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Oral administration of Centella asiatica (L.) Urb leave aqueous extract ameliorates cerebral oxidative stress, inflammation, and apoptosis in male rats with type-2 diabetes

Giribabu N, Karim K, Kilari EK, Nelli SR, Salleh N

Inflammopharmacology, 2020 Dec;28(6):1599-1622.
PMID: 32588370 DOI: 10.1007/s10787-020-00733-3

Centella asiatica is claimed to have a neuroprotective effect; however, its ability to protect the cerebrum against damage in diabetes has never been identified. The aims were to identify the possibility that C. asiatica ameliorates inflammation, oxidative stress, and apoptosis in the cerebrum in diabetes. C. asiatica leave aqueous extract (C. asiatica) (50, 100, and 200 mg/kg/b.w.) were given to diabetic rats for 28 days. Changes in rats' body weight, food and water intakes, and insulin and FBG levels were monitored. Following sacrificed, cerebrum was harvested and subjected for histological, biochemical, and molecular biological analyses. The results revealed treatment with C. asiatica was able to ameliorate the loss in body weight, the increase in food and water intakes, the decrease in insulin, and the increase in FBG levels in diabetic rats. Additionally, histopathological changes in the cerebrum and levels of p38, ERK, JNK, cytosolic Nrf2, Keap-1, LPO, RAGE, and AGE levels decreased; however, PI3K, AKT, IR, IRS, GLUT-1, nuclear Nrf2, Nqo-1, Ho-1, and anti-oxidative enzymes (SOD, CAT, and GPx) levels increased in diabetic rats receiving C. asiatica. Furthermore, C. asiatica treatment also caused cerebral inflammation and apoptosis to decrease as indicated by decreased inflammatory markers (cytosolic NF-κB p65, p-Ikkβ, Ikkβ, iNOS, COX-2, TNF-α, IL-6, and IL-1β), decreased pro-apoptosis markers (Casp-3, 9, and Bax), but increased anti-apoptosis marker, Bcl-2. Activity level of Na+/K+, Mg2+, and Ca2+-ATPases in the cerebrum also increased by C. asiatica treatment. Conclusions: C. asiatica treatment helps to prevent cerebral damage and maintain near normal cerebral function in diabetes.

Matched MeSH terms: Triterpenes/pharmacology*
Fulltext Capilliposide B blocks VEGF-induced angiogenesis in vitro in primary human retinal microvascular endothelial cells

Han H, Yang Y, Wu Z, Liu B, Dong L, Deng H, et al.

Biomed Pharmacother, 2021 Jan;133:110999.
PMID: 33227710 DOI: 10.1016/j.biopha.2020.110999

Abnormal angiogenesis is associated with intraocular diseases such as proliferative diabetic retinopathy and neovascular age-related macular degeneration, and current therapies for these eye diseases are not satisfactory. The purpose of this study was to determine whether capilliposide B (CPS-B), a novel oleanane triterpenoid saponin derived from Lysimachia capillipes Hemsl, can inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis signaling events and cellular responses in primary human retinal microvascular endothelial cells (HRECs). Our study revealed that the capilliposide B IC50 for HRECs was 8.5 μM at 72 h and that 1 μM capilliposide B specifically inhibited VEGF-induced activation of VEGFR2 and its downstream signaling enzymes Akt and Erk. In addition, we discovered that this chemical effectively blocked VEGF-stimulated proliferation, migration and tube formation of the HRECs, suggesting that capilliposide B is a promising prophylactic for angiogenesis-associated diseases such as proliferative diabetic retinopathy.

Matched MeSH terms: Triterpenes/pharmacology*
Fulltext Biophysical characterization of antibacterial compounds derived from pathogenic fungi Ganoderma boninense

Abdullah S, Oh YS, Kwak MK, Chong K

J Microbiol, 2021 Feb;59(2):164-174.
PMID: 33355891 DOI: 10.1007/s12275-021-0551-8

There have been relatively few studies which support a link between Ganoderma boninense, a phytopathogenic fungus that is particularly cytotoxic and pathogenic to plant tissues and roots, and antimicrobial compounds. We previously observed that liquid-liquid extraction (LLE) using chloroformmethanol-water at a ratio (1:1:1) was superior at detecting antibacterial activities and significant quantities of antibacterial compounds. Herein, we demonstrate that antibacterial secondary metabolites are produced from G. boninense mycelia. Antibacterial compounds were monitored in concurrent biochemical and biophysical experiments. The combined methods included high performance thin-layer chromatography (HPTLC), gas chromatography-mass spectrometry (GC-MS), high-performance liquid chromatography (HPLC), fourier transform infrared (FTIR), and nuclear magnetic resonance (NMR) spectroscopy. The antibacterial compounds derived from mycelia with chloroform-methanol extraction through LLE were isolated via a gradient solvent elution system using HPTLC. The antibacterial activity of the isolated compounds was observed to be the most potent against Staphylococcus aureus ATCC 25923 and multidrug-resistant S. aureus NCTC 11939. GC-MS, HPLC, and FTIR analysis confirmed two antibacterial compounds, which were identified as 4,4,14α-trimethylcholestane (m/z = 414.75; lanostane, C30H54) and ergosta-5,7,22-trien-3β-ol (m/z = 396.65; ergosterol, C28H44O). With the aid of spectroscopic evaluations, ganoboninketal (m/z = 498.66, C30H42O6), which belongs to the 3,4-seco-27-norlanostane triterpene family, was additionally characterized by 2D-NMR analysis. Despite the lack of antibacterial potential exhibited by lanostane; both ergosterol and ganoboninketal displayed significant antibacterial activities against bacterial pathogens. Results provide evidence for the existence of bioactive compounds in the mycelia of the relatively unexplored phytopathogenic G. boninense, together with a robust method for estimating the corresponding potent antibacterial secondary metabolites.

Matched MeSH terms: Triterpenes/pharmacology
Fulltext Natural Compound 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al from Momordica charantia Acts as PPARγ Ligand

Noruddin NAA, Hamzah MF, Rosman Z, Salin NH, Shu-Chien AC, Muhammad TST

Molecules, 2021 May 03;26(9).
PMID: 34063700 DOI: 10.3390/molecules26092682

Momordica charantia is a popular vegetable associated with effective complementary and alternative diabetes management in some parts of the world. However, the molecular mechanism is less commonly investigated. In this study, we investigated the association between a major cucurbitane triterpenoid isolated from M. charantia, 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (THCB) and peroxisome proliferator activated receptor gamma (PPARγ) activation and its related activities using cell culture and molecular biology techniques. In this study, we report on both M. charantia fruit crude extract and THCB in driving the luciferase activity of Peroxisome Proliferator Response Element, associated with PPARγ activation. Other than that, THCB also induced adipocyte differentiation at far less intensity as compared to the full agonist rosiglitazone. In conjunction, THCB treatment on adipocytes also resulted in upregulation of PPAR gamma target genes expression; AP2, adiponectin, LPL and CD34 at a lower magnitude compared to rosiglitazone's induction. THCB also induced glucose uptake into muscle cells and the mechanism is via Glut4 translocation to the cell membrane. In conclusion, THCB acts as one of the many components in M. charantia to induce hypoglycaemic effect by acting as PPARγ ligand and inducing glucose uptake activity in the muscles by means of Glut4 translocation.

Matched MeSH terms: Triterpenes/pharmacology
Cimigenoside functions as a novel γ-secretase inhibitor and inhibits the proliferation or metastasis of human breast cancer cells by γ-secretase/Notch axis

Jia H, Liu M, Wang X, Jiang Q, Wang S, Santhanam RK, et al.

Pharmacol Res, 2021 Jul;169:105686.
PMID: 34022397 DOI: 10.1016/j.phrs.2021.105686

Breast cancer (BC) occurrence and development tremendously affect female health. Currently breast cancer targeted drugs are still scarce. Natural products have become the main source of targeted drug for breast cancer due to low toxicity and high efficiency. Cimigenoside, natural compound isolated and purified from Cimicifuga dahurica (Turcz.) Maxim has been suggested to utilize for breast cancer treatment, however the mechanism of action has not been elucidated yet. In this article, the antitumor potential of Cimigenoside against breast cancer in vitro and in vivo study. Moreover, we further predicted the possible binding mode of Cimigenoside with γ-secretase through molecular docking studies. The results show that Cimigenoside has a significant inhibitory effect towards the proliferation or metastasis of breast cancer cells via suppressing the Notch signaling pathway-mediated mitochondrial apoptosis and EMT (epithelial mesenchymal transition). In terms of mechanism, Cimigenoside could inhibit the activation of PSEN-1, the catalytic subunit of γ-secretase, and also by cleaving the Notch protein mediated by PSEN-1. Overall, our findings provide scientific support to utilize Cimigenoside as an effective targeted drug for clinical treatment of BC.

Matched MeSH terms: Triterpenes/pharmacology*
In vitro evaluation of the involvement of Nrf2 in maslinic acid-mediated anti-inflammatory effects in atheroma pathogenesis

Ooi BK, Phang SW, Yong PVC, Chellappan DK, Dua K, Khaw KY, et al.

Life Sci, 2021 Aug 01;278:119658.
PMID: 34048809 DOI: 10.1016/j.lfs.2021.119658

AIMS: Maslinic acid (MA) is a naturally occurring pentacyclic triterpene known to exert cardioprotective effects. This study aims to investigate the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2) for MA-mediated anti-inflammatory effects in atheroma pathogenesis in vitro, including evaluation of tumor necrosis factor-alpha (TNF-α)-induced monocyte recruitment, oxidized low-density lipoprotein (oxLDL)-induced scavenger receptors expression, and nuclear factor-kappa B (NF-ĸB) activity in human umbilical vein endothelial cells (HUVECS) and human acute monocytic leukemia cell line (THP-1) macrophages.
MATERIALS AND METHODS: An in vitro monocyte recruitment model utilizing THP-1 and HUVECs was developed to evaluate TNF-α-induced monocyte adhesion and trans-endothelial migration. To study the role of Nrf2 for MA-mediated anti-inflammatory effects, Nrf2 inhibitor ML385 was used as the pharmacological inhibitor. The expression of Nrf2, monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), cluster of differentiation 36 (CD36), and scavenger receptor type A (SR-A) in HUVECs and THP-1 macrophages were investigated using RT-qPCR and Western blotting. The NF-κB activity was determined using NF-κB (p65) Transcription Factor Assay Kit.
KEY FINDINGS: The results showed opposing effects of MA on Nrf2 expression in HUVECs and THP-1 macrophages. MA suppressed TNF-α-induced Nrf2 expression in HUVECs, but enhanced its expression in THP-1 macrophages. Combined effects of MA and ML385 suppressed MCP-1, VCAM-1, and SR-A expressions. Intriguingly, at the protein level, ML385 selectively inhibited SR-A but enhanced CD36 expression. Meanwhile, ML385 further enhanced MA-mediated inhibition of NF-κB activity in HUVECs. This effect, however, was not observed in THP-1 macrophages.
SIGNIFICANCE: MA attenuated foam cell formation by suppressing VCAM-1, MCP-1, and SR-A expression, as well as NF-κB activity, possibly through Nrf2 inhibition. The involvement of Nrf2 for MA-mediated anti-inflammatory effects however differs between HUVECs and macrophages. Future investigations are warranted for a detailed evaluation of the contributing roles of Nrf2 in foam cells formation.

Matched MeSH terms: Triterpenes/pharmacology*
A new cycloartane triterpene bisdesmoside from the rhizomes of Actaea vaginata

Zhang M, Yang Q, Zhang X, Wu H

Nat Prod Res, 2021 Oct;35(20):3426-3431.
PMID: 31821060 DOI: 10.1080/14786419.2019.1700509

A new cycloartane triterpene bisdesmoside, soulieoside T (1), and one known compound, oleanolic acid (2), were isolated from the ethanolic extract of the rhizomes of Actaea vaginata. Their structures were elucidated by spectroscopic methods and by comparison with data reported in the literature. Compound 1 was evaluated for cytotoxic activities against three human cancer cell lines.

Matched MeSH terms: Triterpenes/pharmacology*
Fulltext Mechanistic role of boswellic acids in Alzheimer's disease: Emphasis on anti-inflammatory properties

Siddiqui A, Shah Z, Jahan RN, Othman I, Kumari Y

Biomed Pharmacother, 2021 Dec;144:112250.
PMID: 34607104 DOI: 10.1016/j.biopha.2021.112250

The resin/gum of Boswellia species belonging to the family of Burseraceae is a naturally occurring mixture of bioactive compounds, which was traditionally used as a folk medicine to treat conditions like chronic inflammation. Several research studies have also explored its' therapeutic potential against multiple neurodegenerative diseases such as Alzheimer's disease (AD). The main chemical constituents of this gum include boswellic acids (BAs) like 3-O-acetyl-11-keto-β boswellic acid (AKBA) that possess potent anti-inflammatory and neuroprotective properties in AD. It is also involved in inhibiting the acetylcholinesterase (AChE) activity in the cholinergic pathway and improve choline levels as well as its binding with nicotinic receptors to produce anti-inflammatory effects. Multiple shreds of evidence have demonstrated that BAs modulate key molecular targets and signalling pathways like 5-lipoxygenase/cyclooxygenase, Nrf2, NF-kB, cholinergic, amyloid-beta (Aβ), and neurofibrillary tangles formation (NFTs) that are involved in AD progression. The present review focuses on the possible mechanistic therapeutic role of BAs in modulating the 5-LOX/COX pathway in arachidonic acid metabolism, activating Nrf2 through binding of ARE, inhibiting NF-kB and AChE activity. In addition, an inhibition of amyloid plaques (Aβ) and neurofibrillary tangles (NFTs) induced neurotoxicity and neuroinflammation in AD by BAs is also discussed in this review. We have also highlighted that BAs possess beneficial effects in AD by targeting multiple molecular pathways and makes it an emerging drug candidate for treating neurodegenerative diseases.

Matched MeSH terms: Triterpenes/pharmacology*
Chemical Compounds and Computational Prediction of Their Inhibitory Effects on the HIV-1 gp120 Receptor by Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), with Antler-Like Morphology of Fruiting Bodies

Cheng PG, Teoh TC, Rizman-Idid M

Int J Med Mushrooms, 2021;23(7):63-77.
PMID: 34375519 DOI: 10.1615/IntJMedMushrooms.2021038682

In this study, crude extracts of Ganoderma lucidum (NGCs) were compared to the crude extracts of G. lucidum that has antler-like fruiting bodies (AGCs) for their cytotoxicity, inhibitory effects on the attachment of human immunodeficiency virus (HIV)-1 glycoprotein 120 (gp120) to cluster of differentiation 4 (CD4), identification and molecular docking simulations of chemical compounds to predict the best ligand inhibitor and the binding mechanism. Results showed that AGCs had a higher percentage of inhibition (54.3% ± 6.2%) at 150 ppm and higher cytotoxicity (half maximal cytotoxic concentration [CC50] < 300 ppm) than NGCs (CC50 < 400 ppm). Quadrupole time-of-flight (QTOF) liquid chromatography- mass spectrometry (LC-MS) results successfully identified 32 chemical compounds in AGCs and NGCs, comprising mostly ganoderic acids (62%) and their derivatives. Molecular docking simulations of ganolucidic acid A/D and ganoderic acid A/B predicted the strongest binding affinity via hydrogen bonding, suggesting the inhibition of HIV-1 gp120 attachment to CD4. The highest and lowest occupied molecular orbital (HOMO and LUMO, respectively) gap energies of ganoderic acids tended to have less negative HOMO energy and smaller HOMO-LUMO gap energy, implying increased interactions of ligands to the gp120 protein receptor. AGCs showed higher inhibition against HIV-1 gp120 than NGCs due to a higher abundance of ganoderic and ganolucidic acids, whereby both acids contributed the highest number of hydrogen bonds and polar interactions from the hydroxyl and carboxylic functional groups.

Matched MeSH terms: Triterpenes/pharmacology
Arjunolic acid downregulates elevated blood sugar and pro-inflammatory cytokines in streptozotocin (STZ)-nicotinamide induced type 2 diabetic rats

Aamir K, Khan HU, Hossain CF, Afrin MR, Jusuf PR, Waheed I, et al.

Life Sci, 2022 Jan 15;289:120232.
PMID: 34919901 DOI: 10.1016/j.lfs.2021.120232

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a worldwide health issue primarily due to failure of pancreatic β-cells to release sufficient insulin.
PURPOSE: The present work aimed to assess the antidiabetic potential of arjunolic acid (AA) isolated from Terminalia arjuna in type 2 diabetic rats.
STUDY DESIGN: After extraction, isolation and purification, AA was orally administered to type 2 diabetic Sprague Dawley rats to investigate antidiabetic effect of AA.
METHOD: T2DM was induced via single intraperitoneal injection of streptozotocin-nicotinamide (STZ-NIC) in adult male rats. After 10 days, fasting and random blood glucose (FBG and RBG), body weight (BW), food and water intake, serum C-peptide, insulin and glycated hemoglobin (HbA1c) was measured to confirm T2DM development. Dose dependent effects of orally administered AA (25 and 50 mg/kg/day) for 4 weeks was investigated by measuring BW variation, fasting and postprandial hyperglycemia, oral glucose tolerance test (OGTT), and levels of serum HbA1c, serum total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), serum and pancreatic C-peptide, insulin, growth differentiation factor 15 (GDF-15), serum and pancreatic inflammatory cytokines.
RESULTS: The oral administration of AA in preclinical model of T2DM significantly normalized FBG and RBG, restored BW, controlled polyphagia, polydipsia and glucose tolerance. In addition, AA notably reduced serum HbA1c, TC, TG, LDL with non-significant increase in HDL. On the other hand, significant increase in serum and pancreatic C-peptide and insulin was observed with AA treatment, while serum and pancreatic GDF-15 were non-significantly altered in AA treated diabetic rats. Moreover, AA showed dose dependent reduction in serum and pancreatic proinflammatory cytokines including TNF-α, IL-1β and IL-6.
CONCLUSION: For the first time our findings highlighted AA as a potential candidate in type 2 diabetic conditions.

Matched MeSH terms: Triterpenes/pharmacology*
Fulltext Celastrol: A Potential Natural Lead Molecule for New Drug Design, Development and Therapy for Memory Impairment

Amir Yusri MA, Sekar M, Wong LS, Gan SH, Ravi S, Subramaniyan V, et al.

Drug Des Devel Ther, 2023;17:1079-1096.
PMID: 37064431 DOI: 10.2147/DDDT.S389977

Celastrol is a naturally occurring chemical isolated from Tripterygium wilfordii Hook. f., root extracts widely known for their neuroprotective properties. In this review, we focus on the efficacy of celastrol in mitigating memory impairment (MI) in both in vivo and in vitro models. Scopus, PubMed and Web of Science databases were utilised to locate pertinent literatures that explore the effects of celastrol in the brain, including its pharmacokinetics, bioavailability, behavioral effects and some of the putative mechanisms of action on memory in many MI models. To date, preclinical studies strongly suggest that celastrol is highly effective in enhancing the cognitive performance of MI animal models, particularly in the memory domain, including spatial, recognition, retention and reference memories, via reduction in oxidative stress and attenuation of neuro-inflammation, among others. This review also emphasised the challenges and potential associated enhancement of medication delivery for MI treatment. Additionally, the potential structural alterations and derivatives of celastrol in enhancing its physicochemical and drug-likeness qualities are examined. The current review demonstrated that celastrol can improve cognitive performance and mitigate MI in several preclinical investigations, highlighting its potential as a natural lead molecule for the design and development of a novel neuroprotective medication.

Matched MeSH terms: Pentacyclic Triterpenes/pharmacology

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