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Cancer is a multifactorial disease characterized by various hallmarks, including uncontrolled cell growth, evasion of apoptosis, sustained angiogenesis, tissue invasion, and metastasis, among others. Traditional cancer therapies often target specific hallmarks, leading to limited efficacy and the development of resistance. Thus, there is a growing need for alternative strategies that can address multiple hallmarks concomitantly. Ursolic acid (UA), a naturally occurring pentacyclic triterpenoid, has recently emerged as a promising candidate for multitargeted cancer therapy. This review aims to summarize the current knowledge on the anticancer properties of UA, focusing on its ability to modulate various cancer hallmarks. The literature reveals that UA exhibits potent anticancer effects through diverse mechanisms, including the inhibition of cell proliferation, induction of apoptosis, suppression of angiogenesis, inhibition of metastasis, and modulation of the tumor microenvironment. Additionally, UA has demonstrated promising activity against different cancer types (e.g., breast, lung, prostate, colon, and liver) by targeting various cancer hallmarks. This review discusses the molecular targets and signaling pathways involved in the anticancer effects of UA. Notably, UA has been found to modulate key signaling pathways, such as PI3K/Akt, MAPK/ERK, NF-κB, and Wnt/β-catenin, which play crucial roles in cancer development and progression. Moreover, the ability of UA to destroy cancer cells through various mechanisms (e.g., apoptosis, autophagy, inhibiting cell growth, dysregulating cancer cell metabolism, etc.) contributes to its multitargeted effects on cancer hallmarks. Despite promising anticancer effects, this review acknowledges hurdles related to UA's low bioavailability, emphasizing the need for enhanced therapeutic strategies. [ABSTRACT FROM AUTHOR]

Melanoma is one of the most dangerous forms of skin cancer, characterized by early metastasis and rapid development. In search for effective treatment options, much attention is given to triterpenoids of plant origin, which are considered promising drug candidates due to their well described anticancer properties and relatively low toxicity. This paper comprehensively summarizes the antimelanoma potential of natural triterpenoids, that are also used as scaffolds for the development of more effective derivatives. These include betulin, betulinic acid, ursolic acid, maslinic acid, oleanolic acid, celastrol and lupeol. Some lesser-known triterpenoids that deserve attention in this context are 22β-hydroxytingenone, cucurbitacins, geoditin A and ganoderic acids. Recently described mechanisms of action are presented, together with the results of preclinical in vitro and in vivo studies, as well as the use of drug delivery systems and pharmaceutical technologies to improve the bioavailability of triterpenoids. This paper also reviews the most promising structural modifications, based on structure–activity observations. In conclusion, triterpenoids of plant origin and some of their semi-synthetic derivatives exert significant cytotoxic, antiproliferative and chemopreventive effects that can be beneficial for melanoma treatment. Recent data indicate that their poor solubility in water, and thus low bioavailability, can be overcome by complexing with cyclodextrins, or the use of nanoparticles and ethosomes, thus making these compounds promising antimelanoma drug candidates for further development. [ABSTRACT FROM AUTHOR]

The results of the most recent investigation of triterpenoid-based antiviral agents namely in the HIV-1 and HSV-1 treatment were reviewed and summarized. Several key historical achievements are included to stress consequences and continuity in this research. Most of the agents studied belong to a series of compounds derived from betulin or betulinic acid, and their synthetic derivative is called bevirimat. A termination of clinical trials of bevirimat in Phase IIb initiated a search for more successful compounds partly derived from bevirimat or designed independently of bevirimat structure. Surprisingly, a majority of bevirimat mimics are derivatives of betulinic acid, while other plant triterpenoids, such as ursolic acid, oleanolic acid, glycyrrhetinic acid, or other miscellaneous triterpenoids, are relatively rarely involved in a search for a novel antiviral agent. Therefore, this review article is divided into three parts based on the leading triterpenoid core structure. [ABSTRACT FROM AUTHOR]

Ursolic acid (UA) is a pentacyclic triterpenoid, which exhibits many biological activities, particularly in anti‐cardiovascular and anti‐diabetes. The further application of UA is greatly limited due to its low bioavailability and poor water solubility. Up to date, various UA derivatives have been designed to overcome these shortcomings. In this paper, the authors reviewed the development of UA derivatives as the anti‐diabetes anti‐cardiovascular reagents. [ABSTRACT FROM AUTHOR]

Heliotropium elongatum is used to treat inflammation, cough, and flu. This study aimed to characterize the phytochemical profile and determine the total phenolic content (TPC), antioxidant and cytogenotoxic activity of the ethanolic extract (EE), and fractions of H. elongatum leaves. In the phytochemical profile analysis, organic acids, reducing sugars, flavonoids, saponins, anthraquinones, steroids/triterpenes, and depsides/depsidones were detected in the EE and/or fractions (hexanic/FH, chloroformic/FC, ethyl acetate/FAE, and hydromethanolic/FHM). The highest TPC and highest antioxidant activity (DPPH and ABTS) was detected in FHM. In FH, 16 compounds were identified by GC-MS, and ursolic acid was isolated by 1H NMR and 13C NMR. HPLC-DAD from EE, FAE, and FHM demonstrated characteristic wavelengths for flavonoids, flavonols, flavones, and anthraquinones. ESI-IT/MSn analysis of EE, FC, FAE, and FHM revealed alkaloids, steroids, terpenoids, flavonoids, and phenolic acids. In Allium cepa assay there was no significant cytotoxic effect initiated by EE (62.5 to 1,000 µg/ml), FHM (1,000 µg/ml), and FAE (62.5 µg/ml). Genotoxicity was evidenced only with EE at 500 and 1,000 µg/ml, and FHM (62.5 to 1,000 µg/ml) as evidenced by presence of micronuclei (MN) and nuclear buds (NB). Our results identified compounds of medicinal interest with antioxidant activity; however observed cytogenotoxic changes indicated the need for caution when using these compounds for therapeutic purposes. [ABSTRACT FROM AUTHOR]

Triterpenic acids, specifically Betulinic, Oleanolic, and Ursolic acids, are essential bioactive compounds found in jujube Ziziphus jujuba mill. fruit, possessing therapeutic properties for various diseases, including cancer. However, the amount of these triterpenic acids can vary depending on geographical and cultivation conditions. For this purpose, jujubes grown in orchards of 29 different habitats in different provinces located in the east, northeast, south, center, and west of Iran were sampled at the end of the summer season. The triterpenic acids present in the dried jujube powder were extracted using 96% ethanol as a solvent, with a liquid-to-solid ratio of 15 mL/g, under ultrasonic waves at a temperature of 40 ℃ for 35 minutes. The extracted acids were quantified using high-performance liquid chromatography coupled with a UV detector. The obtained data were subjected to subsequent nested analysis and the Tukey test. The results revealed that only the average amount of betulinic acid significantly varied among the ecotypes. Furthermore, a hierarchical cluster analysis based on the diversity of these three triterpenic acids, the studied ecotypes were divided into four clusters. Cluster 1, representing Iran's eastern and northeastern regions, exhibited the highest amounts of these triterpenic acids. However, the analysis of variance among the clusters showed no significant difference among them. The results showed that the climatic conditions, soil quality, seed, and agricultural methods can be effective in changing or not changing the amounts of triterpenic acids in jujube. [ABSTRACT FROM AUTHOR]

In response to the reduction of food production and economic losses caused by plant bacterial diseases, it is necessary to develop new, efficient, and green pesticides. Natural products are rich and sustainable source for the development of new pesticides due to their low toxicity, easy degradation, and eco-friendliness. In this study, we prepared three series of ursolic acid derivatives and assessed their antibacterial ability. Most target compounds exhibited outstanding antibacterial activities. Among them, the relative optimal EC50 values of Xanthomonas oryzae pv. oryzae and Xanthomonas axonopodis pv. citri were 2.23 (A17) and 1.39 (A16) µg·mL−1, respectively. The antimicrobial mechanism showed that compound A17 induced an excessive accumulation and production of reactive oxygen species in bacteria and damaged the cell membrane integrity to kill bacteria. More interestingly, the addition of low concentrations of exogenous hydrogen peroxide enhanced the antibacterial efficacy of compound A17 against Xanthomonas oryzae pv. oryzae. These entertaining results suggested that compound A17 induced an apparent apoptotic behavior in the tested bacteria. Overall, we developed the promising antimicrobial agents that destroyed the redox system of phytopathogenic bacteria, further demonstrating the unprecedented potential of ursolic acid for agricultural applications. [ABSTRACT FROM AUTHOR]

