Anti-inflammatory Diterpenoids Research Articles

Edaravone Dexborneol mitigates pathology in animal and cell culture models of Alzheimer’s disease by inhibiting neuroinflammation and neuronal necroptosis

BackgroundAlzheimer’s disease (AD) is the most prevalent neurodegenerative disease with limited disease-modifying treatments. Drug repositioning strategy has now emerged as a promising approach for anti-AD drug discovery. Using 5×FAD mice and Aβ-treated neurons in culture, we tested the efficacy of Y-2, a compounded drug containing the antioxidant Edaravone (Eda), a pyrazolone and (+)-Borneol, an anti-inflammatory diterpenoid from cinnamon, approved for use in amyotrophic lateral sclerosis patients.ResultsWe examined effects of Y-2 versus Eda alone by i.p. administered in 8-week-old 5×FAD mice (females) for 4 months by comparing cognitive function, Aβ pathologies, neuronal necroptosis and neuroinflammation. Using primary neurons and astrocytes, as well as neuronal and astrocytic cell lines, we elucidated the molecular mechanisms of Y-2 by examining neuronal injury, astrocyte-mediated inflammation and necroptosis. Here, we find that Y-2 improves cognitive function in AD mice. Histopathological data show that Y-2, better than Eda alone, markedly ameliorates Aβ pathologies including Aβ burden, astrogliosis/microgliosis, and Tau phosphorylation. In addition, Y-2 reduces Aβ-induced neuronal injury including neurite damage, mitochondrial impairment, reactive oxygen species production and NAD+ depletion. Notably, Y-2 inhibits astrocyte-mediated neuroinflammation and attenuates TNF-α-triggered neuronal necroptosis in cell cultures and AD mice. RNA-seq further demonstrates that Y-2, compared to Eda, indeed upregulates anti-inflammation pathways in astrocytes.ConclusionsOur findings infer that Y-2, better than Eda alone, mitigates AD pathology and may provide a potential drug candidate for AD treatment.

Diterpenoid Compounds Isolated from Chloranthus oldhamii Solms Exert Anti-Inflammatory Effects by Inhibiting the IKK/NF-κB Pathway.

Chloranthus oldhamii Solms (CO) is a folk medicine for treating infection and arthritis pain but its pharmacological activity and bioactive compounds remain mostly uncharacterized. In this study, the anti-inflammatory compounds of C. oldhamii were identified using an LPS-stimulated, NF-κB-responsive RAW 264.7 macrophage reporter line. Three diterpenoid compounds, 3α-hydroxy-ent-abieta-8,11,13-triene (CO-9), 3α, 7β-dihydroxy-ent-abieta-8,11,13-triene (CO-10), and decandrin B (CO-15) were found to inhibit NF-κB activity at nontoxic concentrations. Moreover, CO-9 and CO-10 suppressed the expression of IL-6 and TNF-α in LPS-stimulated RAW 264.7 cells. The inhibitory effect of CO-9 on TNF-α and IL-6 expression was further demonstrated using LPS-treated bone marrow-derived macrophages. Furthermore, CO-9, CO-10, and CO-15 suppressed LPS-triggered COX-2 expression and downstream PGE2 production in RAW 264.7 cells. CO-9 and CO-10 also reduced LPS-triggered iNOS expression and nitrogen oxide production in RAW 264.7 cells. The anti-inflammatory mechanism of the most effective compound, CO-9, was further investigated. CO-9 attenuated LPS-induced NF-κB activation by reducing the phosphorylation of IKKα/β (Ser176/180), IκBα (Ser32), and p65 (Ser534). Conversely, CO-9 did not affect the LPS-induced activation of MAPK signaling pathways. In summary, this study revealed new anti-inflammatory diterpenoid compounds from C. oldhamii and demonstrated that the IKK-mediated NK-κB pathway is the major target of these compounds.

Populusene A, an Anti-inflammatory Diterpenoid with a Bicyclo[8,4,1]pentadecane Scaffold from Populus euphratica Resins.

Populusene A (1), an unprecedented carbon skeleton featuring a bicyclo[8.4.1]pentadecane nucleus and a bridgehead double bond (anti-Bredt system), and populusin A (2), a cembrane-type diterpenoid possessing an uncommon dioxatricyclo[6.6.1.12,5]hexadecane scaffold, were isolated from the exudates of Populus euphratica. Their structures were elucidated by spectroscopic, computational, and crystallographic methods. A plausible biosynthetic route for 1 and 2 was proposed. Compounds 1 and 2 were found to significantly inhibit the production of TNF-α and IL-6 and the expression of iNOS, COX-2, and p-NF-κB at 125 nM in RAW264.7 cells.

The genome of the medicinal plant Andrographis paniculata provides insight into the biosynthesis of the bioactive diterpenoid neoandrographolide.

Andrographis paniculata is a herbaceous dicot plant widely used for its anti-inflammatory and anti-viral properties across its distribution in China, India and other Southeast Asian countries. A.paniculata was used as a crucial therapeutic treatment during the influenza epidemic of 1919 in India, and is still used for the treatment of infectious disease in China. A.paniculata produces large quantities of the anti-inflammatory diterpenoid lactones andrographolide and neoandrographolide, and their analogs, which are touted to be the next generation of natural anti-inflammatory medicines for lung diseases, hepatitis, neurodegenerative disorders, autoimmune disorders and inflammatory skin diseases. Here, we report a chromosome-scale A.paniculata genome sequence of 269Mb that was assembled by Illumina short reads, PacBio long reads and high-confidence (Hi-C) data. Gene annotation predicted 25428 protein-coding genes. In order to decipher the genetic underpinning of diterpenoid biosynthesis, transcriptome data from seedlings elicited with methyl jasmonate were also obtained, which enabled the identification of genes encoding diterpenoid synthases, cytochrome P450 monooxygenases, 2-oxoglutarate-dependent dioxygenases and UDP-dependent glycosyltransferases potentially involved in diterpenoid lactone biosynthesis. We further carried out functional characterization of pairs of class-I and -II diterpene synthases, revealing the ability to produce diversified labdane-related diterpene scaffolds. In addition, a glycosyltransferase able to catalyze O-linked glucosylation of andrograpanin, yielding the major active product neoandrographolide, was also identified. Thus, our results demonstrate the utility of the combined genomic and transcriptomic data set generated here for the investigation of the production of the bioactive diterpenoid lactone constituents of the important medicinal herb A.paniculata.

Anti-inflammatory abietanes diterpenoids isolated from Tripterygium hypoglaucum

Tripterygium hypoglaucum (H. Lév.) Hutch. has been used to remedy rheumatoid arthritis, however, it shows frequent toxicity to the body. In this study, liquid chromatograph-mass spectrometer (LC-MS) was guided to characterize abietanes diterpenoids with anti-inflammatory activity from the stem of T. hypoglaucum. Thirteen undescribed abietanes diterpenoids were isolated and purified, and their chemical structure was identified using various spectroscopic methods. These compounds belonged to abietanes with splitting C ring, abietanes with benzenoid rings, diterpene quinoids, diterpene quinoids with lactone rings, and abietanes with benzenoid and lactone rings, respectively. Lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages was used to evaluate anti-inflammatory activity of the compounds. The results indicated that hypoglicin B-G and hypoglicin J-M exhibited inhibitory activity of NO production with the IC50 values of 6.01, 25.21, 8.29, 3.63, 0.72, 0.89, 36.91, 0.82, 2.85, 11.92 μM, respectively. Among these compounds, compound hypoglicin L showed high anti-inflammatory activity and low toxicity (SI = 5.02 × 104). Further QPCR analysis revealed that hypoglicin D and hypoglicin L can inhibit the mRNA expression of iNOS in LPS-stimulated RAW264.7 cells at doses of 12.5 and 3.13 μM, respectively. Taken together, ten anti-inflammatory diterpenoids were found from T. hypoglaucum in this study.

In vitro metabolism of the anti-inflammatory clerodane diterpenoid polyandric acid A and its hydrolysis product by human liver microsomes and recombinant cytochrome P450 and UDP-glucuronosyltransferase enzymes

1. The metabolism of the anti-inflammatory diterpenoid polyandric acid A (PAA), a constituent of the Australian Aboriginal medicinal plant Dodonaea polyandra, and its de-esterified alcohol metabolite, hydrolysed polyandric acid A (PAAH) was studied in vitro using human liver microsomes (HLM) and recombinant UDP-glucuronosyltransferase (UGT) and cytochrome P450 (CYP) enzymes.2. Hydrolysis of PAA to yield PAAH occurred upon incubation with HLM. Further incubations of PAAH with HLM in the presence of UGT and CYP cofactors resulted in significant depletion, with UGT-mediated depletion as the major pathway.3. Reaction phenotyping utilising selective enzyme inhibitors and recombinant human UGT and CYP enzymes revealed UGT2B7 and UGT1A1, and CYP2C9 and CYP3A4 as the major enzymes involved in the metabolism of PAAH.4. Analysis of incubations of PAAH with UDP-glucuronic acid-supplemented HLM and recombinant enzymes by UPLC/MS/MS identified three glucuronide metabolites. The metabolites were further characterised by β-glucuronidase and mild alkaline hydrolysis. The acyl glucuronide of PAAH was shown to be the major metabolite.5. This study demonstrates the in vitro metabolism of PAA and PAAH and represents the first systematic study of the metabolism of an active constituent of an Australian Aboriginal medicinal plant.

Marine Diterpenoids as Potential Anti-Inflammatory Agents.

The inflammatory response is a highly regulated process, and its dysregulation can lead to the establishment of chronic inflammation and, in some cases, to death. Inflammation is the cause of several diseases, including rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, and asthma. The search for agents inhibiting inflammation is a great challenge as the inflammatory response plays an important role in the defense of the host to infections. Marine invertebrates are exceptional sources of new natural products, and among those diterpenoids secondary metabolites exhibit notable anti-inflammatory properties. Novel anti-inflammatory diterpenoids, exclusively produced by marine organisms, have been identified and synthetic molecules based on those structures have been obtained. The anti-inflammatory activity of marine diterpenoids has been attributed to the inhibition of Nuclear Factor-κB activation and to the modulation of arachidonic acid metabolism. However, more research is necessary to describe the mechanisms of action of these secondary metabolites. This review is a compilation of marine diterpenoids, mainly isolated from corals, which have been described as potential anti-inflammatory molecules.

Anti-inflammatory diterpenoids and other secondary metabolites from Dodonaea polyandra; a traditional medicine used by Kaanju people in North Eastern Australia

Collaborative research guided by the traditional Indigenous knowledge of Northern Kaanju people, Cape York Peninsula, Australia has recently led to the isolation of four new clerodane diterpenoids from the leaves of Dodonaea polyandra (Sapindaceae). These compounds have shown high levels of anti-inflammatory activity in a TPA mouse ear oedema model of inflammation. Dose-response studies revealed compound CS004 (below) was the most potent of these displaying a linear dose-response relationship.

Andrographolide Inhibits Human Hepatoma-Derived Hep3B Cell Growth through the Activation of c-Jun N-Terminal Kinase

Andrographolide (Andro) is a potentially anti-inflammatory diterpenoid lactone isolated from the traditional herbal medicine ANDROGRAPHIS PANICULATA, which has been effectively used for the treatment of infection, inflammation, cold, fever and diarrhea in China for centuries. In the current study, we found that Andro significantly decreased the number of surviving hepatoma-derived Hep3B cells in the MTT assay and induced cell apoptosis. Further study showed that Andro induced activation of mitogen-activated protein kinases (MAPKs) including p38 kinase, c-Jun N-terminal kinase (JNK) and extracellular signal-related kinases (ERK1/2), but had no significant effect on caspase-3, Bcl-xL and Bcl-2, which are apoptosis-related proteins. Moreover, inhibition of JNK activation partially rescued the toxic effect of Andro on Hep3B cells. Therefore, our results indicate that the JNK signaling pathway plays an important role in the toxic effect of Andro on Hep3B cells.

