Metabolites

17 pages, 2694 KiB

Open AccessArticle

Quantification of the Tissue Oxygenation Delay Induced by Breath-Holding in Patients with Carotid Atherosclerosis

by Andrés Quiroga, Sergio Novi, Giovani Martins, Luis Felipe Bortoletto, Wagner Avelar, Ana Terezinha Guillaumon, Li Min Li, Fernando Cendes and Rickson C. Mesquita

Metabolites 2022, 12(11), 1156; https://doi.org/10.3390/metabo12111156 - 21 Nov 2022

Viewed by 1621

Abstract

Carotid artery stenosis (CAS) is a common vascular disease with long-term consequences for the brain. Although CAS is strongly associated with impaired cerebral hemodynamics and neurodegeneration, the mechanisms underlying hemodynamic impairment in the microvasculature remain unknown. In this work, we employed functional near-infrared [...] Read more.

Carotid artery stenosis (CAS) is a common vascular disease with long-term consequences for the brain. Although CAS is strongly associated with impaired cerebral hemodynamics and neurodegeneration, the mechanisms underlying hemodynamic impairment in the microvasculature remain unknown. In this work, we employed functional near-infrared spectroscopy (fNIRS) to introduce a methodological approach for quantifying the temporal delay of the evoked hemodynamic response. The method was validated during a vasodilatory task (breath-holding) in 50 CAS patients and 20 controls. Our results suggest that the hemodynamic response to breath-holding can be delayed by up to 6 s in the most severe patients, a significant increase from the median 4 s measured for the control group (p = 0.01). In addition, the fraction of brain regions that responded to the task decreased as the CAS severity increased, from a median of 90% in controls to 73% in the most severe CAS group (p = 0.04). The presence of collateral circulation increases the response to breath-holding and decreases the average time delays across the brain, although the number of communicating arteries alone cannot predict these fNIRS-based hemodynamic variables (p > 0.09). Overall, this work proposes a method to quantitatively assess impaired cerebral hemodynamics in CAS patients. Full article

(This article belongs to the Special Issue Optical Assessment of Metabolism)

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13 pages, 14605 KiB

Open AccessArticle

Molecular Dynamics Study on Selected Bioactive Phytochemicals as Potential Inhibitors of HIV-1 Subtype C Protease

by Francis Oluwole Shode, John Omo-osagie Uhomoibhi, Kehinde Ademola Idowu, Saheed Sabiu and Krishna Kuben Govender

Metabolites 2022, 12(11), 1155; https://doi.org/10.3390/metabo12111155 - 21 Nov 2022

Cited by 3 | Viewed by 1186

Abstract

Acquired immunodeficiency syndrome (AIDS), one of the deadliest global diseases, is caused by the Human Immunodeficiency Virus (HIV). To date, there are no known conventional drugs that can cure HIV/AIDS, and this has prompted continuous scientific efforts in the search for novel and [...] Read more.

Acquired immunodeficiency syndrome (AIDS), one of the deadliest global diseases, is caused by the Human Immunodeficiency Virus (HIV). To date, there are no known conventional drugs that can cure HIV/AIDS, and this has prompted continuous scientific efforts in the search for novel and potent anti-HIV therapies. In this study, molecular dynamics simulation (MDS) and computational techniques were employed to investigate the inhibitory potential of bioactive compounds from selected South African indigenous plants against HIV-1 subtype C protease (HIVpro). Of the eight compounds (CMG, MA, UA, CA, BA, UAA, OAA and OA) evaluated, only six (CMG (−9.9 kcal/mol), MA (−9.3 kcal/mol), CA (−9.0 kcal/mol), BA (−8.3 kcal/mol), UAA (−8.5 kcal/mol), and OA (−8.6 kcal/mol)) showed favourable activities against HIVpro and binding landscapes like the reference FDA-approved drugs, Lopinavir (LPV) and Darunavir (DRV), with CMG and MA having the highest binding affinities. Using the structural analysis (root-mean-square deviation (RMSD), fluctuation (RMSF), and radius of gyration (RoG) of the bound complexes with HIVpro after 350 ns, structural evidence was observed, indicating that the six compounds are potential lead candidates for inhibiting HIVpro. This finding was further corroborated by the structural analysis of the enzyme–ligand complexe systems, where structural mechanisms of stability, flexibility, and compactness of the study metabolites were established following binding with HIVpro. Furthermore, the ligand interaction plots revealed that the metabolites interacted hydrophobically with the active site amino residues, with identification of other key residues implicated in HIVpro inhibition for drug design. Overall, this is the first computational report on the anti-HIV-1 activities of CMG and MA, with efforts on their in vitro and in vivo evaluations underway. Judging by the binding affinity, the degree of stability, and compactness of the lead metabolites (CMG, MA, CA, BA, OA, and UAA), they could be concomitantly explored with conventional HIVpro inhibitors in enhancing their therapeutic activities against the HIV-1 serotype. Full article

(This article belongs to the Section Nutrition and Metabolism)

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13 pages, 1525 KiB

Open AccessReview

Metabolomics—A Tool to Find Metabolism of Endocrine Cancer

by Raziyeh Abooshahab, Hamidreza Ardalani, Maryam Zarkesh, Koroush Hooshmand, Ali Bakhshi, Crispin R. Dass and Mehdi Hedayati

Metabolites 2022, 12(11), 1154; https://doi.org/10.3390/metabo12111154 - 21 Nov 2022

Cited by 7 | Viewed by 2046

Abstract

Clinical endocrinology entails an understanding of the mechanisms involved in the regulation of tumors that occur in the endocrine system. The exact cause of endocrine cancers remains an enigma, especially when discriminating malignant lesions from benign ones and early diagnosis. In the past [...] Read more.

Clinical endocrinology entails an understanding of the mechanisms involved in the regulation of tumors that occur in the endocrine system. The exact cause of endocrine cancers remains an enigma, especially when discriminating malignant lesions from benign ones and early diagnosis. In the past few years, the concepts of personalized medicine and metabolomics have gained great popularity in cancer research. In this systematic review, we discussed the clinical metabolomics studies in the diagnosis of endocrine cancers within the last 12 years. Cancer metabolomic studies were largely conducted using nuclear magnetic resonance (NMR) and mass spectrometry (MS) combined with separation techniques such as gas chromatography (GC) and liquid chromatography (LC). Our findings revealed that the majority of the metabolomics studies were conducted on tissue, serum/plasma, and urine samples. Studies most frequently emphasized thyroid cancer, adrenal cancer, and pituitary cancer. Altogether, analytical hyphenated techniques and chemometrics are promising tools in unveiling biomarkers in endocrine cancer and its metabolism disorders. Full article

(This article belongs to the Section Advances in Metabolomics)

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27 pages, 3207 KiB

Open AccessReview

Natural Products Targeting Hsp90 for a Concurrent Strategy in Glioblastoma and Neurodegeneration

by Sarmistha Mitra, Raju Dash, Yeasmin Akter Munni, Nusrat Jahan Selsi, Nasrin Akter, Md Nazim Uddin, Kishor Mazumder and Il Soo Moon

Metabolites 2022, 12(11), 1153; https://doi.org/10.3390/metabo12111153 - 21 Nov 2022

Cited by 2 | Viewed by 2618

Abstract

Glioblastoma multiforme (GBM) is one of the most common aggressive, resistant, and invasive primary brain tumors that share neurodegenerative actions, resembling many neurodegenerative diseases. Although multiple conventional approaches, including chemoradiation, are more frequent in GBM therapy, these approaches are ineffective in extending the [...] Read more.

Glioblastoma multiforme (GBM) is one of the most common aggressive, resistant, and invasive primary brain tumors that share neurodegenerative actions, resembling many neurodegenerative diseases. Although multiple conventional approaches, including chemoradiation, are more frequent in GBM therapy, these approaches are ineffective in extending the mean survival rate and are associated with various side effects, including neurodegeneration. This review proposes an alternative strategy for managing GBM and neurodegeneration by targeting heat shock protein 90 (Hsp90). Hsp90 is a well-known molecular chaperone that plays essential roles in maintaining and stabilizing protein folding to degradation in protein homeostasis and modulates signaling in cancer and neurodegeneration by regulating many client protein substrates. The therapeutic benefits of Hsp90 inhibition are well-known for several malignancies, and recent evidence highlights that Hsp90 inhibitors potentially inhibit the aggressiveness of GBM, increasing the sensitivity of conventional treatment and providing neuroprotection in various neurodegenerative diseases. Herein, the overview of Hsp90 modulation in GBM and neurodegeneration progress has been discussed with a summary of recent outcomes on Hsp90 inhibition in various GBM models and neurodegeneration. Particular emphasis is also given to natural Hsp90 inhibitors that have been evidenced to show dual protection in both GBM and neurodegeneration. Full article

(This article belongs to the Special Issue Effects of Plant Active Components on Cell Metabolism and Their Anti-tumor Properties)

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19 pages, 3136 KiB

Open AccessArticle

Mining Small Molecules from Teredinibacter turnerae Strains Isolated from Philippine Teredinidae

by Jamaine B. Villacorta, Camille V. Rodriguez, Jacquelyn E. Peran, Jeremiah D. Batucan, Gisela P. Concepcion, Lilibeth A. Salvador-Reyes and Hiyas A. Junio

Metabolites 2022, 12(11), 1152; https://doi.org/10.3390/metabo12111152 - 21 Nov 2022

Viewed by 2492

Abstract

Endosymbiotic relationship has played a significant role in the evolution of marine species, allowing for the development of biochemical machinery for the synthesis of diverse metabolites. In this work, we explore the chemical space of exogenous compounds from shipworm endosymbionts using LC-MS-based metabolomics. [...] Read more.

Endosymbiotic relationship has played a significant role in the evolution of marine species, allowing for the development of biochemical machinery for the synthesis of diverse metabolites. In this work, we explore the chemical space of exogenous compounds from shipworm endosymbionts using LC-MS-based metabolomics. Priority T. turnerae strains (1022X.S.1B.7A, 991H.S.0A.06B, 1675L.S.0A.01) that displayed antimicrobial activity, isolated from shipworms collected from several sites in the Philippines were cultured, and fractionated extracts were subjected for profiling using ultrahigh-performance liquid chromatography with high-resolution mass spectrometry quadrupole time-of-flight mass analyzer (UHPLC-HRMS QTOF). T. turnerae T7901 was used as a reference microorganism for dereplication analysis. Tandem MS data were analyzed through the Global Natural Products Social (GNPS) molecular networking, which resulted to 93 clusters with more than two nodes, leading to four putatively annotated clusters: lipids, lysophosphatidylethanolamines, cyclic dipeptides, and rhamnolipids. Additional clusters were also annotated through molecular networking with cross-reference to previous publications. Tartrolon D cluster with analogues, turnercyclamycins A and B; teredinibactin A, dechloroteredinibactin, and two other possible teredinibactin analogues; and oxylipin (E)-11-oxooctadec-12-enoic acid were putatively identified as described. Molecular networking also revealed two additional metabolite clusters, annotated as lyso-ornithine lipids and polyethers. Manual fragmentation analysis corroborated the putative identification generated from GNPS. However, some of the clusters remained unclassified due to the limited structural information on marine natural products in the public database. The result of this study, nonetheless, showed the diversity in the chemical space occupied by shipworm endosymbionts. This study also affirms the use of bioinformatics, molecular networking, and fragmentation mechanisms analysis as tools for the dereplication of high-throughput data to aid the prioritization of strains for further analysis. Full article

(This article belongs to the Collection Metabolome Mining)

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13 pages, 1943 KiB

Open AccessArticle

A Time-Series Metabolomic Analysis of SARS-CoV-2 Infection in a Ferret Model

by Avinash V. Karpe, Thao V. Nguyen, Rohan M. Shah, Gough G. Au, Alexander J. McAuley, Glenn A. Marsh, Sarah Riddell, Seshadri S. Vasan and David J. Beale

Metabolites 2022, 12(11), 1151; https://doi.org/10.3390/metabo12111151 - 21 Nov 2022

Cited by 1 | Viewed by 1594

Abstract

The global threat of COVID-19 has led to an increased use of metabolomics to study SARS-CoV-2 infections in animals and humans. In spite of these efforts, however, understanding the metabolome of SARS-CoV-2 during an infection remains difficult and incomplete. In this study, metabolic [...] Read more.

The global threat of COVID-19 has led to an increased use of metabolomics to study SARS-CoV-2 infections in animals and humans. In spite of these efforts, however, understanding the metabolome of SARS-CoV-2 during an infection remains difficult and incomplete. In this study, metabolic responses to a SAS-CoV-2 challenge experiment were studied in nasal washes collected from an asymptomatic ferret model (n = 20) at different time points before and after infection using an LC-MS-based metabolomics approach. A multivariate analysis of the nasal wash metabolome data revealed several statistically significant features. Despite no effects of sex or interaction between sex and time on the time course of SARS-CoV-2 infection, 16 metabolites were significantly different at all time points post-infection. Among these altered metabolites, the relative abundance of taurine was elevated post-infection, which could be an indication of hepatotoxicity, while the accumulation of sialic acids could indicate SARS-CoV-2 invasion. Enrichment analysis identified several pathways influenced by SARS-CoV-2 infection. Of these, sugar, glycan, and amino acid metabolisms were the key altered pathways in the upper respiratory channel during infection. These findings provide some new insights into the progression of SARS-CoV-2 infection in ferrets at the metabolic level, which could be useful for the development of early clinical diagnosis tools and new or repurposed drug therapies. Full article

(This article belongs to the Section Environmental Metabolomics)

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15 pages, 853 KiB

Open AccessReview

Exploring the Relationship between Obesity, Metabolic Syndrome and Neuroendocrine Neoplasms

by Xiaoyang Lan, Nicola Fazio and Omar Abdel-Rahman

Metabolites 2022, 12(11), 1150; https://doi.org/10.3390/metabo12111150 - 21 Nov 2022

Cited by 1 | Viewed by 1358

Abstract

Obesity is a major burden for modern medicine, with many links to negative health outcomes, including the increased incidence of certain cancer types. Interestingly, some studies have supported the concept of an “Obesity Paradox”, where some cancer patients living with obesity have been [...] Read more.

Obesity is a major burden for modern medicine, with many links to negative health outcomes, including the increased incidence of certain cancer types. Interestingly, some studies have supported the concept of an “Obesity Paradox”, where some cancer patients living with obesity have been shown to have a better prognosis than non-obese patients. Neuroendocrine neoplasms (NENs) are malignancies originating from neuroendocrine cells, in some cases retaining important functional properties with consequences for metabolism and nutritional status. In this review, we summarize the existing evidence demonstrating that obesity is both a risk factor for developing NENs as well as a good prognostic factor. We further identify the limitations of existing studies and further avenues of research that will be necessary to optimize the metabolic and nutritional status of patients living with NENs to ensure improved outcomes. Full article

(This article belongs to the Special Issue Metabolic Syndrome in Neuroendocrine Tumors)

24 pages, 1404 KiB

Open AccessReview

Functional Nutrients to Ameliorate Neurogenic Muscle Atrophy

by Viviana Moresi, Alessandra Renzini, Giorgia Cavioli, Marilia Seelaender, Dario Coletti, Giuseppe Gigli and Alessia Cedola

Metabolites 2022, 12(11), 1149; https://doi.org/10.3390/metabo12111149 - 21 Nov 2022

Cited by 3 | Viewed by 3745

Abstract

Neurogenic muscle atrophy is a debilitating condition that occurs from nerve trauma in association with diseases or during aging, leading to reduced interaction between motoneurons and skeletal fibers. Current therapeutic approaches aiming at preserving muscle mass in a scenario of decreased nervous input [...] Read more.

Neurogenic muscle atrophy is a debilitating condition that occurs from nerve trauma in association with diseases or during aging, leading to reduced interaction between motoneurons and skeletal fibers. Current therapeutic approaches aiming at preserving muscle mass in a scenario of decreased nervous input include physical activity and employment of drugs that slow down the progression of the condition yet provide no concrete resolution. Nutritional support appears as a precious tool, adding to the success of personalized medicine, and could thus play a relevant part in mitigating neurogenic muscle atrophy. We herein summarize the molecular pathways triggered by denervation of the skeletal muscle that could be affected by functional nutrients. In this narrative review, we examine and discuss studies pertaining to the use of functional ingredients to counteract neurogenic muscle atrophy, focusing on their preventive or curative means of action within the skeletal muscle. We reviewed experimental models of denervation in rodents and in amyotrophic lateral sclerosis, as well as that caused by aging, considering the knowledge generated with use of animal experimental models and, also, from human studies. Full article

(This article belongs to the Special Issue Effect of Functional Food on Skeletal Muscle and Metabolic Profile)

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9 pages, 2194 KiB

Open AccessArticle

MALDI Mass Spectrometry Imaging Reveals the Existence of an N-Acyl-homoserine Lactone Quorum Sensing System in Pseudomonas putida Biofilms

by Rattanaburi Pitchapa, Sivamoke Dissook, Sastia Prama Putri, Eiichiro Fukusaki and Shuichi Shimma

Metabolites 2022, 12(11), 1148; https://doi.org/10.3390/metabo12111148 - 21 Nov 2022

Cited by 2 | Viewed by 1847

Abstract

Quorum sensing (QS) is generally used to describe the process involving the release and recognition of signaling molecules, such as N-acyl-homoserine lactones, by bacteria to coordinate their response to population density and biofilm development. However, detailed information on the heterogeneity of QS [...] Read more.

Quorum sensing (QS) is generally used to describe the process involving the release and recognition of signaling molecules, such as N-acyl-homoserine lactones, by bacteria to coordinate their response to population density and biofilm development. However, detailed information on the heterogeneity of QS metabolites in biofilms remains largely unknown. Here, we describe the utilization of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to follow the production of specific metabolites, including QS metabolites, during Pseudomonas putida biofilm development. To do so, a method to grow an agar-based biofilm was first established, and MALDI-MSI was used to detect and visualize the distribution of QS metabolites in biofilms at different cultivation times. This study demonstrated that N-acyl-homoserine lactones are homogeneously produced in the early stages of P. putida biofilm formation. In contrast, the spatial distribution of quinolones and pyochelin correlated with the swarming motility of P. putida in mature biofilms. These two metabolites are involved in the production of extracellular polymeric substances and iron chelators. Our study thus contributes to establishing the specific temporal regulation and spatial distribution of N-acyl-homoserine lactone-related metabolites and quinolone and pyochelin in P. putida biofilms. Full article

(This article belongs to the Special Issue New Frontier in Mass Spectrometry Imaging for Metabolomics and Lipidomics)

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29 pages, 6778 KiB

Open AccessArticle

Spirulina platensis Suppressed iNOS and Proinflammatory Cytokines in Lipopolysaccharide-Induced BV2 Microglia

by Ee-Ling Ngu, Cheng-Yau Tan, Nicole Jean-Yean Lai, Kah-Hui Wong, Siew-Huah Lim, Long Chiau Ming, Kuan-Onn Tan, Siew-Moi Phang and Yoon-Yen Yow

Metabolites 2022, 12(11), 1147; https://doi.org/10.3390/metabo12111147 - 20 Nov 2022

Cited by 2 | Viewed by 1995

Abstract

The disease burden of neurodegenerative diseases is on the rise due to the aging population, and neuroinflammation is one of the underlying causes. Spirulina platensis is a well-known superfood with numerous reported bioactivities. However, the effect of S. platensis Universiti Malaya Algae Culture [...] Read more.

The disease burden of neurodegenerative diseases is on the rise due to the aging population, and neuroinflammation is one of the underlying causes. Spirulina platensis is a well-known superfood with numerous reported bioactivities. However, the effect of S. platensis Universiti Malaya Algae Culture Collection 159 (UMACC 159) (a strain isolated from Israel) on proinflammatory mediators and cytokines remains unknown. In this study, we aimed to determine the anti-neuroinflammatory activity of S. platensis extracts and identify the potential bioactive compounds. S. platensis extracts (hexane, ethyl acetate, ethanol, and aqueous) were screened for phytochemical content and antioxidant activity. Ethanol extract was studied for its effect on proinflammatory mediators and cytokines in lipopolysaccharide (LPS)-induced BV2 microglia. The potential bioactive compounds were identified using liquid chromatography-mass spectrometric (LC-MS) analysis. Ethanol extract had the highest flavonoid content and antioxidant and nitric oxide (NO) inhibitory activity. Ethanol extract completely inhibited the production of NO via the downregulation of inducible NO synthase (iNOS) and significantly reduced the production of tumor necrosis factor (TNF)-α and interleukin (IL)-6. Emmotin A, palmitic amide, and 1-monopalmitin, which might play an important role in cell signaling, have been identified. In conclusion, S. platensis ethanol extract inhibited neuroinflammation through the downregulation of NO, TNF-α and IL-6. This preliminary study provided insight into compound(s) isolation, which could contribute to the development of precision nutrition for disease management. Full article

(This article belongs to the Special Issue Marine Microbes Related Metabolic Studies)

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17 pages, 349 KiB

Open AccessReview

The Effects of Dietary Supplements, Nutraceutical Agents, and Physical Exercise on Myostatin Levels: Hope or Hype?

by Heitor O. Santos, Henrique S. Cerqueira and Grant M. Tinsley

Metabolites 2022, 12(11), 1146; https://doi.org/10.3390/metabo12111146 - 20 Nov 2022

Cited by 4 | Viewed by 3978

Abstract

Myostatin, a secreted growth factor belonging to the transforming growth factor β (TGF-β) family, performs a role in hindering muscle growth by inhibiting protein kinase B (Akt) phosphorylation and the associated activation of hypertrophy pathways (e.g., IGF-1/PI3K/Akt/mTOR pathway). In addition to pharmacological agents, [...] Read more.

Myostatin, a secreted growth factor belonging to the transforming growth factor β (TGF-β) family, performs a role in hindering muscle growth by inhibiting protein kinase B (Akt) phosphorylation and the associated activation of hypertrophy pathways (e.g., IGF-1/PI3K/Akt/mTOR pathway). In addition to pharmacological agents, some supplements and nutraceutical agents have demonstrated modulatory effects on myostatin levels; however, the clinical magnitude must be appraised with skepticism before translating the mechanistic effects into muscle hypertrophy outcomes. Here, we review the effects of dietary supplements, nutraceutical agents, and physical exercise on myostatin levels, addressing the promise and pitfalls of relevant randomized clinical trials (RCTs) to draw clinical conclusions. RCTs involving both clinical and sports populations were considered, along with wasting muscle disorders (e.g., sarcopenia) and resistance training-induced muscle hypertrophy, irrespective of disease status. Animal models were considered only to expand the mechanisms of action, and observational data were consulted to elucidate potential cutoff values. Collectively, the effects of dietary supplements, nutraceutical agents, and physical exercise on myostatin mRNA expression in skeletal muscle and serum myostatin levels are not uniform, and there may be reductions, increases, or neutral effects. Large amounts of research using resistance protocols shows that supplements or functional foods do not clearly outperform placebo for modulating myostatin levels. Thus, despite some biological hope in using supplements or certain functional foods to decrease myostatin levels, caution must be exercised not to propagate the hope of the food supplement market, select health professionals, and laypeople. Full article

(This article belongs to the Special Issue Effect of Functional Food on Skeletal Muscle and Metabolic Profile)

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18 pages, 2081 KiB

Open AccessReview

Recent Updates on Source, Biosynthesis, and Therapeutic Potential of Natural Flavonoid Luteolin: A Review

by Nandakumar Muruganathan, Anand Raj Dhanapal, Venkidasamy Baskar, Pandiyan Muthuramalingam, Dhivya Selvaraj, Husne Aara, Mohamed Zubair Shiek Abdullah and Iyyakkannu Sivanesan

Metabolites 2022, 12(11), 1145; https://doi.org/10.3390/metabo12111145 - 20 Nov 2022

Cited by 28 | Viewed by 2933

Abstract

Nature gives immense resources that are beneficial to humankind. The natural compounds present in plants provide primary nutritional values to our diet. Apart from food, plants also provide chemical compounds with therapeutic values. The importance of these plant secondary metabolites is increasing due [...] Read more.

Nature gives immense resources that are beneficial to humankind. The natural compounds present in plants provide primary nutritional values to our diet. Apart from food, plants also provide chemical compounds with therapeutic values. The importance of these plant secondary metabolites is increasing due to more studies revealing their beneficial properties in treating and managing various diseases and their symptoms. Among them, flavonoids are crucial secondary metabolite compounds present in most plants. Of the reported 8000 flavonoid compounds, luteolin is an essential dietary compound. This review discusses the source of the essential flavonoid luteolin in various plants and its biosynthesis. Furthermore, the potential health benefits of luteolins such as anti-cancer, anti-microbial, anti-inflammatory, antioxidant, and anti-diabetic effects and their mechanisms are discussed in detail. The activity of luteolin and its derivatives are diverse, as they help to prevent and control many diseases and their life-threatening effects. This review will enhance the knowledge and recent findings regarding luteolin and its therapeutic effects, which are certainly useful in potentially utilizing this natural metabolite. Full article

(This article belongs to the Special Issue Research Progress of Plant Compounds for Diabetes and Its Complications)

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15 pages, 2712 KiB

Open AccessArticle

The Impact of Sleep Disturbance on Gut Microbiota, Atrial Substrate, and Atrial Fibrillation Inducibility in Mice: A Multi-Omics Analysis

by Kun Zuo, Chen Fang, Yuan Fu, Zheng Liu, Ye Liu, Lifeng Liu, Yuxing Wang, Hongjiang Wang, Xiandong Yin, Xiaoqing Liu, Jing Li, Jiuchang Zhong, Mulei Chen, Xinchun Yang and Li Xu

Metabolites 2022, 12(11), 1144; https://doi.org/10.3390/metabo12111144 - 20 Nov 2022

Viewed by 1631

Abstract

This study examined the effect of sleep disturbance on gut microbiota (GM), atrial substrate, and atrial fibrillation (AF) inducibility. C57BL/6 mice were subjected to six weeks of sleep deprivation (SD) using the method of modified multiple-platform. Transesophageal burst pacing was performed to evaluate [...] Read more.

This study examined the effect of sleep disturbance on gut microbiota (GM), atrial substrate, and atrial fibrillation (AF) inducibility. C57BL/6 mice were subjected to six weeks of sleep deprivation (SD) using the method of modified multiple-platform. Transesophageal burst pacing was performed to evaluate AF inducibility. Feces, plasma, and an atrium were collected and analyzed by 16s rRNA sequencing, liquid chromatography–mass spectrometry (LC-MS)-based metabolome, histological studies, and transcriptome. Higher AF inducibility (2/30 of control vs. 15/30 of SD, p = 0.001) and longer AF duration (p < 0.001), concomitant with aggravated fibrosis, collagen, and lipid accumulation, were seen in the SD mice compared to control mice. Meanwhile, elevated alpha diversity, higher abundance of Flavonifractor, Ruminococcus, and Alloprevotella, as well as imbalanced functional pathways, were observed in the gut of SD mice. Moreover, the global patterns for the plasma metabolome were altered, e.g., the decreased butanoate metabolism intermediates in SD mice. In addition, disrupted metabolic homeostasis in the SD atrium, such as fatty acid metabolism, was analyzed by the transcriptome. These results demonstrated that the crosstalk between GM and atrial metabolism might be a promising target for SD-mediated AF susceptibility. Full article

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14 pages, 3048 KiB

Open AccessArticle

Comparative Transcriptome Analysis of MeJA Responsive Enzymes Involved in Phillyrin Biosynthesis of Forsythia suspensa

by Xiaoran Liu, Jiaqi Zhang, Hao Liu, Huixiang Shang, Xingli Zhao, Huawei Xu, Hongxiao Zhang and Dianyun Hou

Metabolites 2022, 12(11), 1143; https://doi.org/10.3390/metabo12111143 - 20 Nov 2022

Cited by 1 | Viewed by 1509

Abstract

Forsythia suspensa (Thunb.) has been widely used in traditional medicines in Asia. According to the 2020 edition of Chinese Pharmacopoeia, phillyrin is the main active ingredient in F. suspensa, which is effective in clearing heat, reducing swelling, and dispersing nodules. F. suspensa [...] Read more.

Forsythia suspensa (Thunb.) has been widely used in traditional medicines in Asia. According to the 2020 edition of Chinese Pharmacopoeia, phillyrin is the main active ingredient in F. suspensa, which is effective in clearing heat, reducing swelling, and dispersing nodules. F. suspensa leaf is a non-toxic substance and it can be used to make a health tea. Here, we combine elicitors and transcriptomics to investigate the inducible biosynthesis of the phillyrin from the F. suspensa. After the fruits and leaves of F. suspensa were treated with different concentrations of methyl jasmonate (MeJA), the content of phillyrin in the fruits reached a peak at 200 µM MeJA for 12 h, but which was decreased in leaves. To analyze the differences in key enzyme genes involved in the phillyrin biosynthesis, we sequenced the transcriptome of F. suspensa leaves and fruits treated with 200 µM MeJA for 12 h. We hypothesized that nine genes related to coniferin synthesis including: F. suspensa UDP-glycosyltransferase (FsUGT); F. suspensa 4-coumarate coenzyme CoA ligase (Fs4CL); and F. suspensa Caffeoyl-CoA O-methyltransferase (FsCCoAOMT) etc. The qRT-PCR analysis of genes related to phillyrin biosynthesis was consistent with RNA-seq analysis. We also investigated the dynamic changes of genes in F. suspensa leaves and fruits at different time points after 200 µM MeJA treatment, which laid the foundation for further study of the molecular mechanisms regulating the biosynthesis of phillyrin. Full article

(This article belongs to the Special Issue Plant Metabolic Genetic Engineering)

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14 pages, 1150 KiB

Open AccessEditor’s ChoiceArticle

Integration of Liver Glycogen and Triglyceride NMR Isotopomer Analyses Provides a Comprehensive Coverage of Hepatic Glucose and Fructose Metabolism

by Ivan Viegas, Giada Di Nunzio, Getachew D. Belew, Alejandra N. Torres, João G. Silva, Luis Perpétuo, Cristina Barosa, Ludgero C. Tavares and John G. Jones

Metabolites 2022, 12(11), 1142; https://doi.org/10.3390/metabo12111142 - 19 Nov 2022

Cited by 2 | Viewed by 3718

Abstract

Dietary glucose and fructose are both efficiently assimilated by the liver but a comprehensive measurement of this process starting from their conversion to sugar phosphates, involvement of the pentose phosphate pathway (PPP), and conversion to glycogen and lipid storage products, remains incomplete. Mice [...] Read more.

Dietary glucose and fructose are both efficiently assimilated by the liver but a comprehensive measurement of this process starting from their conversion to sugar phosphates, involvement of the pentose phosphate pathway (PPP), and conversion to glycogen and lipid storage products, remains incomplete. Mice were fed a chow diet supplemented with 35 g/100 mL drinking water of a 55/45 fructose/glucose mixture for 18 weeks. On the final night, the sugar mixture was enriched with either [U-¹³C]glucose or [U-¹³C]fructose, and deuterated water (²H₂O) was also administered. ¹³C-isotopomers representing newly synthesized hepatic glucose-6-phosphate (glucose-6-P), glycerol-3-phosphate, and lipogenic acetyl-CoA were quantified by ²H and ¹³C NMR analysis of post-mortem liver glycogen and triglyceride. These data were applied to a metabolic model covering glucose-6-P, PPP, triose-P, and de novo lipogenesis (DNL) fluxes. The glucose supplement was converted to glucose-6-P via the direct pathway, while the fructose supplement was metabolized by the liver to gluconeogenic triose-P via fructokinase–aldolase–triokinase. Glucose-6-P from all carbohydrate sources accounted for 40–60% of lipogenic acetyl-CoA and 10–12% was oxidized by the pentose phosphate pathway (PPP). The yield of NADPH from PPP flux accounted for a minority (~30%) of the total DNL requirement. In conclusion, this approach integrates measurements of glucose-6-P, PPP, and DNL fluxes to provide a holistic and informative assessment of hepatic glucose and fructose metabolism. Full article

(This article belongs to the Special Issue Advances in Metabolic Profiling of Biological Samples)

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7 pages, 512 KiB

Open AccessArticle

Normal Thermostability of p.Ser113Leu and p.Arg631Cys Variants of Mitochondrial Carnitine Palmitoyltransferase II (CPT II) in Human Muscle Homogenate

by Pushpa Raj Joshi, Maria Gräfin zu Stolberg-Stolberg, Leila Motlagh Scholle, Beate Meinhardt, Elena Pegoraro and Stephan Zierz

Metabolites 2022, 12(11), 1141; https://doi.org/10.3390/metabo12111141 - 19 Nov 2022

Cited by 1 | Viewed by 1014

Abstract

Previous fibroblast and recombinant enzyme studies showed a markedly thermolabile p.Ser113Leu variant compared to the wild-type (WT) in muscle carnitine palmitoyltransferase II (CPT II) deficiency. Additionally, it has been shown that cardiolipin (CLP) stimulated or inhibited the p.Ser113Leu recombinant variant depending on the [...] Read more.

Previous fibroblast and recombinant enzyme studies showed a markedly thermolabile p.Ser113Leu variant compared to the wild-type (WT) in muscle carnitine palmitoyltransferase II (CPT II) deficiency. Additionally, it has been shown that cardiolipin (CLP) stimulated or inhibited the p.Ser113Leu recombinant variant depending on the pre-incubation temperatures. In this study, the thermolabilities of mitochondrial enzyme CPT II in muscle homogenates of patients with the p.Ser113Leu (n = 3) and p.Arg631Cys (n = 2) variants were identified to be similar to that of WT. Pre-incubation with CLP on ice stimulated the WT enzyme more than both variants. However, CLP stimulated the variants and WT at 46 °C to about 6–18-fold. The present data indicate that the thermostability of CPT II variant in muscle homogenate is similar to that of WT. This is in contrast to the increased thermolability of enzymes derived from fibroblast and that of recombinant enzymes. Hence, it can be speculated that the disruption of the compartmentation in muscle homogenate mediates a protective effect on the thermolability of the native variant. However, the exact mechanism remains unclear. However, the activating effect of CLP on CPT II in muscle homogenate seems to align with those on recombinant enzymes. Full article

(This article belongs to the Special Issue The Interface of Mitochondrial Genetics, Epigenetics and Energetics in Muscle Metabolism)

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11 pages, 563 KiB

Open AccessArticle

Altered Urinary Metabolomics in Hereditary Angioedema

by Xue Wang and Yuxiang Zhi

Metabolites 2022, 12(11), 1140; https://doi.org/10.3390/metabo12111140 - 19 Nov 2022

Cited by 2 | Viewed by 1227

Abstract

Hereditary angioedema (HAE) is a rare and potentially life-threatening disease with heterogeneous clinical symptoms. The metabolomic profile of HAE remains unknown. Uncovering the metabolic signatures of HAE may provide inspiration for a comprehensive understanding of HAE pathogenesis and may help explore potential new [...] Read more.

Hereditary angioedema (HAE) is a rare and potentially life-threatening disease with heterogeneous clinical symptoms. The metabolomic profile of HAE remains unknown. Uncovering the metabolic signatures of HAE may provide inspiration for a comprehensive understanding of HAE pathogenesis and may help explore potential new metabolic biomarkers. We performed a comprehensive metabolic analysis using high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS). Urine samples from 34 HAE patients and 82 healthy controls (HCs) were collected to characterize the metabolic signatures associated with HAE. The metabolomes of HAE patients carrying different mutation types were also compared. A total of 795 metabolites were accurately detected and quantified. We considered 73 metabolites as differential metabolites in HAE patients (with an importance in projection (VIP) value > 1.0, q-value < 0.05, and fold change (FC) ≥ 1.2 or FC ≤ 0.8). Several metabolites associated with riboflavin metabolism, the citrate cycle, oxidative stress, and inflammation, including xanthine, oxypurinol, vitamin B2, and isocitrate, were significantly altered in HAE patients. No significantly different metabolites were found in HAE patients carrying different mutation types. The present study highlights that metabolic disturbances in the purine metabolism, riboflavin metabolism, and TCA cycle may be involved in the pathogenesis of HAE. Although biochemical significance requires further experimental verification, these findings may help to identify novel candidate metabolite biomarkers associated with HAE. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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13 pages, 1416 KiB

Open AccessArticle

Identifying Genetic Variants and Metabolites Associated with Rapid Estimated Glomerular Filtration Rate Decline in Korea Based on Genome–Metabolomic Integrative Analysis

by Sangjun Lee, Miyeun Han, Sungji Moon, Kyungsik Kim, Woo Ju An, Hyunjin Ryu, Kook-Hwan Oh and Sue K. Park

Metabolites 2022, 12(11), 1139; https://doi.org/10.3390/metabo12111139 - 19 Nov 2022

Cited by 1 | Viewed by 1372

Abstract

Identifying the predisposing factors to chronic or end-stage kidney disease is essential to preventing or slowing kidney function decline. Therefore, here, we investigated the genetic variants related to a rapid decline in the estimated glomerular filtration rate (eGFR) (i.e., a loss of >5 [...] Read more.

Identifying the predisposing factors to chronic or end-stage kidney disease is essential to preventing or slowing kidney function decline. Therefore, here, we investigated the genetic variants related to a rapid decline in the estimated glomerular filtration rate (eGFR) (i.e., a loss of >5 mL/min/1.73 m² per year) and verified the relationships between variant-related diseases and metabolic pathway signaling in patients with chronic kidney disease. We conducted a genome-wide association study that included participants with diabetes, hypertension, and rapid eGFR decline from two Korean data sources (N = 115 and 69 for the discovery and the validation cohorts, respectively). We identified a novel susceptibility locus: 4q32.3 (rs10009742 in the MARCHF1 gene, beta = −3.540, P = 4.11 × 10⁻⁸). Fine-mapping revealed 19 credible, causal single-nucleotide polymorphisms, including rs10009742. The pimelylcarnitine and octadecenoyl carnitine serum concentrations were associated with rs10009742 (beta = 0.030, P = 7.10 × 10⁻⁵, false discovery rate (FDR) = 0.01; beta = 0.167, P = 8.11 × 10⁻⁴, FDR = 0.08). Our results suggest that MARCHF1 is associated with a rapid eGFR decline in patients with hypertension and diabetes. Furthermore, MARCHF1 affects the pimelylcarnitine metabolite concentration, which may mediate chronic kidney disease progression by inducing oxidative stress in the endoplasmic reticulum. Full article

(This article belongs to the Section Endocrinology and Clinical Metabolic Research)

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14 pages, 1446 KiB

Open AccessArticle

Running for Your Life: Metabolic Effects of a 160.9/230 km Non-Stop Ultramarathon Race on Body Composition, Inflammation, Heart Function, and Nutritional Parameters

by Daniel A. Bizjak, Sebastian V. W. Schulz, Lucas John, Jana Schellenberg, Roman Bizjak, Jens Witzel, Sarah Valder, Tihomir Kostov, Jan Schalla, Jürgen M. Steinacker, Patrick Diel and Marijke Grau

Metabolites 2022, 12(11), 1138; https://doi.org/10.3390/metabo12111138 - 18 Nov 2022

Cited by 2 | Viewed by 2469

Abstract

Moderate endurance exercise leads to an improvement in cardiovascular performance, stress resilience, and blood function. However, the influence of chronic endurance exercise over several hours or days is still largely unclear. We examined the influence of a non-stop 160.9/230 km ultramarathon on body [...] Read more.

Moderate endurance exercise leads to an improvement in cardiovascular performance, stress resilience, and blood function. However, the influence of chronic endurance exercise over several hours or days is still largely unclear. We examined the influence of a non-stop 160.9/230 km ultramarathon on body composition, stress/cardiac response, and nutrition parameters. Blood samples were drawn before (pre) and after the race (post) and analyzed for ghrelin, insulin, irisin, glucagon, cortisol, kynurenine, neopterin, and total antioxidant capacity. Additional measurements included heart function by echocardiography, nutrition questionnaires, and body impedance analyses. Of the 28 included ultra-runners (7f/21m), 16 participants dropped out during the race. The remaining 12 finishers (2f/10m) showed depletion of antioxidative capacities and increased inflammation/stress (neopterin/cortisol), while energy metabolism (insulin/glucagon/ghrelin) remained unchanged despite a high negative energy balance. Free fat mass, protein, and mineral content decreased and echocardiography revealed a lower stroke volume, left end diastolic volume, and ejection fraction post race. Optimizing nutrition (high-density protein-rich diet) during the race may attenuate the observed catabolic and inflammatory effects induced by ultramarathon running. As a rapidly growing discipline, new strategies for health prevention and extensive monitoring are needed to optimize the athletes’ performance. Full article

(This article belongs to the Special Issue Metabolic Flexibility in Exercise Performances and Metabolic Diseases)

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10 pages, 541 KiB

Open AccessArticle

Carbohydrate Intake and Closed-Loop Insulin Delivery System during Two Subsequent Pregnancies in Type 1 Diabetes

by Ana Munda, Chiara Kovacic and Drazenka Pongrac Barlovic

Metabolites 2022, 12(11), 1137; https://doi.org/10.3390/metabo12111137 - 18 Nov 2022

Cited by 7 | Viewed by 1562

Abstract

Carbohydrate intake is one of the main determinants of glycemic control. In pregnancy, achievement of tight glycemic control is of utmost importance; however, data on the role of hybrid closed-loop systems (HCLs) in pregnancy are scarce. Therefore, we aimed to assess glycemic control [...] Read more.

Carbohydrate intake is one of the main determinants of glycemic control. In pregnancy, achievement of tight glycemic control is of utmost importance; however, data on the role of hybrid closed-loop systems (HCLs) in pregnancy are scarce. Therefore, we aimed to assess glycemic control achieved through the use of HCLs, and its association with carbohydrate intake in type 1 diabetes pregnancy. We included data from women with a sensor-augmented pump (SAP) during their first pregnancy and HCL use during the subsequent pregnancy. Student’s paired t-test was used to compare data between both pregnancies. Six women were identified, with age 30.2 ± 3.6 vs. 33.0 ± 3.6 years, diabetes duration 23 ± 5 vs. 26 ± 5 years, and baseline HbA_1c 6.7 ± 0.7% (50.1 ± 7.7 mmol/mol) vs. 6.3 ± 0.6% (45.2 ± 6.5 mmol/moll) in the first and second pregnancies, respectively. Time with glucose in the range 3.5–7.8 mmol/L was 69.1 ± 6.7 vs. 78.6 ± 7.4%, p = 0.045, with the HCLs compared to SAP. Higher meal frequency, but not the amount of carbohydrate consumption, was associated with more time spent in the target range and lower glycemic variability. HCLs and meal frequency were associated with better glycemic control in a small series of pregnant women with type 1 diabetes. Whether this translates to better perinatal outcomes remains to be seen. Full article

(This article belongs to the Special Issue Functional Foods and Diabetes)

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15 pages, 2332 KiB

Open AccessArticle

Effect of Breastmilk Microbiota and Sialylated Oligosaccharides on the Colonization of Infant Gut Microbial Community and Fecal Metabolome

by Juan Ding, Runze Ouyang, Sijia Zheng, Yanfeng Wang, Yan Huang, Xiao Ma, Yuxin Zou, Rong Chen, Zhihong Zhuo, Zhen Li, Qi Xin, Lina Zhou, Surong Mei, Jingyu Yan, Xin Lu, Zhigang Ren, Xinyu Liu and Guowang Xu

Metabolites 2022, 12(11), 1136; https://doi.org/10.3390/metabo12111136 - 18 Nov 2022

Cited by 6 | Viewed by 1973

Abstract

The complex microbiota and sialylated oligosaccharides in breastmilk are important bioactive components that affect the gut microbiota. However, the effect of breastmilk microbiota and sialylated oligosaccharides on the gut microbiota during the neonatal period has been largely overlooked. Here, 16S rRNA gene sequencing [...] Read more.

The complex microbiota and sialylated oligosaccharides in breastmilk are important bioactive components that affect the gut microbiota. However, the effect of breastmilk microbiota and sialylated oligosaccharides on the gut microbiota during the neonatal period has been largely overlooked. Here, 16S rRNA gene sequencing and metabolomics analysis were applied to the breastmilk and feces of 69 newborns to clarify the link between breastmilk components and the newborn gut. Results showed that Staphylococcus, Enterococcus, and Bacteroides were commonly shared and positively correlated between breastmilk and the neonatal intestine and they were the main bacteria of breastmilk that interacted with the newborn fecal metabolome. Breastmilk Staphylococcus mainly interacted with amino acids, whereas Bacteroides was involved in the tryptophan, nucleotide, and vitamin metabolism. Breastmilk sialylated oligosaccharides were related to Bacteroides and amino acids of the newborn fecal metabolites. Moreover, Bacteroides was related to the interaction between breastmilk 3′-sialyllactose and newborn fecal metabolites in the mediation effect models. Finally, we pointed out that breastmilk Bacteroides was important in the milk–gut interaction, and it was negatively associated with waist circumference in infants aged 1 year. Our study provides a scientific basis for understanding the role of breastmilk in the development of newborn gut microbiota and metabolome. Full article

(This article belongs to the Section Nutrition and Metabolism)

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19 pages, 3328 KiB

Open AccessEditor’s ChoiceArticle

Exposure to Environmentally Relevant Levels of PFAS Causes Metabolic Changes in the Freshwater Amphipod Austrochiltonia subtenuis

by Georgia M. Sinclair, Sara M. Long, Navneet Singh, Timothy L. Coggan, Matthew P. J. Askeland and Oliver A. H. Jones

Metabolites 2022, 12(11), 1135; https://doi.org/10.3390/metabo12111135 - 18 Nov 2022

Viewed by 2103

Abstract

Per and polyfluoroalkyl substances (PFAS) are of concern to environmental regulators due to their widespread occurrence, persistence and reported toxicity. However, little data exist on the effects of PFAS at environmentally relevant concentrations. The development of molecular markers for PFAS exposure would therefore [...] Read more.

Per and polyfluoroalkyl substances (PFAS) are of concern to environmental regulators due to their widespread occurrence, persistence and reported toxicity. However, little data exist on the effects of PFAS at environmentally relevant concentrations. The development of molecular markers for PFAS exposure would therefore be useful to better understand the environmental risks of these compounds. In this study, we assessed if such markers could be developed using Gas Chromatography–Mass Spectrometry-based metabolomics. We exposed the freshwater amphipod Austrochiltonia subtenuis to a range of environmentally relevant concentrations of perfluoro-octane sulfonic acid (PFOS), hexafluoropropylene oxide dimer acid (GenX) and perfluorohexanesulphonic acid (PFHxS) for 7 days at five concentrations. A metabolic response was detected in all concentrations and treatments even though the survival rates only differed significantly at the highest exposure levels. The metabolic response differed between compounds but all three PFAS induced changes in the levels of amino acids, fatty acids, and cholesterol, in line with the literature. PFOS was found to bioaccumulate. Both GenX and PFHxS were eliminated from the amphipods, but PFHxS was eliminated at a slower rate than GenX. This information improves our understanding of the sublethal effects of PFAS as well as their environmental fate and behaviour. Full article

(This article belongs to the Special Issue Integrated Systems Biology: Challenges and Future Perspectives)

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19 pages, 353 KiB

Open AccessReview

Mechanisms and Outcomes of Metabolic Surgery in Type 2 Diabetes

by Mansor Fazliana and Zubaidah Nor Hanipah

Metabolites 2022, 12(11), 1134; https://doi.org/10.3390/metabo12111134 - 17 Nov 2022

Viewed by 1705

Abstract

This review is aimed at synthesizing the mechanisms and outcomes of metabolic surgery on the endocrine system, microbiome, metabolomics, and at the molecular level. We review the hormonal, adipokine, microbiota, microRNA, and metabolomic changes in human and animal models following metabolic surgery for [...] Read more.

This review is aimed at synthesizing the mechanisms and outcomes of metabolic surgery on the endocrine system, microbiome, metabolomics, and at the molecular level. We review the hormonal, adipokine, microbiota, microRNA, and metabolomic changes in human and animal models following metabolic surgery for the treatment of obesity and diabetes. The most relevant studies in this area over the past 17 years have been considered for this review. In most cases, metabolic procedures, especially those that include intestinal bypass components, showed the remission of type 2 diabetes. This involves a variety of weight-independent mechanisms to improve glucose homeostasis, improving insulin sensitivity and secretion, gut microbiota, and bile acid cross-talk. Full article

(This article belongs to the Special Issue New Therapeutic Targets and Treatment Options in Metabolic Syndrome)

16 pages, 3860 KiB

Open AccessArticle

Anti-Diabetic and Cytotoxic Evaluation of Phlomis stewartii Plant Phytochemicals on Cigarette Smoke Inhalation and Alloxan-Induced Diabetes in Wistar Rats

by Mamoon Ur Rasheed, Syed Ali Raza Naqvi, Nasir Rasool, Syed Adnan Ali Shah and Zainul Amiruddin Zakaria

Metabolites 2022, 12(11), 1133; https://doi.org/10.3390/metabo12111133 - 17 Nov 2022

Cited by 3 | Viewed by 1626

Abstract

The generation of free radicals in body causes oxidative stress and consequently different metabolic disorders. There are numerous environmental and emotional factors that trigger free radical generation, cigarette smoke (CS) is one of them. In addition to free radical production, it also increases [...] Read more.

The generation of free radicals in body causes oxidative stress and consequently different metabolic disorders. There are numerous environmental and emotional factors that trigger free radical generation, cigarette smoke (CS) is one of them. In addition to free radical production, it also increases the risk of developing type II diabetes, cancer, and has adverse effects on other organs such as liver and kidneys. In the present study, extracts of leaves, flower, and whole plant of P. stewartii Hf. in methanol were analyzed using LC-ESI-MS and investigated for their cytotoxic properties against HepG2 cell line and CS alloxan-induced diabetes in Wistar albino rats model. A total of 24 rats were kept in aerated cage for eight weeks and exposed to CS following the administration of single dose of alloxan@140 mg/kg body weight at the end of six weeks to induce diabetes mellitus (DM). The cytotoxic activity of extracts against HepG2 was recorded in the order; leaves methanol (LM) > flower methanol (FM) and whole plant methanol (WPM). The IC50(1/4) values were in the order of 187 (LM) > 280 (FM) > 312 (WPM) µg/mL against HepG2. In positive control group, CS- and alloxan-induced diabetes significantly increased (p < 0.05) the level of alanine alkaline phosphatase (ALP), aminotransferase (ALT), aspartate aminotransferase (AST), low density lipoprotein (LDL), bilirubin, total protein, creatinine, uric acid, blood urea, globulin, total oxidant status (TOS), and malondialdehyde (MDA), as compared to negative control group. In conclusion, according to the results of this study, P. Stewartii methanol extracts showed good antioxidant, anticancer activity and worked well to recover the tested clinical parameters in CS/alloxan-induced diabetes animals, which indicated the extracts also possess good antidiabetic, hepatoprotective, and nephroprotective potential. Full article

(This article belongs to the Special Issue The Role of Phytonutrients in Metabolic Disorders)

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13 pages, 13032 KiB

Open AccessArticle

Palmitic Acid Promotes Lung Metastasis of Melanomas via the TLR4/TRIF-Peli1-pNF-κB Pathway

by Xuedan Zhang, Xiaoyu Li, Guohang Xiong, Fang Yun, Yu Feng, Qinxuan Ni, Na Wu, Lijuan Yang, Zihan Yi, Qiao Zhang, Zhe Yang, Yingmin Kuang, Buqing Sai and Yuechun Zhu

Metabolites 2022, 12(11), 1132; https://doi.org/10.3390/metabo12111132 - 17 Nov 2022

Cited by 7 | Viewed by 1538

Abstract

A high-fat diet plays an important role in aggravating cancers. Palmitic acid (PA) is one of the components of saturated fatty acids; it has been reported to promote tumor proliferation in melanomas, but the signal transduction pathway mediated by palmitic acid remains unclear. [...] Read more.

A high-fat diet plays an important role in aggravating cancers. Palmitic acid (PA) is one of the components of saturated fatty acids; it has been reported to promote tumor proliferation in melanomas, but the signal transduction pathway mediated by palmitic acid remains unclear. This study showed that palmitic acid can promote the lung metastasis of melanomas. Moreover, the interaction between palmitic acid and toll-like receptor 4 (TLR4) was predicted by molecular docking. The experimental results proved that palmitic acid could promote the TLR4 and Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF) expression. The expression of Pellino1 (Peli1) and the phosphorylation of NF-kappa B (pNF-κB) were downregulated after the suppression of TLR4 and the silencing of Peli1 also inhibited the phosphorylation of NF-κB. Therefore, we concluded that palmitic acid promoted the lung metastasis of melanomas through the TLR4/TRIF-Peli1-pNF-κB pathway. Full article

(This article belongs to the Special Issue Diet, Physical Activity, Obesity, and Metabolic Profiles in Relation to Cancer)

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14 pages, 3040 KiB

Open AccessArticle

5-Aza-2′-Deoxycytidine Regulates White Adipocyte Browning by Modulating miRNA-133a/Prdm16

by Jia Liang, Ying Jia, Huixin Yu, Haijing Yan, Qingyu Shen, Yong Xu, Yana Li and Meizi Yang

Metabolites 2022, 12(11), 1131; https://doi.org/10.3390/metabo12111131 - 17 Nov 2022

Cited by 1 | Viewed by 1629

Abstract

The conversion of white adipocytes into brown adipocytes improves their thermogenesis and promotes energy consumption. Epigenetic modifications affect related genes and interfere with energy metabolism, and these are the basis of new ideas for obesity treatment. Neonatal mice show high levels of DNA [...] Read more.

The conversion of white adipocytes into brown adipocytes improves their thermogenesis and promotes energy consumption. Epigenetic modifications affect related genes and interfere with energy metabolism, and these are the basis of new ideas for obesity treatment. Neonatal mice show high levels of DNA hypermethylation in white adipose tissue early in life and low levels in brown adipose tissue. Thus, we considered that the regulation of DNA methylation may play a role in the conversion of white adipose to brown. We observed growth indicators, lipid droplets of adipocytes, brown fat specific protein, and miRNA-133a after treatment with 5-Aza-2′-deoxycytidine. The expression of Prdm16 and Ucp-1 in adipocytes was detected after inhibiting miRNA-133a. The results showed a decrease in total lipid droplet formation and an increased expression of the brown fat specific proteins Prdm16 and Ucp-1. This study indicated that 5-Aza-2′-deoxycytidine promotes white adipocyte browning following DNA demethylation, possibly via the modulation of miR-133a and Prdm16. Full article

(This article belongs to the Special Issue Treatment of Obesity and Its Metabolic Complications)

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13 pages, 11136 KiB

Open AccessArticle

Harmonization of Rapid Evaporative Ionization Mass Spectrometry Workflows across Four Sites and Testing Using Reference Material and Local Food-Grade Meats

by Martin Kaufmann, Pierre-Maxence Vaysse, Adele Savage, Ala Amgheib, András Marton, Eftychios Manoli, Gabor Fichtinger, Steven D. Pringle, John F. Rudan, Ron M. A. Heeren, Zoltán Takáts, Júlia Balog and Tiffany Porta Siegel

Metabolites 2022, 12(11), 1130; https://doi.org/10.3390/metabo12111130 - 17 Nov 2022

Viewed by 1358

Abstract

Rapid evaporative ionization mass spectrometry (REIMS) is a direct tissue metabolic profiling technique used to accurately classify tissues using pre-built mass spectral databases. The reproducibility of the analytical equipment, methodology and tissue classification algorithms has yet to be evaluated over multiple sites, which [...] Read more.

Rapid evaporative ionization mass spectrometry (REIMS) is a direct tissue metabolic profiling technique used to accurately classify tissues using pre-built mass spectral databases. The reproducibility of the analytical equipment, methodology and tissue classification algorithms has yet to be evaluated over multiple sites, which is an essential step for developing this technique for future clinical applications. In this study, we harmonized REIMS methodology using single-source reference material across four sites with identical equipment: Imperial College London (UK); Waters Research Centre (Hungary); Maastricht University (The Netherlands); and Queen’s University (Canada). We observed that method harmonization resulted in reduced spectral variability across sites. Each site then analyzed four different types of locally-sourced food-grade animal tissue. Tissue recognition models were created at each site using multivariate statistical analysis based on the different metabolic profiles observed in the m/z range of 600–1000, and these models were tested against data obtained at the other sites. Cross-validation by site resulted in 100% correct classification of two reference tissues and 69–100% correct classification for food-grade meat samples. While we were able to successfully minimize between-site variability in REIMS signals, differences in animal tissue from local sources led to significant variability in the accuracy of an individual site’s model. Our results inform future multi-site REIMS studies applied to clinical samples and emphasize the importance of carefully-annotated samples that encompass sufficient population diversity. Full article

(This article belongs to the Special Issue Advances in Ambient Ionization Techniques for Mass Spectrometry Volume 2)

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12 pages, 2809 KiB

Open AccessArticle

BAM15 Relieves Neurodegeneration in Aged Caenorhabditis elegans and Extends Lifespan

by Injeong Cho, Hyun-Ok Song, Ha Eun Ji, Sungtae Yang and Jeong Hoon Cho

Metabolites 2022, 12(11), 1129; https://doi.org/10.3390/metabo12111129 - 17 Nov 2022

Cited by 5 | Viewed by 1815

Abstract

BAM15 was recently screened as a protonophore uncoupler specifically for the mitochondrial membrane but not the plasma membrane. It is equally as potent as FCCP, but less toxic. Previously, mitochondrial uncoupling via DNP alleviates neurodegeneration in the nematode Caenorhabditis elegans during aging. Therefore, [...] Read more.

BAM15 was recently screened as a protonophore uncoupler specifically for the mitochondrial membrane but not the plasma membrane. It is equally as potent as FCCP, but less toxic. Previously, mitochondrial uncoupling via DNP alleviates neurodegeneration in the nematode Caenorhabditis elegans during aging. Therefore, we investigated whether BAM15 uncouplers could phenotypically and functionally reduce neuronal defects in aged nematodes. We observed green fluorescence protein-tagged mechanosensory neurons and performed touch and chemotaxis assays during aging. Wild-type animals treated with both 50 µM BAM15 and 10 µM DNP showed reduced mechanosensory neuronal defects during aging, which correlates with the maintenance of touch responses and short-term memory during aging. Uncoupler mutant ucp-4 also responded the same way as the wild-type, reducing neurodegeneration in 50 µM BAM15 and 10 µM DNP-treated animals compared to the DMSO control. These results suggest that 50 µM BAM15 alleviates neurodegeneration phenotypically and functionally in C. elegans during aging, potentially through mitochondrial uncoupling. In accordance with the preserved neuronal shape and function in aged C. elegans, 50 µM BAM15 extended the mean lifespan of both wild-type and ucp-4 mutants. Full article

(This article belongs to the Special Issue Metabolites and Metabolic Regulation in the Nematode Nervous System: Behavior and Ecology)

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14 pages, 4079 KiB

Open AccessArticle

Glycyrrhizic Acid Mitigates Tripterygium-Glycoside-Tablet-Induced Acute Liver Injury via PKM2 Regulated Oxidative Stress

by Qixin Wang, Yuwen Huang, Yu Li, Luyun Zhang, Huan Tang, Junzhe Zhang, Guangqing Cheng, Minghong Zhao, Tianming Lu, Qian Zhang, Piao Luo, Yinhua Zhu, Fei Xia, Ying Zhang, Dandan Liu, Chen Wang, Haiyan Li, Chong Qiu, Jigang Wang and Qiuyan Guo

Metabolites 2022, 12(11), 1128; https://doi.org/10.3390/metabo12111128 - 17 Nov 2022

Cited by 5 | Viewed by 1626

Abstract

Tripterygium glycoside tablet (TGT), as a common clinical drug, can easily cause liver damage due to the narrow therapeutic window. Glycyrrhizic acid (GA) has a hepatoprotective effect, but the characteristics and mechanism of GA’s impact on TGT-induced acute liver injury by regulating oxidative [...] Read more.

Tripterygium glycoside tablet (TGT), as a common clinical drug, can easily cause liver damage due to the narrow therapeutic window. Glycyrrhizic acid (GA) has a hepatoprotective effect, but the characteristics and mechanism of GA’s impact on TGT-induced acute liver injury by regulating oxidative stress remain unelucidated. In this study, TGT-induced acute liver injury models were established in vitro and in vivo. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), catalase (CAT), lactate dehydrogenase (LDH), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) were quantified. The anti-apoptotic effect of GA was tested using flow cytometry. Potential target proteins of GA were profiled via activity-based protein profiling (ABPP) using a cysteine-specific (IAA-yne) probe. The results demonstrate that GA markedly decreased the concentrations of ALT, AST, AKP, MDA, LDH, TNF-α, IL-1β and IL-6, whereas those of SOD, GSH and CAT increased. GA could inhibit TGT-induced apoptosis in BRL-3A cells. GA bound directly to the cysteine residue of PKM2. The CETSA and enzyme activity results validate the specific targets identified. GA could mitigate TGT-induced acute liver injury by mediating PKM2, reducing oxidative stress and inflammation and reducing hepatocyte apoptosis. Full article

(This article belongs to the Special Issue Response to Oxidative Stress as a Welfare Parameter)

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11 pages, 791 KiB

Open AccessArticle

Investigation of Genetic Variants Associated with Tryptophan Metabolite Levels via Serotonin and Kynurenine Pathways in Patients with Bipolar Disorder

by Claudia Pisanu, Alessio Squassina, Pasquale Paribello, Stefano Dall’Acqua, Stefania Sut, Sofia Nasini, Antonella Bertazzo, Donatella Congiu, Anna Meloni, Mario Garzilli, