN1 identified as a significant risk factor for OP through the nomogram. Validation of RPN1 differential expression in OP patients was performed using the GSE56116 dataset. The impact of RPN1 on immune alterations and biological processes was explored. Predictive ceRNA regulatory networks associated with RPN1 were generated via miRanda, miRDB, and TargetScan databases. Molecular docking estimated the binding model between kaempferol and RPN1. The targeting mechanism of kaempferol on RPN1 was confirmed through pathological HE staining and immunohistochemistry in ovariectomized (OVX) rats.
Results:RPN1 was abnormally overexpressed in the OP cohort, associated with TNF signaling, hematopoietic cell lineage, and NF-kappa B pathway. Immune infiltration analysis showed a positive correlation between RPN1 expression and CD8+ T cells and resting NK cells, while a negative correlation with CD4+ naive T cells, macrophage M1, T cell gamma delta, T cell follicular helper cells, activated mast cells, NK cells, and dendritic cells, was found. Four miRNAs and 17 lncRNAs associated with RPN1 were identified. Kaempferol exhibited high binding affinity (-7.2 kcal/mol) and good stability towards the RPN1. The experimental results verified that kaempferol could improve bone microstructure destruction and reverse the abnormally high expression of RPN1 in the femur of ovariectomized rats.
Conclusion:RPN1 may be a new diagnostic biomarker in patients with OP, and may serve as a new target for kaempferol to improve OP.
1611-1628
On Certain Degree Based and Bond-additive Topological Indices of Dodeca-benzo-circumcorenene
Abstract
Background:Chemical graph theory has been used to mathematically model the various physical and biological aspects of chemical substances. A mathematical formulation that may be applied to any graph and can characterise a molecule structure is known as a topological index or molecular descriptor.
Objective:It is convenient and efficient to analyse the mathematical values and further research on various physical properties of a molecule based on these molecular descriptors. They provide useful alternatives to lengthy, expensive, and labour-intensive laboratory experiments. The topological indices can be used to predict the chemical structures, physicochemical properties, and biological activities using quantitative structure-activity relationships (QSARs) and quantitative structure-property relationships (QSPRs).
Result:In this study, the molecular descriptors of the Dodeca-benzo-circumcorenene compounds are derived based on their corresponding molecular structures.
Conclusion:The computed indices are then compared graphically to study their relationship with the molecular structure and with each other.
1629-1641
DPP2/7 is a Potential Predictor of Prognosis and Target in Immunotherapy in Colorectal Cancer: An Integrative Multi-omics Analysis
Abstract
Background::Colorectal cancer (CRC) ranks among the leading causes of cancerrelated deaths.
Objective::This study aimed to illuminate the relationship between DPP7 (also known as DPP2) and CRC through a combination of bioinformatics and experimental methodologies.
Methods::A multi-dimensional bioinformatic analysis on DPP7 was executed, covering its expression, survival implications, clinical associations, functional roles, immune interactions, and drug sensitivities. Experimental validations involved siRNA-mediated DPP7 knockdown and various cellular assays.
Results::Data from the Cancer Genome Atlas (TCGA) identified high DPP7 expression in solid CRC tumors, with elevated levels adversely affecting patient prognosis. A shift from the N0 to the N2 stage in CRC was associated with increased DPP7 expression. Functional insights indicated the involvement of DPP7 in cancer progression, particularly in extracellular matrix disassembly. Immunological analyses showed its association with immunosuppressive entities, and in vitro experiments in CRC cell lines underscored its oncogenic attributes.
Conclusion::DPP7 could serve as a CRC prognosis marker, functioning as an oncogene and representing a potential immunotherapeutic target.
1642-1660
The Role of Emodin in the Treatment of Bladder Cancer Based on Network Pharmacology and Experimental Verification
Abstract
Background and Purpose:Emodin, a compound derived from rhubarb and various traditional Chinese medicines, exhibits a range of pharmacological actions, including antiinflammatory, antiviral, and anticancer properties. Nevertheless, its pharmacological impact on bladder cancer (BLCA) and the underlying mechanism are still unclear. This research aimed to analyze the pharmacological mechanisms of Emodin against BLCA using network pharmacology analysis and experimental verification.
Methods::Initially, network pharmacology was employed to identify core targets and associated pathways affected by Emodin in bladder cancer. Subsequently, the expression of key targets in normal bladder tissues and BLCA tissues was assessed by searching the GEPIA and HPA databases. The binding energy between Emodin and key targets was predicted using molecular docking. Furthermore, in vitro experiments were carried out to confirm the predictions made with network pharmacology.
Results::Our analysis identified 148 common genes targeted by Emodin and BLCA, with the top ten target genes including TP53, HSP90AA1, EGFR, MYC, CASP3, CDK1, PTPN11, EGF, ESR1, and TNF. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated a significant correlation between Emodin and the PI3KAKT pathway in the context of BLCA. Molecular docking investigations revealed a strong affinity between Emodin and critical target proteins. In vitro experiments demonstrated that Emodin inhibits T24 proliferation, migration, and invasion while inducing cell apoptosis. The findings also indicated that Emodin reduces both PI3K and AKT protein and mRNA expression, suggesting that Emodin may mitigate BLCA by modulating the PI3K-AKT signaling pathway.
Conclusion::This study integrates network pharmacology with in vitro experimentation to elucidate the potential mechanisms underlying the action of Emodin against BLCA. The results of this research enhance our understanding of the pharmacological mechanisms by which Emodin may be employed in treating BLCA.
1661-1675
Potential Antidiabetic Activity of β-sitosterol from Zingiber roseum Rosc. via Modulation of Peroxisome Proliferator-activated Receptor Gamma (PPARγ)
Abstract
Aim::To evaluate the antidiabetic potential of β-sitosterol from Zingiber roseum.
Background::Diabetes mellitus is a cluster of metabolic disorders, and 90% of diabetic patients are affected with Type II diabetes (DM2). For the treatment of DM2, thiazolidinedione drugs (TZDs) were proposed, but recent studies have shown that TZDs have several detrimental effects, such as weight gain, kidney enlargement (hypertrophy), fluid retention, increased risk of bone fractures, and potential harm to the liver (hepatotoxicity). That is why a new molecule is needed to treat DM2.
Objective::The current research aimed to assess the efficacy of β-Sitosterol from methanolic extract of Zingiber roseum in managing diabetes via PPARγ modulation.
Methods::Zingiber roseum was extracted using methanol, and GC-MS was employed to analyze the extract. Through homology modeling, PPARγ structure was predicted. Molecular docking, MD simulation, free binding energies, QSAR, ADMET, and bioactivity and toxicity scores were all used during the in-depth computer-based research.
Results::Clinically, agonists of synthetic thiazolidinedione (TZDs) have been used therapeutically to treat DM2, but these TZDs are associated with significant risks. Hence, GC-MS identified phytochemicals to search for a new PPAR-γ agonist. Based on the in-silico investigation, β-sitosterol was found to have a higher binding affinity (-8.9 kcal/mol) than standard drugs. MD simulations and MMGBSA analysis also demonstrated that β-sitosterol bound to the PPAR-γ active site stably.
Conclusion::It can be concluded that β-sitosterol from Z. roseum attenuates Type-II diabetes by modulating PPARγ activity.
1676-1699