Publications by authors named "Jin-Ming Gao"

203 Publications

Cognitive enhancement and neuroprotective effects of OABL, a sesquiterpene lactone in 5xFAD Alzheimer's disease mice model.

Redox Biol 2022 Jan 8;50:102229. Epub 2022 Jan 8.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, Shaanxi, PR China. Electronic address:

Alzheimer's disease (AD) is a neurodegenerative disease in which oxidative stress and neuroinflammation were demonstrated to be associated with neuronal loss and cognitive deficits. However, there are still no specific treatments that can prevent the progression of AD. In this study, a screening of anti-inflammatory hits from 4207 natural compounds of two different molecular libraries indicated 1,6-O,O-diacetylbritannilactone (OABL), a 1,10-seco-eudesmane sesquiterpene lactone isolated from the herb Inula britannica L., exhibited strong anti-inflammatory activity in vitro as well as favorable BBB penetration property. OABL reduced LPS-induced neuroinflammation in BV-2 microglial cells as assessed by effects on the levels of inflammatory mediators including NO, PGE, TNF-α, iNOS, and COX-2, as well as the translocation of NF-κB. Besides, OABL also exhibited pronounced neuroprotective effects against oxytosis and ferroptosis in the rat pheochromocytoma PC12 cell line. For in vivo research, OABL (20 mg/kg B.W., i.p.) for 21 d attenuated the impairments in cognitive function observed in 6-month-old 5xFAD mice, as assessed with the Morris water maze test. OABL restored neuronal damage and postsynaptic density protein 95 (PSD95) expression in the hippocampus. OABL also significantly reduced the accumulation of amyloid plaques, the Aβ expression, the phosphorylation of Tau protein, and the expression of BACE1 in AD mice brain. In addition, OABL attenuated the overactivation of microglia and astrocytes by suppressing the expressions of inflammatory cytokines, and increased glutathione (GSH) and reduced malondialdehyde (MDA) and super oxide dismutase (SOD) levels in the 5xFAD mice brain. In conclusion, these results highlight the beneficial effects of the natural product OABL as a novel treatment with potential application for drug discovery in AD due to its pharmacological profile.
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http://dx.doi.org/10.1016/j.redox.2022.102229DOI Listing
January 2022

-Related Myofibrillar Myopathy Presenting as Hypercapnia: A Case Report and Literature Review.

Chin Med Sci J 2021 Dec;36(4):265-278

Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.

Objective -related myopathy is a rare condition so far reported in twenty patients worldwide. The purpose of this study was to draw attention to this rare disease and to the fact that -related myopathy should be considered as a rare differential diagnosis of hypercapnia. Methods We report a sporadic case of a 14-year-old Chinese girl with a p.Pro209Leu mutation in and reviewed the literatures for reported cases related to this mutation. Results We described a 14-year-old Chinese girl who presented with gradually appearing symptoms of hypercapnia that required assisted ventilation. The muscle biopsy and the blood whole-exome sequencing results confirmed the diagnosis of myofibrillar myopathy with a p.Pro209Leu mutation in . Totally twenty-one patients from twenty families with a confirmed diagnosis of -related myopathy were reported to date, including this patient and literature review. The male to female ratio was 11:10 and most showed initial symptoms in the first decade of life. Most patients presented toe/clumsy walking or running as the onset symptom, followed by muscle weakness or atrophy. Creatine kinase levels were elevated in fourteen patients and were normal in three. Eighteen patients developed respiratory insufficiency during the disease course and thirteen (one could not tolerate non-invasive assisted ventilation) required non-invasive assisted ventilation for treatment. Except for one not reported, heart involvement was found in seventeen patients during the disease course and seven underwent heart transplantation. Z-disk streaming and aggregation could be observed in most of the patients' muscle histology. In the long-term follow-up, five patients died of cardiac or respiratory failure. Conclusion -associated myopathy is a rare type of myofibrillar myopathy. It should be considered as a rare differential diagnosis of hypercapnia.
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http://dx.doi.org/10.24920/003883DOI Listing
December 2021

Structurally Diverse Sesquiterpenoid Glycoside Esters from with Anti-neuroinflammatory Activity.

J Nat Prod 2022 Jan 3. Epub 2022 Jan 3.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China.

Thirteen new sesquiterpenoid glycoside esters, including 11 aromadendrane-type compounds, pitqinlingosides A-K (-), one cadinane-type compound, pitqinlingoside L (), and one eudesmane-type compound, pitqinlingoside M (), together with seven known analogues (-) were isolated from the twigs, fruits, and leaves of Structures were elucidated by analysis of spectroscopic data, gas chromatography mass spectrometry (GC-MS), and chemical methods. The absolute configuration was confirmed by single-crystal X-ray crystallography analysis or electronic circular dichroism spectra. Unusual glycoside esters are characterized by the presence of polyacylated β-d-fucopyranosyl, β-d-glucopyranosyl, and β-d-xylopyranosyl units. Pitqinlingosides A (), B (), D (), and F (), pittosporanoside A acetate (), and pittosporanoside A () showed significant nitric oxide production inhibition in lipopolysaccharide (LPS)-induced BV-2 microglial cells with IC values ranging from 0.95 to 24.12 μM. Structure-activity relationships of the isolated compounds are discussed.
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http://dx.doi.org/10.1021/acs.jnatprod.1c00544DOI Listing
January 2022

Identification of NLRP3 as a covalent target of 1,6-O,O-diacetylbritannilactone against neuroinflammation by quantitative thiol reactivity profiling (QTRP).

