Combinatorial Chemistry & High Throughput Screening - Volume 26, Issue 12, 2023

Alzheimer’s disease (AD) is an increasingly common neurodegenerative disease that attracts the attention of researchers and medical community in order to develop new, safe and more effective drugs. Currently available drugs could only slow the AD progression and relieve the symptoms, in addition to being linked to moderate-to-severe side effects. N-methyl D-aspartate (NMDA) receptors antagonists were reported to have the ability to block the glutamate-mediated excitotoxic activity being good therapeutic targets for several neurodegenerative diseases, including AD. Based on data obtained so far, this review provides an overview over the use of NMDA antagonists for AD treatment, starting with a key emphasis on present features and future aspects regarding the use of NMDA antagonists for AD, and lastly a key focus is also given on its use in precision medicine.

Alzheimer's Disease (AD), the most common and major disability issue in our society, has a substantial economic impact. Despite substantial advances in aetiology, diagnosis, and therapy, the fundamental causes of the disease remain unknown, accurate biomarkers are not well characterized, and current pharmaceutical medications are not cost-effective. Effective care for Alzheimer's disease and other types of dementia is crucial for patients' long-term health. Pathogenesis advances have aroused the scientific community's interest in the creation of new pharmacological treatments that target recognized disease targets throughout the previous two decades. Pharmacological therapy has recently been assigned 10 - 20% of the direct costs of AD. Less than 20% of Alzheimer's patients respond somewhat to standard medicines with questionable cost-effectiveness (donepezil, galantamine, memantine and rivastigmine). Therefore, currently known treatment approaches address the condition indirectly, as acetyl cholinesterase related inhibitors and the Nmethyl d-aspartate as receptor and antagonists have little effect on the sickness. Novel targets and specific small molecules must also be found in order to be useful in the therapy of AD. This chapter examines a wide spectrum of Alzheimer's disease targets as well as contemporary progress in the discovery of disease inhibitors. In addition, brief in-silico investigations were highlighted and provided to understand how the theoretical lead in AD treatment development is attainable.

Toll-like receptors (TLRs) control both innate and adaptive immunity with a wide expression on renal epithelial cells and leukocytes. Activation of TLRs results in the production of cytokines, chemokines and interferons along with activation of the transcription factor NF-ΚB, resulting in inflammatory perturbations. TLR4 signaling pathway is the most extensively studied of TLRs. TLR4 is expressed on renal microvascular endothelial and tubular epithelial cells. So, targeting TLR4 modulation could be a therapeutic approach to attenuate kidney diseases that are underlined by inflammatory cascade. Medicinal plants with anti-inflammatory activities display valuable effects and are employed as alternative sources to alleviate renal disease linked with inflammation. Flavonoids and other phytochemicals derived from traditional medicines possess promising pharmacological activities owing to their relatively cheap and high safety profile. Our review focuses on the potent anti-inflammatory activities of twenty phytochemicals to verify if their potential promising renoprotective effects are related to suppression of TLR4 signaling in different renal diseases, including sepsis-induced acute kidney injury, renal fibrosis, chemotherapy-induced nephrotoxicity, diabetic nephropathy and renal ischemia/reperfusion injury. Additionally, molecular docking simulations were employed to explore the potential binding affinity of these phytochemicals to TLR4 as a strategy to attenuate renal diseases associated with activated TLR4 signaling.

Objective: This study aimed to verify miRNAs and the molecular mechanisms of diagnostic and prognostic biomarkers for rectal adenocarcinoma. Methods: Two miRNA datasets of rectal adenocarcinoma were obtained from GEO and TCGA. GEO2R tool, Venn diagram, Kaplan-Meier survival analysis, KEGG pathway analyses, DIANA TOOLS, and Wilcoxon rank-sum test were used for biological information analysis. The diagnostic utility of miRNAs and immune infiltration of tumors in Chinese patients were validated by RTqPCR and immunofluorescence analysis. Results: MiR-21-5P and miR-455-5p were both found to have a significant correlation with poor prognosis and higher expression in rectal adenocarcinoma. Besides, the ability to prognosis was independent of the clinicopathological stage. MiR-21-5P and miR-455-5p were enriched in the TGF-beta, Wnt, MAKP, and PI3K-AKT signaling pathways. Meanwhile, the high expression phenotype of miR-21-5P and miR-455-5p decreased CD4⁺ and CD8⁺ T cells. Conclusion: In summary, we found two significant diagnostic and prognostic miRNAs of rectal adenocarcinoma via integrated bioinformatics approach and clinical trials, which might decrease CD4⁺ and CD8⁺ T cells.

Background: Xinfeng capsule (XFC) is a well-known drug against rheumatoid arthritis (RA). However, the combination mechanisms of XFC on RA remain unclear. Objective: The purpose of this study is to explore the mechanisms of XFC against RA in terms of compounds, targets, and signaling pathways via network pharmacology. Methods: The bioactive compounds and potential targets of XFC were extracted from TCMSP and BATMAN-TCM database, and the putative RA-related targets were determined from the DisGeNET, PHGKB, PharmGKB, and CTD database. The approach of protein-protein interaction, gene ontology analysis, and kyoto encyclopedia of genes and genomes pathway enrichment analysis were constructed, respectively. In animal experiments, we evaluated the expression of core targets. Results: We found that XFC handled 30 active compounds and 131 common target genes. Among them, mairin, folic acid, cholesterol, and triptolide in XFC were selected as the central active compounds against RA. The mechanisms of XFC on RA which concerned critical targets were protein kinase B (AKT1) and tumor necrosis factor (TNF). In vivo, we found that the expression levels of AKT1 and TNF in the modeling group were significantly increased but reversed by XFC. Conclusion: The combination mechanisms of XFC were elucidated in terms of components and targets and signaling pathways, which may be related to inhibiting the proliferation of synovial cells and inflammation.

Background: Non-small cell lung cancer (NSCLC) has been the subject of intense scholarly debate. We aimed to identify the potential biomarkers via bioinformatics analysis. Methods: Three datasets were downloaded from gene expression omnibus database (GEO). R software was applied to screen differentially expressed genes (DEGs)and analyze immune cell infiltrates. Gene set enrichment analysis (GSEA) showed significant function and pathway in two groups. The diagnostic markers were further investigated by multiple machine learning algorithms (least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE)). Various online analytic platforms were utilized to explore the expression and prognostic value of differential genes. Furthermore, western blotting was performed to test the effects of genes on cell proliferation in vitro. Results: We identified 181 DEGs shared by two datasets and selected nine diagnostic markers. Those genes were also significantly overexpressed in the third dataset. Topoisomerase II alpha (TOP2A) is overexpressed in lung cancer and associated with a poor prognosis, which was confirmed using immunohistochemistry (IHC) and Western blotting. Additionally, TOP2A showed a negative correlation with immune cells, such as CD8⁺ T cells, eosinophils and natural killer (NK) cell. Conclusion: Collectively, for the first time, we applied multiple machine learning algorithms, online databases and experiments in vitro to show that TOP2A is a potential biomarker for lung adenocarcinoma and could facilitate the development of new treatment strategies.

Background: Acute pancreatitis can eventually lead to morbidity and mortality. The present study aimed to identify the differentially expressed microRNAs (miRNAs) that are related to acute pancreatitis and explore the in vitro functional role of miR-92b in acute pancreatitis. Methods: Bioinformatics analysis was used to identify differentially expressed miRNAs in caerulein- induced acute pancreatitis samples when compared to normal controls. The role of miR-92b in acute pancreatitis was examined by in vitro functional assays. Results: MiRNA-network analysis revealed 12 miRNAs that function as “core regulatory miRNAs”. Further validation studies revealed that six miRNAs (miR-216a, miR-216b, miR-217, miR- 92b, miR-375 and miR-148a) were differentially expressed in the serum samples from patients with acute pancreatitis. These six miRNAs have fair diagnostic potential for severe acute pancreatitis. Caerulein induced cell injury and inflammatory response and repressed miR-92b expression in AR42J cells. MiR-92b overexpression attenuated caerulein-induced cell injury and inflammatory responses in AR42J cells. Luciferase reporter assay showed that mitogen-activated protein kinase 4 (MAP2K4) was a direct target of miR-92b. MiR-92b overexpression repressed MAP2K4 expression, while caerulein up-regulated MAP2K4 expression in AR42J cells. The rescue experiments showed that enforced expression of MAP2K4 partially reversed the miR-92b-mediated protective effects on caerulein-induced AR42J cell injury. Conclusion: In conclusion, we identified miR-216a, miR-216b, miR217, miR-92b, miR-375 and miR-148a as new candidate biomarkers for acute pancreatitis. Further in vitro functional studies revealed that miR-92b attenuated caerulein-induced cell injury and inflammatory responses in AJ42R cells partially via targeting MAP2K4.

Objective: The aim of this research was to investigate the expression of PIEZO2 and its potential clinical significance in gastric cancer (GC). Methods: In this study, we detected the protein expression levels of PIEZO2 in GC tissues and adjacent normal tissues by immunohistochemistry (IHC) and analysed the relationship between the protein expression levels of PIEZO2 and clinicopathological parameters of GC patients. Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan–Meier Plotter were used to verify the diagnostic and prognostic values of PIEZO2. Proteins interacting with PIEZO2 were predicted using the SRING database. Results: Our results showed that the protein expression levels of PIEZO2 in GC tissues were lower than those in adjacent normal tissues (all P < 0.05), and the protein expression level of PIEZO2 was correlated with lymph node metastasis and TNM stage of GC patients (all P < 0.05). Aberrant overexpression of PIEZO2 was associated with poor prognosis of GC patients. Proteins such as VR1, TRPV1, LHFPL5, STOM, TRPA1 and STOML3 had obvious interactions with PIEZO2 (P = 0.00213). Conclusion: In summary, our current study identified PIEZO2 as a promising target for early diagnosis and as a potential prognostic biomarker in GC patients.

Background and Objective: Depressive disorder (DD) is a common chronic and highly disabling disease. Polygoni Multiflori Caulis (PMC), a traditional Chinese medicine, has been listed in the 2020 edition of the Chinese Pharmacopoeia. Here, the antidepressant effects and mechanisms of PMC were explored for the first time. Methods: We observed the safety of PMC at a 10-fold clinically equivalent dose. Depressed mice were induced by chronic unpredictable mild stress (CUMS) and were used to evaluate the antidepressant effects of PMC via the sucrose preference test and the tail suspension test. The composition of PMC was identified by ultra-high performance liquid chromatography coupled with quadrupole exactive orbitrap mass spectrometer, and the active components, important targets, and potential mechanism of PMC in DD treatment were predicted via network pharmacology. Investigation included active compounds and DD-related targets screening, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation, PMC-compound-target-pathway- DD network construction, and Molecular docking. Results: In the safety evaluation of PMC, no toxic side effects or deaths occurred. There were no significant differences in liver function (ALT, AST, and TP; P > 0.05) and kidney function (BUN, CRE, and UA; P > 0.05) in each group of mice. Compared to the control group, the model group of mice showed significantly decreased sucrose preference and significantly increased immobility time (P < 0.01 or P < 0.05). Compared with the model group, the mice in the PMC low, medium, and high dose groups showed a significant decrease in immobility time and a significant increase in sucrose preference. In the PMC-Compound-Target-Pathway-DD network, 54 active compounds, 83 common targets, and 13 major signaling pathways were identified for the treatment of DD. Molecular docking verified that the active compounds could effectively bind with the hub targets. Conclusion: PMC is a relatively safe antidepressant herbal medicine with its potential mechanism involving multiple compounds, targets, and pathways.

Objective: Lung adenocarcinoma (LUAD) is the most common type of lung cancer. However, predictive biomarkers for early efficacy and prognosis evaluation in patients with surgically resected LUAD are not completely explained. Methods: Differentially expressed genes (DEGs), gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were identified by RNA sequencing (RNA-Seq) between thirteen LUAD tissues and five normal lung tissues. The expression of DEGs was confirmed by qRT-PCR and a validated cohort from GEPIA. Protein-protein interaction (PPI) network of the top 5% DEGs was constructed by STRING and visualized in Cytoscape. Immunofluorescence results were acquired from clinical specimens from LUAD patients. The expression of FHL1 was analyzed by ImageJ. Survival analysis was performed using the GEPIA dataset. Results: Consistent with the RNA-Seq data, validation of DEGs expression by qRT-PCR and GEPIA cohort showed that FHL1 and SLIT3 were down-regulated in LUAD patient tissues compared with non-tumor tissues. Moreover, FHL1 was significantly reduced in LUAD cell lines compared to the bronchial epithelium cell line (P < 0.01). However, SLIT3 was elevated in A549 and H1299 cells (wide type EGFR) (P < 0.05) while decreased in HCC827 and PC9 cells (mutant EGFR) compared to BESA-2B cells (P < 0.01). PPI network revealed the most significant cluster with 10 nodes and 43 edges. Immunofluorescent staining also showed that the expression of FHL1 was lower in LUAD tissues compared with that in normal lung tissues (P < 0.01). The expressions of SLIT3 and FHL1 were positively correlated. Specifically, the higher expression level of SLIT3 and FHL1 independently predicted a better prognosis (P < 0.01 or P < 0.05). Conclusion: Our findings provide two novel candidates, FHL1 and SLIT3, for prognostic evaluation and treatments after surgery.

Aim: To study the effect of Rhodiola Rosea injection on cardiac function and the reninangiotensin- aldosterone system (RASS) in rats with chronic heart failure. Background: Rhodiola Rosea injection, a traditional Chinese medication for relieving blood stasis and improving blood circulation, is an excellent therapeutic for treating coronary heart disease-angina pectoris. Rhodiola Rosea injection's major component, salidroside, protects the cardiovascular system. But there isn't much first-hand evidence about how injectable Rhodiola Rosea affects heart failure. Objectives: In this study, a rat model of heart failure was established, and the effect of Rhodiola rosea injection on myocardial cell morphology, cardiac function, and ventricular remodelling in rats with heart failure was investigated. Methods: 66 SD male rats were selected; 10 were randomly selected as a blank control group, and 56 were treated intraperitoneally with doxorubicin (4 g/g). After 6 weeks, all animals had LVEF 60%. Established a heart failure model. Each group had 14 rats: model control, low-dose, mediumdose, and high-dose Rhodiola Rosea injection. The 2 mL/kg of Rhodiola Rosea injection was injected into the tail vein once a day for 2 weeks. Both the blank and control groups received normal daily saline. After 2 weeks, the echocardiographic index, RASS-related index, and serum BNP level were assessed in all rats, and myocardial tissue morphology was observed. MiRNA423-5p, miRNA499-5p, and miRNA210-3p were extracted from peripheral blood. Rhodiola rosea injection on its expression was compared to healthy control rats. Results: 6 mL/kg Rhodiola Rosea injection lowered LVEDV and LVESV while increasing LVEF and LVFS. Injections of 6 mL/kg Rhodiola Rosea reduce plasma levels of miR-210-3p, miR-423- 5p, miRNA-499, and BNP in heart failure model rats. The 6 mL/kg Rhodiola Rosea injection can restore the RASS indexes of heart failure rats to the level of the normal group. Conclusion: The present study offers preliminary evidence supporting the use of Rhodiola Rosea injection in the treatment of heart failure and offers a solid foundation for clinical off-label medication use.

Aim: To determine the impact of vitamin D on the occurrence and progression of intestinal disorders, the authors of this study have conducted a systematic review and meta-analysis. Background: Vitamin D regulates inflammation and immunity in association with reducing the disease symptoms of several gastrointestinal diseases, including inflammatory bowel diseases (IBD), Crohn’s disease (CD), ulcerative colitis (UC), and colorectal cancer (CRC). However, the exact role of vitamin D in the occurrence and development of intestinal diseases is unclear so far. Methodology: The relevant studies were searched in PubMed and screened based on inclusion and exclusion criteria. The quality of full-text studies was assessed using National Heart, Lung, and Blood Institute (NIH) scale. The study was conducted as per the PRISMA guidelines. The overall estimate was calculated in terms of risk ratio with a 95% confidence interval. The publication bias was assessed qualitatively using a funnel plot, and heterogeneity among studies was calculated using I2 statistics. All analyses were done using RevMan 5.0. Results: The overall risk ratio using random effect model was found to be 0.89 (0.70, 1.12), which indicates the non-significant role of vitamin D in the occurrence and development of intestinal diseases as compared to the non-vitamin D group. However, after exclusion of studies with low and high sample sizes, a significant reduction in intestinal diseases was observed in the vitamin D group as compared to the non-vitamin D group. Further, no heterogeneity among the studies was observed. Conclusion: Based on available evidence, vitamin D might play a significant role in the reduction of intestinal diseases; however, more studies with high sample sizes are required to draw a valid conclusion.