This work aimed to discover protein tyrosine phosphatase 1B (PTP1B) inhibitors from a small molecule library of natural products (NPs) derived from selected Mexican medicinal plants and fungi to find new hits for developing antidiabetic drugs. The products showing similar IC50 values to ursolic acid (UA) (positive control, IC50 = 26.5) were considered hits. These compounds were canophyllol (1), 5-O-(β-D-glucopyranosyl)-7-methoxy-3′,4′-dihydroxy-4-phenylcoumarin (2), 3,4-dimethoxy-2,5-phenanthrenediol (3), masticadienonic acid (4), 4′,5,6- trihydroxy-3′,7-dimethoxyflavone (5), E/Z vermelhotin (6), tajixanthone hydrate (7), quercetin-3-O-(6″-benzoyl)-β-D-galactoside (8), lichexanthone (9), melianodiol (10), and confusarin (11). According to the double-reciprocal plots, 1 was a non-competitive inhibitor, 3 a mixed-type, and 6 competitive. The chemical space analysis of the hits (IC50 < 100 μM) and compounds possessing activity (IC50 in the range of 100–1,000 μM) with the BIOFACQUIM library indicated that the active molecules are chemically diverse, covering most of the known Mexican NPs’ chemical space. Finally, a structure–activity similarity (SAS) map was built using the Tanimoto similarity index and PTP1B absolute inhibitory activity, which allows the identification of seven scaffold hops, namely, compounds 3, 5, 6, 7, 8, 9, and 11. Canophyllol (1), on the other hand, is a true analog of UA since it is an SAR continuous zone of the SAS map. [ABSTRACT FROM AUTHOR]

Depression presents a significant global health burden, necessitating the search for effective and safe treatments. This investigation aims to assess the antidepressant effect of the hydroethanolic extract of Anacardium occidentale (AO) on depression-related behaviors in rats. The depression model involved 42 days of unpredictable chronic mild stress (UCMS) exposure and was assessed using the sucrose preference and the forced swimming (FST) test. Additionally, memory-related aspects were examined using the tests Y-maze and Morris water maze (MWM), following 21 days of treatment with varying doses of the AO extract (150, 300, and 450 mg/kg) and Imipramine (20 mg/kg), commencing on day 21. The monoamines (norepinephrine, serotonin, and dopamine), oxidative stress markers (MDA and SOD), and cytokines levels (IL-1β, IL-6, and TNF-α) within the brain were evaluated. Additionally, the concentration of blood corticosterone was measured. Treatment with AO significantly alleviated UCMS-induced and depressive-like behaviors in rats. This was evidenced by the ability of the extract to prevent further decreases in body mass, increase sucrose consumption, reduce immobility time in the test Forced Swimming, improve cognitive performance in both tests Y-maze and the Morris water maze by increasing the target quadrant dwelling time and spontaneous alternation percentage, and promote faster feeding behavior in the novelty-suppressed feeding test. It also decreased pro-inflammatory cytokines, corticosterone, and MDA levels, and increased monoamine levels and SOD activity. HPLC-MS analysis revealed the presence of triterpenoid compounds (ursolic acid, oleanolic acid, and lupane) and polyphenols (catechin quercetin and kaempferol). These results evidenced the antidepressant effects of the AO, which might involve corticosterone and monoaminergic regulation as antioxidant and anti-inflammatory activities. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic disorder that causes a rash with itchy, scaly patches. It affects nearly 2–5% of the worldwide population and has a negative effect on patient quality of life. A variety of therapeutic approaches, e.g., glucocorticoid topical therapy, have shown limited efficacy with systemic adverse reactions. Therefore, novel therapeutic agents and physicochemical formulations are in constant need and should be obtained and tested in terms of effectiveness and minimization of side effects. For that reason, the aim of our study was to design and obtain various hybrid systems, nanoemulgel–macroemulsion and nanoemulgel–oleogel (bigel), as vehicles for ursolic acid (UA) and to verify their potential as topical formulations used in psoriasis treatment. Obtained topical formulations were characterized by conducting morphological, rheological, texture, and stability analysis. To determine the safety and effectiveness of the prepared ursolic acid carriers, in vitro studies on human keratinocyte cell-like HaCaT cells were performed with cytotoxicity analysis for individual components and each formulation. Moreover, a kinetic study of ursolic acid release from the obtained systems was conducted. All of the studied UA-loaded systems were well tolerated by keratinocyte cells and had suitable pH values and stability over time. The obtained formulations exhibit an apparent viscosity, ensuring the appropriate time of contact with the skin, ease of spreading, soft consistency, and adherence to the skin, which was confirmed by texture tests. The release of ursolic acid from each of the formulations is followed by a slow, controlled release according to the Korsmeyer–Peppas and Higuchi models. The elaborated systems could be considered suitable vehicles to deliver triterpene to psoriatic skin. [ABSTRACT FROM AUTHOR]

Oral cancer, a disfiguring and life threatening cancer, significantly affects the day-to-day life of not only the patients but also their family members in terms of life quality and financial burden. India records higher incidence of oral cancer every year and is mainly due to the habituation of tobacco products and alcohol abuse. Delay in diagnosis and treatment influences India's higher incidence of oral cancer, where annually 50,000–60,000 oral carcinoma cases are reported. 7,12-dimethylbenz(a)anthracene (DMBA)-induced cancer in the oral cavity mimics human oral cancer in histopathological, molecular, and morphological aspects, and thus, by using this paradigm, the tumor inhibiting efficacy of medicinal plants or herbs and their components is scientifically validated. Ursolic acid, due to its multiple pharmacological effects, has been attracted, in recent years, for chemoprevention research program. Though, ursolic acid has been shown to have beneficial effects, its poor water solubility and bioavailability hinder to exert its 100% efficacy. Therefore, ursolic acid is encapsulated in either natural or synthetic polymers to enhance its therapeutic efficacy. Chitosan is one of the natural polymers that have been employed in the synthesis of nanoparticles to improve the drug efficacy. The present study has thus chosen ursolic acid–loaded chitosan nanoparticles (UACNP) to assess its anticancer efficacy in the DMBA-induced oral carcinoma. The anticancer efficacy of UACNP in experimental oral carcinogenesis was assessed by employing the status of oxidative markers and detoxification cascade as an end point. DMBA-induced abnormalities in the status of oxidative markers and detoxification cascade were reversed by ursolic acid–loaded chitosan nanoparticles. The tumor inhibiting or suppressing effect of UACNP is thus explored in experimental oral carcinogenesis. [ABSTRACT FROM AUTHOR]

Apoptosis, a systematic and harmonized sequential process, eliminates cells that contain potentially dangerous mutations. Cancer cells evade apoptosis by interfering with the functions of pro-apoptotic and anti-apoptotic proteins. The efficiency of ursolic acid-loaded chitosan nanoparticles (UACNP) in modulating pro-apoptotic and anti-apoptotic markers' expression towards tumor inhibition was assessed using immunohistochemistry in 7,12-dimethylbenz(a)anthracene (DMBA)-induced oral carcinoma in golden Syrian hamsters. An oral tumor was developed in the buccal pouch of hamsters by painting with DMBA, three times per week for 14 weeks. While buccal mucosa mutant p53 and Bcl-2 proteins were overexpressed, Bax, Bid, Bad, caspase-3 and 9 were downregulated in tumor-bearing hamsters. UACNP administration (12.5 mg/Kg b.w) to hamsters, on alternative days to DMBA exposure reverted the immunoexpression pattern of apoptotic markers towards the inhibition of tumor formation. The present investigation also observed that UACNP can improve apoptotic marker expression in the chemotherapeutic phase (DMBA = UACNP) as evidenced by the reduction in the number of tumors as well as tumor size. The observed findings thus highlight the apoptotic efficiency of UACNP, which could probably be attributed to its tumor-preventing efficacy in DMBA-induced oral carcinogenesis. [ABSTRACT FROM AUTHOR]

A series of derivatives of ursolic acid (UA) were synthesised, the anti-Toxoplasma gondii activity was tested, and the selectivity index (SI) of these compounds was calculated to determine the derivative with the best anti-Toxoplasma gondii activity. Compound A7 showed the best activity against the Toxoplasma gondii (IC50 in T. gondii infected GES-1 cells: 9.1 ± 7.2 μM), better than the lead compound UA and the positive control drug Spiramycin. Compound A7 was selected for further in vivo research: A7 was tested for its effect on the inhibition rate of tachyzoites in mice and its biochemical parameters, such as alanine aminotransferase, aspartate aminotransferase, glutathione, and malondialdehyde were determined. Compound A7 was evaluated for its anti-Toxoplasma activity and partial damage to the liver. Therefore, the results show that compound A7 could be a potential lead compound for developing a novel anti-Toxoplasma gondii molecule. [ABSTRACT FROM AUTHOR]

Objective Based on the database, the active ingredients and core target genes of Shengji Yuhong ointment in the treatment of diabetic foot ulcer ( DFU ) were screened, and the targeted binding relationship between the active components and core target genes of Shengji Yuhong ointment in the treatment of DFU was further verified. Methods ①Collecting the active ingredients of Shengji Yuhong ointment and their target genes We retrieved data from TCMSP, BATMAN-TCM and SuperPred databases to collect the active ingredients of Shengji Yuhong ointment and their target genes. ②Collecting target genes for the onset of DFU We searched and collected target genes for the onset of DFU in GeneCards, OMIM, PharmGkb, and TTD databases. ③Screening of target genes in the treatment of DFU by Shengji Yuhong ointment and analysis of their biological functions The target genes of the active ingredients of Shengji Yuhong ointment and the target genes for the onset of DFU was intersected to screen the target genes of Shengji Yuhong ointment in the treatment of DFU by Cytoscape3. 8. 0 software. Biological function analysis of the target genes of Shengji Yuhong ointment in the treatment of DFU Using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to analyze the biological functions of target genes of Shengji Yuhong ointment in the treatment of DFU. ④ Screening of core target genes of Shengji Yuhong ointment in the treatment of DFU and prediction and verification of the target binding relationship with the active ingredients of Shengji Yuhong ointment Screening of core target genes of Shengji Yuhong ointment in the treatment of DFU through the GOSemSim package. We predicted the active ingredients of Shengji Yuhong ointment that had targeted binding relationship with core target genes. Using AutoDock and PyMOL software to conduct molecular docking verification of the active ingredients of Shengji Yuhong ointment and the core target genes of DFU. We analyzed the binding ability of Shengji Yuhong ointment's active ingredients and DFU core target genes. Results Totally 371 ingredients including quercetin, ursolic acid, licochalcone A, 1-methyl-2-dodecyl-4- (1H)-quinolone, etc. were the active ingredients of Shengji Yuhong ointment. Totally 1 762 target genes that had targeted binding relationships with the active ingredients of the ointment, mainly including epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), and SRC proto-oncogene (SRC), transforming growth factor- β1 (TGF-β1), and serine/threonine protein kinase 1 (AKT1). ② There were 2 690 target genes for the onset of DFU, including EGFR, STAT3, SRC, TGF-β1, AKT1, etc. ③ There were 39 target genes of Shengji Yuhong ointment in the treatment of DFU, including EGFR, STAT3, AKT1, etc. The target genes of Shengji Yuhong ointment in the treatment of DFU were mainly involved in regulating epithelial cell proliferation, muscle cell proliferation, microRNA (miRNA) transcription, and other biological processes. The target genes were mainly involved in phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT), diabetic complications advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE), and hypoxia-inducible factor-1 (HIF-1) signaling pathway, etc. ④ EGFR, STAT3, TGF-β1, SRC, and AKT1 were the core target genes of Shengji Yuhong ointment in the treatment of DFU. The active ingredients of Shengji Yuhong ointment with targeted binding relationships mainly included Gancao (Glycyrrhizae Radix et Rhizoma), Danggui (Angelicae Sinensis Radix), and Baizhi (Angelicae Dahuricae Radix). The docking score of quercetin with EG-FR was–7. 9 kcal/moL, the docking score of 1-methyl-2-dodecyl-4- (1H)-quinolone with EGFR was–5. 9 kcal/moL, and the docking scores of ursolic acid and licochalcone A with STAT3 were–8. 0 and–6. 3 kcal/moL, respectively. Conclusions The active ingredients of Shengji Yuhong ointment in the treatment of DFU mainly include quercetin, ursolic acid, licochalcone A, etc. The core target genes of Shengji Yuhong ointment in the treatment of DFU mainly include EGFR, STAT3, AKT1, etc. The main active ingredients of Shengji Yuhong ointment have good targeted binding abilities with the key target genes. The key target genes of Shengji Yuhong ointment in the treatment of DFU can participate in the process of promoting epithelial cell proliferation and inhibiting the production of advanced glycation end products by affecting PI3K/AKT, AGE-RAGE and HIF-1 signaling pathways, so as to exert its therapeutic effect on DFU. [ABSTRACT FROM AUTHOR]

Introduction: There is currently evidence suggesting that ursolic acid may exert a favorable influence on both anti-inflammatory and antioxidant impact. Nevertheless, the anti-inflammatory and antioxidant activities of ursolic acid have not been systematically evaluated. Consequently, this study aims to conduct a systematic review and meta-analysis regarding the impact of ursolic acid on markers of inflammatory and antioxidant activity in both animal models and in vitro systems. Methods: The search encompassed databases such as PubMed, Web of Science, Google Scholar, and ScienceDirect, up until May 2023. All eligible articles in English were included in the analysis. Standard mean difference (SMD) was pooled using a random-effects model, and the included studies underwent a thorough assessment for potential bias. Results: The final review comprised 31 articles. In disease-model related studies, animal experiments have consistently shown that ursolic acid significantly reduced the levels of inflammatory parameters IL-1β, IL-6 and TNF-α in mouse tissues. In vitro studies have similarly showed that ursolic acid significantly reduced the levels of inflammatory parameters IL-1β, IL-6, IL-8 and TNF-α. Our results showed that ursolic acid could significantly elevate SOD and GSH levels, while significantly reducing MDA levels in animal tissues. The results of in vitro studies shown that ursolic acid significantly increased the level of GSH and decreased the level of MDA. Discussion: Findings from both animal and in vitro studies suggest that ursolic acid decreases inflammatory cytokine levels, elevates antioxidant enzyme levels, and reduces oxidative stress levels (graphical abstract). This meta-analysis furnishes compelling evidence for the anti-inflammatory and antioxidant properties of ursolic acid. [ABSTRACT FROM AUTHOR]

Loquat (Eriobotrya japonica) leaves contain many bioactive components such as ursolic acid (UA) and amygdalin. We investigated the effects of loquat leaf powder and methanol extract in human neuroglioma H4 cells stably expressing the Swedish-type APP695 (APPNL-H4 cells) and C57BL/6 J mice. Surprisingly, the extract greatly enhanced cellular amyloid-beta peptide (Aβ) 42 productions in APPNL-H4 cells. Administration of leaf powder increased Aβ42 levels after 3 months and decreased levels after 12 months compared to control mice. Leaf powder had no effect on working memory after 3 months, but improved working memory after 12 months. Administration of UA decreased Aβ42 and P-tau levels and improved working memory after 12 months, similar to the administration of leave powder for 12 months. Amygdalin enhanced cellular Aβ42 production in APPNL-H4 cells, which was the same as the extract. Three-month administration of amygdalin increased Aβ42 levels slightly but did not significantly increase them, which is similar to the trend observed with the administration of leaf powder for 3 months. UA was likely the main compound contained in loquat leaves responsible for the decrease in intracerebral Aβ42 and P-tau levels. Also, amygdalin might be one of the compounds responsible for the transiently increased intracerebral Aβ42 levels. [ABSTRACT FROM AUTHOR]

Malaria is a disease that affects many people in the world. In Mexico, malaria remains an active disease in certain regions, particularly in the states of Chiapas and Chihuahua. While antimalarial effects have been attributed to some species of Cecropia in various countries, no such studies have been conducted in Mexico. Therefore, the objective of this study was to evaluate the in silico antimalarial activity of some active compounds identified according to the literature in the species of Cecropia obtusifolia, belonging to the Cecropiaceae family, such as ursolic acid, α-amyrin, chrysin, and isoorientin. These compounds were evaluated with specific molecular docking and molecular dynamics (MD) studies using three different malarial targets with the PDB codes 1CET, 2BL9, and 4ZL4 as well as the prediction of their pharmacokinetic (Pk) properties. Docking analysis revealed the following best binding energies (kcal/mol): isoorientin–1CET (−9.1), isoorientin–2BL9 (−8.8), and chrysin–4ZL4 (−9.6). MD simulation validated the stability of the complexes. Pharmacokinetics analysis suggested that the compounds would generally perform well if administered. Therefore, these results suggest that these compounds may be used as potential drugs for the treatment of malaria. [ABSTRACT FROM AUTHOR]

Background: A number of nonsteroidal anti-inflammatory medications have been shown to lessen pain and inflammation. Unfortunately, there are numerous side effects connected with their use. There are, however, medicinal plants that have anti-inflammatory therapeutic effects with little to no side effects. Momordica dioica is a herb that belongs to the Cucurbitaceae family. There are numerous phytoconstituents in it. Ursolic acid is one of them and a pentacyclic terpenoid that is found in nature and has a number of therapeutic benefits. The current study looked at Ursolic Acid's activities (UA), a secondary plant metabolite, for its anti-inflammatory properties in the Momordica dioica plant. The current study's objective was to create and validate an HPTLC method that was quick, accurate, precise, and specific for determining ursolic acid from Momordica dioica herbal extract. Methodology/Conclusion/Significance: For quick analysis of Ursolic acid determination, The High Performance Thin Layer Chromatography (HPTLC) was established and confirmed. On an aluminium HPTLC plate (60 F254) coated with precoated silica gel with formic acid, ethyl acetate, and toluene (7:3:0,1), chromatographic separation was accomplished. The detection process was carried out at 530 nm. Ursolic acid's Rf value was discovered to be 0.795%. In the 400ng/band concentration range, linearity for ursolic acid was detected. The limits of detection and quantitation for ursolic acid were observed to be 0.04 ng/ band and 0.14 ng/band, respectively. The mean % recovery of rosmarinic acid was (0.54). The method's specificity, robustness, linearity, precision, and accuracy have all been validated in compliance with ICH standards. The created method can be used to evaluate the regularity of ursolic acid in herbal extracts. [ABSTRACT FROM AUTHOR]

