Cycloartenol

1 Euphorbia sp. 2 Garcinia sp. 3 Glycine sp. 4 Larix sp. 5 Ononis sp. 6 Oryza sp. 7 Persea sp. 8 Phytolacca sp. 9 Pistacia sp. 10 Sambucus sp. 11 Smilax sp. 12 Taraxacum sp.

Antibacterial Activity of Boswellia sacra Flueck. Oleoresin Extract against Porphyromonas gingivalis Periodontal Pathogen.[Pubmed:34356781]

Antibiotics (Basel). 2021 Jul 15;10(7). pii: antibiotics10070859.

Boswellia sacra Flueck. oleoresin extract (frankincense) has traditionally been used in the treatment of different diseases, but there are no sufficient studies on its potential activity against periodontal pathogens. Therefore, antibacterial and antibiofilm activity of frankincense extract against Porphyromonas gingivalis clinical isolates were studied. The phytochemical composition of the volatile components of the extract was identified by GC-MS analysis revealing 49 compounds as trans-nerolidyl formate, Cycloartenol acetate, ursenoic acid 3-oxomethyl ester, bisabolene epoxide, and kaur-16-ene. It decreased the growth and increased the leakage of nucleotides in 58.3% and 33.3% of isolates, respectively. Additionally, it reduced the extracellular polysaccharide production and the cell surface hydrophobicity in 41.67% and 50% of the isolates, respectively. Crystal violet assay revealed inhibition of biofilm formation by the tested isolates. Light microscope and scanning electron microscope were used to examine the biofilms and they confirmed the reduction of biofilm formation by frankincense extract. Downregulation of the genes linked to biofilm formation (fimA, hagA, and hagB) was observed using qRT-PCR after treatment with the frankincense extract. This study suggested that the frankincense extract could exhibit antibacterial and antibiofilm activity against P. gingivalis isolates. Thus, the frankincense extract could be used as a treatment approach for periodontitis.

SARS-CoV-2 host cell entry: an in silico investigation of potential inhibitory roles of terpenoids.[Pubmed:34351542]

J Genet Eng Biotechnol. 2021 Aug 5;19(1):113.

BACKGROUND: Targeting viral cell entry proteins is an emerging therapeutic strategy for inhibiting the first stage of SARS-CoV-2 infection. In this study, 106 bioactive terpenoids from African medicinal plants were screened through molecular docking analysis against human angiotensin-converting enzyme 2 (hACE2), human transmembrane protease serine 2 (TMPRSS2), and the spike (S) proteins of SARS-CoV-2, SARS-CoV, and MERS-CoV. In silico absorption-distribution-metabolism-excretion-toxicity (ADMET) and drug-likeness prediction, molecular dynamics (MD) simulation, binding free energy calculations, and clustering analysis of MD simulation trajectories were performed on the top docked terpenoids to respective protein targets. RESULTS: The results revealed eight terpenoids with high binding tendencies to the catalytic residues of different targets. Two pentacyclic terpenoids (24-methylene Cycloartenol and isoiguesteri) interacted with the hACE2 binding hotspots for the SARS-CoV-2 spike protein, while the abietane diterpenes were found accommodated within the S1-specificity pocket, interacting strongly with the active site residues TMPRSS2. 3-benzoylhosloppone and cucurbitacin interacted with the RBD and S2 subunit of SARS-CoV-2 spike protein respectively. These interactions were preserved in a simulated dynamic environment, thereby, demonstrating high structural stability. The MM-GBSA binding free energy calculations corroborated the docking interactions. The top docked terpenoids showed favorable drug-likeness and ADMET properties over a wide range of molecular descriptors. CONCLUSION: The identified terpenoids from this study provides core structure that can be exploited for further lead optimization to design drugs against SARS-CoV-2 cell-mediated entry proteins. They are therefore recommended for further in vitro and in vivo studies towards developing entry inhibitors against the ongoing COVID-19 pandemic.

Transcriptome and proteome of the corm, leaf and flower of Hypoxis hemerocallidea (African potato).[Pubmed:34283859]

PLoS One. 2021 Jul 20;16(7):e0253741.

The corm of Hypoxis hemerocallidea, commonly known as the African potato, is used in traditional medicine to treat several medical conditions such as urinary infections, benign prostate hyperplasia, inflammatory conditions and testicular tumours. The metabolites contributing to the medicinal properties of H. hemerocallidea have been identified in several studies and, more recently, the active terpenoids of the plant were profiled. However, the biosynthetic pathways and the enzymes involved in the production of the terpene metabolites in H. hemerocallidea have not been characterised at a transcriptomic or proteomic level. In this study, total RNA extracted from the corm, leaf and flower tissues of H. hemerocallidea was sequenced on the Illumina HiSeq 2500 platform. A total of 143,549 transcripts were assembled de novo using Trinity and 107,131 transcripts were functionally annotated using the nr, GO, COG, KEGG and SWISS-PROT databases. Additionally, the proteome of the three tissues were sequenced using LC-MS/MS, revealing aspects of secondary metabolism and serving as data validation for the transcriptome. Functional annotation led to the identification of numerous terpene synthases such as nerolidol synthase, germacrene D synthase, and Cycloartenol synthase amongst others. Annotations also revealed a transcript encoding the terpene synthase phytoalexin momilactone A synthase. Differential expression analysis using edgeR identified 946 transcripts differentially expressed between the three tissues and revealed that the leaf upregulates linalool synthase compared to the corm and the flower tissues. The transcriptome as well as the proteome of Hypoxis hemerocallidea presented here provide a foundation for future research.

Bm-miR172c-5p regulates lignin biosynthesis and secondary xylem thickness by altering Ferulate 5 hydroxylase gene in Bacopa monnieri.[Pubmed:34009389]

Plant Cell Physiol. 2021 May 1. pii: 6261939.

MicroRNAs (miRNAs) are small non-coding, endogenous RNAs containing 20-24 nucleotides that regulate the expression of target genes involved in various plant processes. A total 1429 conserved miRNA belonging to 95 conserved miRNA families and 12 novel miRNAs were identified from B. monnieri using small RNA sequencing. The Bm-miRNA target transcripts related to the secondary metabolism were further selected for validation. The Bm-miRNA expression in shoot and root tissues were negatively correlated with their target transcripts. The Bm-miRNA cleavage sites were mapped within the coding or untranslated (UTR) region as depicted by the modified RLM-RACE. In the present study, we validate three miRNA targets, including Asparagine synthetase, Cycloartenol synthase, and Ferulate 5 hydroxylase and elucidate the regulatory role of Bm-miR172c-5p, which cleaves the F5H gene involved in the lignin biosynthesis. Overexpression of Bm-miR172c-5p precursor in B. monnieri suppress F5H gene, leading to reduced lignification and secondary xylem thickness under control and drought stress. In contrast, overexpression of target mimics (eTMs) showed enhanced lignification and secondary xylem thickness leading to better physiological response under drought stress. Taken together, we suggest that Bm-miRNA172c-5p might be a key player in maintaining the native phenotype of B. monnieri under control and different environmental condition.

Semi-Quantitative Targeted Gas Chromatography-Mass Spectrometry Profiling Supports a Late Side-Chain Reductase Cycloartenol-to-Cholesterol Biosynthesis Pathway in Brown Algae.[Pubmed:33986764]

Front Plant Sci. 2021 Apr 27;12:648426.

Sterols are biologically important molecules that serve as membrane fluidity regulators and precursors of signaling molecules, either endogenous or involved in biotic interactions. There is currently no model of their biosynthesis pathways in brown algae. Here, we benefit from the availability of genome data and gas chromatography-mass spectrometry (GC-MS) sterol profiling using a database of internal standards to build such a model. We expand the set of identified sterols in 11 species of red, brown, and green macroalgae and integrate these new data with genomic data. Our analyses suggest that some metabolic reactions may be conserved despite the loss of canonical eukaryotic enzymes, like the sterol side-chain reductase (SSR). Our findings are consistent with the principle of metabolic pathway drift through enzymatic replacement and show that cholesterol synthesis from Cycloartenol may be a widespread but variable pathway among chlorophyllian eukaryotes. Among the factors contributing to this variability, one could be the recruitment of cholesterol biosynthetic intermediates to make signaling molecules, such as the mozukulins. These compounds were found in some brown algae belonging to Ectocarpales, and we here provide a first mozukulin biosynthetic model. Our results demonstrate that integrative approaches can already be used to infer experimentally testable models, which will be useful to further investigate the biological roles of those newly identified algal pathways.

Efficacy of extract from Ononis spinosa L. on ethanol-induced gastric ulcer in rats.[Pubmed:33825407]

J Tradit Chin Med. 2021 Apr;41(2):270-275.

OBJECTIVE: To investigate the efficacy of the extract from Ononis spinosa L. (O. spinosa) on ethanol-induced gastric ulcer in rats. METHODS: Phytochemical constituents of the extract from O. spinosa were analyzed using liquid chromatography-mass spectrometry. Rats were classified into 4 equal groups; ulcer control received oral vehicle; positive control was administered with 40 mg/kg esomeprazole (standard drug) and 2 groups received 0.5 and 1 g/kg of O. spinosa extract, respectively. Gastric ulcer was induced by absolute ethanol (5 mL/kg) orally to all groups. Measurement of ulcer index, cyclooxygenase-2 (COX-2) expression and determination of total glutathione level in gastric mucosa were performed. RESULTS: Oral administration of the extract from O. spinosa at doses 0.5 and 1 g/kg lowered the ulcer indices by 80.39% and 98.71% , respectively, compared to 67.89% by esomeprazole (40 mg/kg). Histologically, treatment with the extract decreased necrosis and hemorrhage in mucosa and edema and infiltration by inflammatory cells in submucosa. Using immunohistochemical technique, it was demonstrated that COX-2 expression increased in mucosa of animals treated with the extract as well as by esomeprazole. O. spinosa and esomeprazole increased total glutathione level in the stomach compared to control. Ononin was the major compound of the extract followed by trifolirhizin, myricitrin, gentisic acid, Cycloartenol and quercetin. CONCLUSION: The present study demonstrated that the extract from O. spinosa was able to protect gastric mucosa from ethanol injury by at least 2 mechanisms, namely the induction of COX-2 and decreasing oxidative stress in the stomach.

Exploring the Oxidative Stress Mechanism of Buyang Huanwu Decoction in Intervention of Vascular Dementia Based on Systems Biology Strategy.[Pubmed:33747352]

Oxid Med Cell Longev. 2021 Mar 3;2021:8879060.

Objective: To explore the oxidative stress mechanism of modified Buyang Huanwu decoction (MBHD) in intervention of vascular dementia (VD) based on systems biology strategy. Methods: In this study, through the reverse virtual target prediction technology and transcriptomics integration strategy, the active ingredients and potential targets of MBHD treatment of VD were analyzed, and the drug-disease protein-protein interaction (PPI) network was constructed. Then, bioinformatics analysis methods are used for Gene Ontology (GO) enrichment analysis and pathway enrichment analysis, and finally find the core biological process. After that, in animal models, low-throughput technology is used to detect gene expression and protein expression of key molecular targets in oxidative stress-mediated inflammation and apoptosis signaling pathways to verify the mechanism of MBHD treatment of VD rats. Finally, the potential interaction relationship between MBHD and VD-related molecules is further explored through molecular docking technology. Results: There are a total of 54 MBHD components, 252 potential targets, and 360 VD genes. The results of GO enrichment analysis and pathway enrichment analysis showed that MBHD may regulate neuronal apoptosis, nitric oxide synthesis and metabolism, platelet activation, NF-kappaB signaling pathway-mediated inflammation, oxidative stress, angiogenesis, etc. Among them, SIRT1, NF-kappaB, BAX, BCL-2, CASP3, and APP may be important targets for MBHD to treat VD. Low-throughput technology (qRT-PCR/WB/immunohistochemical technology) detects oxidative stress-mediated inflammation and apoptosis-related signaling pathway molecules. The molecular docking results showed that 64474-51-7, Cycloartenol, ferulic acid, formononetin, kaempferol, liquiritigenin, senkyunone, wallichilide, xanthinin, and other molecules can directly interact with NF-kappaB p65, BAX, BCL-2, and CASP3. Conclusion: The active compounds of MBHD interact with multiple targets and multiple pathways in a synergistic manner, and have important therapeutic effects on VD mainly by balancing oxidative stress/anti-inflammatory and antiapoptotic, enhancing metabolism, and enhancing the immune system.

Sterol Biosynthesis in Four Green Algae: A Bioinformatic Analysis of the Ergosterol Versus Phytosterol Decision Point.[Pubmed:33713347]

J Phycol. 2021 Aug;57(4):1199-1211.

Animals and fungi produce cholesterol and ergosterol, respectively, while plants produce the phytosterols stigmasterol, campesterol, and beta-sitosterol in various combinations. The recent sequencing of many algal genomes allows the detailed reconstruction of the sterol metabolic pathways. Here, we characterized sterol synthesis in two sequenced Chlorella spp., the free-living C. sorokiniana, and symbiotic C. variabilis NC64A. Chlamydomonas reinhardtii was included as an internal control and Coccomyxa subellipsoidea as a plant-like outlier. We found that ergosterol was the major sterol produced by Chlorella spp. and C. reinhardtii, while C. subellipsoidea produced the three phytosterols found in plants. In silico analysis of the C. variabilis NC64A, C. sorokiniana, and C. subellipsoidea genomes identified 22 homologs of sterol biosynthetic genes from Arabidopsis thaliana, Saccharomyces cerevisiae, and C. reinhardtii. The presence of CAS1, CPI1, and HYD1 in the four algal genomes suggests the higher plant Cycloartenol branch for sterol biosynthesis, confirming that algae and fungi use different pathways for ergosterol synthesis. Phylogenetic analysis for 40 oxidosqualene cyclases (OSCs) showed that the nine algal OSCs clustered with the Cycloartenol cyclases, rather than the lanosterol cyclases, with the OSC for C. subellipsoidea positioned in between the higher plants and the eight other algae. With regard to why C. subellipsoidea produced phytosterols instead of ergosterol, we identified 22 differentially conserved positions where C. subellipsoidea CAS and A. thaliana CAS1 have one amino acid while the three ergosterol producing algae have another. Together, these results emphasize the position of the unicellular algae as an evolutionary transition point for sterols.

[Synergistic effect on biosynthesis of Panax notoginseng saponins by overexpressing a transcription factor PnbHLH and RNA interference of cycloartenol synthase gene].[Pubmed:33645057]

Zhongguo Zhong Yao Za Zhi. 2021 Jan;46(1):94-102.

This study cloned the transcription factor gene PnbHLH which held an open reading frame of 966 bp encoding 321 amino acids. This study constructed the overexpression vector of transcription factor PnbHLH of Panax notoginseng. The combination of PnbHLH overexpression and RNAi of the key enzyme gene PnCAS involved in the phytosterol biosynthesis was achieved in P. notoginseng cells, thus exploring the biosynthetic regulation of P. notoginseng saponins(PNS) by the synergistic effect of PnbHLH overexpression and PnCAS RNAi. The results showed that the PnbHLH transcription factor interacted with the promoters of key enzyme genes PnDS, PnSS and PnSE in the biosynthetic pathway of PNS, and then regulated the expression levels of key enzyme genes and affected the biosynthesis of saponins indirectly. Further study indicated that the synergistic effect of PnbHLH overexpression and PnCAS RNAi was a more effective approach to regulate the biosynthesis of saponins. Compared with the wild type and PnCAS RNAi cells of P. notoginseng, the contents of total saponins and monomeric saponins(Rd, Rb_1, Re, Rg_1 and R_1) were increased to some extent in the cell lines of PnbHLH overexpression and PnCAS RNAi. This indicated that the two ways of forward regulation and reverse regulation of saponin biosynthesis showed superposition effect. This study explored a more rational and efficient regulation strategy of PNS biosynthesis based on the advantages of multi-point regulation of transcription factors as well as the down-regulation of by-product synthesis of saponins.

Methyl Jasmonate and Methyl-beta-Cyclodextrin Individually Boost Triterpenoid Biosynthesis in Chlamydomonas Reinhardtii UVM4.[Pubmed:33562714]

Pharmaceuticals (Basel). 2021 Feb 5;14(2). pii: ph14020125.

The commercialisation of valuable plant triterpenoids faces major challenges, including low abundance in natural hosts and costly downstream purification procedures. Endeavours to produce these compounds at industrial scale using microbial systems are gaining attention. Here, we report on a strategy to enrich the biomass of the biotechnologically-relevant Chlamydomonas reinhardtii strain UVM4 with valuable triterpenes, such as squalene and (S)-2,3-epoxysqualene. C. reinhardtii UVM4 was subjected to the elicitor compounds methyl jasmonate (MeJA) and methyl-beta-cyclodextrine (MbetaCD) to increase triterpene yields. MeJA treatment triggered oxidative stress, arrested growth, and altered the photosynthetic activity of the cells, while increasing squalene, (S)-2,3-epoxysqualene, and Cycloartenol contents. Applying MbetaCD to cultures of C. reinhardtii lead to the sequestration of the two main sterols (ergosterol and 7-dehydroporiferasterol) into the growth medium and the intracellular accumulation of the intermediate Cycloartenol, without compromising cell growth. When MbetaCD was applied in combination with MeJA, it counteracted the negative effects of MeJA on cell growth and physiology, but no synergistic effect on triterpene yield was observed. Together, our findings provide strategies for the triterpene enrichment of microalgal biomass and medium.

Limonoid biosynthesis 3: Functional characterization of crucial genes involved in neem limonoid biosynthesis.[Pubmed:33524856]

Phytochemistry. 2021 Apr;184:112669.

Neem (Azadirachta indica L.) is well known for its medicinal, agricultural, and pesticidal applications since ages. The secondary metabolites, limonoids, confer these biological properties, wherein over 150 different limonoids have been reported from neem. To understand limonoid biosynthesis, we analyzed tissue-specific (kernel, pericarp, leaves, and flower) transcriptome that resulted in the identification of one farnesyl diphosphate synthase (AiFDS), one squalene synthase (AiSQS), three squalene epoxidases (AiSQE1, AiSQE2, and AiSQE3), two triterpene synthases (AiTTS1 and AiTTS2), Cycloartenol synthase (AiCAS), two cytochrome P450 reductases, and ten cytochrome P450 systems. Comparative tissue-expression analysis indicated that AiFDS, AiSQS, AiSQE3, and AiTTS1 are expressed higher in the kernel than in the other tissues. Heterologously expressed recombinant AiTTS1 produced tirucalla-7,24-dien-3beta-ol as the sole product. Expression profile data, phylogeny with triterpene synthases from Meliaceae and Rutaceae families, real-time PCR of different tissues, and transient transformation revealed the involvement of tirucalla-7,24-dien-3beta-ol synthase (AiTTS1) in limonoid biosynthesis. Further, mutagenesis studies of AiTTS1 indicated that Y125 and F260 are probably involved in stabilization of dammarenyl cation. A 2.6-fold increase in production of tirucalla-7,24-dien-3beta-ol was observed when AiSQE1 was co-expressed with mutant AiTTS1 in a yeast system. Furthermore, we functionally characterized the highly expressed cytochrome P450 reductases and Cycloartenol synthase. This study helps in further analysis and identification of genes involved in limonoid biosynthesis in Meliaceae/Rutaceae and their production in a metabolically tractable heterologous system.

Overexpression of Key Sterol Pathway Enzymes in Two Model Marine Diatoms Alters Sterol Profiles in Phaeodactylum tricornutum.[Pubmed:33371196]

Pharmaceuticals (Basel). 2020 Dec 21;13(12). pii: ph13120481.

Sterols are a class of triterpenoid molecules with diverse functional roles in eukaryotic cells, including intracellular signaling and regulation of cell membrane fluidity. Diatoms are a dominant eukaryotic phytoplankton group that produce a wide diversity of sterol compounds. The enzymes 3-hydroxy-3-methyl glutaryl CoA reductase (HMGR) and squalene epoxidase (SQE) have been reported to be rate-limiting steps in sterol biosynthesis in other model eukaryotes; however, the extent to which these enzymes regulate triterpenoid production in diatoms is not known. To probe the role of these two metabolic nodes in the regulation of sterol metabolic flux in diatoms, we independently over-expressed two versions of the native HMGR and a conventional, heterologous SQE gene in the diatoms Thalassiosira pseudonana and Phaeodactylum tricornutum. Overexpression of these key enzymes resulted in significant differential accumulation of downstream sterol pathway intermediates in P. tricornutum. HMGR-mVenus overexpression resulted in the accumulation of squalene, Cycloartenol, and obtusifoliol, while Cycloartenol and obtusifoliol accumulated in response to heterologous NoSQE-mVenus overexpression. In addition, accumulation of the end-point sterol 24-methylenecholesta-5,24(24')-dien-3beta-ol was observed in all P. tricornutum overexpression lines, and campesterol increased three-fold in P. tricornutum lines expressing NoSQE-mVenus. Minor differences in end-point sterol composition were also found in T. pseudonana, but no accumulation of sterol pathway intermediates was observed. Despite the successful manipulation of pathway intermediates and individual sterols in P. tricornutum, total sterol levels did not change significantly in transformed lines, suggesting the existence of tight pathway regulation to maintain total sterol content.

