Publications by authors named "Cong Guo"

96 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

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

Imidazolylacetophenone oxime-based multifunctional neuroprotective agents: Discovery and structure-activity relationships.

Eur J Med Chem 2022 Jan 1;228:114031. Epub 2021 Dec 1.

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:

Alzheimer's disease (AD) possesses a complex pathogenetic mechanism. Nowadays, multitarget agents are considered to have potential in effectively treating AD via triggering molecules in functionally complementary pathways at the same time. Here, based on the screening (∼1400 compounds) against neuroinflammation, an imidazolylacetophenone oxime ether (IOE) was discovered as a novel hit. In order to obtain SARs, a series of imidazolylacetophenone oxime derivatives were constructed, and their C=N bonds were confirmed as the Z configuration by single crystals. These derivatives exhibited potential multifunctional neuroprotective effects including anti-neuroinflammatory, antioxidative damage, metal-chelating, inhibition of acetylcholinesterase (AChE) properties. Among these derivatives, compound 12i displayed the most potent inhibitory activity against nitric oxide (NO) production with EC value of 0.57 μM 12i can dose-dependently suppress the expression of iNOS and COX-2 but not change the expression of HO-1 protein. Moreover, 12i exhibited evidently neuroprotective effects on HO-induced PC12 cells damage and ferroptosis without cytotoxicity at 10 μM, as well as selectively metal chelating properties via chelating Cu. In addition, 12i showed a mixed-type inhibitory effect on AChE in vitro. The structure-activity relationships (SARs) analysis indicated that dioxolane groups on benzene ring and rigid oxime ester can improve the activity. Parallel artificial membrane permeation assay (PAMPA) also verified that 12i can overcome the blood-brain barrier (BBB). Overall, this is the first report on imidazolylacetophenone oxime-based multifunctional neuroprotective effects, suggesting that this type of compounds might be novel multifunctional agents against AD.
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http://dx.doi.org/10.1016/j.ejmech.2021.114031DOI Listing
January 2022

N-glucosyltransferase GbNGT1 from ginkgo complements the auxin metabolic pathway.

Hortic Res 2021 Nov 1;8(1):229. Epub 2021 Nov 1.

Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.

As auxins are among the most important phytohormones, the regulation of auxin homeostasis is complex. Generally, auxin conjugates, especially IAA glucosides, are predominant at high auxin levels. Previous research on terminal glucosylation focused mainly on the O-position, while IAA-N-glucoside and IAA-Asp-N-glucoside have been neglected since their discovery in 2001. In our study, IAA-Asp-N-glucoside was found to be specifically abundant (as high as 4.13 mg/g) in the seeds of 58 ginkgo cultivars. Furthermore, a novel N-glucosyltransferase, termed GbNGT1, was identified via differential transcriptome analysis and in vitro enzymatic testing. It was found that GbNGT1 could catalyze IAA-Asp and IAA to form their corresponding N-glucosides. The enzyme was demonstrated to possess a specific catalytic capacity toward the N-position of the IAA-amino acid or IAA from 52 substrates. Docking and site-directed mutagenesis of this enzyme confirmed that the E15G mutant could almost completely abolish its N-glucosylation ability toward IAA-Asp and IAA in vitro and in vivo. The IAA modification of GbNGT1 and GbGH3.5 was verified by transient expression assay in Nicotiana benthamiana. The effect of GbNGT1 on IAA distribution promotes root growth in Arabidopsis thaliana.
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http://dx.doi.org/10.1038/s41438-021-00658-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558338PMC
November 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

Synthesis of core-heteroshell structure for ZIF-67/VTM and its efficient activation of peroxymonosulfate in treatment of levofloxacin from an aqueous solution.

Environ Res 2022 03 2;204(Pt A):111986. Epub 2021 Sep 2.

School of Ecology and Environment, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, PR China; Henan International Joint Laboratory of Water Cycle Simulation and Environmental Protection, Zhengzhou, 450001, PR China; Zhengzhou Key Laboratory of Water Resource and Environment, Zhengzhou, 450001, China; Yellow River Institute for Ecological Protection and Regional Coordination Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, PR China; Henan Key Laboratory of Water Pollution Control and Rehabilitation Technology, Pingdingshan, Henan, 467036, China. Electronic address:

A core-heteroshell structural magnetic composite of ZIF-67/Vanadium-titanium magnetite (VTM) was successfully synthesized through a feasible solvothermal method and efficiently used in activation of peroxymonosulfate (PMS) for the treatment of levofloxacin (LVF) in an aqueous solution. The catalytic activity of the ZIF-67/VTM composite in LVF degradation was thoroughly evaluated, demonstrating the LVF removal rate could reach up to 93.3% within 60 min at ZIF-67/VTM composite dosage of 100 mg/L, PMS concertation of 75 mg/L, and the natural pH of 6.4. It is quite interesting that the carbon organic skeleton (in the ZIF-67 shell) have accelerated the internal electron transformation rate of the ZIF-67/VTM composite, thus efficiently promoting the O-O band (in PMS) breakage and the redox cycle of cobalt, further favoring the free radicals generation. The quenching experiments and EPR analysis results demonstrated that ·SO would play a crucial role in the LVF degradation process. Surprisingly, we have found that the introduction of Cl (at some certain dosage) would not always decrease the LVF degradation ratio, for a new reactive oxygen species (singlet oxygen) was emerged in this system. What's more, the ZIF-67 (as the wrapping structure) could stabilize the VTM (the inner structure) in changing reaction conditions, prompting a good adaptability at a wider pH range (3-10) for inhibiting the leaching of various metal ions into the aqueous solution. This novel ZIF-67/VTM composite could provide new ideas and routes for the removal of emerging pollutants from an aqueous solution.
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http://dx.doi.org/10.1016/j.envres.2021.111986DOI Listing
March 2022

Multi-Strain Tropical spp. as a Potential Probiotic Biocontrol Agent for Large-Scale Enhancement of Mariculture Water Quality.

Front Microbiol 2021 11;12:699378. Epub 2021 Aug 11.

State Key Laboratory of Marine Resource Utilization in the South China Sea, Hainan University, Haikou, China.

Aquaculture is suffering from long-term water eutrophication in intensive models, whereas the knowledge of multi-strain/specie for improving water quality is extremely limited. Herein, we aimed to develop multi-strain tropical spp. as a potential probiotic biocontrol agent for large-scale enhancement of mariculture water quality. Given the practical application, the optimum multi-strain tropical spp. ( QG-3, NS-4, and XCG-6 with the proportion 5: 5: 4) as a probiotic biocontrol agent was screened and obtained, which effectively improved water quality by removing chemical oxygen demand (COD), ammonia-nitrogen, and nitrate and significantly inhibited spp. even at relatively low bacterial concentrations (10 CFU/ml) in artificial feed wastewater and large-scale shrimp aquaculture ponds. More importantly, we found that the initial proportion of these three sp. strains of multi-strain tropical spp. markedly affected the final purification effects, whereas the initial concentration of that only influenced the purification rates at the early stage (0-48 h) instead of final purification effects. We reason that this multi-strain tropical spp. as a good probiotic biocontrol agent could perform multiple actions, such as COD-degrading, nitrifying, denitrifying, and antagonistic actions, for large-scale enhancement of tropical aquaculture water. Additionally, the multi-strain tropical spp. was safe for shrimp and could be stored for at least 240 days in spore form at room temperature. This multi-strain probiotic biocontrol agent may facilitate its adoption for further marine recirculating aquaculture system development and large-scale commercial application.
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http://dx.doi.org/10.3389/fmicb.2021.699378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385719PMC
August 2021

Multipronged Regulatory Functions of Serum Albumin in Early Stages of Amyloid-β Aggregation.

ACS Chem Neurosci 2021 07 23;12(13):2409-2420. Epub 2021 Jun 23.

Department of Physics and International Centre for Quantum and Molecular Structures, College of Sciences, Shanghai University, 99 Shangda Road, Shanghai 200444, China.

Human serum albumin (HSA) is a major interacting-partner of Alzheimer's amyloid-β (Aβ) peptide in the plasma and has emerged as a promising therapeutic target. HSA inhibits Aβ fibrillization, but the underlying molecular mechanism is not well elucidated. In this work, we investigated the role of HSA in the early stages of Aβ aggregation by simulating the binding process of multiple Aβ monomers and protofibrils to HSA with extensive molecular dynamics simulations. HSA could simultaneously trap multiple Aβ monomers and accommodate the formation of nonfibrillar Aβ oligomers after binding. In particular, domains I and III show stronger binding capacities and hold preferable interaction sites for oligomers. Consequently, HSA prevents the formation of fibrillar oligomers in water, thus interfering with the nucleation process. On the other aspect, when protofibrils are preformed, HSA tends to block the β-strand spanning the central hydrophobic core located at the protofibril end, preventing the addition of monomers to protofibrils. Furthermore, Aβ protofibril structures are severely disrupted both globally and locally. Thus, further growth of protofibrils to fibrils is impeded by HSA. Our results collectively indicate that HSA performs multipronged regulatory functions in the early stages of Aβ aggregation. Our work advances the understanding of the amyloid inhibition of Aβ by HSA and provides theoretical guidance for developing rational therapies of Alzheimer's disease.
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http://dx.doi.org/10.1021/acschemneuro.1c00150DOI Listing
July 2021

Enhanced luminescence of Si(111) surface by localized surface plasmons of silver islands.

Nanotechnology 2021 Apr 30;32(29). Epub 2021 Apr 30.

Department of Physics, Nanchang University, Nanchang 330031, People's Republic of China.

The role of silver localized surface plasmons (LSPs) on the luminescence of a Si(111)-(7 × 7) surface has been investigated by scanning tunneling microscopy (STM) with a silver tip at 77 K. On a bare Si(111)-(7 × 7) surface, a characteristic peak at 1.85 eV dominates the STM-induced luminescence spectrum, although the luminescence intensity is extremely weak. Once Ag atoms are deposited onto the Si surface to form islands with a few atomic layers, it is found that the intensity of the characteristic peak from the Si surface underneath the Ag islands is significantly enhanced by about one order. In addition to the luminescence from the Si surface, light emission originating from the irradiation decay of the Ag plasmons is also detected. Such great enhancement of the luminescence from the Si surface is attributed to the strong coupling between the surface states of the Si and the LSPs of the Ag islands.
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http://dx.doi.org/10.1088/1361-6528/abf3f0DOI Listing
April 2021

Albumin Alters the Conformational Ensemble of Amyloid-β by Promiscuous Interactions: Implications for Amyloid Inhibition.