Bioorg Chem 2021 Dec 5;119:105536. Epub 2021 Dec 5.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China. Electronic address:

Neuroinflammation plays a key etiological role in the progressive neuronal damage of neurodegenerative diseases. Our phenotypic-based screening discovered 1,6-O,O-diacetylbritannilactone (OABL, 1) from Inula britannica exhibited the potential anti-neuroinflammatory activity as well as a favorable blood-brain barrier penetration. 1 and its active derivative Br-OABL (2) with insert of Br at the C-14 position both modulated TLR4/NF-kB/MAPK pathways. However, proteome-wide identification of 1 binding proteins remains unclear. Here, we employed an adapted isoTOP-ABPP, quantitative thiol reactivity profiling (QTRP) approach, to identify and quantify thiol reactivity binding proteins in murine microglia BV-2 cells. We screened out 15 proteins co-targeted by 1 and 2, which are involved in cellular response to oxidative stress and negative regulation NF-κB transcription factor in biological processes. In site-specific profiling, NLRP3 was identified as a covalent target of 1 and 2 for the first time, and the Cys of NLRP3 NACHT domain was identified as one active-site of NLRP3 cysteine residues that can be covalently modified by the α-methylene-γ-lactone moiety. Furthermore, NLRP3 was validated to be directly binded by 1 and 2 by cellular thermo shift assay (CETSA) and activity-based protein profiling (ABPP), and NLRP3 functions were also verified by small interfering RNA approach. Notably, OABL treatment (i.p., 20 mg/kg/day) for 21 days reduced inflammation in 5XFAD mice brain. Together, we applied the QTRP to uncover the binding proteins of OABL in BV-2 cells, among which NLRP3 was revealed as a new covalent target of 1 and 2 against neuroinflammation.
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http://dx.doi.org/10.1016/j.bioorg.2021.105536DOI Listing
December 2021

Cassane diterpenoids from and their anti-inflammatory and -glycosidase inhibitory activities.

Nat Prod Res 2021 Nov 28:1-9. Epub 2021 Nov 28.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry and Pharmacy, Northwest A&F University, Yangling, P. R. China.

Three undescribed cassane-type diterpenoids (CAs), caesalpulcherrins K-M (-), together with three known ones (-) were isolated from the aerial parts of (L.) Sw (Fabaceae). Their structures were elucidated via analysis of NMR (1 D and 2 D) and HRESIMS data. The character for caesalpulcherrin K possessing the olefin bond at C-11 and C-12 in its cassane skeleton was observed, which belonged to a small group among more than 450 CAs. That is, only fifteen derivatives have been reported up to now, to our knowledge. Biological evaluation revealed that compounds - exhibited moderate anti-inflammatory activity, with an IC value from 6.04 ± 0.34 to 8.92 ± 0.65 μM. Furthermore, compounds and exhibited significant -glucosidase inhibitory activity at 10 μM.
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http://dx.doi.org/10.1080/14786419.2021.2007096DOI Listing
November 2021

Structures of ganorbifates C-I, seven previously undescribed lanostanoids from the mushroom Ganoderma orbiforme, and insights of computed biosynthesis with DFT.

Phytochemistry 2022 Feb 25;194:113004. Epub 2021 Nov 25.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, Shaanxi, China. Electronic address:

Ganorbifates C-I, seven undescribed biosynthetically related polyoxygenated 3,4-seco-27-norlanostanoid congeners, were isolated from the edible mushroom, Ganoderma orbiforme. Ganorbifate C features a unique cyclobutene ring constructed at C19/C11, and both D and E incorporate an unusual cyclopropane ring formed by C-19/C-9 linkage. Their structures, including the absolute configurations, were determined by spectroscopic methods and ECD calculations. The proposed Norrish-Yang cyclization-based key biosynthetic pathway for ganorbifates C-E is revealed by density functional theory (DFT) calculations. The computational studies uncover the formation of both cyclobutene and cyclopropane rings in the isolates and the stereoselectivity centers of these steps are consistent with those in the natural products. All compounds exhibited NO generation inhibition in LPS-induced BV-2 microglial cells, among them ganorbifate C was the most promising one with the IC values of 4.37 μM.
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http://dx.doi.org/10.1016/j.phytochem.2021.113004DOI Listing
February 2022

Total Synthesis and Anti-Tobacco Mosaic Virus Activity of the Furofuran Lignan (±)-Phrymarolin II and Its Analogues.

J Nat Prod 2021 Nov 3;84(11):2937-2944. Epub 2021 Nov 3.

College of Plant Protection, Northwest A&F University, 3 Taicheng Road, Yangling 712100, Shaanxi, China.

Phrymarolin II, a furofuran lignan isolated from L., features a 3,7-dioxabicyclo[3.3.0]octane skeleton. Herein, we report an alternative total synthesis of (±)-phrymarolin II (), which was performed in 9 steps from commercially available sesamol. The key steps of the synthesis included a zinc-mediated Barbier-type allylation and a copper-catalyzed anomeric -arylation. Our total synthesis allowed the synthesis of analogues of (±)-phrymarolin II. Most derivatives displayed good to excellent activity against tobacco mosaic virus (TMV). (±)-Phrymarolin II () and compounds (±)- and (±)- exhibited similar or higher activity than commercial ningnanmycin, which indicated that phrymarolin lignans are a promising new class of plant virus inhibitors.
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http://dx.doi.org/10.1021/acs.jnatprod.1c00763DOI Listing
November 2021

Sesamol Attenuates Amyloid Peptide Accumulation and Cognitive Deficits in APP/PS1 Mice: The Mediating Role of the Gut-Brain Axis.

J Agric Food Chem 2021 Nov 20;69(43):12717-12729. Epub 2021 Oct 20.

Department of Food Science, Cornell University, Ithaca, New York 14853, United States.

Alzheimer's disease (AD), a neurodegenerative disease, is the leading cause of dementia. Sesamol is a lignan extracted from sesame oil and has been found to exert neuroprotective effects. The present study aimed to investigate the neuroprotective effects of sesamol on APPswe/PS1dE9 transgenic AD mice. The AD mice were fed with a diet supplemented with sesamol (0.075 w/w %). Sesamol treatment improved spatial memory and learning ability in AD mice, improved neuronal damage, and decreased Aβ accumulation. Sesamol protected the synaptic ultrastructure and inhibited neuroinflammatory responses in the brain of AD mice. Sesamol also significantly inhibited the overactivated microglia and reduced the overexpression of TNF-α and IL-1β in the brain of AD mice. Notably, sesamol reshaped gut microbiota by significantly decreasing the relative abundance of , , and Bacillaceae, enhancing the relative abundance of Rikenellaceae and in AD mice. It has been found that sesamol protected the gut barrier integrity and prevented the LPS leakage into the serum. Importantly, sesamol remarkably enhanced the content of SCFAs, including acetate, propionate, isobutyrate, butyrate, and valerate, in AD mice. Correlation analysis indicated that there was a strong correlation between the levels of SCFAs and cognitive functions. These results demonstrated that sesamol attenuated AD-related cognitive dysfunction and neuroinflammatory responses, which could be partly explained by its role in mediating the gut microbe-SCFA-brain axis. Thus, sesamol is a promising nutritional intervention strategy to prevent AD via the microbiota-gut-brain axis.
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http://dx.doi.org/10.1021/acs.jafc.1c04687DOI Listing
November 2021

Ganoderterpene A, a New Triterpenoid from , Attenuates LPS-Induced Inflammation and Apoptosis via Suppressing MAPK and TLR-4/NF-κB Pathways in BV-2 Cells.

J Agric Food Chem 2021 Nov 20;69(43):12730-12740. Epub 2021 Oct 20.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100 Shaanxi, People's Republic of China.

An investigation of the fruiting bodies of edible mushroom produced 13 steroids, containing one new lanostane-type triterpene compound, named ganoderterpene A (). Nuclear magnetic resonance and high-resolution electrospray ionization mass spectrometry data were used to deduce these structures. All the isolates were evaluated for their ability to suppress NO generation in BV-2 microglial cells treated with lipopolysaccharide (LPS) and exhibited moderate to strong inhibition effects, with IC values in the range 7.15-36.88 M. Among the tested compounds, compound exhibited the most marked activity with an IC value of 7.15 M, and the structure-activity relationships were studied. This study showed that compound significantly suppressed the activation of MAPK and TLR-4/NF-κB signaling pathways, as evidenced by an immunofluorescence assay and a molecular docking experiment. Furthermore, compound effectively improved the LPS-induced mitochondrial membrane potential and apoptosis. These findings suggest that ganoderterpene A could exert protective effects in microglial cells from apoptosis by restraining the inflammatory response. Hence, could be used as a novel preventative agent for neurodegenerative disorders.
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http://dx.doi.org/10.1021/acs.jafc.1c04905DOI Listing
November 2021

Structures and absolute configurations of butenolide derivatives from the isopod-associated fungus Pidoplitchkoviella terricola.

Phytochemistry 2022 Jan 13;193:112981. Epub 2021 Oct 13.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, Shaanxi, China. Electronic address:

In this research, twenty aromatic and branched aliphatic polyketides, including seven previously undescribed butenolide derivatives, piterriones A-G and one known analogue, along with twelve known altenusin derivatives, were isolated from the isopod-associated fungus Pidoplitchkoviella terricola. Their structures were elucidated by analysis of NMR (1D and 2D) and mass spectrometry data, and their absolute configurations were determined by Mosher's method, microscale derivatization, and comparison of their specific rotations and ECD spectra. Dihydroaltenuene B exhibited mushroom tyrosinase inhibitory activity with an IC value of 38.33 ± 1.59 μM, which was comparable to that of the positive control, kojic acid (IC = 39.72 ± 1.34 μM). A molecular-docking study disclosed the hydrogen bonding interactions between the 3-OH and 4'-OH of dihydroaltenuene B and the His244, Met280 and Gly281 residues of tyrosinase.
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http://dx.doi.org/10.1016/j.phytochem.2021.112981DOI Listing
January 2022

Eremophilane Sesquiterpenoids with Antibacterial and Anti-inflammatory Activities from the Endophytic Fungus .

J Agric Food Chem 2021 Oct 4;69(40):11878-11889. Epub 2021 Oct 4.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China.

Fourteen eremophilane sesquiterpenoids (-), including nine new congeners, septoreremophilanes A-I (-), together with three known sesquiterpenes (-), two known tetralone derivatives (, ), and two known cholesterol analogues (, ), were isolated from the endophytic fungus . Compounds - and belong to the family of the highly oxygenated eremophilane sesquiterpenoids with a 6/6/5 tricyclic system and bearing a hemiacetal moiety. The inhibitions of all metabolites against eight bacteria were estimated , and nine new metabolites (-) were tested for antineuroinflammatory activity. Notably, the effects of against pv. and against displayed potent inhibitory, with the MIC values of 6.25 and 6.25 M, respectively. Further, scanning electron microscopy analyses indicated that and were to change the outer configuration of bacterial cells, respectively, and the investigations demonstrated that and may act as potential structure templates for the development of the agrochemical bactericides. Additionally, compound displayed potent inhibition of NO generation in lipopolysaccharide-induced BV-2 microglial cells (IC = 12.0 ± 0.32 M), and the conceivable anti-inflammatory mechanisms implicated were also investigated by molecular docking. Thus, the bioactive metabolites of the strain may serve as a novel resource to be developed.
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http://dx.doi.org/10.1021/acs.jafc.1c04131DOI Listing
October 2021

Chemical characterization and multifunctional neuroprotective effects of sesquiterpenoid-enriched Inula britannica flowers extract.

