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Natural products have been used since ancient times to treat various ailments and have been recognized for many years as a source of therapeutic agents and structural diversity. Plant-derived products have thus served as dietary components but also to maintain a state of wellbeing and health by preventing different diseases both of inflammatory and infective nature. Pentacyclic triterpenoids, particularly ursolic acid (UA) and oleanolic acid (OA), are well-studied natural products endowed with complex biological profiles. In this mini-review, we summarized the most advanced results on extraction methodologies and antimicrobial activity of UA and OA, focusing on their potential role as antimicrobic adjuvants, bacterial biofilm inhibitors and related mechanisms of action. This offers a theoretical basis and inspiration for further studies on their bioactivity mechanism. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes is associated with increased inflammation and a risk of Alzheimer's disease (AD). This study aimed to assess the impact of exercise with ursolic acid (UA) on some protein levels in the brains of aged male Wistar rats with diet-induced Type 2. We investigated the effects of exercise with UA on protein levels in rats with type 2 diabetes. The rats were divided into seven groups and underwent different exercise or UA protocols. Results: The results showed that type 2 diabetes led to increased levels of tau, IL-1β, TNF-α, and c-Jun, and decreased levels of IRS2 protein. Endurance training improved tau, Jun, and IRS2 levels. UA reduced increased levels of tau, IL-1β, TNF-α, and c-Jun, and increased IRS2 levels. Combining the supplement with training led to further improvements. Conclusions: These findings suggest that combining training and UA partially reversed the inflammation in the Type 2 diabetes model. However, further research is needed to understand how UA consumption with or without training protocols can reduce the risk of AD in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Ursolic acid (UA) and its derivatives have garnered significant attention due to their extensive pharmacological activity. UA is a pentacyclic triterpenoid found in a variety of plants, such as apples, rosemary, thyme, etc., and it possesses a range of pharmacological properties. Researchers have synthesized various derivatives of UA through structural modifications to enhance its potential pharmacological properties. Various in vitro and in vivo studies have indicated that UA and its derivatives possess diverse biological activities, such as anticancer, antifungal, antidiabetic, antioxidant, antibacterial, anti-inflammatory and antiviral properties. This review article provides a review of the biological activities of UA and its derivatives to show their valuable therapeutic properties useful in the treatment of different diseases, mainly focusing on the relevant structure-activity relationships (SARs), the underlying molecular targets/pathways, and modes of action. [ABSTRACT FROM AUTHOR]

Gastrointestinal malignancies are one of the major worldwide health concerns. In the present review, we have assessed the plausible therapeutic implication of Ursolic Acid (UA) against gastrointestinal cancer. By modulating several signaling pathways critical in cancer development, UA could offer anti-inflammatory, antiproliferative, and anti-metastatic properties. However, being of low oral bioavailability and poor permeability, its clinical value is restricted. To deliver and protect the drug, liposomes and polymer micelles are two UA nanoformulations that can effectively increase medicine stability. The use of UA for treating cancers is safe and appropriate with low toxicity characteristics and a predictable pharmacokinetic profile. Although the bioavailability of UA is limited, its nanoformulations could emerge as an alternative to enhance its efficacy in treating GI cancers. Further optimization and validation in the clinical trials are necessary. The combination of molecular profiling with nanoparticle-based drug delivery technologies holds the potential for bringing UA to maximum efficacy, looking for good prospects with GI cancer treatment. [ABSTRACT FROM AUTHOR]

Four previously unreported triterpenoid saponins named 3β-hydroxy-23-oxours-12-en-28-oic acid 28-O-β-D-glucopyranosyl ester (mannioside G) (1), 23-O-acetyl-3β-hydroxyurs-12-en-28-oic acid 28-O-β-D-glucopyranosyl ester (mannioside H) (2), ursolic acid 28-O-[α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl] ester (mannioside I) (3), and 3β-hydroxy-23-oxolup-20(29)-en-28-oic acid 28-O-β-D-glucopyranosyl ester (mannioside J) (4) were isolated as minor constituents from the EtOAc soluble fraction of the MeOH extract of the leaves of Schefflera mannii along with the known compounds 23-hydroxyursolic acid 28-O-β-D-glucopyranosyl ester (5), ursolic acid 28-O-β-D-glucopyranosyl ester (6), pulsatimmoside B (7) betulinic acid 28-O-[α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl] ester (8), 23-hydroxy-3-oxo-urs-12-en-28-oic acid (9), hederagenin (10), ursolic acid (11), betulinic acid (12), and lupeol (13). Their structures were elucidated by a combination of 1D and 2D NMR analysis and mass spectrometry. The MeOH extract, the EtOAc and n-BuOH fractions, and some of the isolated compounds were evaluated for their antibacterial activity against four bacteria: Staphylococcus aureus ATCC1026, Staphylococcus epidermidis ATCC 35984, Escherichia coli ATCC10536, and Klepsiella pnemoniae ATCC13882. They were also screened for their antioxidant properties, but no significant results were obtained. [ABSTRACT FROM AUTHOR]

Cancer is a global health problem, with the incidence rate estimated to reach 40% of the population by 2030. Although there are currently several therapeutic methods, none of them guarantee complete healing. Plant-derived natural products show high therapeutic potential in the management of various types of cancer, with some of them already being used in current practice. Among different classes of phytocompounds, pentacyclic triterpenoids have been in the spotlight of research on this topic. Ursolic acid (UA) and its structural isomer, oleanolic acid (OA), represent compounds intensively studied and tested in vitro and in vivo for their anticancer and chemopreventive properties. Since natural compounds can rarely be used in practice as such due to their characteristic physico-chemical properties, to tackle this problem, their derivatization has been attempted, obtaining compounds with improved solubility, absorption, stability, effectiveness, and reduced toxicity. This review presents various UA and OA derivatives that have been synthesized and evaluated in recent studies for their anticancer potential. It can be observed that the most frequent structural transformations were carried out at the C-3, C-28, or both positions simultaneously. It has been demonstrated that conjugation with heterocycles or cinnamic acid, derivatization as hydrazide, or transforming OH groups into esters or amides increases anticancer efficacy. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory disease that affects around 2–3% of the world's population. The treatment for this autoimmune disease still remains centered around conventional methods using synthetic substances, even though more recent advancements focus on biological therapies. Given the numerous side effects of such treatments, current research involves plant extracts and constituents that could prove useful in treating psoriasis. The aim of this narrative review is to highlight the most known representatives belonging to classes of natural compounds such as polyphenols (e.g., astilbin, curcumin, hesperidin, luteolin, proanthocyanidins, and resveratrol), alkaloids (e.g., berberine, capsaicin, and colchicine), coumarins (psoralen and 8-methoxypsoralen), and terpenoids (e.g., celastrol, centelloids, and ursolic acid), along with plants used in traditional medicine that could present therapeutic potential in psoriasis. The paper also provides an overview of these compounds' mechanisms of action and current inclusion in clinical studies, as well as an investigation into their potential incorporation in various nanotechnological systems, such as lipid-based nanocarriers or polymeric nanomaterials, that may optimize their efficacy during treatment. [ABSTRACT FROM AUTHOR]

Although many natural product-derived compounds possess anti-leishmanial activities in vitro and in vivo, their molecular targets in the Leishmania parasite remain elusive. This is a major challenge in optimizing these compounds into leads. The Leishmania pteridine reductase (PTR1) is peculiar for folate and pterin metabolism and has been validated as a drug target. In this study, 17 compounds with anti-leishmanial activities were screened against Leishmania major PTR1 (LmPTR1) using molecular docking and molecular dynamics (MD) simulations. All ligands were bound in the active site pocket of LmPTR1 with binding affinities ranging from -11.2 to -5.2 kcal/mol. Agnuside, betulin, betulinic acid, gerberinol, ismailin, oleanolic acid, pristimerin, and ursolic acid demonstrated binding affinities similar to a known inhibitor, methyl 1-(4-{[2,4-diaminopteridin-6-yl) methyl] amino} benzoyl) piperidine-4-carboxylate (DVP). MD simulations revealed that betulin, betulinic acid, ismailin, oleanolic acid, pristimerin, and ursolic acid formed stable complexes with LmPTR1. The binding free energies of the complexes were very good (-87 to -148 kJ/mol), and much higher than the complex of the standard DVP inhibitor and LmPTR1 (-27 kJ/mol). Betulin, betulinic acid, ismailin, oleanolic acid, pristimerin, and ursolic acid likely exert their antileishmanial action by inhibiting PTR1 and could thus be used as a basis for the development of potential antileishmanial chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Rice brown spot is an important disease of rice worldwide that inflicts substantial yield losses. The antimicrobial potential of methanol, acetone and dimethyl sulfoxide (DMSO) extracts of different medicinal plants, viz., Syzygium aromaticum, Saussurea costus, Acorus calamus, Bergenia ciliate, Geranium pratense, Mentha longifolia, Inula racemosa, Podophyllum hexandrum, Heracleum candicans and Picrorhiza kurroa, against the brown spot pathogen Bipolaris oryzae in vitro was evaluated via mycelial growth inhibition and spore germination inhibition assays. Among the plant extracts tested, 100% mycelial inhibition was observed for the methanol extract of Syzygium aromaticum at all three concentrations (2000 ppm, 3000 ppm and 4000 ppm), followed by the methanol extract of Inula racemosa (90.33%) at 4000 ppm. A maximum conidial germination inhibition of 83.54% was exhibited by the Heracleum candicans leaf extract. Phytochemical profiling of Syzygium aromaticum and Inula racemosa through liquid chromatography and mass spectrometry (HR-LCMS) revealed the presence of several compounds, such as eugenol, ursolic acid, quercetin, chlorogenic acid, and noscapine. A molecular docking approach was used to identify key inhibitory molecules against B. oryzae. Among the compounds detected in S. aromaticum and Inula racemosa, ursolic acid and noscapine were found to have the greatest binding affinity for the Big Mitogen Activated Protein Kinase (BMK-1) enzyme present in B. oryzae. In conclusion, S. aromaticum and Inula racemosa are potent compounds that could serve as lead compounds for drug discovery in the future. [ABSTRACT FROM AUTHOR]

Background: Despite the potential radiotoxicity in differentiated thyroid cancer (DTC) patients with high-dose 131I therapy, the alterations and regulatory mechanisms dependent on intestinal microecology remain poorly understood. We aimed to identify the characteristics of the gut microbiota and metabolites in DTC patients suffering from high-dose 131I therapy and explore the radioprotective mechanisms underlying arachidonic acid (ARA) treatment. Methods: A total of 102 patients with DTC were recruited, with fecal samples collected before and after 131I therapy for microbiome and untargeted and targeted metabolomic analyses. Mice were exposed to total body irradiation with ARA replenishment and antibiotic pretreatment and were subjected to metagenomic, metabolomic, and proteomic analyses. Results: 131I therapy significantly changed the structure of gut microbiota and metabolite composition in patients with DTC. Lachnospiraceae were the most dominant bacteria after 131I treatment, and metabolites with decreased levels and pathways related to ARA and linoleic acid were observed. In an irradiation mouse model, ARA supplementation not only improved quality of life and recovered hematopoietic and gastrointestinal systems but also ameliorated oxidative stress and inflammation and preserved enteric microecology composition. Additionally, antibiotic intervention eliminated the radioprotective effects of ARA. Proteomic analysis and ursolic acid pretreatment showed that ARA therapy greatly influenced intestinal lipid metabolism in mice subjected to irradiation by upregulating the expression of hydroxy-3-methylglutaryl-coenzyme A synthase 1. Conclusion: These findings highlight that ARA, as a key metabolite, substantially contributes to radioprotection. Our study provides novel insights into the pivotal role that the microbiota-metabolite axis plays in radionuclide protection and offers effective biological targets for treating radiation-induced adverse effects. [ABSTRACT FROM AUTHOR]

The leaves of Ilex paraguariensis (known as Yerba mate), used as a popular beverage, are a very well-recognized plant material with various biological activities, including analeptic (because of caffeine), anti-obesity (phenolics, saponins), antimicrobial, and antiviral (phenolics, saponins). Here, the chemical compositions of the leaves of two European Ilex species (× meserveae and aquifolium) with three varieties each were investigated. The terpenoid, saponin, and polyphenolic fractions were submitted for LC-MS or GC-MS analysis against a standard Mate leaf. In addition, the aroma profiles of all the species were analysed using HS-SPME-Arrow prior to GC-MS analysis. All fractions were subjected to antiviral and cytotoxic assays. We found 86 compounds in all accessions, with limonene, linalool, and p-cymene being predominant. There were minor similarities between the volatile compositions of the European and South American species. We found ursolic and oleanolic acid to be the main compounds in the terpenoid fraction. Mono-caffeoylquinic acids and di-caffeoylquinic acids were the main constituents of the polar fractions. About 180 compounds from the saponin group were tentatively identified, of which 9 and 3 were selected as distinctive markers for I. meserveae and I. aquifolium, respectively. Based on chemical screening, I. aquifolium Silver Queen was chosen as the source of terpenoid and saponin fractions and polyphenol extracts. The most substantial inhibition of cancer cell growth was observed with saponin in the case of the MCF7 (human breast cancer) cell line, while for LoVo and L929 cell lines (human colorectal cancer and reference mouse fibroblasts), it was slightly weaker. These results should be analysed further as a promising chemoprevention of colorectal and gastrointestinal cancers. Saponin and polyphenolic extracts exhibited similar activities against HSV-1 and HAdV-5, with 4-log reduction in virus titres. This study focuses our attention on a field of potential antiviral formulations derived from European holly. [ABSTRACT FROM AUTHOR]

Combination immunotherapy has shown promising potential for enhancing the objective response rate compared to immune checkpoint blockade (ICB) monotherapy. However, combination therapy with multi-drugs is limited by the different properties of the agents and inconsistent synergistic targeted delivery. Herein, based on a universal triterpene template and the anticancer active agent ursolic acid (UA), a cytomembrane-coated biomimetic delivery nanoplatform (UR@M) prepared by the self-assembly of a PD-L1 targeted CRISPR/Cas9 system and UA was designed for hepatocellular carcinoma (HCC) treatment. UR@M showed enhanced tumor accumulation in vivo with homologous tumor targeting, and CRISPR in the nanosystem exhibited potent gene-editing efficiency of 76.53% in vitro and 62.42% in vivo with no off-target effects. UA activated the natural immune system through the TLR-2-MyD88-TRAF6 pathway, which synergistically enhanced the proliferation of natural killer cells and dendritic cells and realized excellent immune cytotoxic T cell infiltration by combining with the ICB of PD-L1. The strategy of work along both lines based on innate immune and adaptive immunity displayed a significant effect in tumor regression. Overall, the UA-templated strategy "killed three birds with one stone" by establishing a self-assembly nanosystem, inducing tumor cell death, and promoting synergistic immunostimulation for HCC treatment. A biomimetic nanodrug UR@M from the triterpenoids-templated self-assembly is developed to deliver CRISPR/Cas9, exhibiting synergistic immunotherapy by activating innate immune by TLR-2 pathway and gene therapy of PD-L1 by CRISPR/Cas9. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Oligospermia is one of the most common reasons for male infertility which is troubling numerous couples of child-bearing age. This investigation scrutinizes the implications and mechanistic underpinnings of ursolic acid's effect on busulfan-induced oligospermia in mouse models. Methods: A singular intraperitoneal injection of busulfan at a dosage of 30 mg/kg induced oligospermia. Two weeks subsequent to this induction, mice were subjected to various dosages of ursolic acid (10, 30, and 50 mg/kg body weight, respectively) on a daily basis for four consecutive weeks. Following this treatment period, a meticulous analysis of epididymal sperm parameters, encompassing concentration and motility, was conducted using a computer-assisted sperm analysis system. The histopathology of the mice testes was performed utilizing hematoxylin and eosin staining, and the cytoskeleton regeneration of the testicular tissues was analyzed via immunofluorescent staining. Serum hormone levels, including testosterone, luteinizing hormone, and follicle-stimulating hormone, as well as reactive oxygen species levels (inclusive of reactive oxygen species and malondialdehyde), were gauged employing specific enzyme-linked immunosorbent assay kits. Differentially expressed genes of testicular mRNA between the oligospermia-induced group and the various ursolic acid treatment groups were identified through RNA sequencing analysis. Results: The results revealed that a dosage of 50 mg/kg ursolic acid treatment could increase the concentration of epididymal sperm in oligospermia mice, promote the recovery of testicular morphology, regulate hormone levels and ameliorate oxidative damage. The mechanism research results indicated that ursolic acid increased the expression level of genes related to motor proteins in oligospermia mice. [ABSTRACT FROM AUTHOR]

A HPLC method was developed for the simultaneous determination of euscaphic acid, 2α,19α-dihydroxy-3-oxo-urs-12-en-28-oic acid, maslinic acid, corosolic acid, oleanic acid, and ursolic acid in Malus doumeri fruits. Analyses were conducted on the distribution and content of these six triterpenic acids in Malus doumeri fruits from six producing areas in Guangxi. Using gradient elution at a flow rate of 0.8 mL/min, a Diamonsil C18 (2) column was used with a mobile phase of 0.1% formic acid aqueous solution/methanol (v/v). The detection wavelength was 210 nm and the column temperature was 30 °C. The results showed that the mass concentrations of the six triterpenic acids had a good linear relationship with the chromatographic peak areas in the linear range. The correlation coefficients were greater than 0.9990, the detection limits were within 0.46-2.00 μg/mL, the lower quantitation limits were within 1.53-6.67 μg/mL, the coefficients of variation were less than 5.0%, and the recovery percentages were within 99.2%-101.3%. Six samples from different production areas contained six triterpenic acids (euscaphic acid, 2α,19α-dihydroxy-3-oxo-urs-12-en-28-oic acid, maslinic acid, corosolic acid, oleanic acid, and ursolic acid). Each of the six triterpenic acids was a pentacyclic triterpenic acid. Among the six triterpenic acids, euscaphic acid and 2α,19α-dihydroxy-3-oxo-urs-12-en-28-oic acid were first detected in Malus doumeri fruits. Ursolic acid, euscaphic acid, and 2α,19α-dihydroxy-3-oxo-urs-12-en-28-oic acid were predominant, accounting for 71.82%-81.38% of the total triterpenic acids. The total triterpenic acids content ranged from 808.74 to 1090.75 μg/g FM. The total triterpenic acids content of fruits from Liujiang district of Liuzhou and Pingle of Guilin were relatively high, reaching 1090.75 μg/g FM and 1045.20 μg/g FM, respectively. Overall, this study's HPLC method can detect the triterpenic acids content of Malus doumeri fruits and provide scientific references for the quality evaluation of Malus doumeri fruit's raw materials and products. [ABSTRACT FROM AUTHOR]

Plasmodium falciparum is the most lethal malaria parasite. Increasing incidences of drug resistance of P. falciparum have prompted the need for discovering new and effective antimalarial compounds with an alternative mode of action. Heat shock protein 90 (PfHsp90) facilitates protein folding and is a promising antimalarial drug target. We have previously reported that iso-mukaadial acetate (IMA) and ursolic acid acetate (UAA) exhibit antimalarial activity. We investigated the abilities of IMA and UAA to bind PfHsp90 by molecular docking and dynamics simulations. The in silico predictions were validated by biochemical assays conducted on recombinant PfHsp90. The interaction between the ligands and PfHsp90 was evaluated using ultraviolet-visible spectroscopy (UV-vis), Fourier transform infrared (FTIR), and surface plasmon resonance (SPR) analysis. The results obtained by docking calculations and MD dynamics simulation predicted that UAA and IMA preferentially bound to PfHsp90 via the N-terminal domain, with UAA binding more stable than IMA. UV-vis-based data suggest that PfHsp90 harbors buried aromatic amino acids, which were exposed in the presence of either IMA or UAA. In addition, data obtained using FTIR suggested that IMA and UAA destabilized the secondary structure of PfHsp90. Of the two compounds, UAA bound to PfHsp90 within the micromolar range based on surface plasmon resonance (SPR)-based binding assay. Furthermore, both compounds disrupted the holdase chaperone function of PfHsp90 as the chaperone failed to suppress heat-induced aggregation of the model proteins, malate dehydrogenase (MDH), luciferase, and citrate synthase in vitro. In addition, both compounds lowered the ATPase activity of PfHsp90. The molecular dynamics simulation analysis indicated that the docked complexes were mostly stable for 100 ns, validating the data obtained through the biochemical assays. Altogether, this study expands the repository of antiplasmodial compounds that have PfHsp90 among their possible targets. [ABSTRACT FROM AUTHOR]

As screening strategies employ better biomarkers and genetics to identify individuals at an increased risk of prostate cancer, there are currently no chemotherapeutic prevention strategies. With any chemoprevention strategy, the population will be younger and healthier; therefore, they will be less tolerant of side effects. This study translated findings from screening a natural product library and pre-clinical evaluation of curcumin (CURC) in combination with ursolic acid (UA) in prostate cancer models. After manufacturing capsules for each compound, 18 subjects were enrolled. The study used a 3 × 3 phase 1 clinical trial to evaluate CURC (1200 mg/day) and UA (300 mg/day) alone and in combination over a 2-week period with endpoints of safety, bioavailability, and microbiome alterations. After enrolling six subjects in each arm, we found no grade 3 or 4 events and only minor changes in the safety laboratory values. In the pooled analysis of groups, we noted a statistically significant difference between median serum levels of UA when administered alone vs administered in the combination (2.7 ng/mL vs 43.8 ng/mL, p = 0.03). Individuals receiving the combination also had a favorable impact on gut microbiome status and a reduction in “microbiome score” predictive of prostate cancer risk.

Cheng Peng,1,2 Shiqi Kang,1,2 Meijun Jiang,1,2 Mingxi Yang,1,2 Xu Gong1,2 1Department of Hand and Podiatric Surgery, Orthopedics Center, The First Hospital of Jilin University, Jilin University, Changchun, 130021, People’s Republic of China; 2Jilin Province Key Laboratory on Tissue Repair, Reconstruction and Regeneration, The First Hospital of Jilin University, Jilin University, Changchun, 130021, People’s Republic of ChinaCorrespondence: Xu Gong; Mingxi Yang, Email gongxu@jlu.edu.cn; yangmxchem@jlu.edu.cnBackground: The formation of adhesion after tendon injury represents a major obstacle to tendon repair, and currently there is no effective anti-adhesion method in clinical practice. Oxidative stress, inflammation, and fibrosis can occur in tendon injury and these factors can lead to tendon adhesion. Antioxidant carbon dots and ursolic acid (UA) both possess antioxidant and anti-inflammatory properties. In this experiment, we have for the first time created RCDs/UA@Lipo-HAMA using red fluorescent carbon dots and UA co-encapsulated liposomes composite hyaluronic acid methacryloyl hydrogel. We found that RCDs/UA@Lipo-HAMA could better attenuate adhesion formation and enhance tendon healing in tendon injury.Materials and Methods: RCDs/UA@Lipo-HAMA were prepared and characterized. In vitro experiments on cellular oxidative stress and fibrosis were performed. Reactive oxygen species (ROS), and immunofluorescent staining of collagens type I (COL I), collagens type III (COL III), and α-smooth muscle actin (α-SMA) were used to evaluate anti-oxidative and anti-fibrotic abilities. In vivo models of Achilles tendon injury repair (ATI) and flexor digitorum profundus tendon injury repair (FDPI) were established. The major organs and blood biochemical indicators of rats were tested to determine the toxicity of RCDs/UA@Lipo-HAMA. Biomechanical testing, motor function analysis, immunofluorescence, and immunohistochemical staining were performed to assess the tendon adhesion and repair after tendon injury.Results: In vitro, the RCDs/UA@Lipo group scavenged excessive ROS, stabilized the mitochondrial membrane potential (ΔΨm), and reduced the expression of COL I, COL III, and α-SMA. In vivo, assessment results showed that the RCDs/UA@Lipo-HAMA group improved collagen arrangement and biomechanical properties, reduced tendon adhesion, and promoted motor function after tendon injury. Additionally, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) in the RCDs/UA@Lipo-HAMA group increased; the levels of cluster of differentiation 68 (CD68), inducible Nitric Oxide Synthase (iNOS), COL III, α-SMA, Vimentin, and matrix metallopeptidase 2 (MMP2) decreased.Conclusion: In this study, the RCDs/UA@Lipo-HAMA alleviated tendon adhesion formation and enhanced tendon healing by attenuating oxidative stress, inflammation, and fibrosis. This study provided a novel therapeutic approach for the clinical treatment of tendon injury.Keywords: tendon adhesion, antioxidant, carbon dots, ursolic acid, liposomes, hydrogel

Background/Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) has become an increasingly important health challenge, with a substantial rise linked to changing lifestyles and global obesity. Ursolic acid, a natural pentacyclic triterpenoid, has been explored for its potential therapeutic effects. Given its multifunctional bioactive properties, this research further revealed the pharmacological mechanisms of ursolic acid on MASLD. Methods Drug target chips and bioinformatics analysis were combined in this study to explore the potential therapeutic effects of ursolic acid on MASLD. Molecular docking simulations, surface plasmon resonance analyses, pull-down experiments, and co-immunoprecipitation assays were used to verify the direct interactions. Gene knockdown mice were generated, and high-fat diets were used to validate drug efficacy. Furthermore, initial CD4+ T cells were isolated and stimulated to demonstrate our findings. Results In this study, the multifunctional extracellular matrix phosphorylated glycoprotein secreted phosphoprotein 1 (SPP1) was investigated, highlighting its capability to induce Th17 cell differentiation, amplifying inflammatory cascades, and subsequently promoting the evolution of MASLD. In addition, this study revealed that in addition to the canonical TGF-β/IL-6 cytokine pathway, SPP1 can directly interact with ITGB1 and CD44, orchestrating Th17 cell differentiation via their joint downstream ERK signaling pathway. Remarkably, ursolic acid intervention notably suppressed the protein activity of SPP1, suggesting a promising avenue for ameliorating the immunoinflammatory trajectory in MASLD progression. Conclusions Ursolic acid could improve immune inflammation in MASLD by modulating SPP1-mediated Th17 cell differentiation via the ERK signaling pathway, which is orchestrated jointly by ITGB1 and CD44, emerging as a linchpin in this molecular cascade.

Abstract Rice brown spot is an important disease of rice worldwide that inflicts substantial yield losses. The antimicrobial potential of methanol, acetone and dimethyl sulfoxide (DMSO) extracts of different medicinal plants, viz., Syzygium aromaticum, Saussurea costus, Acorus calamus, Bergenia ciliate, Geranium pratense, Mentha longifolia, Inula racemosa, Podophyllum hexandrum, Heracleum candicans and Picrorhiza kurroa, against the brown spot pathogen Bipolaris oryzae in vitro was evaluated via mycelial growth inhibition and spore germination inhibition assays. Among the plant extracts tested, 100% mycelial inhibition was observed for the methanol extract of Syzygium aromaticum at all three concentrations (2000 ppm, 3000 ppm and 4000 ppm), followed by the methanol extract of Inula racemosa (90.33%) at 4000 ppm. A maximum conidial germination inhibition of 83.54% was exhibited by the Heracleum candicans leaf extract. Phytochemical profiling of Syzygium aromaticum and Inula racemosa through liquid chromatography and mass spectrometry (HR-LCMS) revealed the presence of several compounds, such as eugenol, ursolic acid, quercetin, chlorogenic acid, and noscapine. A molecular docking approach was used to identify key inhibitory molecules against B. oryzae. Among the compounds detected in S. aromaticum and Inula racemosa, ursolic acid and noscapine were found to have the greatest binding affinity for the Big Mitogen Activated Protein Kinase (BMK-1) enzyme present in B. oryzae. In conclusion, S. aromaticum and Inula racemosa are potent compounds that could serve as lead compounds for drug discovery in the future.

Combination immunotherapy has shown promising potential for enhancing the objective response rate compared to immune checkpoint blockade (ICB) monotherapy. However, combination therapy with multi-drugs is limited by the different properties of the agents and inconsistent synergistic targeted delivery. Herein, based on a universal triterpene template and the anticancer active agent ursolic acid (UA), a cytomembrane-coated biomimetic delivery nanoplatform (UR@M) prepared by the self-assembly of a PD-L1 targeted CRISPR/Cas9 system and UA was designed for hepatocellular carcinoma (HCC) treatment. UR@M showed enhanced tumor accumulation in vivo with homologous tumor targeting, and CRISPR in the nanosystem exhibited potent gene-editing efficiency of 76.53% in vitro and 62.42% in vivo with no off-target effects. UA activated the natural immune system through the TLR-2-MyD88-TRAF6 pathway, which synergistically enhanced the proliferation of natural killer cells and dendritic cells and realized excellent immune cytotoxic T cell infiltration by combining with the ICB of PD-L1. The strategy of work along both lines based on innate immune and adaptive immunity displayed a significant effect in tumor regression. Overall, the UA-templated strategy “killed three birds with one stone” by establishing a self-assembly nanosystem, inducing tumor cell death, and promoting synergistic immunostimulation for HCC treatment.

The significance of Thymus species in the scientific community is growing steadily due to their extensive utilization in traditional medicine, food industry, and pharmaceutical sector, owing to their abundance in essential oil and phytochemical content, rendering them commercially significant species. The current work focuses on conducting a comprehensive analysis of the ethanol extract and essential oil derived from the root and aerial portions of Thymus brachychilus Jalas, an endemic species that has not been previously investigated. Additionally, a novel GC-MS (gas chromatography–mass spectrometry) technique was developed to quantify the levels of triterpenoids, which are frequently found in many plants, particularly those belonging to the Lamiaceae family. The approach was then used to assess the triterpenoid content of the species. While the phenolic content of the species was determined by LC-MS/MS (liquid chromatography–tandem mass spectrometry), the chemical composition of triterpenoid, essential oil and flavor (aroma) of the plant was determined by GC-MS. Eucalyptol was the primary ingredient in both the essential oil and the flavor, accounting for 11.05% and 12.35%, respectively. In the DPPH and ABTS radical scavenging techniques, the root ethanol extract exhibited the greatest antioxidant activity with IC50 values of 26.70 ± 0.23 and 19.16 ± 0.11 µg/mL, respectively. There was a high level of urease (59.54 ± 1.67% at 100 µg/mL) inhibitory activity observed in the root ethanol extract in enzyme inhibition assays, as well as angiotensin (94.80 ± 0.56%), elastase (40.19 ± 0.39%), and collagenase (48.26 ± 0.12%) inhibition in the aerial ethanol extract. Moreover, the MCF-7 cell line for breast cancer had a strong cytotoxic impact when exposed to the essential oil of the species (vitality%: 1.45 ± 0.01 at 200 µg/mL. The LC-MS/MS and GC-MS studies revealed that the roots had a significant concentration of rosmarinic acid (15,801 µg analyte/g extract), but the aerial portions had a substantial quantity of ursolic acid (152,374 µg analyte/g extract). The plant exhibits potential in the food, cosmetic, and pharmaceutical sectors on account of its elevated levels of rosmarinic and ursolic acid, superior antioxidant capacity, and angiotensin and urease inhibitory effect. [ABSTRACT FROM AUTHOR]

Dian Ayu Eka Pitaloka,1,2 Yolani Syaputri,3,4 Puspita Nurlilasari,5 Shafa Fitri Khairunnisa,1 Suryani Saallah6 1Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, 45363, Indonesia; 2Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Sumedang, 45363, Indonesia; 3Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Sumedang, 45363, Indonesia; 4Center for Bioprospection of Natural Fibers and Biological Resources, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Sumedang, 45363, Indonesia; 5Department of Agro-Industrial Technology, Faculty of Agro-Industrial Technology, Universitas Padjadjaran, Sumedang, 45363, Indonesia; 6Biotechnology Research Institute, Universiti Malaysia Sabah, Sabah, 88400, MalaysiaCorrespondence: Dian Ayu Eka Pitaloka, Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, West Java, 45363, Indonesia, Tel +62-22-84288812, Email dian.pitaloka@unpad.ac.idAbstract: Tuberculosis (TB) stands as the second most prevalent cause of global human mortality from infectious diseases. In 2022, the World Health Organization documented an estimated number of global TB cases reaching 7.5 million, which causes death for 1.13 million patients. The continuous growth of drug-resistant TB cases due to various mutations in the Mycobacterium tuberculosis (MTB) strain, raises the urgency of the exploration of novel anti-TB treatments. Ursolic acid (UA) is a natural pentacyclic triterpene found in various plants that has shown potential as a novel anti-TB agent. This review aims to provide an overview of the therapeutic prospects of UA against MTB, with a particular emphasis on in silico, in vitro, and in vivo studies. Various mechanisms of action of UA against MTB are briefly recapped from in silico studies, such as enoyl acyl carrier protein reductase inhibitors, FadA5 (Acetyl-CoA acetyltransferase) inhibitors, tuberculosinyl adenosine transferase inhibitors, and small heat shock protein 16.3 inhibitor. The potential of UA to overcome drug resistance and its synergistic effects with existing antituberculosis drugs are briefly explained from in vitro studies using a variety of methods, such as Microplate Alamar Blue Assay, Mycobacteria Growth Indicator Tube 960 and Resazurin Assays, morphological change evaluation using transmission electron microscopy, and in vivo studies using BALB/C infected with multi drug resistant clinical isolates. Besides its promising mechanism as an antituberculosis drug, its complex chemical composition, limited availability and supply, and lack of intellectual property are also reviewed as those are the most frequently occurring challenges that need to be addressed for the successful development of UA as novel anti-TB agent. Keywords: ursolic acid, tuberculosis, triterpenoid

Over the past few years, there has been a gradual increase in the incidence of cancer, affecting individuals at younger ages. With its refractory nature and substantial fatality rate, cancer presents a notable peril to human existence and wellbeing. Hawthorn, amedicinal food homology plant belonging to the Crataegus genus in the Rosaceae family, holds great value in various applications. Due to its long history of medicinal use, notable effects, and high safety profile, hawthorn has garnered considerable attention and plays a crucial role in cancer treatment. Through the integration of modern network pharmacology technology and traditional Chinese medicine (TCM), a range of anticancer active ingredients in hawthorn have been predicted, identified, and analyzed. Studies have shown that ingredients such as vitexin, isoorientin, ursolic acid, and maslinic acid, along with hawthorn extracts, can effectivelymodulate cancer-related signaling pathways and manifest anticancer properties via diverse mechanisms. This review employs network pharmacology to excavate the potential anticancer properties of hawthorn. By systematically integrating literature across databases such as PubMed and CNKI, the review explores the bioactive ingredients with anticancer effects, underlying mechanisms and pathways, the synergistic effects of drug combinations, advancements in novel drug delivery systems, and ongoing clinical trials concerning hawthorn's anticancer properties. Furthermore, the review highlights the preventive health benefits of hawthorn in cancer prevention, offering valuable insights for clinical cancer treatment and the development of TCM with anticancer properties that can be used for both medicinal and edible purposes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• In silico screening of 35 phytochemicals from Newbouldia laevis against hexokinase 2. • Insight using molecular docking in terms of binding affinities and interacting residues for predicting molecular mechanism. • Assessing the potency of the lead phytochemicals using molecular dynamic simulations and MMPBSA. • Best drug candidates as hexokinase 2 inhibitors were predicted for further pre-clinical and clinical trials. Newbouldia laevis, also known as the African Border Tree or Fever Tree, is a deciduous tree native to West Africa. The plant is valued for its medicinal properties and is used in traditional medicine for its antimicrobial and anti-inflammatory effects. N. laevis, is a storage tank of phytochemicals with huge health benefits and performances globally for the treatment and management of numerous disease conditions. Limited research exists on the usage of N. laevis for hepatocellular carcinoma (HCC) treatment. This study aims to explore the inhibitory activities of phytochemicals from N. laevis against the hexokinase 2 protein, a target in hepatocarcinoma (HCC) treatment. This study presents a unique in silico approach that includes ligand binding site prediction, molecular docking, molecular dynamics simulation, and Molecular Mechanics Poisson–Boltzmann Surface Area (MM/PBSA) methods. A total of 35 phytochemicals with available 3D structures were identified through literature mining. The literature review highlighted the significance of hexokinase 2 protein as a target inhibitor in the treatment of hepatocellular carcinoma (HCC). Molecular docking experiment with the all the identified phytochemicals and hexokinase 2 revealed that all the identified phytochemicals had potential inhibitory activities against the target protein. Moreover, chrysarobin, apigenin and ursolic acid were the best inhibitors with lowest binding energy of −8.9 kcal/mol, −8.7 kcal/mol, and −8.5 kcal/mol, respectively. The docking experiment was validated by comparing the binding affinities with known reference drug Cabozantinib-S-malate (−8.3 kcal/mol). Further, molecular dynamics studies of complexes with the best docking scores and reference drug complexes were described in detail here. The results of 100 ns modeling (RMSD, RMSF, Rg and SASA) show extraordinary stability during the establishment of complexes with apigenin and ursolic acid, as well as favorable binding energy, which was determined theoretically by means of the MM/PBSA method, thereby increase the probability of their acting as promising and likely hexokinase 2 inhibitors. Therefore, the study predicted that apigenin and ursolic acid could be used as a potential inhibitor/antagonist for the hexokinase 2 enzyme. [ABSTRACT FROM AUTHOR]

The current research aimed to conduct bioassay-guided isolation of bioactive compounds from the stem bark of Lannea coromandelica. Using column chromatography and NMR spectroscopy, two compounds -ursolic acid and palmitoleic acid-were isolated from the plant's stem bark. The methanolic stem bark extract possessed higher total phenolic, flavonoid, and antioxidant capacity content than the n-hexane extract. The IC50 value of the methanol and n-hexane stem bark extracts for DPPH free radical scavenging potential was found to be 37.37 and 27.726 µg/mL, respectively, while for nitric oxide, the IC50 value was 14.615 and 22.136 µg/mL, respectively. The n-hexane extract exhibited higher antidiabetic effectiveness (46% blood glucose reduction) than the methanolic extract (37.8% blood glucose reduction) after 3 hours of glucose administration in mice model at a dose of 400 mg/kg body weight (p < 0.001). The methanolic extract demonstrated the highest anti-diarrheal action at a dose of 400 mg/kg body weight (88.70% inhibition of defecation, p < 0.001). Furthermore, the n-hexane extract showed the highest analgesic activity (70.5% inhibition of writhing, p < 0.01). [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD), the most common neurodegenerative ailment, is caused by progressive damage in dopamine-secreting cells in the substantianigra. Oxidative stress plays a major role in the degeneration of dopaminergic neurons in PD. All organisms have developed adaptive responses to oxidative stress that result in increased production of defensive enzymes and antioxidant molecules. The mutations in a-synuclein protein have a role in modulating the dopamine activity. In this study, we have illustrated the protective effects of bioactive compounds of Mucuna monosperma (MM) against paraquat (PQ)-induced oxidative stress in a transgenic Parkinson's disease model (Elav/SNCAA30P) of Drosophila melanogaster. The isolated L-Dopa and Ursolic compounds exhibit antioxidant properties. The activity of antioxidant enzymes and LPO has been measured in L-dopa and Ursolic acid-supplemented PD lines under oxidative stress conditions. The oxidative stress caused by PQ was averted and antioxidant enzyme activity was significantly increased in flies that were fed with a mixture of L-Dopa and Ursolic acid. SOD activities were elevated by 4.2 fold, CAT activates increased by 3.8 fold and G6Pd activates were increased by 4.6 fold under stress conditions. The synergetic effect of these bioactive compounds decreases the LPO activity by 2 fold with the increase of glutathione by 3.36 fold in transgenic PD flies. Based on the findings, we speculate that L-Dopa with Ursolic acid of M. monosperma prevents oxidative stress-related disorders and can be used as a possible therapeutic agent against PD disorder. [ABSTRACT FROM AUTHOR]

This research focuses on the target deconvolution of the natural compound myrianthic acid, a triterpenoid characterized by an ursane skeleton isolated from the roots of Myrianthus arboreus and from Oenothera maritima Nutt. (Onagraceae), using MS-based chemical proteomic techniques. Application of drug affinity responsive target stability (DARTS) and targeted-limited proteolysis coupled to mass spectrometry (t-LiP-MS) led to the identification of the enzyme fatty acid synthase (FAS) as an interesting macromolecular counterpart of myrianthic acid. This result, confirmed by comparison with the natural ursolic acid, was thoroughly investigated and validated in silico by molecular docking, which gave a precise picture of the interactions in the MA/FAS complex. Moreover, biological assays showcased the inhibitory activity of myrianthic acid against the FAS enzyme, most likely related to its antiproliferative activity towards tumor cells. Given the significance of FAS in specific pathologies, especially cancer, the myrianthic acid structural moieties could serve as a promising reference point to start the potential development of innovative approaches in therapy. [ABSTRACT FROM AUTHOR]

The present study is to identify polycyclic aromatic bioactive phytocompounds from Eclipta alba against breast cancer target protein through in silico approach. Among 52 phytocompounds ecliptalbine, wedelolactone, ursolic acid and beta amyrin they have exhibited strong binding affinity against all three screened breast cancer target proteins such as matrix metallo protein (PDB ID 1RM8), estrogen receptor (PDB ID 3ERT) and progesterone receptor (PDB ID 4OAR). In drug likeliness 11 phytocompounds showed zero violations against all five drug likeliness rule, whereas all three anticancer drugs showed three minimal violations against the drug likeliness rule. Docking score of all screened compounds lies in the range of −4.3 Kcal/mol to −9.4 Kcal/mol in that ecliptalbine and ursolic acid show maximal binding affinity with all screened target proteins of breast cancer. Phytocompound ecliptalbine, wedelolactone and ursolic acid has shown excellent simulation trajectories with two screened target proteins in MDS analysis. Further compound ecliptalbine shown good phracokinetic and DFT scores which affirm that reason behind the good binding affinity with breast cancer target proteins. MMGBSA analysis also affirms the excellent binding affinity of ecliptalbine with breast cancer target proteins (–51.42 and −72.74 Kcal/mol) than the standard drug score. Finally ethanolic leaf extract of Eclipta alba showed excellent In vitro antioxidant (DPPH-IC50 83.40 µg/ml and ABTS–IC50 48.80 µg/ml) and cytotoxic potential (IC50 97.20 µg/ml) against triple-negative breast cancer cells (MDA-MB-231). Further these drug candidates can be validated through in vitro and preclinical studies to discover novel drug for breast cancer therapeutics. [ABSTRACT FROM AUTHOR]

A new flavonolignan, sonyamandin (1), along with other known compounds was isolated from the aerial parts and seeds extracts of Silybum marianum (milk thistle) collected from Jordan. The known ones are ursolic acid (2), oleanolic acid (3), maslinic acid (4), oleic acid (5), β-sitosterol (6), β-, sitosteryl glucoside (7), apigenin (8), kaempferol-3-O-rhamnoside (9), apigenin-7-O-β-D-glycoside (10), isosylibin A (11), isosylibin B (12), and silybin B (13). The absolute stereochemistry of 1 was confirmed by 2D NMR and CD analysis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The antibiotics are generally regarded as the first choice approach to treat dairy mastitis, targeting the public health problems associated with the food safety and the emergence of antibioticresistant bacteria. The objective of the study was to evaluate the antibacterial efficacy of ursolic acid (UA) when used to treat Staphylococcus aureus and other isolates associated with bovine mastitis and to clarify the mechanistic basis for these effects. The bacteriostatic properties of UA extracted from Rosmarinus officinalis L. at four different purity levels were assessed by calculating minimum inhibitory concentration (MIC) values, while the synergistic effects of combining 98% UA with antibiotics were evaluated by measuring the fractional inhibitory concentration index (FICI). Changes in biofilm formation and the growth curves of the clinical isolates were assessed to clarify the bacteriostatic effect of UA. Furthermore, the cell wall integrity, protein synthesis, and reactive oxygen species (ROS) production were assessed to determine the antibacterial mechanism of UA treatment. Ultimately, UA was revealed to exhibit robust activity against Gram-positive bacteria including S. aureus (ATCC 25923), Streptococcus dysgalactiae (ATCC27957), Streptococcus agalactiae (ATCC13813), Enterococcus faecalis (ATCC29212), and Streptococcus mutans (ATCC25175). However, it did not affect Escherichia coli (ATCC 25922). The MIC values of UA preparations that were 98, 50, 30, and 10% pure against S. aureus were 39, 312, 625, and 625 µg/mL, respectively, whereas the corresponding MIC for E. coli was >5,000 µg/mL. The minimum bactericidal concentrations of 98% UA when used to treat three clinical S. aureus isolates (S4, S5, and S6) were 78, 78, and 156 µg/mL, respectively. Levels of biofilm formation for clinical S. aureus isolates decreased with increasing 98% UA concentrations. Above the MIC dose, UA treatment resulted in the dissolution of bacterial cell walls and membranes, with cells becoming irregularly shaped and exhibiting markedly impaired intracellular protein synthesis. S. aureus treated with 98% UA was able to rapidly promote intracellular ROS biogenesis. Together, these data highlight the promising utility of UA as a compound that can be used together with other antibiotics for the treatment of infections caused by S. aureus. [ABSTRACT FROM AUTHOR]

Natural products are generally considered safe for human consumption, but this classification is often based on ethnobotanical surveys or their use in traditional medicine over a long period of time. However, edaphoclimatic factors are known to produce different chemotypes, which may affect the safety profile and bioactivities, and are not commonly considered for plants exploited as crops worldwide. Thymus carnosus Boiss., a thyme species with various health-promoting effects, has potential pharmaceutical applications, but edaphoclimatic factors were found to significantly impact its phytochemical composition. Thus, we aimed to assess the safety profile of T. carnosus extracts obtained from plants harvested in two locations over three consecutive years and to establish an association with specific components, an essential study in the search for new sources of nutraceuticals. Thus, the antiproliferative effect of an aqueous decoction (AD), hydroethanolic (HE) extracts, and major extracts' components of T. carnosus was evaluated on intestinal (Caco-2) and hepatic (HepG2) cell models, revealing effects dependent on extract type, cell line, and tested compounds. Flavonoids induced different cytotoxic patterns, which could be attributed to molecular structural differences. Flow cytometry analysis showed apoptosis and necrosis induction, mediated by the modulation of intracellular reactive oxygen species and mitochondrial membrane potential, effects that were dependent on the cell line and phytochemical composition and on the synergism between extracts components, rather than on the activity of an isolated compound. While ursolic acid was the component with the strongest impact on the difference between extraction methods, flavonoids assumed a pivotal role in the response of different cell lines to the extracts. We report for the first time, for Thymus spp. extracts, that variations in the phytochemical composition clearly influence the cellular response, thus highlighting the need for extract standardization for medicinal applications. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental carcinogens accountable to developing skin cancers. Recently, we reported that exposure to benzo[a]pyrene (B[a]P), a common PAH, causes epigenetic and metabolic alterations in the initiation, promotion and progression of non-melanoma skin cancer (NMSC). As a follow-up investigation, this study examines how dietary triterpenoid ursolic acid (UA) regulates B[a]P-driven epigenetic and metabolic pathways in SKH-1 hairless mice. Our results show UA intercepts against B[a]P-induced tumorigenesis at different stages of NMSC. Epigenomic cytosines followed by guanine residues (CpG) methyl-seq data showed UA diminished B[a]P-mediated differentially methylated regions (DMRs) profiles. Transcriptomic RNA-seq revealed UA revoked B[a]P-induced differentially expressed genes (DEGs) of skin cancer-related genes, such as leucine-rich repeat LGI family member 2 (Lgi2) and kallikrein-related peptidase 13 (Klk13), indicating UA plays a vital role in B[a]P-mediated gene regulation and its potential consequences in NMSC interception. Association analysis of DEGs and DMRs found that the mRNA expression of KLK13 gene was correlated with the promoter CpG methylation status in the early-stage comparison group, indicating UA could regulate the KLK13 by modulating its promoter methylation at an early stage of NMSC. The metabolomic study showed UA alters B[a]P-regulated cancer-associated metabolisms like thiamin metabolism, ascorbate and aldarate metabolism during the initiation phase; pyruvate, citrate and thiamin metabolism during the promotion phase; and beta-alanine and pathothenate coenzyme A (CoA) biosynthesis during the late progression phase. Taken together, UA reverses B[a]P-driven epigenetic, transcriptomic and metabolic reprogramming, potentially contributing to the overall cancer interception against B[a]P-mediated NMSC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Enzyme inhibition is one of the leading drug development methods for the treatment of many diseases. Due to the possible side effects and low bioavailability of existing drugs, studies are continuing for the discovery of new drugs. In this study, in vitro elastase, acetylcholinesterase inhibition activities of newly synthesized N,S-substituted polyhalogenated nitrobuta-1,3-dienes derivatives (compounds 3, 4a, 4b, 4c, 4d, 4e, and 4f), as well as their antioxidant properties, were investigated. Results was showed that compounds 4a (IC50 = 22.10 ± 0.49 µM), 4b (IC50 = 53.98 ± 1.77 µM), and 4f (IC50 = 32.01 ± 1.33 µM) showed higher elastase inhibition effect than positive control, ursolic acid (IC50 = 479.11 ± 15.53 µM) and in silico adsorption, distribution, metabolism, excretion, and toxicity (ADMET) and molecular docking studies were carried out in line with the results. As a result of molecular docking studies with iGemdock, DockThor, and Autodock Vina, it was determined that there was a higher binding relevance for compounds 4a (− 84.41/− 8.439 kcal/mol), 4b (− 86.32/− 7.878 kcal/mol), and 4f (− 86.32/− 8.530 kcal/mol) than ursolic acid (− 77.67/− 7.024 kcal/mol) for iGemdock and DockThor. It has been shown by DPPH, ABTS, and reducing power experiments that all compounds also show antioxidant properties. In conclusion, both in vitro and in silico molecular docking studies of compounds 4a, 4b, and 4f show that these three compounds are potent inhibitors of elastase. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The utilization of coffee cascara, a byproduct of coffee cultivation, in cancer therapy research. This research begins with the rationale of exploring medicinal plants, especially coffee, to obtain compounds that can target cancer cells with fewer side effects. Objectivity: This research aims to extract and evaluate the secondary metabolites from robusta coffee cascara, such as friedelin, lupeol, stigmasterol, ursolic acid, caffeine, chlorogenic acid, caffeic acid, and catechin, for their cytotoxic activity against Hela and MCF-7 cells. The aim of this research is also to identify and understand the cytotoxic mechanisms of compounds like stigmasterol, which showed significant cytotoxicity against cancer cells, paving the way for developing targeted cancer therapies from natural sources. Methods: Robusta coffee cascara then goes to the process of extraction using ethanol, fractionation, isolation, purification, and characterization, followed by bioactivity evaluation using in vitro method through breast cancer cell line MCF-7 and cervical cancer cell line HeLa and determination of active compound levels. Results: The cascara, a byproduct of coffee cultivation, is rich in proteins, polysaccharides, and bioactive compounds. Through extraction and purification processes, eight compounds were isolated and characterized, including (1) friedelin, (2) lupeol, (3) Stigmasterol, (4) Ursolic acid, (5) caffeine, (6) Chlorogenic acid, (7) caffeic acid, and (8) catechin. Bioactivity evaluation shows that stigmasterol (3) is the most cytotoxic compound with a value against Hela cells with an IC50 value of 25.85 µg/mL in the toxic category and against MCF-7 cells with an IC50 value of 12.83 µg/mL in the very toxic category. The results of determining the levels of active compounds in robusta coffee cascara extract showed that friedelin (1) 0.539±0.137%; lupeol (2) levels were 0.087±0.015%; (3) stigmasterol 0.126±0.046%; ursolic acid (4) 0.627±0.002%; caffeine (5) 3,203±0.069%; chlorogenic acid (6) 0.679±0.003%; caffeic acid (7) 0.153±0.003% and catechin (8) 0.359 0.012% mg/g extract. Conclusion: The research on robusta coffee cascara extract as a potential source of anticancer compounds. [ABSTRACT FROM AUTHOR]

Background: Artemisia campestris L. (AC) leaves are widely recognized for their importance in traditional medicine. Despite the considerable amount of research conducted on this plant overworld, the chemical composition and the biological activity of the leaves grown in Tunisia remains poorly investigated. In this study of AC, a successive extraction method was employed (hexane, ethyl acetate and methanol) to investigate its bioactive constituents by LC-MS analysis, and their antioxidant, antibacterial, antifungal, and anticancer activities. Results: Data analysis revealed diverse compound profiles in AC extracts. Methanolic and ethyl acetate extracts exhibited higher polyphenolic content and antioxidant activities, while Hexane showed superior phytosterol extraction. Ethyl acetate extract displayed potent antibacterial activity against multi-resistant Staphylococcus aureus and Pseudomonas aeruginosa. Additionally, all extracts demonstrated, for the first time, robust antifungal efficacy against Aspergillus flavus and Aspergillus niger. Cytotoxicity assays revealed the significant impact of methanolic and ethyl acetate extracts on metastatic breast cancer and multiple myeloma, examined for the first time in our study. Moreover, further analysis on multiple myeloma cells highlighted that the ethyl acetate extract induced apoptotic and necrotic cell death and resulted in an S phase cell cycle blockage, underscoring its therapeutic potential. Conclusions: This investigation uncovers novel findings in Tunisian AC, notably the identification of lupeol, oleanolic acid, ursolic acid, stigmasterol and β-sitosterol. The study sheds light on the promising role of AC extracts in therapeutic interventions and underscores the need for continued research to harness its full potential in medicine and pharmaceutical development. [ABSTRACT FROM AUTHOR]

Glutaminase is an important target that is often over-expressed in neurodegenerative and lifestyle-related diseases but few effective inhibitors of this enzyme have yet reached clinical trials. Three compounds isolated from fresh leaves of Diospyros kaki Thunberg, ursolic acid (1), rotungenic acid (2) and barbinervic acid (3), were identified by analyzing their NMR and MS spectral data and comparison of these with reported data. The IC50 values of 1-3 and 6-diazo-5-oxo-L-norleucine (DON) as control were 775, 13, 14, and 434 μM, respectively. Compounds 2 and 3 showed higher glutaminase inhibitory activities than DON. Compounds 2 and 3 may serve as potential lead compounds for the prevention and treatment of neurodegenerative and lifestyle-related diseases by targeting glutaminase. This is the first report on glutaminase inhibitory activities of 2 and 3. [ABSTRACT FROM AUTHOR]

The use of diversified raw materials and various extractant types is justified because the varied chemical composition of extracts obtained via extraction determines their biological activity. Therefore, the objective of this study was (i) to characterize the chemical profile of two types of bearberry extracts (70% ethanolic and water) and (ii) to investigate the biological activity of the analyzed extracts through an assessment of their possible proapoptotic effects on glioma cell lines. The HPLC-UV analysis of individual compounds was performed for the determination of the phytochemical profile of the bearberry extracts, and their total phenolic content (TPC) and total flavonoid content (TFC) were determined spectrophotometrically. The induction of apoptosis, autophagy, and necrosis in anaplastic astrocytoma MOGGCCM and human glioblastoma LN229 cell lines were investigated. The results indicated that the ethanolic (Et) and aqueous (Aq) extracts had different chemical profiles. The TPC in the Et was ca. 60% higher than in the Aq. Similarly, the TFC and methylarbutin (mARB) concentrations were significantly higher in the Et. On the other hand, the concentration of hydroquinone (HQ) was ca. 70% and that of corilagin (COR) was ca. 100% higher in the Aq. In turn, the presence of ursolic acid (UA) and oleanolic acid (OA) was confirmed solely in the Et. In contrast to Aq, Et demonstrated high proapoptotic activity. At the concentration of 2 µL/mL, the level of apoptosis varied between 14.7% and 26% in the case of the MOGGCCM cells and between 12.3% and 33.3% in the case of the LN229 cell line. The knowledge and information obtained in this study indicate a need for further research on the anticancer effect of the studied bearberry phytochemicals on the MOGGCCM and LN229 cell lines and for the elucidation of their molecular anticancer mechanisms. [ABSTRACT FROM AUTHOR]

Kiwifruit is widely consumed in many parts of the world. They contain a variety of bioactive substances that make them a valuable functional food source. For instance, kiwifruit contains vitamin C, polysaccharides, polyphenols (catechin, anthocyanin, chlorogenic acid, gallic acid), alkaloids (aconitine, safranin, actinidine), and terpenoids (ursolic acid, oleanolic acid), which are claimed to exhibit antioxidant, anti-inflammatory, and anticancer effects, as well as protecting against cardiovascular and cerebrovascular diseases. However, the potentially beneficial effects of most of these bioactive substances have still not been confirmed by clinical trials. This article reviews recent research on the type and physiological functions of the main bioactive components in kiwifruit. The techniques required to extract and characterize these components are discussed, as well as current challenges in kiwifruit processing. Several innovative extraction techniques have been utilized to extract bioactive substances from kiwifruits, including ultrasound- and microwave-assisted methods. Moreover, several non-thermal processing methods (such as ultrasound, high-pressure, and pulsed electric field processing) are being used to reduce the losses and increase the activity of bioactive substances, preserve the sensory qualities of the fruit, and reduce the allergenicity of kiwifruit. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is a kind of autoimmune disease with systemic vasculitis as the main pathological change. It is critical to explore potential new therapeutic agents to address KD disease and its complications. Ursolic acid (UA) is a pentacyclic triterpene (PT) carboxylic acid that has a number of important pharmacological activities, however, the possible effects of UA on the progression of KD and the mechanism are still unclear. Here we investigated the effects of UA on KD. We revealed that UA improved arterial injury in KD mice. UA improved vascular inflammation in KD mice. In addition, Ursolic suppressed NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation. We further found UA restrained vascular smooth muscle cell (VSMC) dedifferentiation, therefore suppressing KD progression. In summary, UA suppressed NLRP3 inflammasome activation as well as alleviated vascular smooth muscle injury in KD. We thought UA could act as a drug of KD. [ABSTRACT FROM AUTHOR]

The Oldenlandia genus comprises approximately 240 species of plants, yet only a limited number of these have been investigated for their chemical composition and medicinal properties. These species contain a wide range of compounds such as iridoids, anthraquinones, triterpenes, phytosterols, flavonoids, anthocyanidins, vitamins, essential oils, phenolic acids, and coumarins. These diverse phytochemical profiles underscore the pharmacological potential of Oldenlandia plants for various medical purposes. Among other chemical constituents, ursolic acid stands out as the most important active compound in Oldenlandia, owing to its proven anticancer, anti-inflammatory, antimicrobial, and hepatoprotective properties. The evaluation of Oldenlandia's pharmacological prospects indicates that the holistic utilization of the entire plant yields the most significant effects. Oldenlandia diffusa showcases anticancer and anti-inflammatory capabilities attributed to its varying constituents. Across a broad spectrum of pharmacological capacities, anticancer research predominates, constituting the majority of medical uses. Oldenlandia diffusa emerges as a standout for its remarkable anticancer effects against diverse malignancies. Antioxidant applications follow, with O. corymbosa demonstrating potent antioxidant properties alongside O. umbellata and O. diffusa. Subsequent priority lies in anti-inflammatory studies, wherein O. diffusa exhibits noteworthy efficacy, trailed by O. corymbosa also takes the lead in antimicrobial activity, with O. umbellata as a strong contender. Additional investigation is essential to ascertain the relative significance of these species in various pharmacological applications. This comprehensive assessment underscores the multifaceted potential of Oldenlandia as a versatile herbal resource, offering diverse pharmacological capacities. The call for sustained exploration and research remains essential to unlock the full extent of Oldenlandia's medicinal benefits. [ABSTRACT FROM AUTHOR]

Ursolic acid (UA), a pentacyclic triterpenoid, exhibits various pharmacological actions, such as anti-inflammation, anti-tumor, anti-diabetes, heart protection, and liver protection. However, the role of nuclear factor E2-related factor 2 (NRF2)-mediated regulation of uridine diphosphate glucuronosyltransferase (UGT2B7) and bile salt export pump (BSEP)/multidrug resistance-associated protein 2 (MRP2) in UA against cholestatic liver injury has not been cleared. The purpose of this study is to explore the effect of UA on cholestatic liver injury and its potential mechanism. The results of the liver pathology sections and blood biochemical indices demonstrated that UA significantly attenuated the cholestatic liver injury induced by alpha-naphthylisothiocyanate (ANIT) in a dose-dependent manner. The mRNA and protein levels of UGT2B7 and BSEP/MRP2 were remarkably increased in the liver of ANIT rats and HepG2 cells pretreated with UA, but this activation was suppressed with NRF2 silenced. In conclusion, our findings demonstrate that UA prevents cholestasis, which may be associated with NRF2-mediated regulation of UGT2B7, BSEP/MRP2. [ABSTRACT FROM AUTHOR]

Background Triple-negative breast cancer (TNBC) lacks effective therapeutic targets. Scutellaria barbata D.Don (SB) has been revealed to have anti-breast cancer (BC) effect, but the effect of SB extract in TNBC is still unclear. Herein, this research delves into the underlying mechanism. Methods SB was extracted by solvent extraction, and the main components were identified using an Agilent 6,520 HPLC-Chip/Q-TOF (Chip/Q-TOF) MS system. In vitro cell experiments were conducted. The effects of SB extract alone, SB extract plus EGF, GSK alone, GSK plus Ezrin overexpression, or SB extract plus Ezrin overexpression on cell viability, invasion, migration, and apoptosis were examined by cell function experiments. The apoptosis- and RhoA/ROCK1 pathway-related protein levels were analyzed by western blot assay. Results Mass spectrometry analysis exhibited that SB extract mainly contains long-chain fatty acids and ursolic acid. SB extract mitigated TNBC cell biological phenotypes, apoptosis- and RhoA/ROCK1 pathway-related marker expressions, which were reversed by EGF. The further results found that GSK obviously weakens TNBC cell biological behaviors, apoptosis- and RhoA/ROCK1 signaling-related protein levels, while oe-Ezrin treatment reverses the effect of GSK on TNBC cells. Moreover, SB extract regulated Ezrin-mediated function of TNBC cells by impeding the RhoA/ROCK1 pathway. Conclusion Our findings demonstrated that SB extract regulated Ezrin-mediated proliferation, migration, invasion, and apoptosis of TNBC cells via suppressing the RhoA /ROCK1 signaling. Our results offer the experimental foundation for further investigation of the anti-cancer role of SB in TNBC cells. Highlights SB extract inhibits the biological phenotypes of TNBC cells. SB extract inhibits the biological behaviors of TNBC cells through the RhoA/ROCK1 pathway. SB extract modulates Ezrin-mediated TNBC cell proliferation, migration, invasion, and apoptosis via restraining the RhoA/ROCK1 signaling. [ABSTRACT FROM AUTHOR]

Psoriasis, a prevalent inflammatory skin disorder affecting a significant percentage of the global population, poses challenges in its management, necessitating the exploration of novel cost-effective and widely accessible therapeutic options. This study investigates the potential of ursolic acid (UA), a triterpenoid known for its anti-inflammatory and pro-apoptotic properties, in addressing psoriasis-related inflammation and keratinocyte hyperproliferation. The research involved in vitro models employing skin and immune cells to assess the effects of UA on psoriasis-associated inflammation. The presented research demonstrates the limiting effects of UA on IL-6 and IL-8 production in response to the inflammatory stimuli and limiting effects on the expression of psoriatic biomarkers S100A7, S100A8, and S100A9. Further, the study reveals promising outcomes, demonstrating UA's ability to mitigate inflammatory responses and hyperproliferation of keratinocytes by the induction of non-inflammatory apoptosis, as well as a lack of the negative influence on other cell types, including immune cells. Considering the limitations of UA's poor solubility, hybrid systems were designed to enhance its bioavailability and developed as hybrid nano-emulsion and bi-gel topical systems to enhance bioavailability and effectiveness of UA. One of them in particular–bi-gel–demonstrated high effectiveness in limiting the pathological response of keratinocytes to pro-psoriatic stimulation; this was even more prominent than with ursolic acid alone. Our results indicate that topical formulations of ursolic acid exhibit desirable anti-inflammatory activity in vitro and may be further employed for topical psoriasis treatment. [ABSTRACT FROM AUTHOR]

Gastrointestinal malignancies are one of the major worldwide health concerns. In the present review, we have assessed the plausible therapeutic implication of Ursolic Acid (UA) against gastrointestinal cancer. By modulating several signaling pathways critical in cancer development, UA could offer anti-inflammatory, anti-proliferative, and anti-metastatic properties. However, being of low oral bioavailability and poor permeability, its clinical value is restricted. To deliver and protect the drug, liposomes and polymer micelles are two UA nanoformulations that can effectively increase medicine stability. The use of UA for treating cancers is safe and appropriate with low toxicity characteristics and a predictable pharmacokinetic profile. Although the bioavailability of UA is limited, its nanoformulations could emerge as an alternative to enhance its efficacy in treating GI cancers. Further optimization and validation in the clinical trials are necessary. The combination of molecular profiling with nanoparticle-based drug delivery technologies holds the potential for bringing UA to maximum efficacy, looking for good prospects with GI cancer treatment.

The objective of this study was to investigate the potential targets and mechanisms of UA in the treatment of PD. The efficacy of UA in PD was assessed through network pharmacology, molecular docking, and experimental methods. Common target protein-protein interaction (PPI) networks were constructed and visualized using Cytoscape. As a result, 9 key genes, namely CASP3, IL6, IL1B, PTGS2, CREB1, TNF, MAPK3, JUN, and CASP8, were selected. Molecular docking simulations were performed using Discovery Studio 2019 to validate the correlation between UA and the core targets. The results demonstrated a favorable binding affinity between UA and CASP8, IL1B, CASP3, TNF, MAPK3 and IL6. In vivo studies showed UA ameliorated motor dysfunction, and UA can significantly increase the protein expression of tyrosine hydroxylase (TH) in PD mice model. In addition, in vitro experiments confirmed that UA effectively reduced the protein expression of CASP8, CASP3 and MAPK3 in PD cell models and suppressed the gene expression of TNF-α, IL-6, and IL-1β. These findings indicate that the therapeutic effects of UA on PD could be due to its influence on various targets within both the apoptosis and neuroinflammatory signaling pathways. Consequently, this study provides a methodological and theoretical foundation for further elucidating the pharmacological mechanism of UA.