The neuroinflammatory response after intracerebral hemorrhage (ICH) causes a large amount of neuronal loss, and inhibiting the inflammatory response can improve the prognosis. In previous laboratory studies and clinical trials, ursolic acid (UA) inhibited the inflammatory response, but whether it can be administered to inhibit the neuroinflammatory response after cerebral hemorrhage is unknown. The aim of this study was to investigate the effects of ursolic acid after cerebral hemorrhage. Online databases were used to obtain potential therapeutic targets of ursolic acid for the treatment of cerebral hemorrhage, and possible mechanisms were analyzed by KEGG, GO, and molecular docking. A rat model of cerebral hemorrhage was established using collagenase, and an in vitro cerebral hemorrhage model was constructed by adding hemin to BV2 cell culture medium. Enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), immunofluorescence, TUNEL staining, and calcein/PI staining were used to investigate the degree of microglial M1 polarization, changes in the levels of inflammatory factors, activation of the NF-κB pathway, and changes in the indicators of cellular death after ursolic acid treatment. In addition, phorbol 12-myristate 13-acetate (PMA) was used to activate the NF-κB pathway to verify that ursolic acid exerts its anti-neuroinflammatory effects by regulating the NF-κB/NLRP3/GSDMD pathway. Network pharmacology and bioinformatics analyses revealed that ursolic acid may exert its therapeutic effects on cerebral hemorrhage through multiple pathways. Together, in vivo and in vitro experiments showed that ursolic acid inhibited microglial M1 polarization and significantly reduced the levels of p-NF-κB, GSDMD-N, cleaved caspase-1, TNF-α, IL-6, and IL-1β, which were significantly inhibited by the use of PMA. Ursolic acid inhibits microglial pyroptosis via the NF-κB/NLRP3/GSDMD pathway to alleviate neuroinflammatory responses after cerebral hemorrhage. [ABSTRACT FROM AUTHOR]

Sarcopenia is characterized by a gradual slowing of movement due to loss of muscle mass and quality, decreased power and strength, increased risk of injury from falls, and often weakness. This review will focus on recent research trends in nutritional and pharmacological approaches to controlling sarcopenia. Because nutritional studies in humans are fairly limited, this paper includes many results from nutritional studies in mammals. The combination of resistance training with supplements containing amino acids is the gold standard for preventing sarcopenia. Amino acid (HMB) supplementation alone has no significant effect on muscle strength or muscle mass in sarcopenia, but the combination of HMB and exercise (whole body vibration stimulation) is likely to be effective. Tea catechins, soy isoflavones, and ursolic acid are interesting candidates for reducing sarcopenia, but both more detailed basic research on this treatment and clinical studies in humans are needed. Vitamin D supplementation has been shown not to improve sarcopenia in elderly individuals who are not vitamin D-deficient. Myostatin inhibitory drugs have been tried in many neuromuscular diseases, but increases in muscle mass and strength are less likely to be expected. Validation of myostatin inhibitory antibodies in patients with sarcopenia has been positive, but excessive expectations are not warranted. [ABSTRACT FROM AUTHOR]

As a lethal infectious disease, tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb). Its complex pathophysiological process limits the effectiveness of many clinical treatments. By regulating host cell death, Mtb manipulates macrophages, the first line of defense against invading pathogens, to evade host immunity and promote the spread of bacteria and intracellular inflammatory substances to neighboring cells, resulting in widespread chronic inflammation and persistent lung damage. Autophagy, a metabolic pathway by which cells protect themselves, has been shown to fight intracellular microorganisms, such as Mtb, and they also play a crucial role in regulating cell survival and death. Therefore, host-directed therapy (HDT) based on antimicrobial and anti-inflammatory interventions is a pivotal adjunct to current TB treatment, enhancing anti-TB efficacy. In the present study, we showed that a secondary plant metabolite, ursolic acid (UA), inhibited Mtb-induced pyroptosis and necroptosis of macrophages. In addition, UA induced macrophage autophagy and enhanced intracellular killing of Mtb. To investigate the underlying molecular mechanisms, we explored the signaling pathways associated with autophagy as well as cell death. The results showed that UA could synergistically inhibit the Akt/mTOR and TNF-α/TNFR1 signaling pathways and promote autophagy, thus achieving its regulatory effects on pyroptosis and necroptosis of macrophages. Collectively, UA could be a potential adjuvant drug for host-targeted anti-TB therapy, as it could effectively inhibit pyroptosis and necroptosis of macrophages and counteract the excessive inflammatory response caused by Mtb-infected macrophages via modulating the host immune response, potentially improving clinical outcomes. [ABSTRACT FROM AUTHOR]

This study was designed to investigate whether the glucose lowering effects of Potentilla fulgens acts by modulating GLUT4, AKT2 and AMPK expression in the skeletal muscle and liver tissues. Alloxan-induced diabetic mice treated with Potentilla fulgens was assessed for their blood glucose and insulin level, mRNA and protein expression using distinguished methods. Additionally, GLUT4, AKT2 and AMPK were docked with catechin, epicatechin, kaempferol, metformin, quercetin and ursolic acid reportedly present in Potentilla fulgens. Potentilla fulgens ameliorates hyperglycaemia and insulin sensitivity via activation of AKT2 and AMPK, increases the expression of GLUT4, AKT2, AMPKα1 and AMPKα2 whose levels are reduced under diabetic condition. Molecular docking revealed interacting residues and their binding affinities (−4.56 to −8.95 Kcal/mol). These findings provide more clarity vis-avis the mechanism of action of the phytoceuticals present in Potentilla fulgens extract which function through their action on GLUT4, PKB and AMPK. [ABSTRACT FROM AUTHOR]

Based on ursolic acid, 3 compounds with isothiocyanate groups located at different distances from C-17 of the triterpenoid core have been synthesized through ursane-derived primary amines. To obtain terpene hybrids with thioureas and N,S-containing heterocycles, series of amines and ammonia were reacted with novel isothiocyanates. In the reactions with propargylamine, 3 triterpenoid hybrids with 4,5-dihydrothiazol-2-yl-amine have been selectively obtained in 81%–91% yields. Isothiocyanates containing several bonds between the -CNS group and the triterpenoid backbone reacted with (1-aryl-1H-1,2,3-triazole-4-yl)methanamines, as well as with ammonia, to form thiourea derivatives (78%–94%). The nor-compound with a -CNS group at C-17 of the triterpenoid was the least reactive due to deactivation by a donor terpene branched substituent and reacted readily only with sufficiently strong nucleophiles, such as primary and secondary aliphatic amines. The reaction of the nor-derivative of isothiocyanate 7 with ammonia at elevated temperature led to the unexpected formation of 3β-acetoxy-28-norurs-12-en-17-yl-amine, the precursor of isothiocyanate, as the main product (82%). [ABSTRACT FROM AUTHOR]

Background: Ursolic acid is a powerful drug that possesses many therapeutic properties, such as hepatoprotection, immunomodulation, anti‐inflammatory, antidiabetic, antibacterial, antiviral, antiulcer, and anticancer activity. Centella asiatica (L.) Urban (Umbelliferae) contains a triterpene called asiatic acid, which has been used effectively in traditional Chinese and Indian medicine system for centuries. Anticancer, anti‐inflammatory, and neuroprotective properties are only some of the many pharmacological actions previously attributed to asiatic acid. Aim: The present work developed an optimized combinatorial drug‐loaded nano‐formulation by Quality by design approach. Materials and Methods: The optimize transliposome for accentuated dermal delivery of dual drug. The optimization of drug‐loaded transliposome was done using the "Box–Behnken design." The optimized formulation was characterized for vesicles size, entrapment efficiency (%), and in vitro drug release. Additionally, transmission electron microscopy (TEM), confocal laser scanning microscopy (CLSM), and dermatokinetic study were performed for further evaluation of drug‐loaded optimized transliposome formulation. Results: The optimized combinatorial drug‐loaded transliposome formulation showed a particle size of 86.36 ± 2.54 nm, polydispersity index (PDI) 0.230 ± 0.008, and an entrapment efficiency of 87.43 ± 2.66% which depicted good entrapment efficiency. In vitro drug release of ursolic acid and asiatic acid transliposomes was found to be 85.12 ± 2.54% and 80.23 ± 3.23%, respectively, as compared to optimized ursolic acid and asiatic acid transliposome gel drug release that was 67.18 ± 2.85% and 60.28 ± 4.12%, respectively. The skin permeation study of ursolic and asiatic acid conventional formulation was only 32.48 ± 2.42%, compared with optimized combinatorial drug‐loaded transliposome gel (79.83 ± 4.52%) at 12 h. After applying combinatorial drug‐loaded transliposome gel, rhodamine was able to more easily cross rat skin, as observed by confocal laser scanning microscopy, in comparison with when the rhodamine control solution was used. Discussion: The UA_AA‐TL gel formulation absorbed more ursolic acid and asiatic acid than the UA_AA‐CF gel formulation, as per dermatokinetic study. Even after being incorporated into transliposome vesicles, the antioxidant effects of ursolic and asiatic acid were still detectable. In most cases, transliposomes vesicular systems generate depots in the skin's deeper layers and gradually release the medicine over time, allowing for fewer applications. Conclusion: In overall our studies, it may be concluded that developed dual drug‐loaded transliposomal formulation has great potential for effective topical drug delivery for skin cancer. [ABSTRACT FROM AUTHOR]

Exploring the effect of bile salts on the properties of emulsion carriers containing hydrophobic bioactive compounds is particularly critical to understanding the stability and bioavailability of these hydrophobic bioactive compounds in the digestive process. In this study, the effects of bile salts on the stability and digestive characteristics of the ursolic acid (UA) self-stabilized water-in-oil (W/O) emulsion were investigated via static and dynamic (with or without enzyme) in vitro simulated digestive systems. The results showed that under the static system, the basic conditions had less interference, while the bile salts had a significant effect on the appearance and microstructure of the emulsion. The primary mechanism of emulsion instability is hydrophobic binding and depletion flocculation. Under the dynamic condition, it was found that the low concentrations of bile salts can promote the release amount and the rate of free fatty acids via displacement, while high concentrations of bile salts inhibit the decomposition of lipid, which may be related to the secondary coverage formed at the interface by the bile salts. These findings provide a theoretical basis for understanding the digestive behavior of the UA emulsion and its interaction with bile salts, which are conducive to developing and designing new emulsions to improve the bioaccessibility of UA. [ABSTRACT FROM AUTHOR]

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Nuclear receptors (NRs) form a family of druggable transcription factors that are regulated by ligand binding to orchestrate multifaceted physiological functions, including reproduction, immunity, metabolism, and growth. NRs represent attractive and valid targets for the management and treatment of a vast array of ailments. Pentacyclic triterpenes (PTs) are ubiquitously distributed natural products in medicinal and aromatic plants, of which ursolic acid (UA) is an extensively studied member, due to its diverse bio-pertinent activities against different cancers, inflammation, aging, obesity, diabetes, dyslipidemia, and liver injury. In fact, PTs share a common lipophilic structure that resembles NRs' endogenous ligands. Herein, we present a review of the literature on UA's effect on NRs, showcasing the resulting health benefits and potential therapeutic outcomes. De facto, UA exhibited numerous pharmacodynamic effects on PPAR, LXR, FXR, and PXR, resulting in remarkable anti-inflammatory, anti-hyperlipidemic, and hepatoprotective properties, by lowering lipid accumulation in hepatocytes and mitigating non-alcoholic steatohepatitis (NASH) and its subsequent liver fibrosis. Furthermore, UA reversed valproate and rifampicin-induced hepatic lipid accumulation. Additionally, UA showed great promise for the treatment of autoimmune inflammatory diseases such as multiple sclerosis and autoimmune arthritis by antagonizing RORγ. UA exhibited antiproliferative effects against skin, prostate, and breast cancers, partially via PPARα and RORγ pathways. Herein, for the first time, we explore and provide insights into UA bioactivity with respect to NR modulation. [ABSTRACT FROM AUTHOR]

Found in many fruits and plants, Ursolic acid (UA), a pentacyclic triterpene that occurs naturally, is recognized for its anti-cancer effects, especially in combating glioblastoma. However, the intricate molecular mechanisms underpinning its anti-tumor actions are still not fully understood, despite the recognition of these effects. By examining the functions of epithelial-mesenchymal transition (EMT) and angiogenesis, crucial for glioblastoma progression, and their regulation through Transforming Growth Factor Beta (TGFβ) – a key marker for glioblastoma, our research aims to fill this knowledge gap. This study explores how ursolic acid can block the progression of glioblastoma by precisely targeting TGFβ-triggered EMT and angiogenesis. The findings show that UA successfully blocks the spread, movement, and invasion of glioblastoma cells. Accompanying this, there is a significant reduction in the expression of TGFβ and crucial EMT indicators like snail and vimentin. Furthermore, UA shows a reduction in angiogenesis that depends on the dosage, highlighted by decreased vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells (HUVECs). Interestingly, increased TGFβ expression in U87 and U251 glioblastoma cell lines was found to weaken UA's anti-tumor properties, shedding more light on TGFβ′s critical function in glioblastoma's pathology. Supporting these laboratory results, UA also showed considerable inhibition of tumor growth in a glioblastoma xenograft mouse model. Overall, our research emphasizes Ursolic acid's promise as a new treatment for glioblastoma and clarifies its action mechanism, mainly by inhibiting TGFβ signaling and thereby EMT and angiogenesis.

Background: Scrophulariae Radix (SR) is a commonly used medicinal plant. Alzheimer's disease (AD) is a neurodegenerative disease for which there is no effective treatment. This study aims to initially clarify the potential mechanism of SR in the treatment of AD based on network pharmacology and molecular docking techniques. Methods: The principal components and corresponding protein targets of SR were conducted by HPLC analysis and searched on TCMSP. AD targets were searched on DrugBank, Chemogenomics, TTD, OMIM and GeneCards databases. The compound-target network was constructed by Cytoscape3.8.2. The intersection of compound target and disease target was obtained and the coincidence target was imported into STRING database to construct a PPI network. We further performed GO and KEGG enrichment analysis on the targets. Meanwhile, molecular docking study and cell experiments were approved for the core target and the active compound. Results: Through multidatabase retrieval and integration, it was found that 17 components of SR could exert anti-AD effects against 40 targets. KEGG enrichment analysis indicated that Alzheimer's disease (hsa05010) was one of the most significant AD enrichment signalling pathways. Combined with the gene expression profile information in the AlzData database, 15 targets were found to be associated with tau or beta-amyloid protein (Aβ). GO analysis indicated that the primary molecular functions of SR in the treatment of AD were neurotransmitter receptor activity (GO:0007268), postsynaptic neurotransmitter receptor activity (GO:0070997), and acetylcholine receptor activity (GO:0050435). Moreover, we explored the anti-AD effects of SR extract and ursolic acid (UA) using SH-SY5Y cells. Treatment of SH-SY5Y cells with 20 μM UA significantly reduced the oxidative damage to these neuronal cells. Conclusion: This study reveals the active ingredients and potential molecular mechanism of SR in the treatment of AD, and provides a theoretical basis for further basic research and clinical application.

Luying Qiu,1 Yaxuan Wang,2 Yuye Wang,1,3 Fang Liu,1 Shumin Deng,1 Weishuang Xue,1 Yanzhe Wang1 1Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Anesthesiology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China; 3Department of Neurology, China-Japan Friendship Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Yanzhe Wang, Department of Neurology, Key Laboratory for Neurological Big Data of Liaoning Province, The First Affiliated Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang, Liaoning Province, 110001, People’s Republic of China, Tel +86-15040289417, Email yanzhewangcmu@126.comPurpose: The oxygen and glucose deprivation-reoxygenation (OGDR) model is widely used to evaluate ischemic stroke and cerebral ischemia-reperfusion (I/R) injury in vitro. Excessively activated microglia produce pro-inflammatory mediators such as matrix metalloproteinases [MMPs] and their specific inhibitors, tissue inhibitors of metalloproteinases [TIMPs], causing neuronal damage. Ursolic acid (UA) acts as a neuroprotective agent in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model keeping the MMP/TIMP balance with underlying mechanisms unclear. Our study used OGDR model to determine whether and how UA reduces neuronal damage by reversing MMP/TIMP imbalance caused by microglia in I/R injury in vitro.Methods: SH-SY5Y cells were first cultured with 95% N2 and 5% CO2 and then cultivated regularly for OGDR model. Cell viability was tested for a proper UA dose. We established a co-culture system with SH-SY5Y cells and microglia-conditioned medium (MCM) stimulated by lipopolysaccharide (LPS) and interferon-gamma (IFNγ). MMP9 and TIMP1 levels were measured with ELISA assay to confirm the UA effect. We added recombinant MMP9 (rMMP9) and TIMP1 neutralizing antibody (anti-TIMP1) for reconfirmation. Transmission electron microscopy was used to observe cell morphology, and flow cytometry and Annexin V-FITC and PI labeling for apoptotic conditions. We further measured the calcium fluorescence intensity in SH-SY5Y cells.Results: The MCM significantly reduced cell viability of SH-SY5Y cells after OGDR (p

Background & Aims: Alpelisib and Ursolic acid are two compounds that have been shown to have potential as anti-cancer agents. Alpelisib is a selective inhibitor of the PI3K pathway, while Ursolic acid is a natural pentacyclic triterpene compound found in various plants that reveals anti-cancer, antioxidant and anti-inflammatory characteristics. The hypoxia-inducible factor 1α (HIF1α) is a transcription factor that plays a key role in regulating tumor cell survival, apoptosis, tumorigenesis and growth in low-oxygen environments. This study aims to determine the effects of Ursolic acid and Alpelisib on the expression of HIF1α gene on 4T1 cell line. Materials & Methods: In the current experimental study, IC50 concentrations of both Ursolic acid and Alpelisib were determined on 4T1 cells. Then cells were treated with determined IC50 concentrations of Ursolic acid, Alpelisib and the combination of half of the IC50 concentration of both drugs for 24 hours. After the treatment, viability was assessed with MTT assay and the expression of HIF1α gene was appraised by Real-time PCR. Finally, statistical analysis was accomplished by ANOVA using GraphPad Prism 8.4 software. Results: The results of this study showed that the anti-proliferative effect of the drug combination was synergistic and concentration-dependent. The maximum decrease (74.17 % with UA and 64.04 % with Alp) in viability was observed in high doses of treatment with drugs. IC50 values of Ursolic acid and Alpelisib were 168.314 µM and 6.377 µM, respectively. Based on the real-time PCR results, HIF1α gene expression was significantly decreased in both single- treatment and combination groups, compared to the control group (P

Repetitive motion or exercise is associated with oxidative stress and muscle inflammation, which can lead to declining grip strength and muscle damage. Oleanolic acid and ursolic acid have anti-inflammatory and antioxidant properties and can be extracted from Chaenomeles speciosa through ultrasonic sonication. We investigated the association between grip strength declines and muscle damage induced by lambda carrageenan (LC) injection and exercise exposure in rats. We also assessed the reparative effects of transdermal pretreatment and post-treatment with C. speciosa extracts (CSEs) by using a supersonic atomizer. The half-maximal inhibitory concentration (IC50) of CSEs for cells was 10.5 mg/mL. CSEs significantly reduced the generation of reactive oxygen species and inflammatory factors (interleukin [IL]-6 and IL-1β) in in vitro cell tests. Rats subjected to LC injection and 6 weeks of exercise exhibited significantly increased inflammatory cytokine levels (IL-1β, TNF-α, and IL-6). Hematoxylin and eosin staining revealed inflammatory cell infiltration and evident muscle damage in the gastrocnemius muscle, which exhibited splitting and the appearance of the endomysium and perimysium. The treated rats’ grip strength significantly declined. Following treatment with CSEs, the damaged muscles exhibited decreased IL-1β, TNF-α, and IL-6 levels and normal morphologies. Moreover, grip strength significantly recovered. Pretreatment with CSEs yielded an immediate and significant increase in grip strength, with an increase of 180% and 165% occurring in the rats exposed to LC injection and exercise within the initial 12 h period, respectively, compared with the control group. Pretreatment with CSEs delivered transdermally using a supersonic atomizer may have applications in sports medicine and training or competitions.

Ultraviolet B (UVB) exposure can contribute to photoaging of skin. Cornus officinalis is rich in ursolic acid (UA), which is beneficial to the prevention of photoaging. Because UA is hardly soluble in water, the Cornus officinalis extract (COE) was obtained using water as the antisolvent to separate the components containing UA from the crude extract of Cornus officinalis. The effect of COE on UVB damage was assessed using Caenorhabditis elegans. The results showed that COE could increase the lifespan and enhance the antioxidant enzyme activity of C. elegans exposed to UVB while decreasing the reactive oxygen species (ROS) level. At the same time, COE upregulated the expression of antioxidant-related genes and promoted the migration of SKN-1 to the nucleus. Moreover, COE inhibited the expression of the skn-1 downstream gene and the extension of the lifespan in skn-1 mutants exposed to UVB, indicating that SKN-1 was required for COE to function. Our findings indicate that COE mainly ameliorates the oxidative stress caused by UVB in C. elegans via the SKN-1/Nrf2 pathway.

Smart polymeric micelles (PMs) are of great interest in drug delivery owing to their low critical micellar concentration and sizes. In the present study, two different pH-sensitive poly(2-vinyl pyridine)-b-poly(ethylene oxide) (P2VP-b-PEO) copolymer samples were used for the encapsulation of paclitaxel (PTX), ursolic acid (UA), and dual loading of PTX and UA. Based on the molecular features of copolymers, spherical PMs with sizes of around 35 nm and 140 nm were obtained by dialysis for P2VP55-b-PEO284 and P2VP274-b-PEO1406 samples, respectively. The micellar sizes increased after loading of both drugs. Moreover, drug encapsulation and loading efficiencies varied from 53 to 94% and from 3.2 to 18.7% as a function of the copolymer/drug ratio, molar mass of copolymer sample, and drug type. By FT-IR spectroscopy, it was possible to demonstrate the drug loading and the presence of some interactions between the polymer matrix and loaded drugs. In vitro viability was studied on 4T1 mammary carcinoma mouse cells as a function of time and concentration of drug-loaded PMs. UA-PMs and free PMs alone were not effective in inhibiting the tumor cell growth whereas a viability of 40% was determined for cells treated with both PTX- and PTX/UA-loaded PMs. A synergic effect was noticed for PTX/UA-loaded PMs.

Objective: This study aimed to improve the application range and bioavailability of ursolic acid. Methods: The W/O/W pickering emulsion was prepared by a two-step process with ursolic acid as emulsifier and pectin as external aqueous phase. The preparation conditions of W/O emulsion were optimized by a single factor experiment, and the effects of pectin mass concentration on physicochemical properties, microstructure, rheological properties and long-term stability of W/O/W pickering emulsion were studied. Results: The optimal preparation technology of W/O emulsion was ursolic acid mass concentration of 4 g/100 mL, water-oil mass ratio of 2∶3, homogenization speed of 9 000 r/min, homogenization time of 5 min. The particle size of the double emulsion prepared with pectin as the external aqueous phase was between 30～40 μm. The absolute value of zeta potential, rheological property and storage stability of the emulsion at 4 ℃ were significantly improved with the increase of pectin mass concentration. Conclusion: The stable pickering double emulsion could be prepared when the mass concentration of pectin was 0.3, 0.4, 0.5 g/100 mL.

Abstract Background The most common species in the Satureja genus is Satureja montana (family Lamiaceae). The present work aims to use the molecular docking study to predict the isolated constituents against an immune system immunomodulator and tested alcoholic extract as an in-vitro immunomodulatory agent. Methods All isolated compound's structures were determined using various chromatographic and spectroscopic techniques. Anti-inflammatory and antioxidant profiles were studied for an alcoholic extract of the plant; the molecular docking study was performed for the isolated compounds (1–4). Results In this work, four recognized compounds were extracted from the ethyl acetate fraction of S. montana (Sm) methanolic extract and identified as two triterpenes ursolic acid (1) and oleanolic acid (2), one phenolic acid as ellagic acid (3), and one flavonoidal compound as isoscutellarein (4). The total alcoholic extract exhibited good in vitro anti-inflammatory, antioxidant, and apoptotic activity. Its IC50 was 10.12 compared to 15.1 μg/ml of standard celecoxib. It also showed potent antioxidant activity with IC50 10.4, 11.3, 14.6, and 22.3 IU/ml for SOD, MDA, catalase, and TAC, respectively. According to the drug similarity and ADMET tests, their ligands may have favorable pharmacokinetic characteristics with minimal carcinogenic influence. The molecular docking study was performed for the isolated compounds (1–4). Conclusions The alcoholic extract of the plant showed promising anti-inflammatory, antioxidant, and antiapoptotic properties. The theoretical studies for the isolated compounds showed promising binding affinity against all the examined enzymes.

Objective: To explore the mechanism of ursolic acid (UA) against acute B lymphoblastic leukaemia (B-ALL) based on network pharmacological analysis, molecular docking and experimental verification. Methods: The core targets, functional processes, and biological pathways of UA in B-ALL were predicted by network pharmacology and molecular docking. The efficacy and mechanism of UA against B-ALL were verified through in vitro experiments such as cell viability assays, CCK-8 assays, LDH assays, AO/EB staining, flow cytometry, and Western blot assays. Results: Network pharmacology analysis of the core targets indicated that the effects of UA on B-ALL were related to programmed cell death (apoptosis and pyroptosis). Molecular docking results showed that FOS, CASP8, MAPK8, IL-1β and JUN were the key targets of UA against B-ALL. The MTS assay showed that UA decreased the viability of Reh cells in a concentration- and time-dependent manner. Cellular and Western blot experiments found that UA induced Reh cell apoptosis and pyroptosis by upregulating the JNK signalling pathway. Conclusions: Our findings demonstrated that UA could induce Reh cell apoptosis and pyroptosis by activating the JNK signalling pathway to exert anti-B-ALL effects. This indicates that UA may become a potential drug for the effective treatment of B-ALL.

The aim of this work was to evaluate the vasorelaxant and antihypertensive effects of a standardized precipitate of the hydroalcoholic extract from Agastache mexicana (PPAm), comprising ursolic acid, oleanolic acid, acacetin, luteolin and tilianin, among others. In the ex vivo experiments, preincubation with L-NAME (nonspecific inhibitor of nitric oxide synthases) reduced the relaxation induced by PPAm; nevertheless, preincubation with indomethacin (nonspecific inhibitor of cyclooxygenases) did not generate any change in the vasorelaxation, and an opposed effect was observed to the contraction generated by CaCl2 addition. Oral administration of 100 mg/kg of PPAm induced a significant acute decrease in diastolic (DBP) and systolic (SBP) blood pressure in spontaneously hypertensive rats, without changes in heart rate. Additionally, PPAm showed a sustained antihypertensive subacute effect on both DBP and SBP for 10 days compared to the control group. On the other hand, human umbilical vein cells treated with 10 µg/mL of PPAm showed a significant reduction (p < 0.05) in intracellular adhesion molecule-1, compared to the control, but not on vascular cell adhesion molecule-1. In conclusion, PPAm induces a significant antihypertensive effect in acute- and subacute-period treatments, due to its direct vasorelaxant action on rat aortic rings through NO production and Ca2+ channel blockade. [ABSTRACT FROM AUTHOR]

Filipendula ulmaria, commonly known as meadowsweet, is a wild herbaceous flowering plant that is widely distributed in Europe. A range of salicylic acid derivatives and flavonol glycosides have been previously associated with the antirheumatic and diuretic properties of F. ulmaria. In the present work, a hydroalcoholic extract from F. ulmaria aerial parts was extensively profiled using an efficient NMR-based dereplication strategy. The approach involves the fractionation of the crude extract by centrifugal partition chromatography (CPC), 13C NMR analysis of the fractions, 2D-cluster mapping of the entire NMR dataset, and, finally, structure elucidation using a natural metabolite database, validated by 2D NMR data interpretation and liquid chromatography coupled with mass spectrometry. The chemodiversity of the aerial parts was extensive, with 28 compounds unambiguously identified, spanning various biosynthetic classes. The F. ulmaria extract and CPC fractions were screened for their potential to enhance skin epidermal barrier function and skin renewal properties using in vitro assays performed on Normal Human Epidermal Keratinocytes. Fractions containing quercetin, kaempferol glycosides, ursolic acid, pomolic acid, naringenin, β-sitosterol, and Tellimagrandins I and II were found to upregulate genes related to skin barrier function, epidermal renewal, and stress responses. This research is significant as it could provide a natural solution for improving hydration and skin renewal properties. [ABSTRACT FROM AUTHOR]

Hippo/YAP signaling hinders cancer progression. Inactivation of this pathway contributes to the development of esophageal cancer by activation of Akt. However, the possible interaction between Akt and Hippo/YAP pathways in esophageal cancer progression is unclear. In this study, we found that ursolic acid (UA) plus 3′3-diindolylmethane (DIM) efficiently suppressed the oncogenic Akt/Gsk-3β signaling pathway while activating the Hippo tumor suppressor pathway in esophageal cancer cells. Moreover, the addition of the Akt inhibitor LY294002 and the PI3K inhibitor 3-methyladenine enhanced the inhibitory effects of UA plus DIM on Akt pathway activation and further stimulated the Hippo pathway, including the suppression of YAP nuclear translocation in esophageal cancer cells. Silencing YAP under UA plus DIM conditions significantly increased the activation of the tumor suppressor PTEN in esophageal cancer cells, while decreasing p-Akt activation, indicating that the Akt signaling pathway could be down-regulated in esophageal cancer cells by targeting PTEN. Furthermore, in a xenograft nude mice model, UA plus DIM treatment effectively diminished esophageal tumors by inactivating the Akt pathway and stimulating the Hippo signaling pathway. Thus, our study highlights a feedback loop between the PI3K/Akt and Hippo signaling pathways in esophageal cancer cells, implying that a low dose of UA plus DIM could serve as a promising chemotherapeutic combination strategy in the treatment of esophageal cancer. [ABSTRACT FROM AUTHOR]

Background: The search for new antimalarial drugs remains elusive prompting research into antimalarial combinations from medicinal plants due to their cheapness, efficacy and availability. Azadirachta indica (AI), Morinda lucida (ML) and Mangifera indica (MI) have all been reported as potent antimalarial plants. Purpose: This study evaluated the efficacy of an antimalarial combination therapeutics prepared from leaves of AI, ML and MI using in vitro, in vivo and molecular methods. Methods: Refined extracts of the plants combination was made by partitioning the aqueous extract of plants combinations (AI + MI, AI + ML, MI + ML, AI + MI + ML) using methanol and ethyl acetate consecutively. The resulting ethyl acetate partitioned fraction was evaluated for its antimalarial activity. Molecular docking and molecular dynamics simulation were employed to determine the possible mechanism of action of the constituent of the most active combination against four important P. falciparum proteins. Results: The result revealed that the refined extract from combinations AI + ML and MI + ML at 16 mg/kg bodyweight have the highest chemo-suppressive effect of 90.7% and 91.0% respectively compared to chloroquine's 100% at 10 mg/kg. Also, refined extract from MI + ML combination improved PCV levels significantly (p < 0.05) compared to controls. Molecular docking revealed oleanolic acid and ursolic acid as multiple inhibitors of plasmepsin II, hiso-aspartic protease, falcipain-2 and P. falciparum Eonyl acyl-carrier protein reductase with relative stability during 100 ns of simulation. Conclusion: The study unveiled the potentials of ML and MI as good candidates for antimalarial combination therapy and further established their use together as revealed in folklore medicine. [ABSTRACT FROM AUTHOR]

The three triterpenic acids, betulinic acid, oleanolic acid, and ursolic acid, are some of the prominent components with medicinal characteristics in jujube fruit (Ziziphus jujuba mill.) HPLC methods can be used to determine them, but the simultaneous determination of these triterpenic acids with a similar structure is difficult. The classical HPLC method needs more time to achieve separated peaks with a satisfactory resolution, and the procedure is costly. Still, chemometric methods coupled with overlapped HPLC peaks can help to make the process faster with less cost. Here, multilayer perceptron networks were used as a chemometric method coupled with HPLC–UV data. In the MLP–HPLC–UV method, the peak area does not require measurement. Instead, spectral data of the analytes in the heavily overlapped peaks were studied. This method was tested by analyzing the synthetic mixture of triterpenic acids. The standard addition method was applied to observe the effect of interferences and recovery evaluation on the yield value of the triterpenic acids in jujube (Ziziphus jujuba mill.) extract. Consequently, prediction data are more accurate, and good recoveries of analytes were obtained. Using a simple mobile phase, shorter run time without internal standard, and complex gradient elution conditions are the superiority of this method over the classical HPLC method. [ABSTRACT FROM AUTHOR]

Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor which has various mechanisms in different tumors. Ursolic acid (UA), a natural compound that exists in many herbs, is known to prevent tumor progression and has anticancer effects on many human cancers. The present study was to evaluate the antitumor effect of UA on gastric cancer (GC) through KLF4 and the Hippo pathway. Our data showed that UA inhibited the growth of GC in vivo and in vitro. UA treatment significantly increased the expression of KLF4 and decreased the expression of CTGF. The overexpression of KLF4 inhibited the proliferation and cell cycle of GC and decreased the expression of CTGF, whereas the knockdown of KLF4 attenuated the effects of UA. Furthermore, the inhibition of CTGF arrested tumor cells in G2/M which blocked proliferation progress. Confocal laser scanning and molecular simulation software MOE showed that KLF4 combined with YAP1 which may block the formation of the TEADs-YAP1 complex to interrupt the expression of CTGF and the downstream oncogenic process. In conclusion, UA can inhibit GC growth both in vivo and in vitro, and it activated KLF4 which may competitively bind with YAP1 against TEADs and block the oncogenic Hippo pathways. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress is crucial in experimental autoimmune myocarditis (EAM)-induced inflammatory myocardial injury. Ursolic acid (UA) is an antioxidantenriched traditional Chinese medicine formula. The present study aimed to investigate whether UA could alleviate inflammatory cardiac injury and determine the underlying mechanisms. Methods: Six-week-old male BALB/c mice were randomly assigned to one of the three groups: Sham, EAM group, or UA intervention group (UA group) by gavage for 2 weeks. An EAM model was developed by subcutaneous injection of a-myosin heavy chain derived polypeptide (a-MyHC peptide) into lymph nodes on days 0 and 7. Echocardiography was used to assess cardiac function on day 21. The inflammation level in the myocardial tissue of each group was compared using hematoxylin and eosin staining (HE) of heart sections and Interleukin-6 (IL-6) immunohistochemical staining. Masson staining revealed the degree of cardiac fibrosis. Furthermore, Dihydroethidium staining, Western blot, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) were used to determine the mechanism of cardioprotective effects of UA on EAMinduced cardiac injury, and the level of IL-6, Nrf2, and HO-1. Results: In EAM mice, UA intervention significantly reduced the degree of inflammatory infiltration and myocardial fibrosis while improving cardiac function. Mechanistically, UA reduced myocardial injury by inhibiting oxidative stress (as demonstrated by a decrease of superoxide and normalization of proand antioxidant enzyme levels). Interestingly, UA intervention upregulated the expression of antioxidant factors such as Nrf2 and HO-1. In vitro experiments, specific Nrf2 inhibitors reversed the antioxidant and antiapoptotic effects of ursolic acid, which further suggested that the amelioration of EAM by UA was in a Nrf2/HO-1 pathway-dependent manner. Conclusion: These findings indicate that UA is a cardioprotective traditional Chinese medicine formula that reduces EAM-induced cardiac injury by upregulating Nrf2/HO-1 expression and suppressing oxidative stress, making it a promising therapeutic strategy for the treatment of EAM. [ABSTRACT FROM AUTHOR]

