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In biotechnology processes, increasing the production of biomass and secondary metabolites is one of the economic factors of such projects. The present study was conducted to investigate the effects of magnetic field as an abiotic elicitor on increase of biomass and secondary metabolites of Ganoderma lucidum. Mycelium with a diameter of 1 cm of pured fungi was exposed to magnetism at four levels including 0, 20, 40, and 60 mT for 0, 30, 60, and 90 min with three replications. The best treatment was selected based on growth rate and antioxidant activity. The amounts of secondary compounds in mycelium under selected magnetic field (60 mT for 90 min) including betulin, betulinic acid, ascorbic acid, astaxanthin, total polysaccharide, and antioxidants were measured and compared with control and natural fungi. The results showed that magnetization increased betulin (a potent anticancer triterpene) more than 2.5 times compared to natural fungi and 3.7 times compared to control mycelium. Polysaccharides concentration in the treated mycelium and control media was obtained 5.05 and 5.17 times more than natural fungi, respectively. Ganoderic acid content was measured in the treated mycelium (intracellular) and PDB medium (extracellular). The highest amount of ganoderic acid (1.9 mg.ml-1) was obtained in the treated mycelium. Natural fungi and PBD medium had almost the same amount of this compound (1.87 and 1.86 mg.ml-1). The amount of betulinic acid (an anticancer compound derived from betulin), ascorbic acid, and astaxanthin was obtained high in natural fungus followed by 90 min magnetization at 60mT level treatment and control, respectively. Antioxidants percentage was about 85% in control and about 75% in natural fungi and treated mycelium. According to the results, there seems to be a good prospect to use in vitro cultures of Ganoderma instead of using natural fungi and also constructing costly farms. [ABSTRACT FROM AUTHOR]

Natural products have important pharmacological activities. This study sought to investigate the activity of the compound betulinic acid (BA) against different strains of bacteria and fungi. The minimum inhibitory concentration (MIC) was determined and then the minimum bactericidal concentration (MBC) and minimum fungicidal concentration (MFC). After performing the in vitro tests, molecular modeling studies were carried out to investigate the mechanism of action of BA against the selected microorganisms. The results showed that BA inhibited the growth of microbial species. Among the 12 species (Staphylococcus aureus, S. epidermidis, Pseudomonas aeruginosa, Escherichia coli, Mycobacterium tuberculosis, Candida albicans, C. tropicalis, C. glabrata, Aspergillus flavus, Penicillium citrinum, Trichophyton rubrum, and Microsporum canis) investigated, 9 (75%) inhibited growth at a concentration of 561 µM and 1 at a concentration of 100 µM. In general, the MBC and MFC of the products were between 561 and 1122 μM. In silico studies showed that BA presented a mechanism of action against DNA gyrase and beta-lactamase targets for most of the bacteria investigated, while for fungi the mechanism of action was against sterol 14α-demethylase (CYP51) targets and dihydrofolate reductase (DHFR). We suggest that BA has antimicrobial activity against several species. [ABSTRACT FROM AUTHOR]

Viral diseases affecting both humans and animals are a serious public problem. Chemical modifications of the structure of compounds of natural origin, e.g., betulin, seem to be a promising model in the search for new antiviral agents. The subject of our work was to conduct preliminary tests on the antiviral activity of phosphonic derivatives of betulin and betulinic acid and to assess the pharmacokinetic profile of target compounds. Human (HHV-1, HAdV-5) and animal viruses (BEV, VSV) were used in the in vitro tests. Additionally, this paper presents the results of research using in silico methods (ADMET and molecular docking). Two compounds (betulin 29-phosphonate 3 and 3-(3′,3′-dimethylsuccinyl)betulin acid 29-phosphonate 8a) showed antiviral activity against BEV, and compound 3 was also active against HAdV-5. For compound 3, which showed advantageous pharmacokinetic parameters, molecular docking was performed to determine possible interactions with the cellular target HAdV-5 endopeptidase, which plays an important role in various functions of the virus. Selecting the most active derivatives makes it possible to plan tests on an animal model.

Betulinic acid is a naturally occurring compound that can be obtained through methanolic or ethanolic extraction from plant sources, as well as through chemical synthesis or microbial biotransformation. Betulinic acid has been investigated for its potential therapeutic properties, and exhibits anti-inflammatory, antiviral, antimalarial, and antioxidant activities. Notably, its ability to cross the blood–brain barrier addresses a significant challenge in treating neurological pathologies. This review aims to compile information about the impact of betulinic acid as an antitumor agent, particularly in the context of glioblastoma. Importantly, betulinic acid demonstrates selective antitumor activity against glioblastoma cells by inhibiting proliferation and inducing apoptosis, consistent with observations in other cancer types. Compelling evidence published highlights the acid’s therapeutic action in suppressing the Akt/NFκB-p65 signaling cascade and enhancing the cytotoxic effects of the chemotherapeutic agent temozolomide. Interesting findings with betulinic acid also suggest a focus on researching the reduction of glioblastoma’s invasiveness and aggressiveness profile. This involves modulation of extracellular matrix components, remodeling of the cytoskeleton, and secretion of proteolytic proteins. Drawing from a comprehensive review, we conclude that betulinic acid formulations as nanoparticles and/or ionic liquids are promising drug delivery approaches with the potential for translation into clinical applications for the treatment and management of glioblastoma.

Betulinic acid (BetA), a triterpenoid derivative found abundantly in the plant kingdom, has emerged as a promising candidate for promoting longevity. Many research studies have shown its antioxidant, anti-inflammatory, antiviral, and anticancer activities, making it an interesting subject for investigating its potential influence on lifespan. This study aimed to investigate the effects of BetA on longevity and the mechanisms associated with it using the fruit fly Drosophila melanogaster as the organism model. The results showed that 50 μM BetA supplementation extended the mean lifespan of fruit flies by 13% in males and 6% in females without any adverse effects on their physiology, such as fecundity, feeding rate, or locomotion ability reduction. However, 50 μM BetA supplementation failed to increase the lifespan in mutants lacking functional silent information regulator 2 (Sir2) and Forkhead box O (FoxO)-null, implying that the longevity effect of BetA is related to Sir2 and FoxO activation. Our study contributes to the knowledge in the field of anti-aging research and inspires further investigations into natural compounds such as BetA to enhance organismal healthspan.

Birch outer bark extract (BBE), containing pentacyclic triterpenes such as betulin, lupeol, and betulinic acid, is a widely recognized natural product renowned for its diverse pharmacological effects. However, its limited water solubility restricts its bioavailability. Therefore, the main objective is to enhance the bioavailability of BBE for pharmaceutical use. In this study, we aimed to develop a dispersion system utilizing a unique oleogel-producing method through the recrystallization of BBE from an ethanol solution in the oil phase. We generated an oleogel that demonstrates a notable 42–80-fold improvement in betulin and lupeol peroral bioavailability from BBE in Wistar rats, respectively. A physical paste-like BBE hydrogel developed with antisolvent precipitation showed a 16–56-fold increase in the bioavailability of betulin and lupeol from BBE in rat blood plasma, respectively. We also observed that the repeated administration of the BBE oleogel did not exhibit any toxicity at the tested dose (38.5 mg/kg betulin, 5.2 mg/kg lupeol, 1.5 mg/kg betulinic acid daily for 7 days). Betulin and betulinic acid were not detected in rat heart, liver, kidney, or brain tissues after the peroral administration of the oleogel daily for 7 days. Lupeol was found in rat heart, liver, and kidney tissues.

Kidney diseases are common health problems worldwide. Various etiologies ultimately lead to the development of chronic kidney disease and end-stage renal disease. Natural compounds from herbs or medicinal plants are widely used for therapy and prevention of various ailments, among which is Inonotus obliquus. I. obliquus is rich in triterpenoids and the main active ingredients include betulinic acid, trametenolic acid, inotodiol, and ergosterol. New evidence suggests that I. obliquus triterpenes may be an effective drug for the treatment and protection of various kidney diseases. The aim of this review is to highlight the pharmacological activities and potential role of I. obliquus triterpenes in the kidney disease treatment and protection.

In this article, a series of betulinic acid derivatives (3a ∼ 3u, 4a ∼ 4e) were synthesized through a stepwise structure optimization and evaluated for their anti-α-glucosidase activities. All synthesized derivatives exhibited stronger anti-α-glucosidase activities (IC50: 0.56 ± 0.05 ∼ 3.99 ± 0.23 μM) than betulinic acid (IC50: 7.21 ± 0.58 μM) and acarbose (IC50: 611.45 ± 15.51 μM). Compound 3q presented the outstanding inhibitory activity (IC50: 0.56 ± 0.05 μM), which was ∼ 1100 time stronger than that of acarbose. Compound 3q was revealed as a reversible and noncompetitive α-glucosidase inhibitor by inhibitory mechanism assay. Fluorescence spectra, 3D fluorescence and CD spectra results showed that the interaction of compound 3q with α-glucosidase caused the conformational and secondary structure content change of α-glucosidase. Finally, the molecular docking simulated the interaction between compound 3q with α-glucosidase and the physicochemical parameter was assessed using SwissADME software.

Betulinic acid is found in the several foods and plants, such as sour jujube fruits, papaya, persimmon, betulinic acid exhibits low toxicity and a wide range of anticancer activities. Ferritinophagy and ferroptosis are related to tumor formation and therapeutic effects, both of which are controlled by iron metabolism and inextricably linked. In this study, we discovered that betulinic acid could suppress proliferation and migration of hepatoma cells, raised ROS level and inhibited antioxidation level in cells. Ferrostatin-1 was used to determine the death way of hepatoma cells induced by betulinic acid. Betulinic acid could cause ferritinophagy-related phenomenon in vivo and in vitro, promote ferritinophagy-protiens expressions, induce ferritinophagy to inhibit tumours finally. In vivo studies revealed the low toxicity of betulinic acid in mice, the dose of human was about 10 times that of mice, the using dose of human could also be achievable. These findings illustrate the potential of betulinic acid for treatment of cancer.

Cancer stemness is the process by which cancer cells acquire chemoresistance and self-renewal in the tumor microenvironment. Glucose-regulated protein 78 (GRP78) is a biomarker for gastric cancer and is involved in cancer stemness. By inducing cancer stemness in various types of cancer, the polarization of macrophages into tumor-associated macrophages (TAMs) controls tumor progression. Betulinic acid (BA) is a bioactive natural compound with anticancer properties. However, whether GRP78 regulates TAM-mediated cancer stemness in the tumor microenvironment and whether BA inhibits GRP78-mediated cancer stemness in gastric cancer remain unknown. In this study, we investigated the role of GRP78 in gastric cancer stemness in a tumor microenvironment regulated by BA. The results indicated that BA inhibited not only GRP78-mediated stemness-related protein expression and GRP78-TGF-β-mediated macrophage polarization into TAMs, but also TAM-mediated cancer stemness. Therefore, BA is a promising candidate for clinical application in combination-chemotherapy targeting cancer stemness. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Betulinic acid is pentacyclic triterpenoid known to exert antitumor effects by modulating many cellular pathways in various human malignancies. However, its modulatory role in autophagy in renal cell carcinoma remains unclear. Here, we observed how betulinic acid affects autophagy in renal cell carcinoma cells. METHODS: After treating cells with betulinic acid, we determined the gene expression and protein levels of Beclin-1 and ATG-5 by qPCR and ELISA assay to observe its effects on autophagy. RESULTS: The qPCR results demonstrated that Beclin-1 expression level was low in untreated metastatic renal adenocarcinoma ACHN cells and increased in response to 25 µM and 50 µM betulinic acid treatment. ATG-5 expression level was decreased in primary clear cell renal cell carcinoma CAKI-2 cells treated with 50 µM betulinic acid. In the ELISA assay results, we observed that betulinic acid caused a decrease in Beclin-1 protein level at 25 µM concentration and in ATG-5 protein level at 50 µM concentration in CAKI-2 cells. CONCLUSION: In current study, it was concluded that the role of autophagy may differ in renal cell carcinoma cells depending on their origin and that the effects of betulinic acid on autophagy in these cells may vary accordingly (Fig. 4, Ref. 40). [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is known for motor impairments. Betulinic acid (BA) is a natural compound with antioxidant activity. The present study addresses the question of whether BA affects motor and non-motor dysfunctions and molecular changes in the rat model of PD. The right medial forebrain bundle was lesioned by injection of 6-hydroxydopamine in Male Wistar rats (10–12 weeks old, 270–320 g). Animals were divided into Sham, PD, 3 treated groups with BA (0.5, 5, and 10 mg/kg, IP), and a positive control group received L-dopa (20 mg/kg, P.O) for 7 days. rigidity, anxiety, analgesia, and memory were assessed by bar test, open-field, elevated plus-maze (EPM), tail-flick, and shuttle box. Additionally, the malondialdehyde (MDA), Superoxide dismutase (SOD), glutathione peroxidase (GPx) activity, Brain-derived neurotrophic factor (BDNF) and Interleukin 10 (IL10) levels in the whole brain were measured. BA significantly reversed the 6-hydroxydopamine-induced motor and memory complication in the bar test and shuttle box. It modified anxiety-like behavior neither in open-field nor in EPM. It only decreased the time spent in open arms. Moreover, no significant changes were found in the tail-flick between treatment and sham groups. On the other hand, the level of MDA & IL10 were decreased, while the activity of GPx levels of SOD & BDNF in the rats' brains was increased. Our results showed that BA as a free radical scavenger can account for a possible promise as a good therapeutic agent for motor and non-motor complications in PD however further studies may be needed. [ABSTRACT FROM AUTHOR]

Immunotherapy combined with effective therapeutics such as chemotherapy and photodynamic therapy have been shown to be a successful strategy to activate anti-tumor immune responses for improved anticancer treatment. However, developing multifunctional biodegradable, biocompatible, low-toxic but highly efficient, and clinically available transformed nano-immunostimulants remains a challenge and is in great demand. Herein, we report and design of a novel carrier-free photo-chemotherapeutic nano-prodrug COS-BA/Ce6 NPs by combining three multifunctional components—a self-assembled natural small molecule betulinic acid (BA), a water-soluble chitosan oligosaccharide (COS), and a low toxic photosensitizer chlorin e6 (Ce6)—to augment the antitumor efficacy of the immune adjuvant anti-PD-L1-mediated cancer immunotherapy. We show that the designed nanodrugs harbored a smart and distinctive "dormancy" characteristic in chemotherapeutic effect with desired lower cytotoxicity, and multiple favorable therapeutic features including improved 1O 2 generation induced by the reduced energy gap of Ce6, pH-responsiveness, good biodegradability, and biocompatibility, ensuring a highly efficient, synergistic photochemotherapy. Moreover, when combined with anti-PD-L1 therapy, both nano-coassembly based chemotherapy and chemotherapy/photodynamic therapy (PDT) could effectively activate antitumor immunity when treating primary or distant tumors, opening up potentially attractive possibilities for clinical immunotherapy. Natural small-molecule-mediated photosensitive pro-drug nano-assemblies that harbored a distinctive chemotherapeutic dormancy function, which can effectively generate robust immunological responses with the assistance of anti-PD-L1 to cause highly efficient, safe, and synergistic anti-tumor chemotherapy/photodynamic therapy/immunotherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Xanthoceras sorbifolium Bunge leaves (XLs) are the agricultural by-products of Xanthoceras sorbifolium Bunge, which are widely cultivated in the north of China. For recycling XLs, in this study, the extraction optimization, construction of purification models, identification of saponins components and the antimicrobial and antioxidant activities were firstly investigated. Ultrasonic-assisted extraction of saponins from XLs using Box–Behnken design (BBD) method of response surface methodology (RSM) was investigated. The optimum conditions were as follows: the temperature 60.79 °C, ethanol concentration 71.56%, liquid/solid ratio 30.67 (v/m). Under these conditions, the optimization of the extraction with maximize yield of 7.36 ± 0.078% was obtained. Corresponding adsorption models were established to analyze the maximum yield of saponins during the adsorption process, and AB-8 resin was used for the purification of saponins using static adsorption/desorption with final purity was 38.48 ± 2.51%. Then, ten saponins, including ginsenoside-Rg1, ginsenoside-F, ginsenoside-Rg2, alpha-hederin, hederagenin, licoricesaponin G2, betulinic acid, ursolic acid, betulonic acid, and dehydro (11,12) ursolic acid lactone, were identified using ultra performance liquid chromatography-mass spectrometry (UPLC-MS). Biological evaluations showed that XLs saponins possessed good scavenging activity on DPPH and ABTS, and exerted obvious inhibitory effect on E. coli (Gram-negative bacteria) and S. areus (Gram-positive bacteria). Results indicated that the saponins extracted from XLs can be used as a natural antimicrobial and antioxidant agent to the food products. This study provided a theoretical basis for the development and utilization of the by-product saponins from the bio-products resources XLs. [ABSTRACT FROM AUTHOR]

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Pancreatic cancer (PC) is one of the most aggressive solid malignancies with poor treatment response and low survival rates. Herbal medicines such as betulinic acid (BA) have shown potential in treating various solid tumours, but with limitations that can be circumvented by polymer-drug conjugation. Polyethylene glycol-BA (PEG-BA) polymer-drug conjugate has previously shown selective anticancer activity against PC cells. Here, we elucidate the mechanism of cell death and the cell death pathway, anti-inflammatory and antioxidant activities of PEG-BA. PEG-BA induced apoptotic cell death by arresting MIA-PaCa-2 cells in the Sub-G1 phase of the cell cycle compared with BA and untreated cells (39.50 ± 5.32% > 19.63 ± 4.49% > 4.57 ± 0.82%). NFκB/p65 protein expression was moderately increased by PEG-BA (2.70 vs. 3.09 ± 0.42 ng/mL; p = 0.1521). However, significant (p < 0.05) overexpression of the proapoptotic genes TNF (23.72 ± 1.03) and CASPASE 3 (12,059.98 ± 1.74) compared with untreated cells was notable. The antioxidant potential of PEG-BA was greater (IC50 = 15.59 ± 0.64 µM) compared with ascorbic acid (25.58 ± 0.44 µM) and BA-only (>100 µM) and further confirmed with the improved reduction of hydroperoxide levels compared with BA-only (518.80 ± 25.53 µM vs. 542.43 ± 9.70 µM). In conclusion, PEG-BA activated both the intrinsic and extrinsic pathways of apoptosis and improved antioxidant activities in PC cells, suggesting enhanced anticancer activity upon conjugation. [ABSTRACT FROM AUTHOR]

One of several promising strategies for increasing the bioavailability and therapeutic potential of high-lipophilic biologically active compounds is gold nanoparticle formulation. The current study describes the synthesis and biological antimelanoma evaluation of three triterpen-functionalized gold nanoparticles, obtained using our previously reported antimelanoma benzotriazole-triterpenic acid esters. Functionalized gold nanoparticle (GNP) formation was validated through UV-VIS and FTIR spectroscopy. The conjugate's cytotoxic effects were investigated using HaCaT healthy keratinocytes and A375 human melanoma cells. On A375 cells, all three conjugates demonstrated dose-dependent cytotoxic activity, but no significant cytotoxic effects were observed on normal HaCaT keratinocytes. GNP-conjugates were found to be more cytotoxic than their parent compounds. After treatment with all three GNP-conjugates, 4,6′-diamidino-2-phenylindole (DAPI) staining revealed morphological changes consistent with apoptosis in A375 melanoma cells. Quantitative real-time polymerase chain reaction (RT-qPCR) analysis revealed that the triterpene-GNP conjugate treated A375 melanoma cells had a fold change increase in Bcl-2-associated X protein (BAX) expression and a fold change decrease in B-cell lymphoma 2 (Bcl-2) expression. In A735 melanoma cells, high-resolution respirometry studies revealed that all three GNP-conjugates act as selective inhibitors of mitochondrial function. Furthermore, by examining the effect on each mitochondrial respiratory rate, the results indicate that all three conjugates are capable of increasing the production of reactive oxygen species (ROS), an apoptosis trigger in cancer cells. [ABSTRACT FROM AUTHOR]

The pursual of novel anticancer molecules from natural sources has gained worthwhile appreciation, and a significant fraction of conceptual knowledge has revolutionized our understanding about heterogeneous nature of cancer. Betulinic acid has fascinated interdisciplinary researchers due to its tremendous pharmacological properties. Ground-breaking discoveries have unraveled previously unprecedented empirical proof-of-concept about momentous chemopreventive role of betulinic acid against carcinogenesis and metastasis. Deregulation of cell signaling pathways has been reported to play a linchpin role in cancer progression and colonization of metastatically competent cancer cells to the distant organs for the development of secondary tumors. Importantly, betulinic acid has demonstrated unique properties to mechanistically modulate oncogenic transduction cascades. In this mini-review, we have attempted to provide a sophisticated compendium of regulatory role of betulinic acid in cancer chemoprevention. We have partitioned this multi-component review into different sections in which we summarized landmark research-works which highlighted betulinic acid mediated regulation of JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, AKT/mTOR and ubiquitination pathways in the inhibition of cancer. In parallel, betulinic acid mediated regulation of signaling cascades and non-coding RNAs will be critically analyzed in cell culture and animal model studies. Better comprehension of the pharmaceutical features of betulinic acid and mapping of the existing knowledge gaps will be valuable in the translatability of preclinical studies into rationally designed clinical trials. [ABSTRACT FROM AUTHOR]

This study targets the evaluation of melanin synthesis inhibition activity of the bamboo shoot skin as agro-waste. The total methanolic extract of bamboo peel extract was evaluated for its skin protective effects via measuring its melanin inhibitory activity and its suppression activity on the expression of tyrosinase mRNA levels. Results showed that bamboo peel extract has a good ability for the inhibition of melanin synthesis so further studies were performed for the isolation of its constituents. Twelve compounds have been isolated from the shoot skin of Phyllostachys pubescens. Their structures were elucidated based on extensive spectroscopic methods. The melanin inhibition potential of the isolates was tested with their collagen-production-promoting activity for the determination of active principles. Results showed that Betulinic acid, tachioside, and 1,2-dilinolenin significantly suppressed melanin production per cell compared to control. Triacontanol, tricin, and (+)-lyoniresinol 9′-O-glucoside also tended to decrease melanin production per cell. These findings indicated that the skin of bamboo shoots, a significant agricultural waste, is a useful natural source for further research on its potential for aging problems such hyperpigmentation and cognitive function impairment. [ABSTRACT FROM AUTHOR]

Betulinic acid (BA) is a natural compound well known for its anti-inflammatory, anti-viral, anti-bacterial, anti-malarial effects and anti-tumor properties. Its enhanced cytotoxicity in tumor cells and induction of cell death in various cancer entities qualifies BA as an interesting candidate for novel treatment concepts. Our analyses showed enhanced cytotoxicity and radiosensitization under hypoxic conditions in human breast cancer cells. So far, the underlying mechanisms are unknown. Therefore, we investigated the BA-treated human breast cancer cell lines MDA-MB-231 and MCF-7 under normoxic and hypoxic conditions based on microarray technology. Hypoxia and BA regulated a variety of genes in both breast cancer cell lines. KEGG pathway analysis identified an enrichment of the p53 pathway in MCF-7 cells (wtp53) under hypoxia. In MDA-MB-231 cells (mtp53) an additional BA incubation was required to activate the p53 signaling pathway. Fourteen down-regulated and up-regulated genes of the p53 pathway were selected for further validation via qRT-PCR in a panel of five breast cancer cell lines. The stress-induced gene Sestrin-2 (SESN2) was identified as one of the most strongly up-regulated genes after BA treatment. Knockdown of SESN2 enhanced BA-induced ROS production, DNA damage, radiosensitivity and reduced autophagy in breast cancer cells. Our results identified SESN2 as an important target to enhance the radiobiological and anti-tumor effects of BA on breast cancer cells. [ABSTRACT FROM AUTHOR]

In order to explore the antibacterial material basis from the root bark of Ailanthus altissima, the silica gel and Sephadex LH-20 were employed to separate and purify methanol extract from the root bark of the A. altissima, and the structures of the compounds were identified by chemical properties and spectral data. Flow cytometry was employed to test the antibacterial activity of the compounds, and kanamycin was used as control group. The results were as follows: Twenty-two compounds were isolated and elucidated from the root bark of A. altissima respectively as pleuchiol(1), withastramonolide(2), 7-ketositosterol(3), betulin(4), betulinic acid methyl ester(5), 1, 2, 4-trimethoxybenzene(6), dimethyl maleate(7), sonderianol(8), dibutyl phthalate(9), pinoresinol(10), p-hydroxybenzoic acid ethyl ester(11), avenalumic acid methyl ester(12), 5, 3'-dihydroxy-3,7, 4'-trimethoxyflavone(13), spathulenol(14), 2-methyl-5-acetonyl-7-hydroxychromone(15), 7, 4'-dihydroxyflavone(16), annphenone(17), 3-hydroxy-4-methoxybenzoic acid(18), 5, 3',4'-trihydroxy-7-methoxyflavanone(19), dibutyl phthalate(20), 4-O-methylgallic acid(21), dioctyl terephthalate(22). All compounds were isolated from the root bark of A. altissima for the first time. The antibacterial activity tests showed that Compound 2 had inhibitory effect on Pseudomonas aeruginosa and Bacillus subtilis. Compound 3 had inhibitory effects on Bacillus subtilis. Compound 8 had inhibitory effects on Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis. Compound 17 had inhibitory effects on Pseudomonas aeruginosa and Staphylococcus aureus. The inhibitory effect of Compound 2 on Bacillus subtilis was not significantly different from kanamycin(P>0.05). This paper aims to clarify the antibacterial substance basis of the root bark of A. altissima, and provide a certain theoretical basis for the development and utilization of the root of A. altissima resources and the research and development of drugs with antibacterial activity. [ABSTRACT FROM AUTHOR]

With the aim to investigate the active chemical constituents for the roots of Indigofera stachyodes, the petroleum ether part of this plant was separated and purified using silica gel column chromatography, Sephadex LH-20 column chromatography, semi-preparative high performance liquid chromatography, and recrystallization methods. The structures of obtained monomeric compounds were identified through modern spectral techniques by detail analysis of their electrospray ionization mass spectrometry, hydrogen and carbon nuclear magnetic resonance spectra data, as well as compared with the reported references. The results were as follows: twenty-two natural compounds were identified as β-sitostenone(1), stigmasta-3,6-di-one(2), 6β-hydroxystigmast-4-en-3-one(3),(22E)-5α,8α-epidioxyergosta-6,22-dien-3β-ol(4), medicarpin(5), sativan(6), 2',4'-dihydroxychaicone(7), 6,7-dimethoxy-4-hydroxy-1-naphthoic acid(8), p-hydroxybenzoic acid ethyl ester(9), 2,4-dihydroxybenzoic acid ethyl ester(10),(9E,11E)-13-oxo-9,11-ocatadecadienoic acid(11),(9E,11E)-13-oxo-9,11-octadecadienoic acid methyl ester(12), 9-oxo-10E,12E-octadecadienoic acid methyl ester(13), 9-hydroxy-10E,12Z-octadecadienoic acid methyl ester(14), pinellic acid(15)and 9-oxo-10E,12E-octadecadienoic acid-(2S)-2,3-dihydroxypropyl ester(16), β-sitosterol(17), betulinic acid(18), 3β-hydroxyolean-12-en-11-one(19), maackiain(20), phellopterin(21), palmitic acid(22). Of these compounds, ten compounds(compounds 1-3, 7, 11-16)were isolated from the Fabaceae for the first time; sixteen compounds(compounds 1-16)were obtained from Indigofera plant for the first time; at the same time, compounds 1-16, 18, 19, 21 were obtained from the roots of Indigofera stachyodes for the first time. Thus, the results of this research enrich the chemical structure types of roots of I. stachyodes, and afford a scientific foundation for its further rational use. [ABSTRACT FROM AUTHOR]

Background: Hyperlipidemia is considered a modifiable risk factor for cardiovascular disease and atherosclerosis. Drugs of first choice, Statins, despite being well tolerable, is accompanied by many adverse effects. To tackle the shortcomings of standard drugs, there is dire demand to make an agent which equates to a better response. This study evaluated the anti-hyperlipidemic and comparative effects of the Zinc complex of Betulinic acid (Zn+BA) with simvastatin (SIM), on high-fat diet-induced hyperlipidemia in rats, and the safety profile of the two treatments was also assessed. Methodology: Hyperlipidemia was induced by giving a high-fat diet. BA +Zn 10 mg/kg and SIM 20 mg/kg were given orally for four weeks. On the final day terminal sampling was done and serum lipid profile (TG, TC, LDL, HDL) and hepatic enzymes (ALT) for assessing hepatotoxicity were estimated. Results: Our results showed that BA+Zn significantly increased HDL levels and significantly reduced serum TC, TG, and LDL (p<0.001) as compared to Simvastatin. Correspondingly serum ALT levels also showed a significant reduction (p<0.001) in comparison with Simvastatin. Conclusion: Our study suggests that BA+Zn effectively attenuates high-fat diet-induced hyperlipidemia while preserving hepatic function and could serve as a better alternative to simvastatin in treating hyperlipidemia. [ABSTRACT FROM AUTHOR]

Betulinic acid, BA, is a lupane derivative that has caught the interest of researchers due to the wide variety of pharmacological properties it exhibits towards tumor cells. Because of their prospective increased anti−proliferative efficacy and improved pharmacological profile, BA derivatives continue to be described in the scientific literature. The current work was conducted in order to determine the antiproliferative activity, under an in vitro environment of the newly developed 1,2,4−triazole derivatives of BA. The compounds and their reaction intermediates were tested on three cancer cell lines, namely RPMI−7951 human malignant melanoma, HT−29 colorectal adenocarcinoma, A549 lung carcinoma, and healthy cell line (HaCaT human keratinocytes). BA−triazole derivatives 4a and 4b revealed lower IC50 values in almost all cases when compared to their precursors, exhibiting the highest cytotoxicity against the RPMI−7951 cell line (IC50: 18.8 μM for 4a and 20.7 μM for 4b). Further biological assessment of these compounds executed on the most affected cell line revealed a mitochondrial level induced apoptotic mechanism where both compounds inhibited mitochondrial respiration in RPMI−7951 cells. Furthermore, the triazole−BA derivatives caused a significant decrease of the anti−apoptotic Bcl−2 gene expression, while increasing the pro−apoptotic BAX gene's expression. [ABSTRACT FROM AUTHOR]

Cancer cells' resistance to anticancer drugs represents a major clinical problem and the most important failure of treatment. Combination chemotherapy is more effective than monotherapy due to additive or synergistic effects. The aim of our research was to assess the effects of the combinations of apple extract's triterpenic compounds, individual triterpenic acids, and doxorubicin (DOX) on human colon adenocarcinoma (HT-29) and human glioblastoma (U-87) cell lines in 2D and 3D cultures. The effect of the combination of apple extracts, the triterpenic standards, and DOX against HT-29 and U-87 cell viability was tested by the MTT and spheroid growth assays. Cell line HT-29 was more sensitive to DOX when incubated with all tested apple extracts than DOX alone. Cell line HT-29 was the most strongly sensitive to DOX when it was treated with 5 µM oleanolic acid (change of EC50 = −64.6% ± 4.4%) and with 5 µM ursolic acid (change of EC50 = −61.9% ± 8.8%) in 2D culture. Meanwhile, cell line U-87 was the most strongly sensitive to DOX when treated with 2 µM betulinic acid (change of EC50 = −45.1% ± 4.5%) in 2D culture. The combination of apple extract (E3) and DOX reduced the viability of HT-29 spheroids the most (spheroid viability reduced from −19.9% to −10.9%, compared to spheroids treated with DOX alone). Our study in 2D and 3D cultures showed that combining apple extract's triterpenic complexes or individual triterpenic acids with DOX may sensitize chemotherapeutic drugs and increase the cytotoxicity effects in HT-29 and U-87 cell lines. [ABSTRACT FROM AUTHOR]

Natural products serve as the single most productive source for the discovery of drugs and pharmaceutical leads. Among the various chemicals derived from microbes, plants, and animals, phytochemicals have emerged as potential candidates for the development of anticancer drugs due to their structural diversities, complexities, and pleiotropic effects. Herein, we discuss betulinic acid (BA), a ubiquitously distributed lupane structured pentacyclic triterpenoid, scrutinized as a promising natural agent for the prevention, suppression, and management of various human malignancies. Ease of availability, common occurrences, cell‐specific cytotoxicity, and astonishing selectivity are the important factors that contribute to the development of BA as an anticancer agent. The current review delineates the mechanistic framework of BA‐mediated cancer suppression through the modulation of multiple signaling pathways and also summarizes the key outcomes of BA in preclinical investigations. [ABSTRACT FROM AUTHOR]