Authors:
Huisi Xie Cong Guo

Front Mol Biosci 2020 23;7:629520. Epub 2021 Feb 23.

Department of Physics and International Centre for Quantum and Molecular Structures, College of Sciences, Shanghai University, Shanghai, China.

Human serum albumin (HSA) is a key endogenous inhibitor of amyloid-β (Αβ) aggregation. In vitro HSA inhibits Aβ fibrillization and targets multiple species along the aggregation pathway including monomers, oligomers, and protofibrils. Amyloid inhibition by HSA has both pathological implications and therapeutic potential, but the underlying molecular mechanism remains elusive. As a first step towards addressing this complex question, we studied the interactions of an Aβ42 monomer with HSA by molecular dynamics simulations. To adequately sample the conformational space, we adapted the replica exchange with solute tempering (REST2) method to selectively heat the Aβ42 peptide in the absence and presence of HSA. Aβ42 binds to multiple sites on HSA with a preference to domain III and adopts various conformations that all differ from the free state. The β-sheet abundances of H14-E22 and A30-M33 regions are significantly reduced by HSA, so are the β-sheet lengths. HSA shifts the conformational ensemble towards more disordered states and alters the β-sheet association patterns. In particular, the frequent association of Q15-V24 and N27-V36 regions into β-hairpin which is critical for aggregation is impeded. HSA primarily interacts with the latter β-region and the N-terminal charged residues. They form promiscuous interactions characterized by salt bridges at the edge of the peptide-protein interface and hydrophobic cores at the center. Consequently, intrapeptide interactions crucial for β-sheet formation are disrupted. Our work builds the bridge between the modification of Aβ conformational ensemble and amyloid inhibition by HSA. It also illustrates the potential of the REST2 method in studying interactions between intrinsically disordered peptides and globular proteins.
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http://dx.doi.org/10.3389/fmolb.2020.629520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940760PMC
February 2021

Reproduction response of Colletotrichum fungi under the fungicide stress reveals new aspects of chemical control of fungal diseases.

Microb Biotechnol 2021 Jan 20. Epub 2021 Jan 20.

Department of Biology, College of Arts and Science, University of Saskatchewan Saskatoon, SK, S7N 5E2, Canada.

Systemic fungicides and antifungals are used as frontline treatments for fungal diseases in plants and humans. It is generally accepted that fungicides will bring significant negative side-effects to the environment and result in fungicide resistance in the pathogenic fungi. Although previous research has focused on fungicide application rates and fungal resistance for a long time, little attention has been paid to fungicide residues after treatment, especially their potential role in fungal growth and sporulation. Here we investigated the effect of fungicides at sublethal concentrations on fungal sporulation. The results showed that two kinds of 14α-demethylase inhibitors (DMIs) fungicides increased the number of isolates of Colletotrichum spp. to sporulate on PDA. Both on PDA medium and plant tissue, low concentration of DMI fungicides could promote spore production of Colletotrichum spp., whereas pyraclostrobin, a quinone outside inhibitor (QoIs), had no significant effects on sporulation of Colletotrichum spp. Transcriptomic analysis suggested that the DMIs fungicide stress signal may be transmitted to the central regulatory pathway through the FluG-mediated signalling pathway, and further confirmed the morphological effect of DMI fungicide on promoting sporulation of Colletotrichum. To our knowledge, this is the first study to provide insights into the reproductive response of fungi in response to fungicide stress. Our findings indicate that fungicides have two-way effects on the growth and reproduction of pathogenic fungi and provide a new basis for the scientific and rational use of fungicides.
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http://dx.doi.org/10.1111/1751-7915.13754DOI Listing
January 2021

UPLC-Q-TOF/MS-Based Serum Metabolomics Reveals the Anti-Ischemic Stroke Mechanism of Nuciferine in MCAO Rats.

ACS Omega 2020 Dec 15;5(51):33433-33444. Epub 2020 Dec 15.

Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16 Nanxiaojie, Dongzhimennei, Beijing 100700, P. R. China.

Nuciferine is an aporphine alkaloid monomer that is extracted from the leaves of the lotus species and Gaertn. Nuciferine was reported to treat cerebrovascular diseases. However, the potential mechanism of the neuroprotective effects of nuciferine at the metabolomics level is still not unclear. The present research used neurological score, infarct volume, cerebral water content, and ultraperformance liquid chromatography to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS)-based serum metabolomics to elucidate the anti-ischemic stroke effect and mechanisms of nuciferine. The results showed that nuciferine significantly improved neurological deficit scores and ameliorated cerebral edema and infarction. Multivariate data analysis methods were used to examine the differences in serum endogenous metabolism between groups, and the biomarkers of nuciferine on ischemic stroke were identified. Approximately 19 metabolites and 7 metabolic pathways associated with nuciferine on treatment of stroke were found, which indicated that nuciferine exerted a positive therapeutic action on cerebral ischemic by regulating metabolism. These results provided some data support for the study of anti-stroke effect of nuciferine from the perspective of metabolomics.
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http://dx.doi.org/10.1021/acsomega.0c05388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774285PMC
December 2020

Network and pathway expansion of genetic disease associations identifies successful drug targets.

Sci Rep 2020 12 1;10(1):20970. Epub 2020 Dec 1.

Bioinformatics, Lonza, Cambridge, UK.