Bioorg Chem 2021 11 28;116:105389. Epub 2021 Sep 28.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry and Pharmacy, Northwest A&F University, Yangling 712100, PR China. Electronic address:

Dried flowers of Inula britannica commercially serve as pharmaceutical/nutraceutical herbs in the manufacture of medicinal products and functional tea that has been reported to possess extensive biological property. However, the neuroprotective constituents in I. britannica flowers are not known. In the current study, phytochemicals of sesquiterpenoid-enriched I. britannica flowers extract and their potential multifunctional neuroprotective effects were investigated. Nineteen structurally diverse sesquiterpenoids, including two new sesquiterpenoid dimers, namely, inubritanolides A and B (1, 2), and four new sesquiterpenoid monomers (3-6), namely, 1-O-acetyl-6-O-chloracetylbritannilactone (3), 6-methoxybritannilactone (4), 1-hydroxy-10β-methoxy-4αH-1,10-secoeudesma-5(6),11(13)-dien-12,8β-olide (5) and 1-hydroxy-4αH-1,10-secoeudesma-5(6),10(14),11(13)-trien-12,8β-olide (6), as well as 13 known congeners (7-19) were isolated from this source. The structures of compounds 1-6 were elucidated by 1D- and 2D- NMR and HR-ESI-MS data, and their absolute configurations were discerned by electronic circular dichroism (ECD) data analysis and single crystal X-ray diffraction. Interestingly, inubritannolide A (1) is a new type [4 + 2] Diels-Alder dimer featuring a hepta-membered cycloether skeleton. Most of the compounds showed potential multifunctional neuroprotective effects, including antioxidative, anti-neuroinflammatory, and microglial polarization properties. Specifically, 1 and 6 displayed slight strong neuroprotective potency against different types of neuronal cells mediated by various inducers including HO, 6-hydroxydopamine (6-OHDA), and lipopolysaccharide (LPS). Overall, this is the first report on multifunctional neuroprotective effects of sesquiterpenoid-enriched I. britannica flowers extract, which supports its potential pharmaceutical/nutraceutical application in neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.bioorg.2021.105389DOI Listing
November 2021

Ulmoidol, an unusual nortriterpenoid from Eucommia ulmoides Oliv. Leaves prevents neuroinflammation by targeting the PU.1 transcriptional signaling pathway.

Bioorg Chem 2021 11 9;116:105345. Epub 2021 Sep 9.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, Shaanxi, People's Republic of China. Electronic address:

Chronic neuroinflammation is closely associated with the development of neurodegenerative diseases, including Alzheimer's disease (AD). In the current study, 13 anti-neuroinflammatory compounds were isolated from Eucommia ulmoides Oliv. leaves. Among these compounds, trans-sinapaldehyde (6), 3',4',5,7-tetrahydroxy-3-methylflavone (7), and amarusine A (13) were isolated from E. ulmoides leaves for the first time. The ursane-type C-triterpenoid, ulmoidol (ULM, 9), significantly inhibited the production of proinflammatory mediators and reduced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, ULM inhibited the cluster of differentiation 14 (CD14)/Toll-like receptor 4 (TLR4) signaling pathway and consequently limited the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Notably, electrophoretic mobility shift assay (EMSA) and molecular docking analyses indicated that ULM could prevent PU box binding-1 (PU.1) from binding to DNA, suggesting that PU.1 might be a potential ULM target. In conclusion, ULM alleviates neuroinflammatory responses in microglia, which could be partly explained by its targeting of PU.1 and the resulting suppression of the TLR4/MAPK/NF-κB signaling pathways. These results suggested that ULM may have therapeutic potential as an agent for treating neuroinflammation-related neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.bioorg.2021.105345DOI Listing
November 2021

1,10-Seco-Eudesmane sesquiterpenoids as a new type of anti-neuroinflammatory agents by suppressing TLR4/NF-κB/MAPK pathways.

Eur J Med Chem 2021 Nov 21;224:113713. Epub 2021 Jul 21.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, Shaanxi, PR China. Electronic address:

Dysregulation of neuroinflammation is a key pathological factor in the progressive neuronal damage of neurodegenerative diseases. An in-house natural products library of 1407 compounds were screened against neuroinflammation in lipopolysaccharide (LPS)-activated microglia cells to identify a novel hit 1,6-O,O-diacetylbritannilactone (OABL) with anti-neuroinflammatory activity. Furthermore, a 1,10-seco-eudesmane sesquiterpenoid library containing 33 compounds was constructed by semisynthesis of a major component 1-O-acetylbritannilactone (ABL) from the traditional Chinese medicinal herb Inula Britannica L. Compound 15 was identified as a promising anti-neuroinflammatory agent by nitrite oxide (NO) production screening. 15 could attenuate tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) productions, and inhibit the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at a submicromolar level. Mechanistic study revealed that 15 significantly modulated TLR4/NF-kB and p38 MAPK pathways, and upregulated the anti-oxidant response HO-1. Besides, 15 promoted the conversion of the microglia from M1 to M2 phenotype by increasing levels of arginase-1 and IL-10. The structure-activity relationships (SARs) analysis indicated that the α-methylene-γ-lactone motifs, epoxidation of C5=C10 bond and bromination of C14 were important to the activity. Parallel artificial membrane permeation assay (PAMPA) also demonstrated that 15 and OABL can overcome the blood-brain barrier (BBB). In all, compound 15 is a promising anti-neuroinflammatory lead with potent anti-inflammatory effects via the blockage of TLR4/NF-κB/MAPK pathways, favorable BBB penetration property, and low cytotoxicity.
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http://dx.doi.org/10.1016/j.ejmech.2021.113713DOI Listing
November 2021