The Ziziphus fruits are recognized as a rich source of biologically active compounds, such as polysaccharides, phenolics, triterpenes, saponins, etc. related to both nutritional and nutraceutical importance. In order to explore more about the phytochemical potential and health benefits of these wild fruits, these have been analyzed by high-performance thin-layer chromatography (HPTLC). Betulinic acid (BA) is a naturally occurring pentacyclic lupane-type triterpenoid distributed widely throughout the plant kingdom. It exhibits a number of biomedical activities like retarding the progression of HIV1 (human immunodeficiency virus 1) infection, selectively killing human melanoma cells while leaving healthy cells alive, anti-inflammatory activity, antibacterial, and anthelmintic properties. The present study was aimed to quantify BA from the methanolic extracts of the wild fruits of two Ziziphus species (Z. mauritiana and Z. nummularia) collected from different parts of Northwest India. The HPTLC‒densitometric determination of BA was performed using the optimized mobile phase of petroleum ether‒ethyl acetate‒toluene (7:2:1, V/V). Post-chromatographic derivatization was done by using anisaldehyde‒sulphuric acid reagent. For densitometry measurements, the plates were scanned at 580 nm absorbance/reflectance wavelength. The amount of compound (% w/w) was observed to be maximum in ZM-10 (0.922 ± 0.006) collected from Sri Ganganagar (Rajasthan), ZN-3 (0.335 ± 0.004) from Dehradun (Uttarakhand) and minimum in ZM-4 (0.042 ± 0.002) from Ponta Sahib (Himachal Pradesh), ZN-1 (0.016 ± 0.003) from Kangra (Himachal Pradesh). The results of the study revealed that the wild fruits of Ziziphus species are rich sources of triterpenoids besides minerals and vitamins and can be further used in the pharmaceutical industry. Therefore, both species can be further explored for the development of potential therapeutic products for the treatment of cancer and inflammation. [ABSTRACT FROM AUTHOR]

Quantification of bioactive markers through modern analytical methods is very essential for establishing the authenticity and creditability of prescription and usage of herbal drugs formulations. In the present study, simultaneous quantification of rosmarinic acid (RA), quercetin (Q), glycyrrhizin (G) and betulinic acid (BA), in polyherbal formulation by high-performance thin-layer chromatography (HPTLC) method was developed. Mobile phase of ethyl acetate‒toluene‒methanol‒formic acid (7:1:0.5:0.5, V/V) was used on pre-coated plate of silica gel 60F254 and quantified by densitometric method. Validation of the method was done to demonstrate its selectivity, linearity, precision and accuracy as per the International Council for Harmonization (ICH) guidelines. Intra-day assay and inter-day assay precision of the analytes were less than 2%, and the average recovery rates obtained were in the range of 98.11‒101.14% for all with percent relative standard deviation (%RSD) below 2%. Correlation coefficient shows that the developed method was accurate and precise. This method can be used in the routine analysis of polyherbal formulations. [ABSTRACT FROM AUTHOR]

Tuberculosis caused by Mycobacterium bovis is a serious problem for animal and human health worldwide. A promising concept for the design of anti-tuberculosis drugs is the conjugation of an immunogenic fraction isolated from bacterial vaccines with a stimulating component. Taking this principle as a basis, conjugates based on BCG antigens with betulin and its derivatives (betulonic and betulinic acids) were designed. The aim of this research was to study the morphological changes in the lymphoid tissue associated with the bronchial mucosa lungs (BALT) in guinea pigs sensitized with experimental conjugates using a model of experimental tuberculosis. The results showed a significant decrease in the BALT response, expressed by a decrease in the diameter of lymphatic follicles and a decrease in their activity when exposed to conjugates based on BCG antigens with betulin and, especially, with betulonic acid, with a visually greater number of plasma cells observed in the lung tissues of guinea pigs of these groups. The absence of tuberculous foci and low BALT activity in the lungs of animals treated with betulin and betulonic acid are probably associated with the activation of humoral immunity under the action of these conjugates. [ABSTRACT FROM AUTHOR]

Target identification of bioactive compounds is important for understanding their mechanisms of action and provides critical insights into their therapeutic utility. While it remains a challenge, unbiased chemoproteomics strategy using clickable photoaffinity probes is a useful and validated approach for target identification. One major limitation of this approach is the efficient synthesis of appropriately substituted clickable photoaffinity probes. Herein, we describe an efficient and consistent method to prepare such probes. We further employed this method to prepare a highly stereo-congested probe based on naturally occurring triterpenoid betulinic acid. With this photoaffinity probe, we identified tropomyosin as a novel target for betulinic acid that can account for the unique biological phenotype on cellular cytoskeleton induced by betulinic acid.

• Novel betulinic acid derivatives containing 1,2,4-triazole- derived schiff base f1–f35 were synthesized and screened against α-glucosidase. • Compound f32 showed the highest α-glucosidase inhibitory with IC 50 of 1.52±0.16 μM. • Inhibition kinetics showed that compound f32 was a non-competitive inhibitor for α-glucosidase. • Spectroscopic studies based on three dimensional fluorescence and circular dichroism and molecular docking suggested that compound f32 interacted with α-glucosidase. • In vivo experiments showed that compound f32 could not only reduce the level of fasting blood glucose, but also improve glucose tolerance and dyslipidemia. A series of novel betulinic acid (BA) derivatives containing 1,2,4-triazole- derived schiff base have been designed and synthesized as α-glucosidase inhibitors. All the title compounds showed higher α-glucosidase inhibitory activity than acarbose and BA, with compound f32 showing the highest α-glucosidase inhibitory activity (IC 50 = 1.52±0.16 μM). Lineweaver-Burk plot analysis suggested that compound f32 was a non-competitive inhibitor for α-glucosidase. 3D fluorescence and circular dichroism spectroscopy disclosed the interaction of compound f32 with α-glucosidase by changing the secondary structure of α-glucosidase. Molecular docking showed that compound f32 could bind to the active site of α-glucosidase through hydrogen bonding and hydrophobic interaction. More importantly, compound f32 could not only reduce the level of fasting blood glucose and postprandial blood glucose in mice, but also ameliorate dyslipidemia. The current findings suggest that compound f32 may serve as a leading compound for the discovery of α-glucosidase inhibitors in the treatment of type 2 diabetes. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Introducing the squalene synthesis pathway into the peroxisomes. • The rate-limiting steps in the accumulation of 2,3-oxidosqualene have been overcome. • Introducing the lupeol synthase and optimizing its expression. • The highest lupeol titer (414.83 ± 1.75 mg/L) reported to date in shake flasks. • The betulinic acid titer reached 205.74 mg/L in a 5-L fermenter. Betulinic acid (BA) is a lupinane-type pentacyclic triterpenoid natural product derived from lupeol that has favorable anti-inflammatory and anti-tumor activities. Currently, BA is mainly produced via botanical extraction, which significantly limits its widespread use. In this study, we investigated the de novo synthesis of BA in Saccharomyces cerevisiae , and to facilitate the synthesis and storage of hydrophobic BA, we adopted a dual-engineering strategy involving peroxisomes and lipid droplets to construct the BA biosynthetic pathway. By expressing Betula platyphylla -derived lupeol C-28 oxidase (BPLO) and Arabidopsis -derived ATR1, we succeeded in developing a BA-producing strain and following multiple expression optimizations of the linker between BPLO and ATR1, the BA titer reached 77.53 mg/L in shake flasks and subsequently reached 205.74 mg/L via fed-batch fermentation in a 5-L bioreactor. In this study, we developed a feasible approach for the de novo synthesis of BA and its direct precursor lupeol in engineered S. cerevisiae. [ABSTRACT FROM AUTHOR]

Pain and inflammation are the most frequent reasons for which people seek medical care. Currently available analgesics against these conditions produce fatal adverse effects. NPK 500 capsules is an alternative herbal analgesic employed to treat dysmenorrhea, peptic ulcer and pain. NPK 500 is produced from Cassia sieberiana. A plant used in traditional medicine to treat pain and inflammation. This study reports the analysis, phytochemical characterization and mechanism of analgesic and anti-inflammatory activities of two NPK 500 capsules, called old and new NPK500 capsules (ONPK500 and NNPK500) respectively. Physicochemical, organoleptic, GC-MS and LC-MS methods were employed to analyze the NPK 500 capsules. Analgesic activity was evaluated using tail immersion, Randall-Selitto and acetic acid induced writing tests. Anti-inflammatory activity was evaluated using carrageenan-induced rat paw inflammation. Additionally, pro-inflammatory mediators such as prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase 1 and 2 (COX-2 and COX-1) were quantified in the sera of the rats using Enzyme Linked Immunosorbent Assay (ELISA) kits. Thirteen major compounds were characterized in the NNPK 500 capsules via the GC-MS and LC-MS spectroscopies. Kaempferol was the major compound characterized in addition to physcion, β-sitosterol 3-O-β-D-glucopyranoside, betulinic acid and nine others. Physicochemical and organoleptic indices of the capsules were also derived for its authentication and quality control. Furthermore, NNPK 500 0.5–1.5 mg/kg p.o. produce significant (P < 0.5) analgesic activity (160–197%) higher than that of ONPK500 (109.8%) and Morphine (101%) in the tail immersion test. The analgesic activity of NNPK 500 0.5–1.5 mg/kg p.o. (171.0–258.3%) and ONPK 500 (179.5%) were also significant (P < 0.01) and higher than that of Aspirin (103.00%) in the Randall-Selitto test. Both capsules also demonstrated significant (P < 0.5) analgesic and anti-inflammatory activities in the acetic acid-induced writhing and carrageenan-indued paw edema tests respectively. The two NPK500 capsules also, significantly (P < 0.5) inhibited PGE2 and iNOS but not COX-2 and COX-1 in the carrageenan-indued paw edema test. These results show that NNPK 500 and ONPK 500 capsules possessed potent analgesic and anti-inflammatory activities via inhibition of PGE2 and iNOS as a result of their chemical constituents. NPK500 capsules thus, relief acute pain and inflammation without causing gastrointestinal, renal or hepatic injuries, since they did not inhibit COX-1. [Display omitted] • The major active ingredient identified in NPK500 capsules was kaempferol. • Physcion, β-sitosterol 3-O-β-D-glucopyranoside and betulinic acid were also present. • Analgesic activity of NPK500 was 171.0–258.3% against 103.00% for Aspirin. • NPK500 also produced significant anti-inflammatory activity. • NPK500 capsules inhibited PGE2 and iNOS during inflammation. [ABSTRACT FROM AUTHOR]

Fifteen betulonic/betulinic acid conjugated with nucleoside derivatives were synthesized to enhance antitumor potency and water solubility. Among these, the methylated betulonic acid-azidothymidine compound (8c) exhibited a broad-spectrum of antitumor activity against three tested tumor cell lines, including SMMC-7721 (IC 50 = 5.02 μM), KYSE-150 (IC 50 = 5.68 μM), and SW620 (IC 50 = 4.61 μM) and along with lower toxicity (TC 50 > 100 μM) estimated by zebrafish embryos assay. Compared to betulinic acid (<0.05 μg/mL), compound 8c showed approximately 40-fold higher water solubility (1.98 μg/mL). In SMMC-7721 cells, compound 8c induced autophagy and apoptosis as its concentration increased. Transcriptomic sequencing analysis was used to understand the potential impacts of the underlying mechanism of 8c on SMMC-7721 cells. Transcriptomic studies indicated that compound 8c could activate autophagy by inhibiting the PI3K/AKT pathway in SMMC-7721 cells. Furthermore, in the xenograft mice study, compound 8c significantly slowed down the tumor growth, as potent as paclitaxel treated group. In conclusion, methylated betulonic acid-azidothymidine compound (8c) not only increases water solubility, but also enhances the potency against hepatocellular carcinoma cells by inducing autophagy and apoptosis, and suppressing the PI3K/Akt/mTOR signaling pathway. [Display omitted] • Conjugated triterpenes with nucleoside derivatives exhibited increased anti-tumor activity and solubility. • The methylated betulonic acid-azidothymidine derivative inducing autophagy and apoptosis in hepatocellular carcinoma cells. • Transcriptomic studies revealed its activation of autophagy by suppressing the PI3K/Akt/mTOR pathway in SMMC-7721 cells. [ABSTRACT FROM AUTHOR]

We isolated ten compounds from methanolic extract of the peels of sacred lotus (Nelumbo nucifera) rhizomes which were identified as β -sitosterol linoleate 1 , β -sitosterol 2 , lupeol 3 , stigmasterol 3- O - β -D-glucoside 4 , oleanolic acid 5 , betulinic acid 6 , pinoresinol 7 , 4-hydroxybenzoic acid 8 , catechin 9 and gallocatechin 10. All of the isolated compounds from the peels of sacred lotus rhizomes are reported for the first time, and were investigated for their anti-allergic activity. We found that three of them, stigmasterol 3- O - β -D-glucoside 4 , oleanolic acid 5 and pinoresinol 7 , were capable of inhibiting A23187-induced degranulation in RBL-2H3 cells with IC 50 values 0.18 ± 0.01 mM, 0.28 ± 0.06 mM, and 0.27 ± 0.01 mM, respectively. With an exception to 4 , compounds 5 and 7 achieved the anti-allergic effect without affecting the cells viability even at higher concentrations with their selectivity indices (SI) being >5. By reducing A23187-induced degranulation, it is suggestive of a mechanism attenuation of Ca2+ elevation. Our findings suggest that, the peels of sacred lotus rhizomes would be beneficial for providing an inexpensive source for the production of bioactive compounds with anti-allergic effect. [Display omitted] • The isolated compounds from peels of sacred lotus (Nelumbo nucifera) roots suppress allergic reactions. • All of the isolated compounds from the peels of lotus roots are reported for the first time. • Compounds 4 , 5 , and 7 inhibited A23187-induced degranulation in RBL-2H3 cells, acting as membrane stabilizers. • Peels of sacred lotus roots would be beneficial for providing inexpensive source for bioactive anti-allergic compounds. [ABSTRACT FROM AUTHOR]

The present study deals with the phytochemical study of the leaf extract of C. klainei , a plant used in folk medicine to treat diabetes, venereal diseases, hypertension, malaria, cough and hemorrhoids. The liquid-liquid extraction and chromatographic separation of the dichloromethane/methanol (1:1) extract of this plant led to the isolation of eleven (11) known compounds identified from the analysis of their spectroscopic and physical data, and in comparison, with data from the literature. These compounds were identified to hentriancontane (1), β -sitosterol (2), stigmasterol (3), β -amyrin (4), betulinic acid (5), sitosterol-3- O - β - D -glucopyranoside (6), diosmetin (7), iristectorigenin A (8) , gallic acid (9), bergenin (10) and scyllitol (11) respectively. Furthermore, the chemotaxonomic significance of these compounds was discussed. [Display omitted] • Many classes of secondary metabolites are found in Coelocaryon klainei. • Nine of the eleven isolated compounds are newly reported from the genus Coelocaryon. • Polyphenols could be considered as chemotaxonomic markers of the genus Coelocaryon. [ABSTRACT FROM AUTHOR]

[Display omitted] • A simple and universal strategy was developed for the fabrication of self-stacked hydrogels of bioactive divalent metal ions coordinated with pharmacological small molecules. • We elucidated and summarised the relationship between the molecular structure and gelling ability of these natural self-stacked small molecule gels. • The synergistic effects of betulinic acid and Mg2+ were harnessed within the self-stacked hydrogel, enhancing its pharmacological impact. • In vivo studies displayed that the BA-Mg/BC composite hydrogel significantly accelerated scar-free wound healing. Despite significant advancements in self-stacked hydrogels of herbal small molecules in recent years, the emergence of new pharmacological small molecule self-stacked hydrogel systems remains largely reliant on serendipity and painstaking efforts. To address this challenge, we proposed a 'bioactive bivalent metal ions-coordinated pharmacological small molecules' strategy. This approach enabled the preparation of triterpenoid betulinic acid-based self-stacked hydrogels with excellent injectable and self-healing properties via a simple two-step method. We extended this strategy to self-stacking hydrogels based on other pentacyclic triterpene small molecules, anthraquinone small molecules, flavonoid small molecules and synthetic steroid small molecules. This universal strategy is capable of extracting hydrophobic pharmacological small molecules to construct novel self-stacked biomaterials in a cost-effective, efficient, large-scale, and environmentally friendly manner. Importantly, we successfully synthesized Mg2+-coordinated betulinic acid (BA-Mg) self-stacked hydrogel at low concentrations in the bacterial cellulose (termed BC) hydrogel network, overcoming the mechanical limitations of self-stacked hydrogels for biomedical applications. The BA-Mg/BC hybrid hydrogel demonstrated exceptional biocompatibility, anti-inflammatory, and angiogenic properties, significantly accelerating the skin wound healing process through the synergistic pharmacological effects of Mg2+ and BA. [ABSTRACT FROM AUTHOR]

• Betulinic acid improves the cognitive functions of zebrafish subsequent TiO 2 NP treatment. • Betulinic acid significantly decreases proinflammatory markers such as TNF-α, IL-1β, and IL-6 in the brain of the zebrafish brain. • Betulinic acid mitigates oxidative stress via activating the Nrf-2/HO-1 signaling in the TiO 2 NP model of zebrafish confirmed from histopathology and immunohistochemistry analysis. Betulinic acid (BA) is a natural triterpenoid extracted from Bacopa monnieri. BA has been reported to be used as a neuroprotective agent, but their molecular mechanisms are still unknown. Therefore, in this study, we attempted to investigate the precise mechanism of BA for its protective effect against Titanium dioxide nanoparticles (TiO2NP) induced neurotoxicity in zebrafish. Hence, our study observation showed that 10 µg/ml dose of TiO2NP caused a rigorous behavioral deficit in zebrafish. Further, biochemical analysis revealed TiO 2 NP significantly decreased GSH, and SOD, and increased MDA, AChE, TNF-α, IL-1β, and IL-6 levels, suggesting it triggers oxidative stress and neuroinflammation. However, BA at doses of 2.5,5,10 mg/kg improved behavioral as well as biochemical changes in zebrafish brain. Moreover, BA also significantly raised the levels of DA, NE, 5-HT, and GABA and decreased glutamate levels in TiO 2 NP-treated zebrafish brain. Our histopathological analysis proved that TiO 2 NP causes morphological changes in the brain. These changes were expressed by increasing pyknotic neurons, which were dose-dependently reduced by Betulinic acid. Likewise, BA upregulated the levels of NRF-2 and HO-1, which can reduce oxidative stress and neuroinflammation. Thus, our study provides evidence for the molecular mechanism behind the neuroprotective effect of Betulinic acid. Rendering to the findings, we can consider BA as a suitable applicant for the treatment of AD-like symptoms. [ABSTRACT FROM AUTHOR]

Betulinic acid (BA), which is a pentacyclic triterpenoid found in the bark of plane, birch, and eucalyptus trees, has emerged as a compound of significant interest in scientific research due to its potential therapeutic applications. BA has a range of well-documented pharmacological and biological effects, including antibacterial, immunomodulatory, diuretic, antiviral, antiparasitic, antidiabetic, and anticancer activities. Although numerous research studies have explored the potential anticancer effects of BA, there is a noticeable gap in the literature, highlighting the need for a more up-to-date and comprehensive evaluation of BA's anticancer potential. The aim of this work is to critically assess the reported cellular and molecular mechanisms underlying the cancer preventive and therapeutic effects of BA. Relevant research on the inhibitory effects of BA against cancerous cells was searched using Science Direct, Scopus, Web of Science, and PubMed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The anticancer properties of BA are mediated by the activation of cell death and cell cycle arrest, production of reactive oxygen species, increased mitochondrial permeability, modulation of nuclear factor-κB and Bcl-2 family signaling. Emerging evidence also underscores the combined anticancer effects of BA with other natural bioactive compounds or approved drugs. Notably, several novel BA nanoformulations have been found to exhibit encouraging antineoplastic activities. BA, whether used alone or in combination, or as a form of nanoformulation, shows significant potential for cancer prevention and treatment. Nevertheless, further detailed studies are necessary to confirm the therapeutic effectiveness of this natural compound. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background Glioblastoma (GBM) is the most common and fatal primary tumor in the central nervous system (CNS). Due to the existence of blood–brain barrier (BBB), most therapeutics cannot efficiently reach tumors in the brain, and as a result, they are unable to be used for effective GBM treatment. Accumulating evidence shows that delivery of therapeutics in form of nanoparticles (NPs) may allow crossing the BBB for effective GBM treatment. Methods Betulinic acid NPs (BA NPs) were synthesized by the standard emulsion approach and characterized by electron microscopy and dynamic light scattering analysis. The resulting NPs were characterized for their anti-tumor effects by cell viability assay, EdU-DNA synthesis assay, cell cycle assay, mitochondrial membrane potential, and PI-FITC apoptosis assay. Further mechanistic studies were carried out through Western Blot and immunostaining analyses. Finally, we evaluated BA NPs in vivo for their pharmacokinetics and antitumor effects in intracranial xenograft GBM mouse models. Results BA NPs were successfully prepared and formed into rod shape. BA NPs could significantly suppress glioma cell proliferation, induce apoptosis, and arrest the cell cycle in the G0/G1 phase in vitro. Furthermore, BA NPs downregulated the Akt/NFκB-p65 signaling pathway in a concentration dependent manner. We found that the observed anti-tumor effect of BA NPs was dependent on the function of CB1/CB2 receptors. Moreover, in the intracranial GBM xenograft mouse models, BA NPs could effectively cross the BBB and greatly prolong the survival time of the mice. Conclusions We successfully synthesized BA NPs, which could cross the BBB and demonstrated a strong anti-tumor effect. Therefore, BA NPs may potentially be used for effective treatment of GBM. Graphical Abstract

Obesity is an ingrained health problem with а multifactorial origin and а long history, thereby innovations in the treatment strategies are of great importance. In the search of a remedy for excessive weight gain, we have directed our investigations to phytochemicals as valuable bioactive compounds. Betulinic acid (BA), among the other triterpenoids, is known for its anti-inflammatory and anti-neoplastic properties. In addition, a previous study of ours has demonstrated а potent anti-adipogenic effect of BA in human adipocytes. Therefore, we aimed here to further verify the anti-obesogenic effect of BA in vivo in Caenorhabditis elegans. Induction of lipid accumulation in the nematodes was modelled with glucose-supplemented media, followed by treatment with BA (10–50 μM) or orlistat (12 μM) as a control anti-obesity medication. Oil red O and Nile red staining were applied to provide quantification of accumulated lipids. Analysis of the relative expression of genes, related to lipid metabolism suggested molecular mechanism of lipid-reducing action of BA in C. elegans. Treatment of nematodes with BA significantly decreased the lipid accumulation, downregulated desaturases involved in lipogenesis (fat-5, fat-6 and fat-7), modulated key transcription factors (nhr-49 and hlh-11) and microRNAs (miR-60, lin-4, let-7 and miR-786) associated with the lipid metabolism. Collectively, the current research provides additional insight on the molecular mechanism of the BA’s anti-obesogenic effect in vivo. Furthermore, it validates the potential of BA as a candidate compound in obesity management by reducing lipid accumulation.

Cancer, in all its types and manifestations, remains one of the most frequent causes of death worldwide; an important number of anticancer drugs have been developed from plants, fungi and animals, starting with natural compounds that were later derivatized in order to achieve an optimized pharmacokinetic/pharmacological profile. Betulinic acid is a pentacyclic triterpenic compound that was identified as an anticancer agent whose main advantage consists in its selective activity, which ensures the almost total lack of cytotoxic side effects. Conjugates of betulinic acid with substituted triazoles, scaffolds with significant pharmacological properties, were synthesized and tested as anticancer agents in order to achieve new therapeutic alternatives. The current paper aims to obtain a C30-1,2,4-triazole derivative of betulinic acid simultaneously acetylated at C3 whose biological activity was tested against RPMI melanoma cells. The compound revealed significant cytotoxic effects at the tested concentrations (2, 10 and 50 μΜ) by significantly decreasing the cell viability to 88.3%, 54.7% and 24.5%, respectively, as compared to the control. The compound's testing in normal HaCaT cells showed a lack of toxicity, which indicates its selective dose-dependent anticancer activity. The investigation of its underlying molecular mechanism revealed an apoptotic effect induced at the mitochondrial level, which was validated through high-resolution respirometry studies. [ABSTRACT FROM AUTHOR]

This study set out to determine the effectiveness of birch leaves extract (BLE) as a corrosion inhibitor against X52 pipeline steel in the pickling solution. Chemical and electrochemical techniques, as well as scanning electron microscope (SEM), Fourier-transform infrared (FT-IR), and adsorption isotherms were used in the research. Various triterpenoids, including betulin, betulinic acid, oleanolic acid, sitosterol, and kaempferol, are unquestionably involved in the corrosion inhibition mechanism, according to the high-performance-liquid-chromatography (HPLC) analysis. The 95% efficiency of the produced BLE extract (at optimum concentration 400 mg L−1) significantly reduced the corrosion rate of X52 pipeline steel in the pickling solution. The adsorption of BLE extract molecules on the X52-steel surface was demonstrated by SEM and FT-IR analysis. The adsorption activity follows the Langmuir adsorption theory. [ABSTRACT FROM AUTHOR]

The ethyl acetate fraction of Psorospermum aurantiacum stems has furnished cadensin H (1) a new compound belonging to the class of xanthonolignoid alongside with six compounds: 1,5,6-trihydroxy-7-methoxyxanthone (2), betulinic acid (3), 1,7-dihydroxyxanthone (4), betulin (5), lupeol (6) and stigmasterol glucoside (7). The crude methanolic extract and ethyl acetate fraction, as well as some major isolated compounds were evaluated for antibacterial and antioxidant activities. Shigella flexneri, Staphylococcus aureus, SSalmonella. typhi, EEscherichia coli and Klebsiella pneumonia , were used as test organisms. The crude extract has moderate activity against Shigella flexneri , methicillin-resistant Staphylococcus aureus, SSalmonella. typhi and EEscherichia. coli strains with MICs values ranging from 125 to 500 µ g/mL, and MBC of 500 µ g/mL for Staphylococcus aureus, SSalmonella. typhi and EEscherichia. coli. While the ethyl acetate fraction has moderate activity against S. flexneri , methicillin resistant S. aureus, SSalmonella. typhi and EEscherichia. coli with MIC ranging from 250 to 1000 µg/mL and MBC from 500 to 1000 µg/mL for S. flexneri, S. aureus, E. coli strains. Among all the compounds tested, only 1,5,6-trihydroxy-7-methoxyxanthone showed moderate activity on all bacterial strains with MICs values from 12.5 to 50 µ g/mL and MBC of 25 µg/mL and 100 µg/mL on methicillin-resistant S. aureus , 100 µg/mL on EEscherichia. coli. DPPH for radical scavenging and iron reducing antioxidant (FRAP) were used to evaluate antioxidant activity. Compound (2) showed important activity with the first reagent while compound (1) showed moderate activity with the second reagent. The structures of the isolated compounds were established using modern spectroscopic methods including 1D and 2D NMR and High-resolution mass spectrometry and by comparing with data reported in the literature. [Display omitted] • Isolation of 7 compounds from the stems of psorospermum aurantiacum (Hypericaceae). • Four of the compounds isolated are found for the first time in the genus psorospermum. • First report of antioxidant activities of compounds isolated from the stems of psorospermu m. [ABSTRACT FROM AUTHOR]

Betulinic acid (BA), a pentacyclic triterpenoid found in certain plant species, has been reported to have several health benefits including antioxidant and anti-apoptotic properties. However, the mechanism by which BA confers these properties is currently unknown. Saccharomyces cerevisiae, a budding yeast with a short life cycle and conserved cellular mechanism with high homology to humans, was used as a model for determining the role of BA in aging and programmed cell death (PCD). Treatment with hydrogen peroxide (H2O2) exhibited significantly increased (30–35%) survivability of antioxidant (sod1Δ, sod2Δ, cta1Δ, ctt1Δ, and tsa1Δ) and anti-apoptotic (pep4Δ and fis1Δ) mutant strains when cells were pretreated with BA (30 µM) as demonstrated in spot and CFU (Colony forming units) assays. Measurement of intracellular oxidation level using the ROS-specific dye H2DCF-DA showed that all tested BA-pretreated mutants exhibited decreased ROS than the control when exposed to H2O2. Similarly, when mutant strains were pretreated with BA and then exposed to H2O2, there was reduced lipid peroxidation as revealed by the reduced malondialdehyde content. Furthermore, BA-pretreated mutant cells showed significantly lower apoptotic activity by decreasing DNA/nuclear fragmentation and chromatin condensation under H2O2-induced stress as determined by DAPI and acridine orange/ethidium bromide staining. In addition, BA treatment also extended the life span of antioxidant and anti-apoptotic mutants by ∼10–25% by scavenging ROS and preventing apoptotic cell death. Our overall results suggest that BA extends the chronological life span of mutant strains lacking antioxidant and anti-apoptotic genes by lowering the impact of oxidative stress, ROS levels, and apoptotic activity. These properties of BA could be further explored for its use as a valuable nutraceutical. [ABSTRACT FROM AUTHOR]

Betulinic acid (BA) is a natural pentacyclic triterpenoid with broad-spectrum anticancer activity, which has great development potential as an anti-cancer drug. In this study, a novel hyaluronic acid (HA)-modified BA liposome (BA-L) was developed for use in targeted liver cancer therapy. The size, polymer dispersity index (PDI), zeta potential, and entrapment efficiency were measured. Cell viability, cell migration and clonogenicity, cellular uptake, immunohistochemistry of CD44, and protein expression of ROCK1/IP3/RAS were also investigated. BA, BA-L, and HA-BA-L had no inhibitory effect on the activity of LO2 normal hepatocytes, but they inhibited the proliferation of HepG2 and SMMC-7721 cells in a dose- and time-dependent manner, with HA-BA-L exhibiting the most prominent inhibitory effect. Compared with the BA-L group, the expression of CD44 in HepG2 cells in the HA-BA-L group was decreased. The results of WB showed that BA, BA-L, and HA-BA-L downregulated the expression of ROCK1, IP3, and RAS in HepG2 cells, and the expression level in the HA-BA-L group was significantly decreased. The easily prepared HA-BA-L was demonstrated to be an excellent CD44-mediated intracellular delivery system capable of targeting effects. Further mechanistic research revealed that the inhibition of HA-BA-L on HepG2 cells may be mediated by blocking the ROCK1/IP3/RAS signaling pathways. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective(s): Parkinson's disease (PD) is a neurodegenerative disorder involving the central nervous system associated with motor and non-motor impairments. Betulinic acid (BA) is a natural substance considered an antioxidative agent. This study aimed to investigate the therapeutic potential of BA on motor dysfunctions and globus pallidus (GP) local EEG power in a 6-hydroxydopamine (6-OHDA)- induced rat model of hemiparkinsonism. Materials and Methods: Adult Wistar rats were categorized into different groups, containing; Sham, PD, and treated groups including different doses of BA (0.5, 5, and 10 mg/kg, IP), and L-dopa (20 mg/ kg, PO, as positive control). The lesion was induced in the right medial forebrain bundle by injection of 6-OHDA (20 µg/kg). The treatment was begun just after the approved rotational test induced by apomorphine, 14 days after 6-OHDA administration. Motor behaviors such as catalepsy and stridelength and non-motor responses, including GP local EEG, were then assessed. Also, the levels of GSH, catalase, and concentration of dopamine in the brain tissue were measured. Results: Treatment of hemiparkinsonian rats with BA significantly improved catalepsy and stridelength (P<0.001 and P<0.01, respectively) and GP frequency bands' powers (P<0.001). Moreover, the activities of GSH (P<0.001), catalase (P<0.001), and the concentration of dopamine (P<0.001) in the brain were increased. Conclusion: Current results proved the potent ability of BA to scavenge free radicals and to remove oxidative agents in the brain tissue. This natural product could be considered a possible therapeutic compound for motor and non-motor disorders in PD. [ABSTRACT FROM AUTHOR]

Betulinic acid (BA) has been extensively studied in recent years mainly for its antiproliferative and antitumor effect in various types of cancers. Limited data are available regarding the pharmacokinetic profile of BA, particularly its metabolic transformation in vivo. In this study, we present the screening and structural investigations by ESI Orbitrap MS in the negative ion mode and CID MS/MS of phase I and phase II metabolites detected in mouse plasma after the intraperitoneal administration of a nanoemulsion containing BA in SKH 1 female mice. Obtained results indicate that the main phase I metabolic reactions that BA undergoes are monohydroxylation, dihydroxylation, oxidation and hydrogenation, while phase II reactions involved sulfation, glucuronidation and methylation. The fragmentation pathway for BA and its plasma metabolites were elucidated by sequencing of the precursor ions by CID MS MS experiments. [ABSTRACT FROM AUTHOR]