Genetic evidence of disease association has often been used as a basis for selecting of drug targets for complex common diseases. Likewise, the propagation of genetic evidence through gene or protein interaction networks has been shown to accurately infer novel disease associations at genes for which no direct genetic evidence can be observed. However, an empirical test of the utility of combining these approaches for drug discovery has been lacking. In this study, we examine genetic associations arising from an analysis of 648 UK Biobank GWAS and evaluate whether targets identified as proxies of direct genetic hits are enriched for successful drug targets, as measured by historical clinical trial data. We find that protein networks formed from specific functional linkages such as protein complexes and ligand-receptor pairs are suitable for even naïve guilt-by-association network propagation approaches. In addition, more sophisticated approaches applied to global protein-protein interaction networks and pathway databases, also successfully retrieve targets enriched for clinically successful drug targets. We conclude that network propagation of genetic evidence can be used for drug target identification.
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http://dx.doi.org/10.1038/s41598-020-77847-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708424PMC
December 2020

Ultra-broadband terahertz fingerprint spectrum of melatonin with vibrational mode analysis.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Feb 4;247:119141. Epub 2020 Nov 4.

Zhangjiang Laboratory, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China; Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Science, Shanghai 201800, China. Electronic address:

Melatonin (MLT), as a neurotransmitter and an endogenous neurohormone, plays an important role in physiological functions through interactions with specific receptors. The conformations of MLT are closely related to its biological activities and functions. However, the internal relationship between the structure and interaction of MLT and its allosteric transition remains unclear. In this work, we obtain the broadband fingerprint terahertz (THz) spectrum of MLT in the range of 0.5-18 THz using the air-plasma terahertz time-domain spectroscopy (THz-TDS) system. DFT calculations are employed to analyze the vibration characteristics of MLT. The result shows that the low-frequency vibrations mainly come from the strong coupling between inter- and intramolecular vibrations, and the contribution of intramolecular vibrations gradually dominates with increasing frequency. Meanwhile, the local vibrations of the different functional groups distribute widely in the THz low-frequency band, relating to the diversity of conformational changes in the molecule. The intermolecular hydrogen bonds (HBs) have distinct resonant responses and play critical roles in the THz low-frequency vibrations. The study reveals the complex characteristics of the resonant coupling of MLT with THz electromagnetic waves. The results will help to understand the conformational preferences of MLT in neural signal transmission processes.
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http://dx.doi.org/10.1016/j.saa.2020.119141DOI Listing
February 2021

[Research progress on mechanisms of traditional Chinese medicine in prevention and treatment of postoperative peritoneal adhesion].

Zhongguo Zhong Yao Za Zhi 2020 Sep;45(18):4358-4363

School of Life Science and Engineering, Southwest Jiaotong University Chengdu 610031, China Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences Beijing 100700, China.

Peritoneal adhesion is one of the common complications after abdominal operation, which could seriously affect the quality of life in patients. Although the development of modern surgical technology and the improvement of doctors' operation level have reduced the incidence of peritoneal adhesion to a certain extent, due to the lack of special treatment drugs, the therapeutic effect still cannot meet the expectations and requirements of clinicians and patients. Traditional Chinese medicines(TCM) have unique advantages and remarkable curative effect in the treatment of peritoneal adhesion, and they can play an important role in regulating multiple pathological links. However, the relevant researches and product development of TCM against peritoneal adhesion have not attracted enough attention from industry scholars. As for the related work that has been carried out, most of the studies on the efficacy and mechanism are not thorough and systematic enough, seriously restricting the industrial development in this field. In this paper, the efficacy and mechanism were systematically described and summarized based on the review of papers in the recent years, so as to provide a reference for the thorough study of TCM in the prevention and treatment of peritoneal adhesions, and promote the deep development and industrialization process of related products.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20200609.601DOI Listing
September 2020

Out-of-Register Parallel β-Sheets and Antiparallel β-Sheets Coexist in 150-kDa Oligomers Formed by Amyloid-β(1-42).

J Mol Biol 2020 07 26;432(16):4388-4407. Epub 2020 May 26.

School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, 311 Ferst Drive NW, Atlanta, GA 30332, USA. Electronic address:

We present solid-state NMR measurements of β-strand secondary structure and inter-strand organization within a 150-kDa oligomeric aggregate of the 42-residue variant of the Alzheimer's amyloid-β peptide (Aβ(1-42)). We build upon our previous report of a β-strand spanned by residues 30-42, which arranges into an antiparallel β-sheet. New results presented here indicate that there is a second β-strand formed by residues 11-24. Contrary to expectations, NMR data indicate that this second β-strand is organized into a parallel β-sheet despite the co-existence of an antiparallel β-sheet in the same structure. In addition, the in-register parallel β-sheet commonly observed for amyloid fibril structure does not apply to residues 11-24 in the 150-kDa oligomer. Rather, we present evidence for an inter-strand registry shift of three residues that likely alternate in direction between adjacent molecules along the β-sheet. We corroborated this unexpected scheme for β-strand organization using multiple two-dimensional NMR and C-C dipolar recoupling experiments. Our findings indicate a previously unknown assembly pathway and inspire a suggestion as to why this aggregate does not grow to larger sizes.
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http://dx.doi.org/10.1016/j.jmb.2020.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387221PMC
July 2020

Serum Metabolic Profiling Reveals the Antidepressive Effects of the Total Iridoids of Jones on Chronic Unpredictable Mild Stress Mice.

Front Pharmacol 2020 20;11:338. Epub 2020 Mar 20.

School of Life Science and Engineering, Southwest Jiao Tong University, Chengdu, China.

Background: Depression is a long-term complex psychiatric disorder, and its etiology remains largely unknown. Jones ex Roxb (V. is used in the clinic for the treatment of depression, but there are insufficient reports of its antidepressive mechanisms and a poor understanding of its endogenous substance-related metabolism. The objective of this study was to identify biomarkers related to depression in serum samples and evaluate the antidepressive effects of the iridoid-rich fraction of V. (IRFV) in a chronic unpredictable mild stress (CUMS) mouse model.

Methods: Here, CUMS was used to establish a mouse model of depression. Behavioral and biochemical indicators were investigated to evaluate the pharmacodynamic effects. A comprehensive serum metabolomics study by nuclear magnetic resonance (NMR) approach was applied to investigate the pharmacological mechanism of IRFV in CUMS mouse. Subsequently, we used multivariate statistical analysis to identify metabolic markers, such as principal component analysis (PCA) and orthogonal projection to latent structure with discriminant analysis (OPLS-DA), to distinguish between the CUMS mouse and the control group.

Results: After IRFV treatment, the immobility time, sucrose preference, and monoamine neurotransmitter were improved. PCA scores showed clear differences in metabolism between the CUMS group and control group. The PLS-DA or OPLS-DA model exhibited 26 metabolites as biomarkers to distinguish between the CUMS mice and the control mouse. Moreover, IRFV could significantly return 21 metabolites to normal levels.

Conclusion: The results confirmed that IRFV exerted an antidepressive effect by regulating multiple metabolic pathways, including the tricarboxylic acid cycle, the synthesis of neurotransmitters, and amino acid metabolism. These findings provide insights into the antidepressive mechanisms of IRFV.
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http://dx.doi.org/10.3389/fphar.2020.00338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099651PMC
March 2020

Isolation of two rare N-glycosides from Ginkgo biloba and their anti-inflammatory activities.

Sci Rep 2020 04 7;10(1):5994. Epub 2020 Apr 7.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.

Two rare N-β-D-glucopyranosyl-1H-indole-3-acetic acid conjugates, N-[2-(1-β-D-glucopyranosyl)-1H-indol-3-yl)acetyl]-L-glutamic acid (1) and N-[2-(1-β-D-glucopyranosyl)-1H-indol-3-yl)acetyl]-L-aspartic acid (2) were isolated from Ginkgo biloba. The structures were elucidated by analyses of HRMS and NMR spectroscopic data. In addition, a simplified and efficient synthetic route for compounds 1 and 2 is also disclosed to determine the absolute configurations of them. This concise syntheses of compounds 1 and 2 may facilitate studies of the biology of this type alkaloids. Compounds 1 and 2 were also tested for their cytotoxic and anti-inflammatory activities. The biological evaluation showed that compounds 1 and 2 led to the decrease of interleukin (IL)-6, nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 at mRNA level in lipopolysaccharide (LPS)-stimulated murine macrophage RAW264.7 cells.
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http://dx.doi.org/10.1038/s41598-020-62884-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138816PMC
April 2020

Influence of different cooking methods on the nutritional and potentially harmful components of peanuts.

Food Chem 2020 Jun 21;316:126269. Epub 2020 Jan 21.

State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, People's Republic of China.

This study investigated the comparative effects of boiling, roasting, deep-frying methods on the content of nutritional and potentially harmful components in peanuts. After cooking, the contents of total reducing sugar, sucrose, unsaturated fatty acids and almost all individual amino acids were reduced. Free methionine disappeared after heating processing, whereas fructose, starch, cis-palmitoleic acid and saturated fatty acids were increased in processed samples. Micronutrients including flavonoids and phenolic reduced significantly after boiling process but increased after roasting process. Both of frying and roasting promoted the formation of potentially harmful components including HMF, acrylamide and furan. The overall compositional difference between samples were further displayed and identified by a combination application of HCA and PCA, which showed that the roasting and frying process had a significant impact on the nutritional composition of peanuts.
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http://dx.doi.org/10.1016/j.foodchem.2020.126269DOI Listing
June 2020

Structural and functional insights into the Asp1/2/3 complex mediated secretion of pneumococcal serine-rich repeat protein PsrP.

Biochem Biophys Res Commun 2020 04 7;524(3):784-790. Epub 2020 Feb 7.

Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230026, China. Electronic address:

The accessory sec system consisting of seven conserved components is commonly distributed among pathogenic Gram-positive bacteria for the secretion of serine-rich-repeat proteins (SRRPs). Asp1/2/3 protein complex in the system is responsible for both the O-acetylation of GlcNAc and delivering SRRPs to SecA2. However, the molecular mechanism of how Asp1/2/3 transport SRRPs remains unknown. Here, we report the complex structure of Asp1/2/3 from Streptococcus pneumoniae at 2.9 Å. Further functional assays indicated that Asp1/2/3 can stimulate the ATPase activity of SecA2. In addition, the deletion of asp1/2/3 gene resulted in the accumulation of a secreted version of PsrP with an altered glycoform in protoplast fraction of the mutant cell, which suggested the modification/transport coupling of the substrate. Altogether, these findings not only provide structural basis for further investigations on the transport process of SRRPs, but also uncover the indispensable role of Asp1/2/3 in the accessory sec system.
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http://dx.doi.org/10.1016/j.bbrc.2020.01.146DOI Listing
April 2020

Surfacing amorphous Ni-B nanoflakes on NiCoO nanospheres as multifunctional bridges for promoting lithium storage behaviors.

Nanoscale 2019 Nov;11(46):22550-22558

Jiangsu Key Laboratory for Optoelectronic Detection of Atmosphere and Ocean, School of Chemistry and Material Science, Nanjing University of Information Science and Technology, Nanjing, Jiangsu 210044, China.

Transition metal oxides (TMOs) have gained enormous research interests as negative materials of next generation lithium-ion batteries due to their higher energy density, lower cost, and better eco-friendliness. However, they are prone to low electronic conductivities and dramatic volume change during charge/discharge and there is also a great challenge in realizing TMO electrodes with satisfactory LIB performances. In this study, for the first time, amorphous nickel-boride (Ni-B) was introduced into porous NiCo2O4 nanospheres by an in situ solution growth route to overcome the existing issues. The coated Ni-B component could not only function as anchors for NiCo2O4 nanospheres to suppress the severe volume expansion but could also act as effective electron-conducting bridges to promote fast electron/charge transfer. Furthermore, the existence of abundant mesopores centered at ∼6.5 nm in this composite could effectively suppress the severe volume variations in the lithiation/delithiation process. As expected, the [email protected] composites delivered a high reversible capacity of 1221 mA h g-1 at 0.2 A g-1 and 865 mA h g-1 at 0.5 A g-1 over 500 cycles; more impressively, at the high rate of 5 A g-1, a capacity of 648 mA h g-1 could be also obtained, showing its good rate capability. As a result, these results demonstrated an effective and facile way to design conversion-type negative electrode materials with superior lithium storage properties.
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http://dx.doi.org/10.1039/c9nr07733bDOI Listing
November 2019

[Grade evaluation of Gardeniae Fructus based on quality constant method].

Zhongguo Zhong Yao Za Zhi 2019 Sep;44(17):3732-3737

Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences Beijing 100700,China.

Grade evaluation method of quality constant is a kind of grading method for Chinese medicinal materials and decoction pieces,combining the external morphological index and internal content index. This method was used in this paper for grade evaluation of Gardeniae Fructus. By measuring the morphological and content indexes of 14 batches of Gardeniae Fructus,a method for calculating the quality constant of fruits was established,and the grade evaluation criteria were formed. At the same time,the NO inhibition effect of different grades of Gardeniae Fructus samples on RAW264. 7 cells induced by LPS was determined to investigate the relationship between the quality grade and pharmacodynamics of decoction pieces. The results showed that the quality constants of Gardeniae Fructus decoction piece samples ranged from 1. 46 to 4. 42. If the percentage quality constant ≥80% was classified into first-class,50%-80%as second-class and the rest as third-class,the quality constant was ≥3. 54 for first-class,2. 21-3. 54 for second-class and <2. 21 for third-class Gardeniae Fructus decoction pieces. The pharmacodynamic results showed that the pharmacodynamic intensity was positively correlated with the grade,which also proved the rationality of the grade evaluation method of quality constant.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20190629.309DOI Listing
September 2019

Engineering Na-Mo-O/Graphene Oxide Composites with Enhanced Electrochemical Performance for Lithium Ion Batteries.

ChemistryOpen 2019 Oct 29;8(10):1225-1229. Epub 2019 Aug 29.

School of Chemistry and Materials Science Nanjing University of Information Science and Technology, Nanjing Jiangsu 210044 China.

Sodium molybdate (Na-Mo-O) wrapped by graphene oxide (GO) composites have been prepared via a simple in-situ precipitation method at room temperature. The composites are mainly constructed with one dimension (1D) ultra-long sodium molybdate nanorods, which are wrapped by the flexible GO. The introduction of GO is expected to not merely provide more active sites for lithium-ions storage, but also improve the charge transfer rate of the electrode. The testing electrochemical performances corroborated the standpoint: The Na-Mo-O/GO composites delivers specific capacities of 718 mAh g after 100 cycles at 100 mA g, and 570 mAh g after 500 cycles at a high rate of 500 mA g; for comparison, the bare Na-Mo-O nanorod shows a severe capacity decay, which deliver only 332 mAh g after 100 cycles at 100 mA g. In view of the cost-efficient and less time-consuming in synthesis, and one-step preparation without further treatment, these Na-Mo-O nanorods/GO composites present potential and prospective anodes for LIBs.
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http://dx.doi.org/10.1002/open.201900205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769431PMC
October 2019

Genome-wide identification and classification of the and gene families in , and transcriptional analysis under heat stress.

PeerJ 2019 29;7:e7312. Epub 2019 Jul 29.

Key Laboratory of Horticultural Plant Biology, Ministry of Education, College of Horticulture and Forestry Sciences, Huazhong Agricultural University, Wuhan, China.

The transcriptional activation of heat shock proteins (Hsps) by heat shock transcription factors (Hsfs) is presumed to have a pivotal role in plant heat stress (HS) response. is an ornamental woody plant with distinctive features, including rich varieties and colors. In this study, 18 Hsfs and 24 small Hsps (sHsps) were identified in . Their chromosomal locations, protein domains, conserved motifs, phylogenetic relationships, and exon-intron structures were analyzed and compared with Hsfs or sHsps. A total of 18 PmHsf members were classified into three major classes, A, B, and C. A total of 24 PmsHsps were grouped into eight subfamilies (CI to CIII, P, endoplasmic reticulum, M, and CI- or P-related). Quantitative reverse transcription PCR analysis revealed that members of the A2, A7, and A9 groups became the prominent Hsfs after heat shock, suggesting their involvement in a key regulatory role of heat tolerance. Most of the genes were up-regulated upon exposure to HS. Overall, our data contribute to an improved understanding of the complexity of the and gene families, and provide a basis for directing future systematic studies investigating the roles of the and gene families.
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http://dx.doi.org/10.7717/peerj.7312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6673427PMC
July 2019

Bayesian estimation of genetic regulatory effects in high-throughput reporter assays.

Bioinformatics 2020 01;36(2):331-338

Duke Center for Statistical Genetics and Genomics, Duke University.

Motivation: High-throughput reporter assays dramatically improve our ability to assign function to noncoding genetic variants, by measuring allelic effects on gene expression in the controlled setting of a reporter gene. Unlike genetic association tests, such assays are not confounded by linkage disequilibrium when loci are independently assayed. These methods can thus improve the identification of causal disease mutations. While work continues on improving experimental aspects of these assays, less effort has gone into developing methods for assessing the statistical significance of assay results, particularly in the case of rare variants captured from patient DNA.

Results: We describe a Bayesian hierarchical model, called Bayesian Inference of Regulatory Differences, which integrates prior information and explicitly accounts for variability between experimental replicates. The model produces substantially more accurate predictions than existing methods when allele frequencies are low, which is of clear advantage in the search for disease-causing variants in DNA captured from patient cohorts. Using the model, we demonstrate a clear tradeoff between variant sequencing coverage and numbers of biological replicates, and we show that the use of additional biological replicates decreases variance in estimates of effect size, due to the properties of the Poisson-binomial distribution. We also provide a power and sample size calculator, which facilitates decision making in experimental design parameters.

Availability And Implementation: The software is freely available from www.geneprediction.org/bird. The experimental design web tool can be accessed at http://67.159.92.22:8080.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999138PMC
January 2020

Interleukin-18 as a drug repositioning opportunity for inflammatory bowel disease: A Mendelian randomization study.

Sci Rep 2019 06 28;9(1):9386. Epub 2019 Jun 28.

Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada.

Support from human genetics increases the probability of success in drug development. However, few examples exist of successful genomically-driven drug repositioning. Given that a Mendelian form of severe enterocolitis is due to up-regulation of the interleukin-18 (IL18) signaling pathway, and pharmacologic inhibition of IL18 has been shown to reverse this enterocolitis, we undertook a Mendelian randomization study to test the causal effect of elevated IL18 levels on inflammatory bowel disease susceptibility (IBD) in 12,882 cases and 21,770 controls. Mendelian randomization is an established method to assess the role of biomarkers in disease etiology in a manner that minimizes confounding and prevents reverse causation. Using three SNPs that explained almost 7% of the variance in IL18 level, we found that each genetically predicted standard deviation increase in IL18 was associated with an increase in IBD susceptibility (odds ratio = 1.22, 95% CI = 1.11-1.34, P-value = 6 × 10). This association was further validated in 25,042 IBD cases and 34,915 controls (odds ratio = 1.13, 95% CI = 1.05-1.20). Recently, an anti-IL18 monoclonal antibody, which decreased free IL18 levels, was found to be safe, yet ineffective in a phase II trial for type 2 diabetes. Taken together, these genomic findings implicated IBD as an alternative indication for anti-IL18 therapy, which should be tested in randomized controlled trials.
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http://dx.doi.org/10.1038/s41598-019-45747-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599045PMC
June 2019

Prediction of fatty acid composition in camellia oil by H NMR combined with PLS regression.

Food Chem 2019 May 12;279:339-346. Epub 2018 Dec 12.

State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, People's Republic of China.

A rapid method for the determination of fatty acid (FA) composition in camellia oils was developed based on the H NMR technique combined with partial least squares (PLS) method. Outliers detection, LVs optimization and data pre-processing selection were explored during the model building process. The results showed the optimal models for predicting the content of C18:1, C18:2, C18:3, saturated, unsaturated, monounsaturated and polyunsaturated FA were achieved by Pareto scaling (Par) pretreatment, with correlation coefficient (R) above 0.99, the root mean square error of estimation and prediction (RMSEE, RMSEP) lower than 0.954 and 0.947, respectively. Mean-centering (Ctr) was more suitable for the model of C16:0 and C18:0 with the best performance indicators (R ≥ 0.945, RMSEE ≤ 0.377, RMSEP ≤ 0.212). This study indicated that H NMR has the potential to be applied as a rapid and routine method for the analysis of FA composition in camellia oils.
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http://dx.doi.org/10.1016/j.foodchem.2018.12.025DOI Listing
May 2019

A new flavanol from the roots of .

J Asian Nat Prod Res 2019 Dec 28;21(12):1215-1220. Epub 2018 Dec 28.

Key Laboratory of Biochemistry and Molecular Biology in Universities of Shandong Province, Weifang University, Weifang 261061, China.

The phytochemical investigation of the roots of yielded six secondary metabolites, including a new flavanol derivative, (2R, 3S)-5,7,4'-trihydroxy-8-methoxycarbonylflavanol (), and five known compounds (-). The molecular structures of the isolated constituents were elucidated on the basis of extensive spectroscopic analysis, including UV, IR, NMR, and MS, and comparison with literature data. Furthermore, the cytotoxic activity of and against A549, HL-60, SMMC-7721, MCF-7, and SW480 cell lines was also described.
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http://dx.doi.org/10.1080/10286020.2018.1530222DOI Listing
December 2019

Vasorelaxant and antihypertensive effects of Tianshu Capsule on rats: An in vitro and in vivo approach.

Biomed Pharmacother 2019 Mar 21;111:188-197. Epub 2018 Dec 21.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, PR China. Electronic address:

Background: Both Chuanxiong (Ligusticum chuanxiong Hort) and Tianma (Gastrodia elata Blume) have the effects of vasorelaxation and antihypertension. However, the effects of Tianshu Capsule (TSC, composed of Chuanxiong and Tianma in the mass ratio of 4:1) on antihypertensive activity have not been explored. This study aimed to investigate the eff ;ects of TSC on vascular tension and blood pressure in rats and to explore the underlying mechanisms.

Methods: The vasorelaxant effect of TSC was explored on thoracic aortic rings (both intact endothelium and denuded) preincubated with phenylephrine (Phe) or potassium chloride (KCL). The mechanism was investigated in the presence of antagonists or blockers on aorta isolated from normotensive rats. The in vivo antihypertensive effect was assessed using a tail-cuff method on spontaneously hypertensive rats (SHRs).

Results: TSC (0.125-4 mg/mL) produced a concentration-dependent vasorelaxation on aortic rings preincubated with Phe (1 μM) or KCL (60 mM). Removal of aorta endothelium markedly attenuated the TSC activity. Pretreatment of aortic rings with β-adrenoceptor blocker propranolol (1 μM), muscarinic receptor antagonist atropine (1 μM), cyclooxygenase inhibitor indomethacin (IDO, 1 μM), adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536, 100 μM), K channel blockers 4-aminopyridine(4-AP, 1 mM) or barium chloride(BaCl, 1 mM) followed by addition of Phe (1 μM) prior to TSC did not influence the TSC-induced relaxation. In contrast, the vasorelaxant effects of TSC were markedly inhibited by the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME, 10 μM), guanylyl cyclase inhibitor 1H- [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 μM), K channel blockers, glibenclamide (100 μM) and clotrimazole (5 mM). Moreover, TSC (2 mg/mL, 4 mg/mL) inhibited CaCl-induced contractions and caused a concentration-dependent rightward shift of the response curves. Additionally, TSC (2 mg/mL, 4 mg/mL) depressed the constriction caused by Phe (1 μM) in the absence of extracellular Ca. Furthermore, TSC (2.15 g/kg) lowered the systolic blood pressure (SBP), with no alteration in heart rate (HR) in SHRs.

Conclusions: These findings demonstrated that TSC induced vasorelaxant effects via both endothelium-dependent and endothelium-independent pathways. The NO/sGC/cGMP pathway, ATP-sensitive K channels, Ca-activated K channels, inhibition of extracellular Ca influx and intracellular Ca2 release were probably involved in this relaxation. The vasorelaxant effects of TSC may make the greatest contribution to the reduction in high blood pressure.
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http://dx.doi.org/10.1016/j.biopha.2018.12.061DOI Listing
March 2019

Fatty Acids Compete with Aβ in Binding to Serum Albumin by Quenching Its Conformational Flexibility.

Biophys J 2019 01 6;116(2):248-257. Epub 2018 Dec 6.

Department of Chemistry and Department of Physics, University of Illinois at Chicago, Chicago, Illinois. Electronic address:

Human serum albumin (HSA) has been identified as an important regulator of amyloid-β (Aβ) fibrillization both in blood plasma and in cerebrospinal fluid. Fatty acids bind to HSA, and high serum levels of fatty acids increase the risk of Alzheimer's disease. In vitro, fatty-acid-loaded HSA (FA·HSA) loses the protective effect against Aβ fibrillization, but the mechanism underlying the interference of fatty acids on Aβ-HSA interactions has been unclear. Here, we used molecular dynamics simulations to gain atomic-level insight on the weak binding of monomeric Aβ40 and Aβ42 peptides with apo and FA·HSA. Consistent with recent NMR data, C-terminal residues of the Aβ peptides have the highest propensities for interacting with apo HSA. Interestingly, the Aβ binding residues of apo and FA·HSA exhibit distinct patterns, which qualitatively correlate with backbone flexibility. In FA·HSA, both flexibilities and Aβ binding propensities are relatively even among the three domains. In contrast, in apo HSA, domain III shows the highest flexibility and is the primary target for Aβ binding. Specifically, deformation of apo HSA creates strong binding sites within subdomain IIIb, around the interface between subdomains IIIa and IIIb, and at the cleft between domains III and I. Therefore, much like disordered proteins, HSA can take advantage of flexibility in forming promiscuous interactions with partners, until the flexibility is quenched by fatty-acid binding. Our work explains the effect of fatty acids on Aβ-HSA binding and contributes to the understanding of HSA regulation of Aβ aggregation.
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http://dx.doi.org/10.1016/j.bpj.2018.11.3133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349961PMC
January 2019
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