Combinatorial Chemistry & High Throughput Screening - Volume 27, Issue 9, 2024

Flavonoids and chalcones are two major classes of chemical moieties that have a vast background of pharmacological activities. Chalcone is a subclass of flavonoids whose therapeutic potential has been implicated due to an array of bioactivities. A lot of research works have shown interest in investigating the neuroprotective effect of these molecules, and have revealed them to be much more potent molecules that can be used to treat neurodegenerative disorders. Beta-site APP cleaving enzyme (BACE1), which is majorly found in the brain, is one of the reasons behind the development of Alzheimer’s disease (AD). Flavonoids and chalcones have proven clinical data that they inhibit the production of Aβ plaques that are involved in the progression of AD. In this article, we have provided a detailed chronological review of the research work on the BACE1 inhibiting potency of both flavonoids and chalcones. Almost all the flavonoids and chalcones mentioned in this article have shown very good in vitro and in vivo BACE1 inhibiting activity. The docking studies and the structural importance of some BACE1-inhibiting flavonoids, as well as chalcones, are also mentioned here.

Background: The use of medicinal plants as a rich resource of therapeutic agents in the treatment and prevention of diseases & ailments has been recognized for millennia and is highly regarded worldwide. Holarrhena antidysenterica (H. antidysenterica), also called kurchi, or kutaj, has been utilized since the dawn of time, Apocynaceae member, also known as H. pubescens, is praised for the medicinal uses of its stem bark, leaves, and seeds in Ayurveda. Objective: The study concentrated on aggregate information regarding H. antidysenterica's therapeutic effects. The purpose of the study was to compile pharmacological activities of H. antidysentrica seeds. Methods: Regardless of its broad variety of biological and possible therapeutic uses, there has been increasing concern regarding the use of H. antidysenterica. Result: Various phytochemicals have been extracted from H. antidysenterica in recent years and have demonstrated typical pharmacological properties, including antibacterial, anti-diarrhoeal, anti-diabetic, anti-oxidant, anti-urolithic, and anti-inflammatory activity. Conclusion: This review paper investigated the in-depth description and pharmacological properties of the plant, which produced significant findings on the chemical components present and also verified the traditionally claimed properties associated with the plant.

The birth of a child is a critical and potentially traumatic experience for women, entailing multiple physiological and psychosocial changes. The psychological effects of childbirth pain can have both immediate and long-term effects on the mother's health and her bond with her child. Many studies investigated the different ranges of synthetic drugs available for pain control in labour, inclusive of neuraxial analgesics, inhaled analgesics, and various opioids. The inadequate efficacy and unfavourable side effects of these synthetic drugs prevent appropriate pharmacotherapy, resulting in a quest for natural therapies for reducing labour pain. Herbal therapies (aromatherapy) using several essential oils obtained from various natural plants are another alternative that calms and manages the mind and body through aromatic compounds that have neurological and physiological effects. The review discussed the safety profile of various synthetic drugs with their dosage information and also deliberated on the mechanism and safety profile of various natural plants that are used in aromatherapy. The review also briefly highlighted the other non-pharmacological miscellaneous techniques such as TENS, hypnosis, immersion in water, acupuncture, massage, and different other tactics that aim to assist women in coping with pain in labour.

Background and Purpose: Coronavirus disease 2019 (COVID-19) is a lifethreatening disease worldwide due to its high infection and serious outcomes resulting from acute lung injury. Qingwen Baidu decoction (QBD), a well-known herbal prescription, has shown significant efficacy in patients with Coronavirus disease 2019. Hence, this study aims to uncover the molecular mechanism of QBD in treating COVID-19-related lung injury. Methods: Traditional Chinese Medicine Systems Pharmacology database (TCMSP), DrugBanks database, and Chinese Knowledge Infrastructure Project (CNKI) were used to retrieve the active ingredients of QBD. Drug and disease targets were collected using UniProt and Online Mendelian Inheritance in Man databases (OMIM). The core targets of QBD for pneumonia were analyzed by the Protein-Protein Interaction Network (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) to reveal the underlying molecular mechanisms. The analysis of key targets using molecular docking and animal experiments was also validated. Results: A compound-direct-acting target network mainly containing 171 compounds and 110 corresponding direct targets was constructed. The key targets included STAT3, c-JUN, TNF-α, MAPK3, MAPK1, FOS, PPARG, MAPK8, IFNG, NFΚB1, etc. Moreover, 117 signaling pathways mainly involved in cytokine storm, inflammatory response, immune stress, oxidative stress and glucose metabolism were found by KEGG. The molecular docking results showed that the quercetin, alanine, and kaempferol in QBD demonstrated the strongest affinity to STAT3, c- JUN, and TNF-α. Experimental results displayed that QBD could effectively reduce the pathological damage to lung tissue by LPS and significantly alleviate the expression levels of the three key targets, thus playing a potential therapeutic role in COVID-19. Conclusion: QBD might be a promising therapeutic agent for COVID-19 via ameliorating STAT3-related signals.

Background and Aim: Nonalcoholic fatty liver disease (NAFLD) is not only the top cause of liver diseases but also a hepatic-correlated metabolic syndrome. This study performed untargeted metabolomics analysis of NAFLD hamsters to identify the key metabolites to discriminate different stages of NAFLD. Methods: Hamsters were fed a high-fat diet (HFD) to establish the NAFLD model with different stages (six weeks named as the NAFLD1 group and twelve weeks as the NAFLD2 group, respectively). Those liver samples were analyzed by untargeted metabolomics (UM) analysis to investigate metabolic changes and metabolites to discriminate different stages of NAFLD. Results: The significant liver weight gain in NAFLD hamsters was observed, accompanied by significantly increased levels of serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Moreover, the levels of TG, LDL-C, ALT, and AST were significantly higher in the NAFLD2 group than in the NAFLD1 group. The UM analysis also revealed the metabolic changes; 27 differently expressed metabolites were detected between the NAFLD2 and NAFLD1 groups. More importantly, the levels of N-methylalanine, allantoin, glucose, and glutamylvaline were found to be significantly different between any two groups (control, NAFLD2 and NAFLD1). Receiver operating characteristic curve (ROC) curve results also showed that these four metabolites are able to distinguish control, NAFLD1 and NAFLD2 groups. Conclusion: This study indicated that the process of NAFLD in hamsters is accompanied by different metabolite changes, and these key differently expressed metabolites may be valuable diagnostic biomarkers and responses to therapeutic interventions.

Purpose: To explore differentially expressed genes (DEGs) associated with autophagy in psoriasis using bioinformatics analysis and verify them in an M5-induced psoriatic cell model. Methods: We obtained gene expression microarray data from patients with psoriasis and normal skin tissues from the dataset GSE78097 of the NCBI Gene Expression Omnibus (GEO) database. R software was used to identify DEGs associated with autophagy in psoriasis. Proteinprotein interaction (PPI) and correlation analyses were used to show interactions between certain genes. Their potential biological roles were determined using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Finally, all the DEGs associated with autophagy in psoriasis were validated in a psoriatic cell model by RT-qPCR. Results: 28 DEGs associated with autophagy were identified. These genes were linked to one another, and the most connected hub gene was VEGFA, according to PPI analysis. GO and KEGG enrichment analyses revealed various biological pathways associated with autophagy. The RT-qPCR findings of the expression of 18 genes in the psoriatic cell model confirmed the bioinformatics analysis results. The five genes with the most significant differences were IL24, CCL2, NAMPT, PPP1R15A, and SPHK1. Conclusion: We identified DEGs associated with autophagy in patients with psoriasis. IL24, CCL2, NAMPT, PPP1R15A, and SPHK1 were identified as important genes that may influence psoriasis development through the regulation of autophagy.

Background: Cancer is a leading threat to humankind, accounting for nearly one million deaths in 2018, and the expected number of cancer-related deaths in 2040 is more than 16 million. The most common causes of cancer deaths are lung, colorectal, stomach, liver and breast cancer, while the highest number of new cancer cases belong to lung, breast, colorectal, prostate, stomach and liver cancer. Introduction: PARP-1 is an enzyme that plays an important role in DNA repair, cell propagation/survival and death due to its influence on numerous biological processes. Quinazolinones represent an important scaffold in medicinal chemistry and have a broad spectrum of biological activities. Methods: In this study, we have synthesized quinazolinones by reaction of 2-aminobenzamide and substituted aldehydes. Molecular docking studies of synthesized compounds were performed for their PARP-1 binding affinities using Schrodinger 2016 software. In silico ADME studies were also performed for the synthesized compounds using the QikProp tool of Schrodinger software. Results: Results of molecular docking studies indicated that synthesized quinazolinones had a good affinity towards active site of PARP-1 and compound 4 had the best docking score (-10.343). Results of ADME studies indicated the drug-like properties of synthesized compounds, which make them suitable drug candidates. Conclusion: All the synthesized compounds have a better docking score than niraparib (-9.05). Further, the synthesized compounds have a favorable ADME profile. Therefore, they may serve as important leads in discovering PARP-1 inhibitors.

Background: The abundance of circulating monocytes is closely associated with the development of atherosclerosis in humans. Objective: This study aimed to further research into diagnostic biomarkers and targeted treatment of carotid atherosclerosis (CAS). Methods: We performed transcriptomics analysis through weighted gene co-expression network analysis (WGCNA) of monocytes from patients in public databases with and without CAS. Differentially expressed genes (DEGs) were screened by R package limma. Diagnostic molecules were derived by the least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE) algorithms. NetworkAnalyst, miRWalk, and Star- Base databases assisted in the construction of diagnostic molecule regulatory networks. The Drug- Bank database predicted drugs targeting the diagnostic molecules. RT-PCR tested expression profiles. Results: From 14,369 hub genes and 61 DEGs, six differentially expressed monocyte-related hub genes were significantly associated with immune cells, immune responses, monocytes, and lipid metabolism. LASSO and SVM-RFE yielded five genes for CAS prediction. RT-PCR of these genes showed HMGB1 was upregulated, and CCL3, CCL3L1, CCL4, and DUSP1 were downregulated in CAS versus controls. Then, we constructed and visualized the regulatory networks of 9 transcription factors (TFs), which significantly related to 5 diagnostic molecules. About 11 miRNAs, 19 lncRNAs, and 39 edges centered on four diagnostic molecules (CCL3, CCL4, DUSP1, and HMGB1) were constructed and displayed. Eleven potential drugs were identified, including ibrutinib, CTI-01, roflumilast etc. Conclusion: A set of five biomarkers were identified for the diagnosis of CAS and for the study of potential therapeutic targets.

Background: Postmenopausal osteoporosis (PMOP) is a classic type of osteoporosis that has gradually become a significant health problem worldwide. There is an urgent need for a safe alternative therapeutic agent considering the poor therapeutic strategies currently available for this disease. The roots and bark of the Morus australis tree (Moraceae) are used to make a traditional Chinese medicine known as "Morusin", and accumulating evidence has demonstrated its multiple activities, such as anti-inflammatory and anti-tumor effects. Objective: In this study, we aim to explore the effect of Morusin on mouse osteoclasts and its mechanism. Methods: In this study, we explored the inhibitory effects of Morusin on murine osteoclasts in vitro and its mechanism, and the protective effect of Morusin on an ovariectomy (OVX)-induced osteoporosis model in vivo. Results: The results showed that Morusin prevented OVX-induced bone loss and dramatically decreased RANKL-induced osteoclastogenesis. Morusin interfered with RANKL-activated NF- ΚB, MAPK, and PI3K/AKT signaling pathways. The expression of three master factors that control osteoclast differentiation, c-Fos, NFATc1, and c-Jun, was reduced by Morusin treatment. Collectively, in vitro results indicated that Morusin has a protective effect on OVX-induced bone loss in a mouse model. Conclusion: Our data provide encouraging evidence that Morusin may be an effective treatment for PMOP.

Introduction: Recent studies have found that circular RNA is an abundant RNA species that belongs to part of the competing endogenous RNA network (ceRNA), which was proven to play an important role in the development, diagnosis and progress of diseases. However, the function of circRNAs in imatinib resistance in Gastrointestinal stromal tumor (GIST) are poorly understood so for. The present study aimed to screen and predict the potential circRNAs in imatinib resistance of GIST using microarray analysis. Methods: We determined the expression of circular RNAs in paired normal gastric tissues (N), primary GIST (gastrointestinal stromal tumor) tissues (YC) and imatinib mesylate secondary resistance GIST tissues (C) with microarray and predicted 8677 dysregulated circular RNAs. Results: Compared with the YC group, we identified 15 circRNAs that were up-regulated and 8 circRNAs that were down-regulated in the C group. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that these host linear transcripts that differentially express circular RNAs are involved in many key biological pathways, predicting the potential tumor-genesis and drug resistance mechanismrelated to HIF-1 pathway, later we draw the cirRNA-miRNA-mRNA network involved in the HIF-1 pathway and found several dysregulated circRNAs and the relationship between circRNA-miRNAs-mRNA, such as circRNA_06551, circRNA_14668, circRNA_04497, circRNA_08683, circRNA_09923(Green, down-regulation) and circRNA_23636, circRNA_15734 (Red, up-regulation). Conclusion: Taken together, we identified a panel of dysregulated circRNAs that may be potential biomarkers even therapy relevant to the GIST, especially imatinib secondary resistance GIST.

Background: To elucidate the detailed mechanisms of citrullination at the molecular level and design drugs applicable to major human diseases, predicting protein citrullination sites (PCSs) is essential. Using experimental approaches to predict PCSs is time-consuming and costly. However, there is a limited scope of the current PCS predictors. In particular, most predictors are commonly used for PCS prediction and have limited performance scores. Objective: This work aims to provide an improved sophisticated predictor of citrullination sites using a benchmark dataset in a machine learning platform. Methods: This study presents a reliable citrullination site predictor based on a benchmark dataset containing a 1:1 ratio of positive and negative samples. We classified citrullination sites using the Composition of the K-Spaced Amino Acid Pairs (CKSAAP) and Support Vector Machine (SVM). Results: We developed PCS predictors using integrated machine-learning methods that produced the highest average scores. Using 10-fold cross-validation on test datasets, the True Positive Rate (TPR) was 98.34%, the True Negative Rate (TNR) was 99.44%, the accuracy was 98.89%, the Mathew Correlation Coefficient (MCC) was 98.21%, the Area Under the ROC Curve (AUC) was 0.999, and the partial Area Under the ROC Curve (pAUC) was 0.1968. Conclusion: According to overall performance, our developed predictor has a significantly higher implementation in comparison with the current tools on the same benchmark dataset. Moreover, it showed better performance metrics on both test and training datasets. Our developed predictor is promising and can be implemented as a complementary technique for identifying fast and precise citrullination sites.

Background: Portulaca grandiflora is a tiny, upright herb that contains a variety of chemical components, including alkaloids, glycosides, mucilage, proteins, tannins, flavonoids, saponins, polysaccharides, and triterpenoids possessing properties that may help with atherosclerosis. The reported pharmacological properties of Portulaca grandiflora are antioxidant, antidiabetic, antiasthmatic, antibacterial, antiulcer and anti-inflammatory properties. Objectives: The yield of methanol extract is higher than that of ethanol and acetone, and its phytoconstituents, like flavonoids and polyphenols, and has potent antioxidant properties. In order to determine the effectiveness of Portulaca grandiflora methanol extract fraction against high-fat diet (HFD)-induced hyperlipidemia, hemodynamic change, antioxidant levels, and vascular dysfunction in rats, a study was carried out on a flavonoid-rich methanol extract fraction of the aerial part of Portulaca grandiflora Hook. Methods: This method involves a study of 30 days involving male Wistar rats (240–250 g) (n=5) that were fed with an Ath diet. Study groups were divided into (i) The Control Group, (ii) the Diseases Control Group, (iii) Disease + Standard drug (Atorvastatin 20mg/kg, orally, (iv) Disease + Test Extract dose 1 (Portulaca grandiflora 200 mg/kg orally), and (v) Disease + Test Extract dose 2 (Portulaca grandiflora 400 mg/kg orally). Both the test drug Portulaca grandiflora and the standard drug Atorvastatin were given orally for 30 days. Results: At the end of the study, blood samples were taken to measure the serum lipid profile, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and levels of oxidative tissue stress. Hemodynamic parameters and aortic staining were performed. Portulaca grandiflora treatment improved the lipid profile and considerably reduced oxidative stress levels. Aortic staining examination revealed a marked reduction in atherosclerotic lesions. Conclusion: These results revealed that Portulaca grandiflora is an effective treatment approach in preventing atherosclerotic lesion progression, which is attributed to its protection against oxidative stress and various enzymatic activities in the Atherogenic model.