Corosolic Acid Research Articles

Triterpenoids from Potentilla chinensis inhibit RANKL-induced osteoclastogenesis in vitro and lipopolysaccharide-induced osteolytic bone loss in vivo.

In this study, a phytochemical investigation on the methanol extract of Potentilla chinensis led to the isolation of eleven triterpenoids including ursolic acid (1), pomolic acid (2), tormentic acid (3), 2-epi-corosolic acid (4), 3-epi-corosolic acid (ECA, 5), 3β-hydroxyurs-11-en-13β(28)-olide (6), euscaphic acid (7), 2-epi-tormentic acid (8), corosolic acid (9), uvaol (10), and 3-O-acetylpomolic acid (11). Among them, ECA (5) showed potential anti-osteoclastogenic activity. To the best of our knowledge, this represents the first isolation of ECA (5) from P. chinensis as well as the first investigation of its effects on osteoclast formation. Further study revealed that ECA inhibited RANKL-induced mature osteoclast formation in vitro without compromising cell viability. Mechanistically, ECA attenuated RANKL-induced mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) activation, leading to the inhibition of c-Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) activation. Moreover, ECA protected against LPS-induced inflammatory bone loss and osteoclast formation in a mouse model. However, ECA did not inhibit LPS-induced inflammatory responses in macrophages. Our findings suggest that ECA mitigates LPS-induced inflammatory bone loss in mice by inhibiting RANKL-induced activation of key osteoclastogenic transcription factors, including c-Fos and NFATc1, and may be a potential natural triterpenoid for preventing or treating osteolytic diseases.

Change Patterns of Major Functional Components in the Loquat Summer Shoot Leaf during Annual Growth

Loquat leaves are widely used in traditional Chinese medicine and food processing as raw materials. To provide a theoretical basis for suitable harvesting periods based on the utilization of distinct components, the change patterns of major functional components in the annual growth of loquat leaves were investigated. In this study, the summer loquat leaves were sampled regularly during their annual growth, and the contents of seven main functional components and 13 monomer components were determined. The results showed that there was a regular change pattern for major functional components during loquat annual growth from Jul 2020 to Jun 2021; however, the change trend was different among different components. Among them, the contents of total flavonoids, total phenols, total triterpenoid acids, vitamin C, asiatic acid, quillaic acid, corosolic acid, and chlorogenic acid presented an overall upward trend. The content of maslinic acid showed a downward trend, whereas the content of neochlorogenic acid did not change much throughout the whole growth period. The content changes in the loquat leaves were affected by the light durations and temperature changes in different seasons, with mutual transit during the flowering and fruit growth processes. Sampling in May to June was found to be a most optimized option when applied in Chinese medicine processing; however, the degree of fibrosis is another indicator when it is used as food raw material. This study revealed the change pattern of major functional components of loquat leaves during the annual growth period and provides a theoretical basis for the reasonable harvesting period of loquat leaves as raw materials for processing different types of products.

Determination of triterpenic acids in Ribes stenocarpum maxim by HPLC-APCI-MS with 2-(12,13-dihydro-7H-dibenzo[a,g]carbazol-7-yl)ethyl4-methylben-zenesulfonate labelling agent

The study utilized a fluorescent labeling reagent called 2-(12,13-dihydro-7H-dibenzo[a,g]carbaz-ol-7-yl)ethyl4-methylben-zenesulfonate (DDCETS) to label of triterpenic acids and the approach was used to measure the amount of triterpenic acids in different organs of the Ribes stenocarpum Maxim. (RSM) from several areas in Qinghai Province. The analytical potential of the reagent was evaluated using six triterpene acids, namely maslinic acid, corosolic acid, betulinic acid, betulonic acid, oleanolic acid and ursolic acid. The results showed that the method successfully determined that the main components of triterpenoids in RSM from different regions of Qinghai Province were oleanolic acid and ursolic acid. The highest content of oleanolic acid and ursolic acid was 2037.59 mg/Kg in branches and 2088.97 mg/Kg in fruits. The least distributed organs of oleanolic acid and ursolic acid in the RSM in each region were seeds, with the lowest content of 460.88 mg/Kg in Dongxia Township, Datong County. And when analyzed in relation to the geographical conditions of the diverse origins, the fruits and leaves of the RSM were more abundant in both types of triterpene acids in areas with lower altitude, temperature and precipitation.

Corosolic acid inhibits EMT in lung cancer cells by promoting YAP-mediated ferroptosis

BackgroundCorosolic acid (CA), a naturally occurring pentacyclic triterpenoid is renowned for its anticancer attributes. Previous studies have predominantly centered on the anticancer properties of CA in lung cancer, specifically its role in inducing apoptosis, however, investigations regarding its involvement in ferroptosis have been scarce. MethodsThe apoptotic and proliferative effects were evaluated by CCK8 and colony formation assay. Cell death and ROS generation were measured to assess the response of CA to iron death induction. Scratch and invasion assays were performed to verify the effect of CA on the invasive ability of lung cancer cells. Protein and mRNA expression were analyzed using Western blotting and qPCR. The CHX assay was carried out to detect protein half-life. Metabolite levels were measured with appropriate kits. Protein expression was detected through IF and IHC. A xenograft tumor model was established to investigate the inhibitory effect of CA on lung cancer in vivo. ResultsThe current findings revealed that CA exerts its anticancer effect by inducing cell death, accompanied by the accumulation of lipid reactive oxygen species (ROS), hinting at the possible involvement of ferroptosis. Our experimental results further substantiated the significance of ferroptosis in the CA anticancer mechanism, as ferroptosis inhibitors were found to effectively rescue CA-induced cell death. Significantly, we demonstrated for the first time that CA could induce ferroptosis further by suppressing EMT in lung cancer cells. Additionally, CA could regulate GPX4 to induce ferroptosis, interestingly, CA downregulated GSH synthetase by inhibiting YAP rather than GPX4, thereby reducing GSH, inducing ferroptosis, and further suppressing EMT in lung cancer cells.We also discovered that GSS is a crucial downstream target of YAP in regulating GSH. Moreover, a xenograft mouse model indicated that CA could trigger ferroptosis in lung cancer cells by regulating YAP expression and GSH levels. ConclusionCA inhibited lung cancer cell metastasis by inducing ferroptosis. Our data offer the first evidence that CA induces ferroptosis in lung cancer cells by regulating YAP/GSS to modulate GSH, thereby further suppressing EMT. These results imply the potential of CA as an inducer of ferroptosis to inhibit lung cancer metastasis.

Pentacyclic Triterpenoid Content in Cranberry Raw Materials and Products

Cranberry fruit extracts have been shown to inhibit expression of pro-inflammatory cytokines in THP-1 cells and reduce colonic tumor burden and tissue inflammation in a mouse model of colitis. These activities are attributed to both the triterpenoid and polyphenol constituents of the fruit. The pentacyclic triterpenoids ursolic acid (UA), oleanolic acid (OA), corosolic acid (CA), maslinic acid (MA), and esters of UA and OA occur in the waxy layer of cranberry peel, and their content in cranberry products is likely to vary with the fruit source and processing methods. UPLC-MS (ultra performance liquid chromatography-mass spectrometry) was applied to determine the four triterpenoid acids and their esters in cranberry products and raw materials. Cranberry pomace, a side stream in juice production, was a rich source at 64,090 µg total triterpenoids/g DW. Cranberry juice beverages ranged from 0.018 to 0.26 µg/g of product, fruit samples ranged from 6542 to 17,070 µg/g DW, and whole berry products contained up to 2665 µg/g DW. Free UA was the most plentiful triterpenoid in all samples. These analyses illustrate the potential value of an underutilized side stream in cranberry juice production and highlight potential benefits of whole fruit products.

Preparation, process optimisation, stability and bacteriostatic assessment of composite nanoemulsion containing corosolic acid

Corosolic acid (CA), a pentacyclic triterpenoid, exhibits remarkably low hydrophilicity, restricting its application in aqueous systems. To enhance its hydrophilicity, we optimised nanoemulsion preparation conditions, resulting in a stable corosolic acid nanoemulsion system. By screening the oil phase, surfactant, and cosurfactant, along with investigating the mass ratio of surfactant and cosurfactant and the preparation temperature, we achieved an optimal corosolic acid nanoemulsion. We measured the particle size, polydispersity coefficient, and Zeta potential of the optimised formulation. The nanoemulsion's sustained-release effect, stability, and antibacterial activity were subsequently examined. The optimised formulation comprised ethyl oleate, cremophor EL, and Tween 80 (1.5:1), combined with ethanol in a ratio of 1:9:2.25 (w/w/w), and was prepared at 30 °C. This optimised corosolic acid nanoemulsion exhibited uniform particle size distribution, favourable dispersion, and notable slow-release capabilities. Importantly, the nanoemulsion demonstrated exceptional stability. In comparison to the positive control's bacteriostatic zone diameter, it was evident that the CA nanoemulsion (1.06 ± 0.11 mm) and blank nanoemulsion (1.03 ± 0.05 mm) both displayed notable inhibitory activity against S. aureus. Our findings established a solid foundation for the potential application of CA nanoemulsion in the food, cosmetics, and pharmaceutical industries. However, the application of CA nanoemulsion in real food or drug systems has not been explored yet.

Identification of Bioactive Substances Derived from the Probiotic-Induced Bioconversion of Lagerstroemia speciosa Pers. Leaf Extract That Have Beneficial Effects on Diabetes and Obesity.

Lagerstroemia speciosa L. (Banaba) has been used as a functional food because of its diuretic, decongestant, antipyretic, anti-hyperglycemic, and anti-adipogenic activities. Triterpene acids, including corosolic acid, oleanolic acid, and asiatic acid, are the principal phytochemicals in Banaba and are potentially anti-diabetic substances, owing to their effect on blood glucose concentration. Bioconversion of Banaba leaf extract (BLE) by Lactobacillus plantarum CBT-LP3 improved the glucose uptake, insulin secretion, and fat browning of this functional food. Furthermore, we identified asiatic acid, which was found to be increased by 3.8-fold during the L. plantarum CBT-LP3-mediated bioconversion process using metabolite profiling. Most previous studies have focused on corosolic acid, another triterpene acid that is a known anti-diabetic compound and is used to standardize BLE preparations. However, asiatic acid is the second most common of the triterpene acids and is also well known to have anti-diabetic properties. The present study has provided strong evidence that asiatic acid represents an alternative to corosolic acid as the most important active compound. These results suggest that the probiotic-mediated bioconversion of BLE may improve the anti-diabetic effects of this functional food. This implies that the consumption of a probiotic should be encouraged for people undergoing BLE treatment to improve its anti-diabetic effects.

Two novel compounds inhibit Flavivirus infection in vitro and in vivo by targeting lipid metabolism.

This study is the inaugural utilization of a lipid compound library in antiviral drug screening. Two lipid compounds, isobavachalcone (IBC) and corosolic acid (CA), emerged from the screening, exhibiting substantial inhibitory effects on the Japanese encephalitis virus (JEV) proliferation in vitro. In vivo experiments underscored their efficacy, with IBC and CA reducing viral loads in the brain and mitigating JEV-induced histopathological changes, effectively shielding mice from fatal JEV infection. Intriguingly, IBC and CA may activate 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) by binding to its active site, curtailing the synthesis of lipid substances, and thus suppressing JEV proliferation. This indicates AMPK as a potential antiviral target. Remarkably, IBC and CA demonstrated suppression of multiple viruses, including Flaviviruses (JEV and Zika virus), porcine herpesvirus (pseudorabies virus), and coronaviruses (porcine deltacoronavirus and porcine epidemic diarrhea virus), suggesting their potential as broad-spectrum antiviral agents. These findings shed new light on the potential applications of these compounds in antiviral research.

Synthesis and comparative analysis of the cytotoxicity and mitochondrial effects of triphenylphosphonium and F16 maslinic and corosolic acid hybrid derivatives

The cytotoxic profile and antiproliferative and mitochondrial effects of triterpene acid conjugates with mitochondriotropic lipophilic triphenylphosphonium (TPP+) and F16 cations were evaluated. Maslinic and corosolic acids chosen as the investigation objects were synthesized from commercially available oleanolic and ursolic acids. Study of the cytotoxic activity of TPP+ and F16 triterpenoid derivatives against six tumor cell lines demonstrated a comparable synergistic effect in the anticancer activity, which was most pronounced in the case of MCF-7 mammary adenocarcinoma cells and Jurkat and THP-1 leukemia cells. The corosolic and maslinic acid hybrid derivatives caused changes in the progression of tumor cell cycle phases when present in much lower doses than their natural triterpene acid precursors. The treatment of tumor cell lines with the conjugates resulted in the cell cycle arrest in the G1 phase and increase in the cell population in the subG1 phase. The cationic derivatives of the acids were markedly superior to their precursors as inducers of hyperproduction of reactive oxygen species and more effectively decreased the mitochondrial potential in isolated rat liver mitochondria. We concluded that the observed cytotoxic effect of TPP+ and F16 triterpenoid conjugates is attributable to the ability of these compounds to initiate mitochondrial dysfunctions. Their cytotoxicity, antiproliferative action, and mitochondrial effects depend little on the type of cationic groups used.

Systematic Review of Chemical Compounds with Immunomodulatory Action Isolated from African Medicinal Plants.

A robust, well-functioning immune system is the cornerstone of good health. Various factors may influence the immune system's effectiveness, potentially leading to immune system failure. This review aims to provide an overview of the structure and action of immunomodulators isolated from African medicinal plants. The research was conducted according to PRISMA guidelines. Full-text access research articles published in English up to December 2023, including plant characteristics, isolated phytochemicals, and immuno-modulatory activities, were screened. The chemical structures of the isolated compounds were generated using ChemDraw® (version 12.0.1076), and convergent and distinctive signaling pathways were highlighted. These phytochemicals with demonstrated immunostimulatory activity include alkaloids (berberine, piperine, magnoflorine), polysaccharides (pectin, glucan, acemannan, CALB-4, GMP90-1), glycosides (syringin, cordifolioside, tinocordiside, aucubin), phenolic compounds (ferulic acid, vanillic acid, eupalitin), flavonoids (curcumin, centaurein, kaempferin, luteolin, guajaverin, etc.), terpenoids (oleanolic acid, ursolic acid, betulinic acid, boswellic acids, corosolic acid, nimbidin, andrographolides). These discussed compounds exert their effects through various mechanisms, targeting the modulation of MAPKs, PI3K-Akt, and NF-kB. These mechanisms can support the traditional use of medicinal plants to treat immune-related diseases. The outcomes of this overview are to provoke structural action optimization, to orient research on particular natural chemicals for managing inflammatory, infectious diseases and cancers, or to boost vaccine immunogenicity.

Comparative transcriptome and metabolite profiling reveal diverse pattern of CYP-TS gene expression during corosolic acid biosynthesis in Lagerstroemia speciosa (L.) Pers.

Extensive leaf transcriptome profiling and differential gene expression analysis of field grown and elicited shoot cultures of L. speciosa suggest that differential synthesis of CRA is mediated primarily by CYP and TS genes, showing functional diversity. Lagerstroemia speciosa L. is a tree species with medicinal and horticultural attributes. The pentacyclic triterpene, Corosolic acid (CRA) obtained from this species is widely used for the management of diabetes mellitus in traditional medicine. The high mercantile value of the compound and limited availability of innate resources entail exploration of alternative sources for CRA production. Metabolic pathway engineering for enhanced bioproduction of plant secondary metabolites is an attractive proposition for which, candidate genes in the pathway need to be identified and characterized. Therefore, in the present investigation, we focused on the identification of cytochrome P450 (CYP450) and oxidosqualene cyclases (OSC) genes and their differential expression during biosynthesis of CRA. The pattern of differential expression of these genes in the shoot cultures of L. speciosa, elicited with different epigenetic modifiers (azacytidine (AzaC), sodium butyrate (NaBu) and anacardic acid (AA)), was studied in comparison with field grown plant. Further, in vitro cultures with varying (low to high) concentrations of CRA were systematically assessed for the expression of CYP-TS and associated genes involved in CRA biosynthesis by transcriptome sequencing. The sequenced samples were de novo assembled into 180,290 transcripts of which, 92,983 transcripts were further annotated by UniProt. The results are collectively given in co-occurrence heat maps to identify the differentially expressed genes. The combined transcript and metabolite profiles along with RT-qPCR analysis resulted in the identification of CYP-TS genes with high sequence variation. Further, instances of concordant/discordant relation between CRA biosynthesis and CYP-TS gene expression were observed, indicating functional diversity in genes.

Corosolic acid attenuates platelet-derived growth factor signaling in macrophages and smooth muscle cells of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease that is characterized by vascular remodeling of the pulmonary artery. Pulmonary vascular remodeling is primarily caused by the excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), which are facilitated by perivascular inflammatory cells including macrophages. Corosolic acid (CRA) is a natural pentacyclic triterpenoid that exerts anti-inflammatory effects. In the present study, the effects of CRA on the viability of macrophages were examined using monocrotaline (MCT)-induced PAH rats and human monocyte-derived macrophages. Although we previously reported that CRA inhibited signal transducer and activator of transcription 3 (STAT3) signaling and ameliorated pulmonary vascular remodeling in PAH, the inhibitory mechanism remains unclear. Therefore, the underlying mechanisms were investigated using PASMCs from idiopathic PAH (IPAH) patients. In MCT-PAH rats, CRA inhibited the accumulation of macrophages around remodeled pulmonary arteries. CRA reduced the viability of human monocyte-derived macrophages. In IPAH-PASMCs, CRA attenuated cell proliferation and migration facilitated by platelet-derived growth factor (PDGF)-BB released from macrophages and PASMCs. CRA also downregulated the expression of PDGF receptor β and its signaling pathways, STAT3 and nuclear factor-κB (NF-κB). In addition, CRA attenuated the phosphorylation of PDGF receptor β and STAT3 following the PDGF-BB simulation. The expression and phosphorylation levels of PDGF receptor β after the PDGF-BB stimulation were reduced by the small interfering RNA knockdown of NF-κB, but not STAT3, in IPAH-PASMCs. In conclusion, CRA attenuated the PDGF-PDGF receptor β-STAT3 and PDGF-PDGF receptor β-NF-κB signaling axis in macrophages and PASMCs, and thus, ameliorated pulmonary vascular remodeling in PAH.

Exploring the Mechanisms of Traditional Chinese Herbal Therapy in Gastric Cancer: A Comprehensive Network Pharmacology Study of the Tiao-Yuan-Tong-Wei decoction.

The use of herbal medicine as an adjuvant therapy in the management of gastric cancer has yielded encouraging outcomes, notably in enhancing overall survival rates and extending periods of disease remission. Additionally, herbal medicines have demonstrated potential anti-metastatic effects in gastric cancer. Despite these promising findings, there remains a significant gap in our understanding regarding the precise pharmacological mechanisms, the identification of specific herbal compounds, and their safety and efficacy profiles in the context of gastric cancer therapy. In addressing this knowledge deficit, the present study proposes a comprehensive exploratory analysis of the Tiao-Yuan-Tong-Wei decoction (TYTW), utilizing an integrative approach combining system pharmacology and molecular docking techniques. This investigation aims to elucidate the pharmacological actions of TYTW in gastric pathologies. It is hypothesized that the therapeutic efficacy of TYTW in counteracting gastric diseases stems from its ability to modulate key signaling pathways, thereby influencing PIK3CA activity and exerting anti-inflammatory effects. This modulation is observed predominantly in pathways such as PI3K/AKT, MAPK, and those directly associated with gastric cancer. Furthermore, the study explores how TYTW's metabolites (agrimoniin, baicalin, corosolic acid, and luteolin) interact with molecular targets like AKT1, CASP3, ESR1, IL6, PIK3CA, and PTGS2, and their subsequent impact on these critical pathways and biological processes. Therefore, this study represents preliminary research on the anticancer molecular mechanism of TYTW by performing network pharmacology and providing theoretical evidence for further experimental investigations.

Morphology, anatomy, and quantitative determination of corosolic acid in Lagerstroemia calyculata Kurz in the Southeast region, Vietnam

Objectives: To describe the morphological characteristics, anatomy (stem, leaves), and quantify the corosolic acid in the leaves of Lagerstroemia calyculata Kurz collected in the Southeast region, Vietnam. Subjects and methods: Using the comparative morphological method to determine the scientific name of species. Studying the microscopic characteristics of Lagerstroemia calyculataKurz according to the research method of N. Ba (2009) [1] and quantifying the content of corosolic acid in the leaves according to the United States Pharmacopeia 2017 (USP 40), with adjustments to suit the conditions of the laboratory. Results: Lagerstroemia calyculata Kurz is tree, deciduous, height 30-35 m, smooth bark. Leaves lanceolate, lateral veins 9-11 pairs, hairy. Inflorescence paniculate, small white flowers. Capsules ovoid, 6-valved. Seeds are numerous, brown, and smooth. The stem has a bicollateral vascular bundle, conduction tissue arranged continuously, double phloem pillars and leaf veins exposed on both sides. The outer epidermis has multicellular stellate hairs. Scattered in soft tissue there are crystalline particles. Stomata are present only on the underside of leaves. The quantification of corosolic acid in three leaf samples of Lagerstroemia calyculata Kurz was from 0.05 to 0.12%. Conclusions: This study has detailed morphological, anatomical characteristics, and quantitative determination of corosolic acid in three leaf samples of Lagerstroemia calyculata Kurz collected in the Southeast region.

Integrated virtual screening and in vitro studies for exploring the mechanism of triterpenoids in Chebulae Fructus alleviating mesaconitine-induced cardiotoxicity via TRPV1 channel.

Background: In traditional Mongolian or Tibetan medicine in China, Chebulae Fructus (CF) is widely used to process or combine with aconitums to decrease the severe toxicity of aconitums. Researches in this area have predominantly focused on tannins, with few research on other major CF components for cardiotoxicity mitigation. The present study aimed to clarify whether triterpenoids can attenuate the cardiotoxicity caused by mesaconitine (MA) and investigate the mechanism of cardiotoxicity attenuation. Methods: Firstly, the pharmacophore model, molecular docking, and 3D-QSAR model were used to explore the mechanism of CF components in reducing the toxicity of MA mediated by the TRPV1 channel. Then three triterpenoids were selected to verify whether the triterpenoids had the effect of lowering the cardiotoxicity of MA using H9c2 cells combined with MTT, Hoechst 33258, and JC-1. Finally, Western blot, Fluo-3AM, and MTT assays combined with capsazepine were used to verify whether the triterpenoids reduced H9c2 cardiomyocyte toxicity induced by MA was related to the TRPV1 channel. Results: Seven triterpenoids in CF have the potential to activate the TRPV1 channel. And they exhibited greater affinity for TRPV1 compared to other compounds and MA. However, their activity was relatively lower than that of MA. Cell experiments revealed that MA significantly reduced H9c2 cell viability, resulting in diminished mitochondrial membrane potential and nuclear pyknosis and damage. In contrast, the triterpenoids could improve the survival rate significantly and counteract the damage of MA to the cells. We found that MA, arjungenin (AR), and maslinic acid (MSA) except corosolic acid (CRA) upregulated the expression of TRPV1 protein. MA induced a significant influx of calcium, whereas all three triterpenoids alleviated this trend. Blocking the TRPV1 channel with capsazepine only increased the cell viability that had been simultaneously treated with MA, and AR, or MSA. However, there was no significant difference in the CRA groups treated with or without capsazepine. Conclusion: The triterpenoids in CF can reduce the cardiotoxicity caused by MA. The MSA and AR function as TRPV1 agonists with comparatively reduced activity but a greater capacity to bind to TRPV1 receptors, thus antagonizing the excessive activation of TRPV1 by MA.

Corosolic acid enhances oxidative stress-induced apoptosis and senescence in pancreatic cancer cells by inhibiting the JAK2/STAT3 pathway.

Pancreatic cancer (PC) is a fatal human malignancy with a poor prognosis. Corosolic acid (CRA) is a triterpenoid, has been reported to have inhibitory effects on tumor growth. However, the role of CRA on PC has not been explored. Here, we aimed to uncover the molecular mechanisms of CRA in PC progression. Cell viability, lactate dehydrogenase (LDH) release, cell apoptosis and senescence were detected by cell counting kit-8 (CCK-8), LDH, flow cytometry and senescence associated-β-galactosidase (SA-β-gal) assay. Levels of relevant proteins and oxidative stress (OS) markers were evaluated by Western blot and enzyme-linked immunosorbent assay (ELISA). A xenograft tumor model was established to explore the in vivo effects of CRA on PC. We found that CRA inhibited PC cell viability and promoted LDH release in a dose-dependent manner, but had no significant effect on human normal pancreatic ductal epithelial cells HPDE6C7. CRA increased OS-induced cell apoptosis and senescence in HAPC and SW1990 cells. And CRA decreased the levels of anti-apoptotic protein Bcl-2, and elevated the expression of pro-apoptotic protein Bax and senescence-associated proteins P21 and P53. Besides, CRA decreased tumor growth in xenograft models. Furthermore, CRA inactivated the Janus kinase-2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway in HAPC and SW1990 cells. Functional experiments demonstrated that activation of the JAK2/STAT3 pathway by the JAK2 activator coumermycin A1 (C-A1) or the STAT3 activator colivelin (col) reduced the contribution effect of OS, apoptosis and senescence by CRA. Taken together, our findings indicated that CRA exerted anti-cancer effects in PC by inhibiting the JAK2/STAT3 pathway.

DOCKING AND MD OF GOTU KOLA (Centella asiatica L.) COMPOUNDS TO AT1 RECEPTORS AS ANTIHYPERTENSIVES

Non-communicable diseases, including hypertension, are a significant source of health issues in developed nations[MOU1] . Angiotensin II Receptor Blocker (ARB) is frequently used as the first-line treatment for hypertension. ARB works by inhibiting Angiotensin II which can cause vasoconstriction of entire blood vessels[l2] . This study aimed to find lead compound of 54 compounds obtained from gotu kola (Centella asiatica L.) in order to determine the antihypertensive activity. The target of drug action chosen in this study was the type 1 angiotensin II receptors (AT1). Molecular docking and molecular dynamics simulation were chosen as the methods in this study to predict the interaction and the affinity and stability of the interaction. Based on the results of molecular docking, it was found that the compound of campesterol, centellasaponin B, and corosolic acid gave good affinity to the targets. The test ligand that the Ki and DG values were close to the natural ligand (Olmesartan) campesterol with a value of -10.79 kcal/mol and 12.28 nM. Meanwhile, in the molecular dynamics simulation test, it was found that corosolic acid has good interaction stability with the targets and was constant from the beginning of the simulation to 100 ns, while for MMGBSA centellasaponin B the lowest total energy value was -71.4347 kcal/mol. It was concluded that the gotu kola (Centella asiatica L.), compound corosolic acid, and centellasaponin B had the potential as a lead compound that had affinity and stability for the interaction with the AT1 receptor as antihypertensives.

Sustainable methods for the carboxymethylation and methylation of ursolic acid with dimethyl carbonate under mild and acidic conditions.

Ursolic acid is a triterpene plant extract that exhibits significant potential as an anti-cancer, anti-tumour, and anti-inflammatory agent. Its direct use in the pharmaceutical industry is hampered by poor uptake of ursolic acid in the human body coupled with rapid metabolism causing a decrease in bioactivity. Modification of ursolic acid can overcome such issues, however, use of toxic reagents, unsustainable synthetic routes and poor reaction metrics have limited its potential. Herein, we demonstrate the first reported carboxymethylation and/or methylation of ursolic acid with dimethyl carbonate (DMC) as a green solvent and sustainable reagent under acidic conditions. The reaction of DMC with ursolic acid, in the presence of PTSA, ZnCl2, or H2SO4-SiO2 yielded the carboxymethylation product 3β-[[methoxy]carbonyl]oxyurs-12-en-28-oic acid, the methylation product 3β-methoxyurs-12-en-28-oic acid and the dehydration product urs-2,12-dien-28-oic acid. PTSA demonstrated high conversion and selectivity towards the previously unreported carboxymethylation of ursolic acid, while the application of formic acid in the system led to formylation of ursolic acid (3β-formylurs-12-en-28-oic acid) in quantitative yields via esterification, with DMC acting solely as a solvent. Meanwhile, the methylation product of ursolic acid, 3β-methoxyurs-12-en-28-oic acid, was successfully synthesised with FeCl3, demonstrating exceptional conversion and selectivity, >99% and 99%, respectively. Confirmed with the use of qualitative and quantitative green metrics, this result represents a significant improvement in conversion, selectivity, safety, and sustainability over previously reported methods of ursolic acid modification. It was demonstrated that these methods could be applied to other triterpenoids, including corosolic acid. The study also explored the potential pharmaceutical applications of ursolic acid, corosolic acid, and their derivatives, particularly in anti-inflammatory, anti-cancer, and anti-tumour treatments, using molecular ADMET and docking methods. The methods developed in this work have led to the synthesis of novel molecules, thus creating opportunities for the future investigation of biological activity and the modification of a wide range of triterpenoids applying acidic DMC systems to deliver novel active pharmaceutical intermediates.

Corosolic Acid Induced Apoptosis via Upregulation of Bax/Bcl-2 Ratio and Caspase-3 Activation in Cholangiocarcinoma Cells.

Cholangiocarcinoma (CCA), an aggressive malignancy arising from the biliary epithelium, exhibits a high incidence in Thailand. CCA usually lacks specific symptoms and is typically diagnosed in its advanced stages, presenting significant treatment challenges. Current CCA therapeutic options, including surgery, chemotherapy, and radiation, have limited success rates and often cause side effects. Nature-derived compounds hold promise for reducing undesirable adverse effects and are an excellent source of anticancer drugs. Corosolic acid (CA), a triterpenoid found in Lagerstroemia speciosa L. leaves, exhibits anticancer properties; however, the effectiveness of CA against CCA and its molecular mechanisms remained unexplored. Herein, the anti-CCA and apoptosis-inducing effects of CA were investigated using various techniques, i.e., the MTT assay, flow cytometry with FITC-labeled Annexin V (Annexin V-FITC) and propidium iodide double staining, JC-1 staining, western blot analysis, caspase-3 activity assay, and molecular dynamics (MD) simulations. CA inhibited the proliferation of KKU-213A and KKU-213B CCA cells and triggered apoptosis through alterations in mitochondrial membrane potential (ΔΨm), and increases in the Bax/Bcl-2 expression ratio, cytochrome c release, and caspase-3 activity. As indicated by MD simulations, CA has the potential to bind to Bcl-2 through hydrogen bonds between amino acid residues R146 and N143. These findings underscore the potential of CA as a promising candidate for treatment of CCA.

Psiguanol, a novel α-pyrone derivative from Psidium guajava leaves and vasorelaxant activity in rat aorta cells through intracellular cGMP-dependent opening of calcium channels

The phytochemical investigation of Psidium guajava leaves led to the isolation of total nineteen compounds which belongs to meroterpenoids, flavonoid, phenolics, and triterpenoids. The compounds were isolated using extensive chromatography techniques and identified as psiguanol (4), as new compound along with guajadial (1), psidial A (2), β-caryophyllene (3), quercetin (5), avicularin (6), guaijaverin (7), hyperin (8), rutin (9), ursolic acid (10), corosolic acid (11), asiatic acid (12), β-sitosterol (13), β-sitosterol-D-glucoside (14), ellagic acid (15), 3,3',4'-trimethylellagic acid 4-O-glucoside (16), protocatechuic acid (17), gallic acid (18), and tricosanoic acid (19) as known molecules. The compound 16 was isolated for the first time from this plant. The isolated compounds were evaluated for vasorelaxation activity in rat aorta cells and it was observed that compound 4 exhibited the most potent vasorelaxation response in the ex-vivo model in isolated rat aorta cells. Mechanistically, the vasorelaxation activity of 4 was mediated through cGMP-dependent BKCa channel opening.