Alkylated Salicylaldehydes and Prenylated Indole Alkaloids from the Endolichenic Fungus and Their Bioactivities.

J Agric Food Chem 2021 Jun 7;69(23):6524-6534. Epub 2021 Jun 7.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry and Pharmacy, Northwest A&F University, Yangling 712100, P. R. China.

Sixteen metabolites, including seven C-alkylated salicylaldehyde derivatives (-) and nine prenylated indole alkaloids (-), three of which are new, namely, asperglaucins A and B ( and ) and neoechinulin F (), were separated from the endolichenic fungus SQ-8. Asperglaucin A () represents an unusual phthalide-like derivative with a benzo[]thiophen-1(3)-one scaffold. All compounds were assessed for antibacterial, antineuroinflammatory, and antioxidant activities. Notably, asperglaucins A and B exhibited potent antibacterial activities against two plant pathogens pv (Psa) and , with an MIC value of 6.25 μM; further SEM analyses illustrated that the possible bacteriostatic mechanisms for compounds and were to alter the external structure of and Psa, and to cause the rupture or deformation of the cell membranes, respectively, and the results suggest that compounds and may serve as potential promising candidates for lead compounds of agrochemical bactericides. Furthermore, compounds and significantly inhibited nitric oxide production with an IC value of ca. 12 μM, and the possible anti-inflammatory mechanisms involved were also studied by molecular docking. Finally, the tested phenolics - showed significant antioxidative effects. Thus, strain SQ-8 represents a novel resource of these bioactive metabolites to be utilized.
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http://dx.doi.org/10.1021/acs.jafc.1c01148DOI Listing
June 2021

Design, synthesis and in vitro antitumor evaluation of novel pyrazole-benzimidazole derivatives.

Bioorg Med Chem Lett 2021 07 9;43:128097. Epub 2021 May 9.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100 Shaanxi, PR China.

A series of novel pyrazole-benzimidazole derivatives (6-42) have been designed, synthesized and evaluated for their in vitro antiproliferative activity against the HCT116, MCF-7 and Huh-7 cell lines. Among them, compounds 17, 26 and 35 showed significant antiproliferative activity against HCT116 cell lines with the IC values of 4.33, 5.15 and 4.84 μM, respectively. Moreover, fluorescent staining studies showed compound 17 could induce cancer cells apoptosis. The flow cytometry assay revealed that compound 17 could induce cell cycle arrest at G0/G1 phase. All in all, these consequences suggest that pyrazole-benzimidazole derivatives could serve as promising compounds for further research to develop novel and highly potent cancer therapy agents.
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http://dx.doi.org/10.1016/j.bmcl.2021.128097DOI Listing
July 2021

Structurally Diverse Sesquiterpenoids with Anti-neuroinflammatory Activity from the Endolichenic Fungus Cryptomarasmius aucubae.

Nat Prod Bioprospect 2021 Jun 7;11(3):325-332. Epub 2021 May 7.

Shaanxi Key Laboratory of Natural Products and Chemical Biology, College of Chemistry and Pharmacy, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China.

Two new sterpurane sesquiterpenoids named sterpurol D (1) and sterpurol E (2), and one skeletally new sesquiterpene, cryptomaraone (3), bearing a 5,6-fused bicyclic ring system, along with five known ones, sterpurol A (4), sterpurol B (5), paneolilludinic Acid (6), murolane-2α, 9β-diol-3-ene (7) and (-)-10,11-dihydroxyfarnesol (8) were isolated from an endolichenic fungus Cryptomarasmius aucubae. The structures of the new compounds were elucidated by analysis of NMR spectroscopic spectra and HRESIMS data. The absolute configurations of 1 and 2 were established by spectroscopic data analysis and comparison of specific optical rotation, as well as the biosynthetic consideration. Additionally, compounds 1, 2, 4-6, and 8 showed significant nitric oxide (NO) production inhibition in Lipopolysaccharide (LPS)-induced BV-2 microglial cells with the IC values ranging from 9.06 to 14.81 μM.
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http://dx.doi.org/10.1007/s13659-021-00299-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141073PMC
June 2021

Design, Synthesis, and Biological Evaluation of Novel 3-Aminomethylindole Derivatives as Potential Multifunctional Anti-Inflammatory and Neurotrophic Agents.

ACS Chem Neurosci 2021 05 22;12(9):1593-1605. Epub 2021 Apr 22.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, P. R. China.

The development of multifunctional molecules that are able to simultaneously interact with several pathological components has been considered as a solution to treat the complex pathologies of neurodegenerative diseases. Herein, a series of aminomethylindole derivatives were synthesized, and evaluation of their application for antineuroinflammation and promoting neurite outgrowth was disclosed. Our initial screening showed that most of the compounds potently inhibited lipopolysaccharide (LPS)-stimulated production of NO in microglial cells and potentiated the action of NGF to promote neurite outgrowth of PC12 cells. Interestingly, with outstanding NO/TNF-α production inhibition and neurite outgrowth-promoting activities, compounds and were capable of rescuing cells after injury by HO. Their antineuroinflammatory effects were associated with the downregulation of the LPS-induced expression of the inflammatory mediators inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Western blotting and immunofluorescence assay results indicated that the mechanism of their antineuroinflammatory actions involved suppression of the MAPK/NF-κB signal pathways. Further studies revealed that another important reason for the high comprehensive antineuroinflammatory activity was the anti-COX-2 capabilities of the compounds. All these results suggest that the potential biochemical multifunctional profiles of the aminomethylindole derivatives provide a new sight for the treatment of neurodegenerative diseases.
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http://dx.doi.org/10.1021/acschemneuro.1c00079DOI Listing
May 2021

The natural product trienomycin A is a STAT3 pathway inhibitor that exhibits potent in vitro and in vivo efficacy against pancreatic cancer.

Br J Pharmacol 2021 06 21;178(12):2496-2515. Epub 2021 Apr 21.

Shaanxi Key Laboratory of Natural Products and Chemical Biology, College of Chemistry and Pharmacy, Northwest A&F University, Xianyang, China.

Background And Purpose: Pancreatic cancer is an exceptionally fatal disease. However, therapeutic drugs for pancreatic cancer have presented a serious shortage over the past few decades. Signal transducer and activator of transcription-3 (STAT3) is persistently activated in many human cancers where it promotes tumour development and progression. Natural products serve as an inexhaustible source of anticancer drugs. Here, we identified the natural product trienomycin A (TA), an ansamycin antibiotic, as a potential inhibitor of the STAT3 pathway with potent activity against pancreatic cancer.

Experimental Approach: Effects of trienomycin A on transcriptional activity of STAT3 were assessed by the STAT3-luciferase (STAT3-luc) reporter system. In vitro and in vivo inhibitory activity of TA against pancreatic cancer made use of molecular docking, surface plasmon resonance (SPR) assay, MTS assay, colony formation assay, transwell migration/invasion assay, flow cytometric analysis, immunofluorescence staining, quantitative real-time polymerase chain reaction (PCR), western blotting, tumour xenograft model, haematoxylin and eosin (H&E) staining and immunohistochemistry.

Key Results: Trienomycin A directly bound to STAT3 and inhibited STAT3 (Tyr705) phosphorylation, thus inhibiting the STAT3 pathway. Trienomycin A also inhibited colony formation, proliferation, migration and invasion of pancreatic cancer cell lines. Trienomycin A also markedly blocked pancreatic tumour growth in vivo. More importantly, trienomycin A did not show obvious toxicity at the effective dose in mice.

Conclusions And Implications: Trienomycin A exerted anti-neoplastic activity by suppressing STAT3 activation in pancreatic cancer. This natural product could be a novel therapeutic candidate for pancreatic cancer.
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http://dx.doi.org/10.1111/bph.15435DOI Listing
June 2021

Insight into the α-glucosidase-inhibiting mechanism of β-PGG, a commonly occurring polyphenol in diets.

Nat Prod Res 2021 Jan 18:1-5. Epub 2021 Jan 18.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, China.

1,2,3,4,6-Penta-O-galloyl-β-D-glucopyranose (β-PGG) is a compound commonly available in vegetables and fruits. It exhibited potential inhibition of α-glucosidase and hypoglycemic effect in . This study explored its dynamics properties inhibiting α-glucosidase by Lineweaver - Burk plots, spectral analysis, docking analysis, and molecular dynamics simulations. β-PGG showed a mix-type inhibition when it was interacting with α-glucosidase. The fluorescence quenching indicated that the PGG-glucosidase complex formed in a spontaneous exothermic process and was driven by enthalpy. The synchronous fluorescence and ECD spectra indicate that β-PGG induced and changed the enzyme conformation in the complex formation. Docking results revealed multiple hydrogen bonds between the phenols and the amino acid residues. Further dynamic simulations indicated that the residues Asp345, Phe153, Arg435, Glu300, Pro305, and Phe296 played a more critical role in the interactions between β-PGG and α-glucosidase.
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http://dx.doi.org/10.1080/14786419.2021.1873983DOI Listing
January 2021

Anti-neuroinflammatory polyoxygenated lanostanoids from Chaga mushroom Inonotus obliquus.

Phytochemistry 2021 Apr 9;184:112647. Epub 2021 Jan 9.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, Shaanxi, China. Electronic address:

Chaga mushroom, Inonotus obliquus, was used as food and nutrient food and traditional herbs in Russia, China and Japan, with anti-inflammatory and anticancer activities. Chemical investigations of the fruiting bodies of Chaga were carried to uncover the bioactive metabolites. As a result, seven undescribed lanostane-type triterpenoids, namely inonotusols H-N, were isolated, and all lanostanoids remarkably inhibited NO production in lipopolysaccharide-stimulated BV-2 microglial cells. Of these, inonotusols I and L presented the most potent inhibitory effects on inducible nitric oxide synthase (iNOS) and NO production without any significant cytotoxicity. Molecular docking studies confirmed the capacity of inonotusols I and L to interact with iNOS protein. Structure-activity relationships were also discussed. These results indicated that the potential anti-inflammatory effects of inonotusols I and L in microglial BV-2 cells may be imparted through suppression of iNOS. These results may support the use of I. obliquus for food and medicinal application.
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http://dx.doi.org/10.1016/j.phytochem.2020.112647DOI Listing
April 2021

Trinor- and tetranor-eremophilane sesquiterpenoids with anti-neuroinflammatory activity from cultures of the fungus Septoria rudbeckiae.

Phytochemistry 2021 Mar 6;183:112642. Epub 2021 Jan 6.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China. Electronic address:

Fifteen eremophilane sesquiterpenoids, including nine undescribed congeners, septeremophilane A-H, and chaetopenoid G, together with four conjugated unsaturated polyketide fatty acids, including an undescribed derivative, were isolated from cultures of the fungus Septoria rudbeckiae, a plant pathogenic fungus isolated from the halophyte Karelinia caspia. Septeremophilane A represents an unprecedented tetranor-eremophilane sesquiterpenoid with an α,β-unsaturated δ-lactone unit bearing a hemiacetal group, while septeremophilane B-H possesses a trinor-eremophilane skeleton. Their structures and absolute configurations were established based on spectroscopic data (NMR and HRESIMS), quantum chemical calculations and electronic circular dichroism (ECD) experiments. All metabolites were tested for nitric oxide (NO) production inhibition in lipopolysaccharide (LPS)-activated BV-2 microglial cells, while dendryphiellin D, septeremophilane D, and septeremophilane E were found to display significant inhibition, with IC values of 11.9 ± 1.0, 8.5 ± 0.1, and 6.0 ± 0.2 μM, respectively.
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http://dx.doi.org/10.1016/j.phytochem.2020.112642DOI Listing
March 2021

Phenolic and Steroidal Metabolites from the Cultivated Edible Mushroom and Their Bioactivities.

J Agric Food Chem 2021 Jan 5;69(2):668-675. Epub 2021 Jan 5.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Xianyang 712100, Shaanxi, People's Republic of China.

A chemical study on the fruiting bodies of cultivated edible mushroom resulted in 14 metabolites including three new hispolon congeners, named inonophenols A-B and one new lanostane triterpenoid, named inonoterpene A. These structures were identified by NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and electronic circular dichroism (ECD) data analysis. All metabolites were assessed for neurotrophic, anti-inflammatory, and antioxidative activities. Among them, inonophenols B and C were the most active in promoting PC-12 cell neurite outgrowth at a concentration of 10 M. The phenolic derivatives reduced NO generation by lipopolysaccharide (LPS)-induced BV-2 microglial cells by suppressing the expression of toll-like receptor-4 (TLR-4) and the nuclear factor-kappa-B (NF-κB) signaling pathway as well as the inflammatory mediators including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, the phenolics showed antioxidant effects in DPPH scavenging assay with the IC values of 9.82-21.43 M. These findings showed that may be a new source of neurotrophic and protective agents against neurodegenerative disorders.
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http://dx.doi.org/10.1021/acs.jafc.0c06822DOI Listing
January 2021

Two new benzophenone glycosides from the aerial parts of .

Nat Prod Res 2020 Dec 28:1-9. Epub 2020 Dec 28.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi, China.

Plants of the genus contain various types of secondary metabolites that exhibited extensive biological activities. In the ongoing efforts to discover natural neuroinflammatory inhibitors with the potential to develop into therapeutic agents for neurodegenerative diseases, two new benzophenone glycosides, hyperewalones A and B ( and ), along with eight known compounds (), were isolated from the aerial parts of . Their structures were elucidated by comprehensive analysis of IR, HRESIMS, 1D and 2D NMR spectra, and chemical derivatization. The anti-neuroinflammatory activity of compounds - was evaluated by determining their ability to inhibit the production of nitric oxide (NO) in lipopolysaccharide (LPS)-activated BV-2 microglial cells. Compounds , , - exhibited significant anti-neuroinflammatory activity with IC values of 0.61-4.90 μM. These findings suggest that the benzophenone, ionone, and flavonoid glycosides isolated from are promising anti-neuroinflammatory compounds worthy of further investigations.
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http://dx.doi.org/10.1080/14786419.2020.1865955DOI Listing
December 2020

Antimicrobial activity and biosynthetic potential of cultivable actinomycetes associated with Lichen symbiosis from Qinghai-Tibet Plateau.

Microbiol Res 2021 Mar 1;244:126652. Epub 2020 Dec 1.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, 3 Taicheng Road, Yangling, 712100, Shaanxi, China.

Actinobacteria that inhabit lichen symbionts are considered a promising yet previously underexplored source of novel compounds. Here, for the first time, we conducted a comprehensive investigation with regard to strain isolation and identification of lichen-associated actinobacteria from Tibet Plateau, antimicrobial activity screening, biosynthetic genes detection, bioactive metabolites identification and activity prediction. A large number of culturable actinomycetes were isolated from lichens around Qinghai Lake, in Qinghai-Tibet Plateau. Twenty-seven strains with distinct morphological characteristics were preliminarily studied. 16S rRNA gene identification showed that 13 strains were new species. The PCR-screening of specific biosynthetic genes indicated that these 27 isolates had abundant intrinsic biosynthetic potential. The antimicrobial activity experiment screened out some potential biological control antagonistic bacteria. The metabolites of 13 strains of Streptomyces with antibacterial activity were analyzed by LC-HRMS, and further 18 compounds were identified by NMR and / or LC-HRMS. The identified compounds were mainly pyrrolidine and indole derivatives, as well as anthracyclines. Seven compounds were identified with less biological activity, then predicted and evaluated their biological activity. The predicted results showed that compound 2 had excellent inhibitory activity on HIV-1 reverse transcriptase. Overall, the results indicate actinobacteria isolated from unexploited plateau lichen are promising sources of biological active metabolite, which could provide important bioactive compounds as potential antibiotic drugs.
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http://dx.doi.org/10.1016/j.micres.2020.126652DOI Listing
March 2021

Four new pyrrole alkaloids from the rhizomes of Amomum koenigii.

J Nat Med 2021 Jan 21;75(1):173-177. Epub 2020 Oct 21.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, China.

Four new pyrrole alkaloids, named amokoens A-D (1-4), together with three known compounds (5-7) were isolated from the rhizomes of Amomum koenigii. Their structures and absolute configurations were established by spectroscopic data, including 1D and 2D NMR, and the optical rotation calculations. All the isolates were evaluated for their effects on nitric oxide (NO) production in lipopolysaccharide-induced RAW264.7 macrophages. Compounds 1-7 inhibited NO production ranging from 27.1 to 82.4% at a concentration of 100 μM, and compounds 5 and 6 showed efficacious inhibitory activities with IC values of 42.2 and 69.3 µM, respectively.
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http://dx.doi.org/10.1007/s11418-020-01461-2DOI Listing
January 2021

Network Pharmacology Analysis and Molecular Characterization of the Herbal Medicine Formulation Qi-Fu-Yin for the Inhibition of the Neuroinflammatory Biomarker iNOS in Microglial BV-2 Cells: Implication for the Treatment of Alzheimer's Disease.

Oxid Med Cell Longev 2020 31;2020:5780703. Epub 2020 Aug 31.

School of Chinese Medicine, The University of Hong Kong, Hong Kong 999077, China.

Aberrant microglial activation drives neuroinflammation and neurodegeneration in Alzheimer's disease (AD). The present study is aimed at investigating whether the herbal formula Qi-Fu-Yin (QFY) could inhibit the inflammatory activation of cultured BV-2 microglia. A network pharmacology approach was employed to predict the active compounds of QFY, protein targets, and affected pathways. The representative pathways and molecular functions of the targets were analyzed by Gene Ontology (GO) and pathway enrichment. A total of 145 active compounds were selected from seven herbal ingredients of QFY. Targets (e.g., MAPT, APP, ACHE, iNOS, and COX-2) were predicted for the selected active compounds based on the relevance to AD and inflammation. As a validation, fractions were sequentially prepared by aqueous extraction, ethanolic precipitation, and HPLC separation, and assayed for downregulating two key proinflammatory biomarkers iNOS and COX-2 in lipopolysaccharide- (LPS-) challenged BV-2 cells by the Western blotting technique. Moreover, the compounds of QFY in 90% ethanol downregulated iNOS in BV-2 cells but showed no activity against COX-2 induction. Among the herbal ingredients of QFY, Angelicae Sinensis Radix and Ginseng Radix et Rhizoma contributed to the selective inhibition of iNOS induction. Furthermore, chemical analysis identified ginsenosides, especially Rg3, as antineuroinflammatory compounds. The herbal formula QFY may ameliorate neuroinflammation via downregulating iNOS in microglia.
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http://dx.doi.org/10.1155/2020/5780703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481926PMC
May 2021

Ganorbifates A and B from , determined by DFT calculations of NMR data and ECD spectra.

Chem Commun (Camb) 2020 Sep;56(70):10195-10198

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry and Pharmacy, Northwest A&F University, Yangling 712100, People's Republic of China.

Ganorbifate A featuring an unprecedented 6/6/6/5/5 pentacyclic system, and ganorbifate B with an unusual 6/4/6/5/8/5 ring system were isolated from the fruiting body of Ganoderma orbiforme. Their structures were established using extensive spectroscopic analysis, including DFT calculations of NMR data and ECD spectra.
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http://dx.doi.org/10.1039/d0cc04679eDOI Listing
September 2020

Draft Genome Sequence of Streptomyces morookaense DSM 40503, an 8-Azaguanine-Producing Strain.

Microbiol Resour Announc 2020 Jul 30;9(31). Epub 2020 Jul 30.

Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi, China

Here, we describe the genome of DSM 40503, an 8-azaguanine-producing strain. The genome is the basis for future study and presents an underexplored taxonomy and biosynthetic potential, which expands our understanding of the diversity of microorganisms that produce nitrogen heterocyclic compounds.
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http://dx.doi.org/10.1128/MRA.00518-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393960PMC
July 2020

Fungal Metabolite Asperaculane B Inhibits Malaria Infection and Transmission.

Molecules 2020 Jul 1;25(13). Epub 2020 Jul 1.

Department of Biological Sciences, Biomolecular Sciences Institute, Florida International University, Miami, FL 33199, USA.

Mosquito-transmitted parasites cause millions of people worldwide to suffer malaria every year. Drug-resistant parasites and insecticide-resistant mosquitoes make malaria hard to control. Thus, the next generation of antimalarial drugs that inhibit malaria infection and transmission are needed. We screened our Global Fungal Extract Library (GFEL) and obtained a candidate that completely inhibited transmission to . The candidate fungal strain was determined as . The bioactive compound was purified and identified as asperaculane B. The concentration of 50% inhibition on transmission (IC) is 7.89 µM. Notably, asperaculane B also inhibited the development of asexual with IC of 3 µM, and it is nontoxic to human cells. Therefore, asperaculane B is a new dual-functional antimalarial lead that has the potential to treat malaria and block malaria transmission.
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http://dx.doi.org/10.3390/molecules25133018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412362PMC
July 2020
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