Phytochemical constituents of sterol-rich fraction from Allium cepa L. and its cytotoxic effect on human embryonic kidney (HEK293) cells.[Pubmed:33326625]

J Food Biochem. 2021 Mar;45(3):e13586.

The present study investigates the cytotoxic effect of the chemical fractions of Allium cepa (yellow variety) on Human Embryonic Kidney (HEK293) cells. Allium cepa was blended into paste and macerated in distilled water before subjecting to liquid-liquid fractionation, yielding the dichloromethane, ethyl acetate (EtOAc), butanol, and aqueous fractions. Their cytotoxicity on HEK293 cells were evaluated via MTT assay. The cytotoxic fraction (EtOAc) was further evaluated for its oxidative, pro-inflammatory, and apoptotic effects on the cells. The incubation of cells with EtOAc led to depleted level of GSH, SOD, and catalase activities, and elevated levels of malondialdehyde, nitric oxide, and myeloperoxidase as well as apoptotic activities. GC-MS analysis of EtOAc revealed allyl ionone, pentadecanoic acid, and phytol acetate as the predominant fatty acids, while ergost-7-en-3beta-ol, campesterol, Cycloartenol-3beta acetate, sitosterol, and fucosterol as the predominant sterols. These results portray the cytotoxic effect of the EtOAc fraction of A. cepa on HEK293 cells. PRACTICAL APPLICATIONS: There have been increasing concerns in the toxicity and safety of foods. Allium cepa (onions) is among the common globally grown and consumed plant food. This study investigated its cytotoxic effect on normal Human Embryonic Kidney (HEK293) Cells. Although only the ethyl acetate fraction was cytotoxic against the cell line, it, however, portrays a need for caution in its usage.

Chemical characterization, antioxidant, antibacterial and enzyme inhibitory properties of Canthium coromandelicum, a valuable source for bioactive compounds.[Pubmed:33011582]

J Pharm Biomed Anal. 2021 Jan 5;192:113620.

The present study aimed at chemical characterization of Canthium coromandelicum leaf extracts (CCLE) and their in vitro pharmacological (antioxidant, enzyme inhibitory, and antibacterial) activities. Chemical characterization includes chemical profile of six extracts of CC by Gas chromatography - Mass spectrometry (GC-MS) analysis and total phenolics and flavonoids by spectrophotometric methods. Antioxidant activity was determined using eight assays. Enzymatic inhibitory property was evaluated by alpha-amylase and alpha-glucosidase inhibitory assays and antibacterial activity was studied against 10 pathogenic bacteria by agar disc diffusion method. GC-MS analysis enabled the identification of 65 compounds with palmitic acid, n-pentacosane, Cycloartenol, linoleic acid, squalene, gamma-sitosterol, nonacosane and alpha-tocopherol as major constituents of CCLE. Highest amount of total phenolics (58.03mg GAE/g extract) and flavonoids (44.40 QE/g) was present in hydroalcoholic extract. Hydroalcoholic, methanolic and aqueous extracts showed significant free radical scavenging abilities and positive correlation was detected between antioxidant assays with recorded phenolics and flavonoids. Hydroalcoholic and methanolic extracts exhibited significant alpha-amylase (IC50 of 44.25mug/mL) and alpha-glucosidase inhibitory activities (IC50 of 30.82mug/mL) respectively.Methanolic and hydroalcoholic extracts at 750mug/mL showed maximum antibacterial activity against S. typhi and S. flexneri respectively. Also, significant correlation was found between V. cholerae and R. equi as well as V. cholerae and S. epidermis. To conclude, C. coromandelicum could be considered as a natural antioxidant and potential source for therapeutic applications. However, widespread study is necessary to screen the role of recorded phytochemicals through in vivo studies to support its use in traditional medicine.

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