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14 pages, 1239 KiB

Open AccessArticle

Relationship between Apolipoprotein E Genotype and Lipoprotein Profile in Patients with Coronary Heart Disease

by Yahui Lin, Qiong Yang, Zhaohui Liu, Baoman Su, Fen Xu, Yang Li, Jinsuo Kang and Zhou Zhou

Molecules 2022, 27(4), 1377; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27041377 - 18 Feb 2022

Cited by 3 | Viewed by 1844

Abstract

(1) Background: Apolipoprotein E(ApoE) plays a critical role in lipid transport. The specific allele of APOE being expressed is associated with the development of coronary heart disease (CHD), however the specific mechanisms by which ApoE drives disease are unclear. In this study, we [...] Read more.

(1) Background: Apolipoprotein E(ApoE) plays a critical role in lipid transport. The specific allele of APOE being expressed is associated with the development of coronary heart disease (CHD), however the specific mechanisms by which ApoE drives disease are unclear. In this study, we investigated the relationship between APOE allele, lipoprotein metabolome, and CHD severity to provide evidence for the efficacy of clinical cholesterol-lowering therapy; (2) Methods: Blood samples were collected from 360 patients with CHD that were actively being treated with statins. The lipoprotein profile, including particle numbers, particle size, and lipoprotein composition concentrates, was measured by nuclear magnetic resonance (NMR) spectroscopy. The severity of CHD was determined by quantifying coronary angiography results using the Gensini scoring system; (3) Results: We found there was no significant difference in low-density lipoprotein cholesterol (LDL-C) levels among ε2+ (ε2 allele carriers, consisting of ε2/ε2 and ε2/ε3 genotypes), ε3 (consisting of ε3/ε3 and ε2/ε4 genotypes), and ε4+ (ε4 allele carriers, consisting of ε3/ε4 and ε4/ε4 genotypes) participants receiving statin treatment. Compared with the ε3 group, patients with the ε2+ genotype showed lower concentrations of total low-density lipoprotein (LDL), small-LDL, and middle-LDL particles, as well as a larger LDL size, higher very low-density lipoprotein (VLDL) composition concentrates, and higher intermediate density lipoprotein (IDL) composition concentrates. The ε4+ group showed higher concentrations of total LDL, small LDL particles, and LDL compositions with smaller LDL size. The higher level of small LDL concentration was associated with a high Gensini score (B = 0.058, p = 0.024). Compared with the ε3 group, the risk of increased branch lesions in the ε2+ group was lower (OR = 0.416, p = 0.027); (4) Conclusions: The specific allele of APOE being expressed can affect the severity of CHD by altering components of the lipoprotein profile, such as the concentration of small LDL and LDL size. Full article

(This article belongs to the Special Issue Biomolecular NMR 2021)

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14 pages, 14181 KiB

Open AccessArticle

NMF-Based Approach for Missing Values Imputation of Mass Spectrometry Metabolomics Data

by Jingjing Xu, Yuanshan Wang, Xiangnan Xu, Kian-Kai Cheng, Daniel Raftery and Jiyang Dong

Molecules 2021, 26(19), 5787; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26195787 - 24 Sep 2021

Cited by 7 | Viewed by 2317

Abstract

In mass spectrometry (MS)-based metabolomics, missing values (NAs) may be due to different causes, including sample heterogeneity, ion suppression, spectral overlap, inappropriate data processing, and instrumental errors. Although a number of methodologies have been applied to handle NAs, NA imputation remains a challenging [...] Read more.

In mass spectrometry (MS)-based metabolomics, missing values (NAs) may be due to different causes, including sample heterogeneity, ion suppression, spectral overlap, inappropriate data processing, and instrumental errors. Although a number of methodologies have been applied to handle NAs, NA imputation remains a challenging problem. Here, we propose a non-negative matrix factorization (NMF)-based method for NA imputation in MS-based metabolomics data, which makes use of both global and local information of the data. The proposed method was compared with three commonly used methods: k-nearest neighbors (kNN), random forest (RF), and outlier-robust (ORI) missing values imputation. These methods were evaluated from the perspectives of accuracy of imputation, retrieval of data structures, and rank of imputation superiority. The experimental results showed that the NMF-based method is well-adapted to various cases of data missingness and the presence of outliers in MS-based metabolic profiles. It outperformed kNN and ORI and showed results comparable with the RF method. Furthermore, the NMF method is more robust and less susceptible to outliers as compared with the RF method. The proposed NMF-based scheme may serve as an alternative NA imputation method which may facilitate biological interpretations of metabolomics data. Full article

(This article belongs to the Special Issue Biomolecular NMR 2021)

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11 pages, 7564 KiB

Open AccessArticle

The DNA Recognition Motif of GapR Has an Intrinsic DNA Binding Preference towards AT-rich DNA

by Qian Huang, Bo Duan, Zhi Qu, Shilong Fan and Bin Xia

Molecules 2021, 26(19), 5776; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26195776 - 24 Sep 2021

Cited by 1 | Viewed by 1490

Abstract

The nucleoid-associated protein GapR found in Caulobacter crescentus is crucial for DNA replication, transcription, and cell division. Associated with overtwisted DNA in front of replication forks and the 3′ end of highly-expressed genes, GapR can stimulate gyrase and topo IV to relax [...] Read more.

The nucleoid-associated protein GapR found in Caulobacter crescentus is crucial for DNA replication, transcription, and cell division. Associated with overtwisted DNA in front of replication forks and the 3′ end of highly-expressed genes, GapR can stimulate gyrase and topo IV to relax (+) supercoils, thus facilitating the movement of the replication and transcription machines. GapR forms a dimer-of-dimers structure in solution that can exist in either an open or a closed conformation. It initially binds DNA through the open conformation and then undergoes structural rearrangement to form a closed tetramer, with DNA wrapped in the central channel. Here, we show that the DNA binding domain of GapR (residues 1–72, GapR^ΔC17) exists as a dimer in solution and adopts the same fold as the two dimer units in the full-length tetrameric protein. It binds DNA at the minor groove and reads the spatial distribution of DNA phosphate groups through a lysine/arginine network, with a preference towards AT-rich overtwisted DNA. These findings indicate that the dimer unit of GapR has an intrinsic DNA binding preference. Thus, at the initial binding step, the open tetramer of GapR with two relatively independent dimer units can be more efficiently recruited to overtwisted regions. Full article

(This article belongs to the Special Issue Biomolecular NMR 2021)

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14 pages, 2866 KiB

Open AccessArticle

Positive Charges in the Brace Region Facilitate the Membrane Disruption of MLKL-NTR in Necroptosis

by Yaqing Yang, Encheng Xie, Lingyu Du, Yu Yang, Bin Wu, Liming Sun, Shuqing Wang and Bo OuYang

Molecules 2021, 26(17), 5194; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26175194 - 27 Aug 2021

Cited by 3 | Viewed by 1769

Abstract

Necroptosis is a type of programmed cell death executed through the plasma membrane disruption by mixed lineage kinase domain-like protein (MLKL). Previous studies have revealed that an N-terminal four-helix bundle domain (NBD) of MLKL is the executioner domain for the membrane permeabilization, which [...] Read more.

Necroptosis is a type of programmed cell death executed through the plasma membrane disruption by mixed lineage kinase domain-like protein (MLKL). Previous studies have revealed that an N-terminal four-helix bundle domain (NBD) of MLKL is the executioner domain for the membrane permeabilization, which is auto-inhibited by the first brace helix (H6). After necroptosis initiation, this inhibitory brace helix detaches and the NBD can integrate into the membrane, and hence leads to necroptotic cell death. However, how the NBD is released and induces membrane rupture is poorly understood. Here, we reconstituted MLKL₂_–154 into membrane mimetic bicelles and observed the structure disruption and membrane release of the first brace helix that is regulated by negatively charged phospholipids in a dose-dependent manner. Using molecular dynamics simulation we found that the brace region in an isolated, auto-inhibited MLKL₂_–154 becomes intrinsically disordered in solution after 7 ns dynamic motion. Further investigations demonstrated that a cluster of arginines in the C-terminus of MLKL₂_–154 is important for the molecular conformational switch. Functional mutagenesis showed that mutating these arginines to glutamates hindered the membrane disruption of full-length MLKL and thus inhibited the necroptotic cell death. These findings suggest that the brace helix also plays an active role in MLKL regulation, rather than an auto-inhibitory domain. Full article

(This article belongs to the Special Issue Biomolecular NMR 2021)

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13 pages, 2622 KiB

Open AccessArticle

Coil Combination of Multichannel Single Voxel Magnetic Resonance Spectroscopy with Repeatedly Sampled In Vivo Data

by Wanqi Hu, Huiting Liu, Dicheng Chen, Tianyu Qiu, Hongwei Sun, Chunyan Xiong, Jianzhong Lin, Di Guo, Hao Chen and Xiaobo Qu

Molecules 2021, 26(13), 3896; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26133896 - 25 Jun 2021

Cited by 3 | Viewed by 3006

Abstract

Magnetic resonance spectroscopy (MRS), as a noninvasive method for molecular structure determination and metabolite detection, has grown into a significant tool in clinical applications. However, the relatively low signal-to-noise ratio (SNR) limits its further development. Although the multichannel coil and repeated sampling are [...] Read more.

Magnetic resonance spectroscopy (MRS), as a noninvasive method for molecular structure determination and metabolite detection, has grown into a significant tool in clinical applications. However, the relatively low signal-to-noise ratio (SNR) limits its further development. Although the multichannel coil and repeated sampling are commonly used to alleviate this problem, there is still potential room for promotion. One possible improvement way is combining these two acquisition methods so that the complementary of them can be well utilized. In this paper, a novel coil-combination method, average smoothing singular value decomposition, is proposed to further improve the SNR by introducing repeatedly sampled signals into multichannel coil combination. Specifically, the sensitivity matrix of each sampling was pretreated by whitened singular value decomposition (WSVD), then the smoothing was performed along the repeated samplings’ dimension. By comparing with three existing popular methods, Brown, WSVD, and generalized least squares, the proposed method showed better performance in one phantom and 20 in vivo spectra. Full article

(This article belongs to the Special Issue Biomolecular NMR 2021)

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13 pages, 2048 KiB

Open AccessArticle

Radiation-Induced Metabolic Shifts in the Hepatic Parenchyma: Findings from ¹⁸F-FDG PET Imaging and Tissue NMR Metabolomics in a Mouse Model for Hepatocellular Carcinoma

by Yi-Hsiu Chung, Cheng-Kun Tsai, Ching-Fang Yu, Wan-Ling Wang, Chung-Lin Yang, Ji-Hong Hong, Tzu-Chen Yen, Fang-Hsin Chen and Gigin Lin

Molecules 2021, 26(9), 2573; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26092573 - 28 Apr 2021

Cited by 5 | Viewed by 2101

Abstract

Purpose: By taking advantage of 18F-FDG PET imaging and tissue nuclear magnetic resonance (NMR) metabolomics, we examined the dynamic metabolic alterations induced by liver irradiation in a mouse model for hepatocellular carcinoma (HCC). Methods: After orthotopic implantation with the mouse liver cancer BNL [...] Read more.

Purpose: By taking advantage of 18F-FDG PET imaging and tissue nuclear magnetic resonance (NMR) metabolomics, we examined the dynamic metabolic alterations induced by liver irradiation in a mouse model for hepatocellular carcinoma (HCC). Methods: After orthotopic implantation with the mouse liver cancer BNL cells in the right hepatic lobe, animals were divided into two experimental groups. The first received irradiation (RT) at 15 Gy, while the second (no-RT) did not. Intergroup comparisons over time were performed, in terms of 18F-FDG PET findings, NMR metabolomics results, and the expression of genes involved in inflammation and glucose metabolism. Results: As of day one post-irradiation, mice in the RT group showed an increased 18F-FDG uptake in the right liver parenchyma compared with the no-RT group. However, the difference reached statistical significance only on the third post-irradiation day. NMR metabolomics revealed that glucose concentrations peaked on day one post-irradiation both, in the right and left lobes—the latter reflecting a bystander effect. Increased pyruvate and glutamate levels were also evident in the right liver on the third post-irradiation day. The expression levels of the glucose-6-phosphatase (G6PC) and fructose-1, 6-bisphosphatase 1 (FBP1) genes were down-regulated on the first and third post-irradiation days, respectively. Therefore, liver irradiation was associated with a metabolic shift from an impaired gluconeogenesis to an enhanced glycolysis from the first to the third post-irradiation day. Conclusion: Radiation-induced metabolic alterations in the liver parenchyma occur as early as the first post-irradiation day and show dynamic changes over time. Full article

(This article belongs to the Special Issue Biomolecular NMR 2021)

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20 pages, 4007 KiB

Open AccessArticle

Aha1 Exhibits Distinctive Dynamics Behavior and Chaperone-Like Activity

by Huifang Hu, Qing Wang, Jingwen Du, Zhijun Liu, Yiluan Ding, Hongjuan Xue, Chen Zhou, Linyin Feng and Naixia Zhang

Molecules 2021, 26(7), 1943; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26071943 - 30 Mar 2021

Cited by 7 | Viewed by 2209

Abstract

Aha1 is the only co-chaperone known to strongly stimulate the ATPase activity of Hsp90. Meanwhile, besides the well-studied co-chaperone function, human Aha1 has also been demonstrated to exhibit chaperoning activity against stress-denatured proteins. To provide structural insights for a better understanding of Aha1’s [...] Read more.

Aha1 is the only co-chaperone known to strongly stimulate the ATPase activity of Hsp90. Meanwhile, besides the well-studied co-chaperone function, human Aha1 has also been demonstrated to exhibit chaperoning activity against stress-denatured proteins. To provide structural insights for a better understanding of Aha1’s co-chaperone and chaperone-like activities, nuclear magnetic resonance (NMR) techniques were used to reveal the unique structure and internal dynamics features of full-length human Aha1. We then found that, in solution, both the two domains of Aha1 presented distinctive thermal stabilities and dynamics behaviors defined by their primary sequences and three-dimensional structures. The low thermal stability (melting temperature of Aha1^28–162: 54.45 °C) and the internal dynamics featured with slow motions on the µs-ms time scale were detected for Aha1’s N-terminal domain (Aha1N). The aforementioned experimental results suggest that Aha1N is in an energy-unfavorable state, which would therefore thermostatically favor the interaction of Aha1N with its partner proteins such as Hsp90’s middle domain. Differently from Aha1N, Aha1C (Aha1’s C-terminal domain) exhibited enhanced thermal stability (melting temperature of Aha1^204–335: 72.41 °C) and the internal dynamics featured with intermediate motions on the ps-ns time scale. Aha1C’s thermal and structural stabilities make it competent for the stabilization of the exposed hydrophobic groove of dimerized Hsp90’s N-terminal domain. Of note, according to the NMR data and the thermal shift results, although the very N-terminal region (M1-W27) and the C-terminal relaxin-like factor (RLF) motif showed no tight contacts with the remaining parts of human Aha1, they were identified to play important roles in the recognition of intrinsically disordered pathological α-synuclein. Full article

(This article belongs to the Special Issue Biomolecular NMR 2021)

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17 pages, 2515 KiB

Open AccessArticle

NMR-Based Metabolomic Analysis for the Effects of α-Ketoglutarate Supplementation on C2C12 Myoblasts in Different Energy States

by Yantong Li, Xiaoyuan Li, Yifeng Gao, Caihua Huang and Donghai Lin

Molecules 2021, 26(7), 1841; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26071841 - 25 Mar 2021

Cited by 6 | Viewed by 2517

Abstract

α-Ketoglutarate (AKG) is attracting much attention from researchers owing to its beneficial effects on anti-aging and cancer suppression, and, more recently, in nutritional supplements. Given that glucose is the main source of energy to maintain normal physiological functions of skeletal muscle, the effects [...] Read more.

α-Ketoglutarate (AKG) is attracting much attention from researchers owing to its beneficial effects on anti-aging and cancer suppression, and, more recently, in nutritional supplements. Given that glucose is the main source of energy to maintain normal physiological functions of skeletal muscle, the effects of AKG supplementation for improving muscle performance are closely related to the glucose level in skeletal muscle. The differences of AKG-induced effects in skeletal muscle between two states of normal energy and energy deficiency are unclear. Furthermore, AKG-induced metabolic changes in skeletal muscles in different energy states also remain elusive. Here, we assessed the effects of AKG supplementation on mouse C2C12 myoblast cells cultured both in normal medium (Nor cells) and in low-glucose medium (Low cells), which were used to mimic two states of normal energy and energy deficiency, respectively. We further performed NMR-based metabolomic analysis to address AKG-induced metabolic changes in Nor and Low cells. AKG supplementation significantly promoted the proliferation and differentiation of cells in the two energy states through glutamine metabolism, oxidative stress, and energy metabolism. Under normal culture conditions, AKG up-regulated the intracellular glutamine level, changed the cellular energy status, and maintained the antioxidant capacity of cells. Under low-glucose culture condition, AKG served as a metabolic substrate to reduce the glutamine-dependence of cells, remarkably enhanced the antioxidant capacity of cells and significantly elevated the intracellular ATP level, thereby ensuring the normal growth and metabolism of cells in the state of energy deficiency. Our results provide a mechanistic understanding of the effects of AKG supplements on myoblasts in both normal energy and energy deficiency states. This work may be beneficial to the exploitation of AKG applications in clinical treatments and nutritional supplementations. Full article

(This article belongs to the Special Issue Biomolecular NMR 2021)

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