Synthetic studies towards the novel diterpenoid rameswaralide: RCM mediated acquisition of the tricyclic core

A synthetic approach towards the novel anti-inflammatory diterpenoid rameswaralide from the cis-Corey lactone involving a tandem RCM and Diels–Alder reaction has been conceived and endeavors so far have led to the acquisition of the BCD ring fragment of the natural product.

A novel diterpenoid labdane from Sideritis javalambrensis inhibits eicosanoid generation from stimulated macrophages but enhances arachidonate release

The diterpenoid ent-8α-hydroxy-labda-13(16),14-dien (“labdane F2”) was obtained from an anti-inflammatory extract of Sideritis javalambrensis. Labdane F2 inhibited prostaglandin E 2 generation in cultured ] mouse peritoneal macrophages, treated with zymosan, ionophore A23187, or arachidonic acid itself, and in J774 macrophage-like cells activated by bacterial lipopolysaccharide (LPS). The mechanism was investigated by prelabelling the macrophages with radiolabelled arachidonic acid or oleic acid, followed by cell activation in the presence or absence of nontoxic concentrations of labdane F2. Surprisingly, under those conditions in which reduced PGE 2 generation was observed, labdane F2 consistently enhanced the release of labelled fatty acid, in a manner similar to that displayed by thimerosal, a known acyl-CoA:lysolecithin transferase inhibitor. Labdane F2, therefore, appears to possess 2 mutually opposing actions on the eicosanoid system in macrophages: potentiation of delivery of substrate following cell activation, followed by inhibition of conversion of substrate to product. It was also found that nontoxic concentrations of labdane F2 reduced the expression of the inducible isoforms of cyclooxygenase and nitric oxide synthase in LPS-treated J774 cells. Thus, this anti-inflammatory diterpenoid labdane possesses a diverse array of effects impinging on enzyme pathways involved in eicosanoid generation and other inflammatory pathways in macrophages. BIOCHEM PHARMACOL 51;6:863–868, 1996.

Structure and stereochemistry of brianolide, a new antiinflammatory diterpenoid from the Okinawan gorgonianBriareum sp.

Brianolide (1), a new antiinflammatory diterpenoid of the briarein class, possessing a beta substituent at C-12 (R), has been isolated from the Okinawan gorgonian Briareum sp. Its structure has been established from spectral data in conjunction with a single crystal X-ray analysis.

Marine soft corals of the genus Pseudopterogorgia: a resource for novel anti-inflammatory diterpenoids.

This paper is a brief review of the diterpenoid chemistry of gorgonian corals of the genus Pseudopterogorgia. Previously described compounds and several new diterpenoids are presented in the context of their potential utilization in the development of anti-inflammatory and analgesic drugs.

Kallolide A, a new antiinflammatory diterpenoid, and related lactones from the Caribbean octocoral Pseudopterogorgia kallos (Bielschowsky)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTKallolide A, a new antiinflammatory diterpenoid, and related lactones from the Caribbean octocoral Pseudopterogorgia kallos (Bielschowsky)Sally A. Look, Mark T. Burch, William Fenical, Qitai Zheng, and Jon ClardyCite this: J. Org. Chem. 1985, 50, 26, 5741–5746Publication Date (Print):December 1, 1985Publication History Published online1 May 2002Published inissue 1 December 1985https://doi.org/10.1021/jo00350a061RIGHTS & PERMISSIONSArticle Views458Altmetric-Citations97LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (800 KB) Get e-AlertsSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts