Search Results (16)

Background/Objectives: Machine learning has emerged as a transformative force in drug discovery, revolutionizing traditional research paradigms and profoundly improving the efficiency, cost-effectiveness, and speed of the drug development cycle for novel drugs. Colorectal cancer is one of the most prevalent malignant tumors and imposes a heavy burden on global public health due to its high morbidity, mortality, and poor prognosis. Cyclooxygenase-2 (COX-2) is a key therapeutic target of colorectal cancer and has been extensively applied in the development of novel anti-colorectal cancer drugs. Methods: In this study, we systematically compared the performance of Random Forest Classifier (RFC), deep learning (DL), and graph neural network (GNN) models, including GAT (Graph Attention Network), GCN (Graph Convolutional Network), and MPNN (Message Passing Neural Network), with diverse features in the classification task of COX-2 inhibitors, based on a custom COX-2 inhibitors dataset and a Traditional Chinese Medicine (TCM)-derived compound library. The optimal model was subsequently used to screen for potential COX-2 inhibitors. Additionally, the key substructures governing COX-2 inhibitory activity were also identified and analyzed. Finally, the prioritized candidate compounds underwent experimental validation. Results: Both RFC and DL models outperformed GNN models. Through further comparative analysis of models’ predictive performance, the RFC model was ultimately verified as the optimal model for activity screening of TCM-derived compounds. The molecular interactions and binding affinities between predicted candidate compounds and COX-2 were further investigated. Finally, the selected lead compound, dehydrocostus lactone, was experimentally confirmed to possess potent COX-2 inhibitory activity. Conclusions: This study highlights that the RFC model is highly effective in screening bioactive components from TCM under small-dataset conditions, providing a solid foundation for subsequent related research in this field. Full article

Background/Objectives: Limitations of conventional treatments for esophageal cancer, which include poor solubility, drug resistance, and undesirable side effects, make it imperative to explore new therapeutic approaches to slow the progression of this disease. This study aims to assess the potential of terpene compounds as anti-cancer agents for esophageal squamous cell carcinoma (ESCC). Methods: This work was carried out following the PRISMA 2020 guidelines to ensure rigorous methodology. Results: A systematic analysis of 34 compounds revealed various mechanisms of action, such as induction of oxidative stress and modulation of apoptotic pathways. The results also show that several compounds, including (1Z,3R,4S,5E,7Z)-1-bromo-3,4,8-trichloro-7-(dichloromethyl)-3-methylocta-1,5,7-triene, dehydrocostus lactone, (3R,4S)-3,4,6,7-tetrachloro-3,7-dimethyl-octene-1-ene, acetyl-macrocalin B, jesridonin, longikaurin A, sphaerococcenol A, DS2, rabdocoestin B, ingenol C, ingenol-3,20-dibenzonate, JDA-202, xerophilusin B, betulinic acid, euphol, and (20S) ginsenoside Rh2, with IC₅₀s below 10 µM, show promising efficacy both in vitro and in vivo, sometimes surpassing certain conventional treatments. Conclusions: However, despite these encouraging prospects, limitations remain, notably a lack of in vivo data and clearly defined mechanisms of action for certain compounds. These challenges require further research to validate their safety and efficacy, facilitating their development as viable therapeutic options for ESCC. Full article

Considering the resistance of weeds to different herbicides with different mechanisms of action, the search for new, more selective compounds with low toxicity to other species in nature has been very important for the development of agriculture. Because of that, considering the biological activity of allelochemicals and natural epoxides, four new epoxy compounds derived from dehydrocostus lactone were synthetized and evaluated for their potential herbicide activity against three species of seeds, Allium cepa (onion), Lepidium sativum (garden cress), and Lactuca sativa (lettuce). In assays with A. cepa, compound 4 inhibited radicle length by 80% at 100 μM. Notably, for L. sativum, compound 4 showed significant inhibition, reducing stalk and radicle lengths by 80% at 100 μM, surpassing the performance of the commercial herbicide Logran. However, diol 5 notably inhibited radicle growth by 28% at 100 μM, making the most significant observed effect. One of the noteworthy lactones studied is epoxide 4. This highlights the importance of the epoxide functional group in affecting both radicle and shoot lengths of seeds. Therefore, the synthesis of these compounds has proven advantageous and holds great potential for the development of new herbicides. Full article

Lactic acid bacteria is well-known as a vital strategy to alleviate or prevent diabetes. Similarly, the plant Saussurea costus (Falc) Lipsch is a preventive power against diabetes. Here, we aimed to determine whether lactic acid bacteria or Saussurea costus is more effective in treating a diabetic rat model in a comparative study manner. An in vivo experiment was conducted to test the therapeutic activity of Lactiplantibacillus plantarum (MW719476.1) and S. costus plants against an alloxan-induced diabetic rat model. Molecular, biochemical, and histological analyses were investigated to evaluate the therapeutic characteristics of different treatments. The high dose of S. costus revealed the best downregulated expression for the IKBKB, IKBKG, NfkB1, IL-17A, IL-6, IL-17F, IL-1β, TNF-α, TRAF6, and MAPK genes compared to Lactiplantibacillus plantarum and the control groups. The downregulation of IKBKB by S. costus could be attributed to dehydrocostus lactone as an active compound with proposed antidiabetic activity. So, we performed another pharmacophore modeling analysis to test the possible interaction between human IkB kinase beta protein and dehydrocostus lactone as an antidiabetic drug. Molecular docking and MD simulation data confirmed the interaction between human IkB kinase beta protein and dehydrocostus lactone as a possible drug. The target genes are important in regulating type 2 diabetes mellitus signaling, lipid and atherosclerosis signaling, NF-κB signaling, and IL-17 signaling pathways. In conclusion, the S. costus plant could be a promising source of novel therapeutic agents for treating diabetes and its complications. Dehydrocostus lactone caused the ameliorative effect of S. costus by its interaction with human IkB kinase beta protein. Further, future studies could be conducted to find the clinical efficacy of dehydrocostus lactone. Full article

Aucklandia costus Falc. (Synonym: Saussurea costus (Falc.) Lipsch.) is a perennial herb of the family Asteraceae. The dried rhizome is an essential herb in the traditional systems of medicine in India, China and Tibet. The important pharmacological activities reported for Aucklandia costus are anticancer, hepatoprotective, antiulcer, antimicrobial, antiparasitic, antioxidant, anti-inflammatory and anti-fatigue activities. The objective of this study was the isolation and quantification of four marker compounds in the crude extract and different fractions of A. costus and the evaluation of the anticancer activity of the crude extract and its different fractions. The four marker compounds isolated from A. costus include dehydrocostus lactone, costunolide, syringin and 5-hydroxymethyl-2-furaldehyde. These four compounds were used as standard compounds for quantification. The chromatographic data showed good resolution and excellent linearity (r² ˃ 0.993). The validation parameters, such as inter- and intraday precision (RSD < 1.96%) and analyte recovery (97.52–110.20%; RSD < 2.00%),revealed the high sensitivity and reliability of the developed HPLC method. The compounds dehydrocostus lactone and costunolide were concentrated in the hexane fraction (222.08 and 65.07 µg/mg, respectively) and chloroform fraction (99.02 and 30.21 µg/mg, respectively), while the n-butanol fraction is a rich source of syringin (37.91 µg/mg) and 5-hydroxymethyl-2-furaldehyde (7.94 µg/mg). Further, the SRB assay was performed for the evaluation of anticancer activity using lung, colon, breast and prostate cancer cell lines. The hexane and chloroform fractions show excellent IC₅₀ values of 3.37 ± 0.14 and 7.527 ± 0.18 µg/mL, respectively, against the prostate cancer cell line (PC-3). Full article

The Mikania genus has been known to possess numerous pharmacological activities. In the present study, we aimed to evaluate the interaction of 26 selected constituents of Mikania species with (i) cyclooxygenase 2 (COX 2), (ii) human neutrophil elastase (HNE), (iii) lipoxygenase (LOX), matrix metalloproteinase ((iv) MMP 2 and (v) MMP 9), and (vi) microsomal prostaglandin E synthase 2 (mPGES 2) inhibitors using an in silico approach. The 26 selected constituents of Mikania species, namely mikamicranolide, kaurenoic acid, stigmasterol, grandifloric acid, kaurenol, spathulenol, caryophyllene oxide, syringaldehyde, dihydrocoumarin, o-coumaric acid, taraxerol, melilotoside, patuletin, methyl-3,5-di-O-caffeoyl quinate, 3,3′,5-trihydroxy-4′,6,7-trimethoxyflavone, psoralen, curcumene, herniarin, 2,6-dimethoxy quinone, bicyclogermacrene, α-bisabolol, γ-elemene, provincialin, dehydrocostus lactone, mikanin-3-O-sulfate, and nepetin, were assessed based on the docking action with COX 2, HNE, LOX, MMP 2, MMP 9, and mPGES 2 using Discovery Studio (in the case of LOX, the Autodock method was utilized). Moreover, STITCH (Search Tool for Interacting Chemicals), physicochemical, drug-likeness, and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analyses were conducted utilizing the STITCH web server, the Mol-inspiration web server, and Discovery Studio, respectively. In the present study, STITCH analysis revealed only six ligands (dihydrocoumarin, patuletin, kaurenol, psoralen, curcumene, and nepetin) that showed interactions with human proteins. Physicochemical analysis showed that seventeen ligands complied well with Lipinski’s rule. ADMET analysis showed eleven ligands to possess hepatotoxic effects. Significantly, the binding free energy estimation displayed that the ligand methyl-3, 5-di-O-caffeoyl quinate revealed the highest binding energy for all the target enzymes, excluding LOX, suggesting that this may have efficacy as a non-steroidal anti-inflammatory drug (NSAID). The current study presents a better understanding of how Mikania is used as a traditional medicinal plant. Specifically, the 26 ligands of the Mikania plant are potential inhibitor against COX 2, HNE, LOX, MMP 2, MMP 9, and mPGES 2 for treatments for acute and/or chronic inflammatory diseases. Full article

Background and Objectives: Aucklandiae Radix is a well-known medicinal herb that is often used to treat gastric ulcer, but its molecular mechanism of anti-ulcer action is poorly understood. This research aimed to reveal the potential active components, core targets, and mechanisms of Aucklandiae Radix in treating gastric ulcer by combining network pharmacology and animal experimentation. Materials and Methods: First, a network pharmacology strategy was used to predict the main components, candidate targets, and potential signaling pathways. Molecular docking was then used to confirm the binding affinity between the main components and primary targets. Finally, rats were treated with indomethacin 30 mg/kg to establish a gastric ulcer model. Aucklandiae Radix extract (0.15, 0.3, and 0.6 g/kg) was pre-treated in rats by oral gavage for 14 days, and the protective effect and candidate targets of network pharmacology were validated through morphological observation, pathological staining, and biochemical index detection. Results: A total of eight potential active components and 331 predicted targets were screened from Aucklandiae Radix, 37 of which were common targets with gastric ulcer. According to the component–target network and protein-protein interaction (PPI) network, stigmasterol, mairin, sitosterol, and dehydrocostus lactone were identified as the key components, and RAC-alpha serine/threonine-protein kinase (AKT1), prostaglandin-endoperoxide synthase 2 (PTGS2), interleukin 1 beta (IL1B), caspase-3 (CASP3), and CASP8 were selected as the core targets. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment results revealed the pharmacological mechanism of Aucklandiae Radix against gastric ulcer related to many biological processes and pathways, including antibacterial, anti-inflammatory, prostaglandin receptor response, and apoptosis. Molecular docking verification showed that the key components and core targets had good binding affinities. In the in vivo experiments, Aucklandiae Radix notably relieved the gastric ulcer by reducing the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and myeloperoxidase (MPO) while improving the gastric histopathological features. Conclusion: The overall findings suggest that Aucklandiae Radix treats gastric ulcer with a multi-component, multi-target, and multi-mechanism model. Full article

Background: Dawa ul Kurkum (Duk) is a widely used Unani formulation. It consists of seven plant herbs, including stigmas of Crocus sativus L., rhizomes of Nardostachys jatamansi (D.Don) DC., the bark of Cinnamomum cassia (L.) J. Presl., shoot of Cymbopogon jwarancusa (Jones ex Roxb.) Schult., the resin of Commiphora wightii (Arn.) Bhandari, roots of Saussurea lappa (Decne.) Sch.Bip., and bark of Cinnamomum zeylanicum Blume. However, no study has been previously conducted to characterize this formulation. Thus, the present study was designed to carry out the pharmacognostic and phytochemical characterization of Duk. Methods: Duk was prepared following the protocols in Bayaz e Kabeer and The National Formulary of Unani Medicine Part-I. The characterization included organoleptic properties, fluorescence analysis, preliminary phytochemical screening, antioxidant activity, and active constituent profiling using HPTLC. Results: Evaluation of Duk showed the presence of carbohydrates, flavonoids, quinones, glycosides, cardiac glycosides, terpenoids, phenols, coumarin, steroids, and phytosterols. The total phenolic and flavonoid content was 5.75 ± 0.23 mg GAE/g and 10 ± 0.18 mg QUE/g, respectively. HPTLC of Duk showed the presence of p-coumaric acid, cinnamaldehyde, citral, crocin, isovaleric acid, guggulsterone, and dehydrocostus lactone. Conclusions: Our findings supported the use of Duk as a conventional medicine, and these results could be used as a reference for the standardization of Duk. Full article

Dehydrocostus lactone (DL) is among the representative ingredients of traditional Chinese medicine (TCM), with excellent anticancer, antibacterial, and anti-inflammatory activities. In this study, an advanced strategy based on ultra-high-performance liquid chromatography–quadrupole-Orbitrap high-resolution mass spectrometry (UHPLC–Q-Orbitrap HRMS) was integrated to comprehensively explore the metabolic fate of DL in rats. First, prior to data collection, all biological samples (plasma, urine, and feces) were concentrated and purified using solid-phase extraction (SPE) pre-treatment technology. Then, during data collection, in the full-scan (FS) data-dependent acquisition mode, FS-ddMS² was intelligently combined with FS-parent ion list (PIL)-dynamic exclusion (DE) means for targeted monitoring and deeper capture of more low-abundance ions of interest. After data acquisition, data-mining techniques such as high-resolution extracted ion chromatograms (HREICs), multiple mass defect filters (MMDFs), diagnostic product ions (DPIs), and neutral loss fragments (NLFs) were incorporated to extensively screen and profile all the metabolites in multiple dimensions. As a result, a total of 71 metabolites of DL (parent drug included) were positively or tentatively identified. The results suggested that DL in vivo mainly underwent hydration, hydroxylation, dihydrodiolation, sulfonation, methylation, dehydrogenation, dehydration, N-acetylcysteine conjugation, cysteine conjugation, glutathione conjugation, glycine conjugation, taurine conjugation, etc. With these inferences, we successfully mapped the “stepwise radiation” metabolic network of DL in rats, where several drug metabolism clusters (DMCs) were discovered. In conclusion, not only did we provide a refined strategy for inhibiting matrix effects and fully screening major-to-trace metabolites, but also give substantial data reference for mechanism investigation, in vivo distribution visualization, and safety evaluation of DL. Full article

An ancient saffron-based polyherbal formulation, Dawa-ul-Kurkum (DuK), has been used to treat liver ailments and other diseases and was recently evaluated for its anticancer potential against hepatocellular carcinoma (HCC) by our research team. To gain further insight into the lead molecule of DuK, we selected ten active constituents belonging to its seven herbal constituents (crocin, crocetin, safranal, jatamansone, isovaleric acid, cinnamaldehyde, coumaric acid, citral, guggulsterone and dehydrocostus lactone). We docked them with 32 prominent proteins that play important roles in the development, progression and suppression of HCC and those involved in endoplasmic reticulum (ER) stress to identify the binding interactions between them. Three reference drugs for HCC (sorafenib, regorafenib, and nivolumab) were also examined for comparison. The in silico studies revealed that, out of the ten compounds, three of them—viz., Z-guggulsterone, dehydrocostus lactone and crocin—showed good binding efficiency with the HCC and ER stress proteins. Comparison of binding affinity with standard drugs was followed by preliminary in vitro screening of these selected compounds in human liver cancer cell lines. The results provided the basis for selecting Z-guggulsterone as the best-acting phytoconstituent amongst the 10 studied. Further validation of the binding efficiency of Z-guggulsterone was undertaking using molecular dynamics (MD) simulation studies. The effects of Z-guggulsterone on clone formation and cell cycle progression were also assessed. The anti-oxidant potential of Z-guggulsterone was analyzed through DPPH and FRAP assays. qRTPCR was utilized to check the results at the in vitro level. These results indicate that Z-guggulsterone should be considered as the main constituent of DuK instead of the crocin in saffron, as previously hypothesized. Full article

Dehydrocostus lactone (DHL), a natural sesquiterpene lactone isolated from the traditional Chinese herbs Saussurea lappa and Inula helenium L., has important anti-inflammatory properties used for treating colitis, fibrosis, and Gram-negative bacteria-induced acute lung injury (ALI). However, the effects of DHL on Gram-positive bacteria-induced macrophage activation and ALI remains unclear. In this study, we found that DHL inhibited the phosphorylation of p38 MAPK, the degradation of IκBα, and the activation and nuclear translocation of NF-κB p65, but enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of Nrf2 and HO-1 in lipoteichoic acid (LTA)-stimulated RAW264.7 cells and primary bone-marrow-derived macrophages (BMDMs). Given the critical role of the p38 MAPK/NF-κB and AMPK/Nrf2 signaling pathways in the balance of M1/M2 macrophage polarization and inflammation, we speculated that DHL would also have an effect on macrophage polarization. Further studies verified that DHL promoted M2 macrophage polarization and reduced M1 polarization, then resulted in a decreased inflammatory response. An in vivo study also revealed that DHL exhibited anti-inflammatory effects and ameliorated methicillin-resistant Staphylococcus aureus (MRSA)-induced ALI. In addition, DHL treatment significantly inhibited the p38 MAPK/NF-κB pathway and activated AMPK/Nrf2 signaling, leading to accelerated switching of macrophages from M1 to M2 in the MRSA-induced murine ALI model. Collectively, these data demonstrated that DHL can promote macrophage polarization to an anti-inflammatory M2 phenotype via interfering in p38 MAPK/NF-κB signaling, as well as activating the AMPK/Nrf2 pathway in vitro and in vivo. Our results suggested that DHL might be a novel candidate for treating inflammatory diseases caused by Gram-positive bacteria. Full article

Inflammatory bowel disease (IBD) is a chronic relapsing disorder modulated by numerous factors. Recent failures of drugs targeting single factors suggest that multitargeting drugs could be useful for the treatment of IBD. Natural medicines may be an alternative option for the treatment of IBD, owing to the complex nature of the disease. However, most natural medicines have poor in vitro and in vivo translational potential because of inadequate pharmacokinetic study. KM1608, a mixture of the medicinal plants Aucklandia lappa, Terminalia chebula, and Zingiber officinale, was examined for its anti-colitis effects and biodistribution using bioimaging. Dehydrocostus lactone, as a marker compound, was analyzed to assess the biodistribution of KM1608. KM1608 significantly attenuated the disease activity of dextran sodium sulfate-induced colitis in mice and suppressed inflammatory mediators such as myeloperoxidase, proinflammatory cytokines (TNF-α and IL-6), and the Th2-type cytokine IL-4 in the colon. Optical fluorescence imaging revealed that KM1608 was distributed in the intestinal area as a target organ. Collectively, our findings suggest that KM1608 is a potential therapeutic formulation for IBD. Full article

Acute lung injury (ALI) is a severe clinical disease marked by dysregulated inflammation response and has a high rate of morbidity and mortality. Macrophages, which play diverse roles in the inflammatory response, are becoming therapeutic targets in ALI. In this study we investigated the effects of dehydrocostus lactone (DHL), a natural sesquiterpene, on macrophage activation and LPS-induced ALI. The macrophage cell line RAW264.7 and primary lung macrophages were incubated with DHL (0, 3, 5, 10 and 30 μmol/L) for 0.5 h and then challenged with LPS (100 ng/mL) for up to 8 hours. C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) to induce acute lung injury (ALI) and then treated with a range of DHL doses intraperitoneally (5 to 20 mg/kg). The results showed that DHL inhibited LPS-induced production of proinflammatory mediators such as iNOS, NO, and cytokines including TNF-α, IL-6, IL-1β, and IL-12 p35 by suppressing the activity of NF-κB via p38 MAPK/MK2 and Akt signaling pathway in macrophages. The in vivo results revealed that DHL significantly attenuated LPS-induced pathological injury and reduced cytokines expression in the lung. NF-κB, p38 MAPK/MK2 and Akt signaling molecules were also involved in the anti-inflammatory effect. Collectively, our findings suggested that DHL is a promising agent for alleviating LPS-induced ALI. Full article

Allelochemicals are the media of allelopathy and form the chemical bases of plant-environment interactions. To determine true allelochemicals and their autotoxic effects, seven compounds were isolated and identified from in-situ sampled rhizosphere soil of cultivated Saussurea lappa. Of these; costunolide (2), dehydrocostus lactone (3) and scopoletin (4) showed significant inhibition on seedling growth in a concentration-dependent manner. Detection and observation demonstrated that the antioxidase system was found to be affected by these chemicals, resulting in the accumulation of ROS and membrane damage. To investigate their release ways, the compounds were traced back and volumes quantified in rhizosphere soil and plant tissues. This work made clear the chemical bases and their physiological effects on the plants. These chemicals were found to be the secondary metabolites of the plants and included in the rhizosphere soil. The findings identified a potential pathway of plant-plant interactions, which provided theoretical basis to overcoming replanting problems. This research was also useful for exploring ecological effects of allelochemicals in green agriculture. Full article

Background: Commercial pharmaceutical herbal products have enabled people to take traditional Chinese medicine (TCM) in a convenient and accessible form. However, the quantity and quality should be additionally inspected. To address the issue, a combination of chemical and physical inspection methods were developed to evaluate the amount of an herbal formula, Xiang-Sha-Liu-Jun-Zi-Tang (XSLJZT), in clinical TCM practice. Methods: A high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS) method with electrospray ionization was developed to measure the herbal biomarkers of guanosine, atractylenolide III, glycyrrhizic acid, dehydrocostus lactone, hesperidin, and oleanolic acid from XSLJZT. Scanning electron microscopy (SEM) photographs and light microscopy photographs with Congo red and iodine–KI staining were used to identify the cellulose fibers and starch content. Furthermore, solubility analysis, swelling power test, and crude fiber analysis were contributed to measure the starch additive in pharmaceutical products. Results: The results demonstrated large variations in the chemical components of different pharmaceutical brands. The SEM photographs revealed that the starch was oval, smooth, and granular, and that the raw herbal powder appears stripy, stretched, and filiform. The stained light microscopy photographs of all of the pharmaceutical products showed added starch and raw herbal powder as extenders. Conclusion: The developed chemical and physical methods provide a standard operating procedure for the quantity control of the herbal pharmaceutical products of XSLJZT. Full article