The chemical investigation of Homotrigona apicalis propolis collected in Binh Dinh province, Vietnam, led to the isolation of nine compounds, including four sesquiterpenes: spathulenol (1), 1αH,5βH-aromandendrane-4β,10α-diol (2), 1β,6α-dihydroxy-4(15)-eudesmene (3), and 1βH,5βH-aromandendrane-4α,10β-diol (4); three triterpenes: acetyl oleanolic acid (5), 3α-hydroxytirucalla-8,24-dien-21-oic acid (6), and ursolic acid (7); and two xanthones: cochinchinone A (8) and α-mangostin (9). Sesquiterpens 1–4 and triterpene 6 were isolated for the first time from stingless bee propolis. Plants in the Cratoxylum and Aglaia genus were suggested as resin sources of the propolis sample. In the antibacterial activity evaluation, the EtOH extract only showed moderate activity on S. aureus, while the isolated compounds 7–9 showed good antibacterial activity, with IC50 values of 0.56 to 17.33 µg/mL. The EtOH extract displayed selective cytotoxicity against the A-549 cancer cell line, with IC50 values of 22.82 ± 0.86 µg/mL, and the xanthones 8 and 9 exhibited good activity against the KB, HepG-2, and A-549 cancer cell lines, with IC50 values ranging from 7.55 ± 0.25 µg/mL to 29.27 ± 2.07 µg/mL. The cytotoxic effects of xanthones 8 and 9 were determined by the inhibition of the EGFR and HER2 pathways using a molecular docking study. Compounds 8 and 9 displayed strong binding affinity with EFGR and HER2, with values of −9.3 to −9.9 kcal/mol. Compounds 5, 8, and 9 showed potential α-glucosidase inhibitory activities, which were further confirmed by computational studies. The binding energies of compounds 5, 8, and 9 were lower than that of arcabose. [ABSTRACT FROM AUTHOR]

In the last decade, gypsogenin has attracted widespread attention from medicinal chemists by virtue of its prominent anti-cancer potential. Despite its late identification, gypsogenin has proved itself as a new anti-proliferative player battling for a frontline position among other classic pentacyclic triterpenes such as oleanolic acid, glycyrrhetinic acid, ursolic acid, betulinic acid, and celastrol. Herein, we present the most important reactions of gypsogenin via modification of its four functional groups. Furthermore, we demonstrate insights into the anti-cancer activity of gypsogenin and its semisynthetic derivatives and go further by introducing our perspective to judiciously guide the prospective rational design. The present article opens a new venue for a better exploitation of gypsogenin chemical entity as a lead compound in cancer chemotherapy. To the best of our knowledge, this is the first review article exploring the anti-cancer activity of gypsogenin derivatives. [ABSTRACT FROM AUTHOR]

Burn management is a natural and distinctly programmed process involving overlapping phases of hemostasis, inflammation, proliferation and remodeling. Burn wound healing involves initiation of inflammation, re-epithelialization, granulation, neovascularization and wound contraction. Despite the availability of multiple preparations for management of burn wound, there is dire need for efficacious alternative agents. Current approaches for burn wound management include pharmaceutical agents and antibiotics. However, high cost of synthetic drugs and accelerated resistance to antibiotics is challenging for both developed and developing nations. Among alternative options, medicinal plants have been a biocompatible, safe and affordable source of preventive/curative approaches. Due to cultural acceptance and patient compliance, there has been a focus on the use of botanical drugs and phytochemicals for burn wound healing. Keeping in consideration of medicinal herbs and phytochemicals as suitable therapeutic/adjuvant agents for burn wound management, this review highlights therapeutic potential of 35 medicinal herbs and 10 phytochemicals. Among these, Elaeis guineensis, Ephedra ciliate and Terminalia avicennioides showed better burn wound healing potential with varied mechanisms such as modulation of TNF-alpha, inflammatory cytokines, nitric oxide, eicosanoids, ROS and leukocyte response. Phytochemicals (oleanolic acid, ursolic acid, kirenol) also showed promising role in burn wound management though various pathways involving such as down regulation of TNF-alpha, IL-6 and inflammatory mediators including plasma proteases and arachidonic acid metabolites. This review provides a pavement for therapeutic/adjuvant use of potential botanical drugs and novel druggable phyto-compounds to target skin burn injury with diverse mechanisms, affordability and safety profile. [ABSTRACT FROM AUTHOR]

A new ursane triterpenoid caffeic acid ester, cratoresbate A, together with seven known ursane triterpenoids (3-O-trans-p-coumaroyltormentic acid, 3-O-cis-p-coumaroyltormentic acid, α-amyrin, ursolic acid, pomolic acid, euscaphic acid, and tormentic acid) were isolated from the twigs and leaves of Crataegus oresbia W. W. Sm. Cratoresbate A showed significant cytotoxicity against HepG2 cells with IC50 value of 1.9 µmol L−1. [ABSTRACT FROM AUTHOR]

It has been reported ursolic acid (UA), one of the naturally abundant pentacyclic triterpenes, possesses a wide range of biological activities including anti‐inflammatory, anti‐atherosclerotic, and anticancer properties. Renal cell carcinoma (RCC) is a severe malignancy due to its asymptomatically spreading ability. Our study aimed to investigate the role and molecular mechanism of UA in RCC. RCC cell proliferation, migration, invasion, and angiogenesis were assessed using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide, Transwell, and tube formation assays. Xenograft tumor models were established to confirm the role of UA and long noncoding RNA ASMTL antisense RNA 1 (ASMTL‐AS1) in vivo. Expression levels of ASMTL‐AS1 and vascular endothelial growth factor (VEGF) were measured using reverse transcriptase quantitative polymerase chain reaction and western blot analysis. The interaction probabilities of ASMTL‐AS1 or VEGF with RNA‐binding protein human antigen R (HuR) were verified by RNA immunoprecipitation experiment. The half‐life period of messenger RNA (mRNA) was determined using actinomycin D. UA inhibited RCC cell growth in vivo and tumorigenesis in vitro. ASMTL‐AS1 was highly expressed in RCC cell lines. Of note, UA downregulated ASMTL‐AS1 expression, and overexpressed ASMTL‐AS1 reversed the UA‐induced suppression on RCC cell migration, invasion, and tube formation. Additionally, ASMTL‐AS1 bound to HuR to maintain the stability of VEGF mRNA. Rescue experiments showed that the suppressed malignancy of RCC cells mediated by ASMTL‐AS1 knockdown was counteracted by overexpression of VEGF. Moreover, silenced ASMTL‐AS1 inhibited RCC tumor growth and metastasis in vivo. The obtained data suggest UA as a promising therapeutic agent to attenuate the development of RCC via regulation of the targeted molecules. [ABSTRACT FROM AUTHOR]

Ursolic acid (UA) is a plant-derived pentacyclic triterpenoid with 30 carbon atoms. UA has anti-inflammatory, antioxidative, antimicrobial, hepato-protective, anticancer, and other biological activities. Most studies on the biological functions of UA have been performed in mammalian cell (in vitro) and rodent (in vivo) models. UA is used in animal husbandry as an anti-inflammatory and antiviral agent, as well as for enhancing the integrity of the intestinal barrier. Although UA has been shown to have significant in vitro bacteriostatic effects, it is rarely used in animal nutrition. The use of UA as a substitute for oral antibiotics or as a novel feed additive in animal husbandry should be considered. This review summarizes the available data on the biological functions of UA and its applications in animal husbandry.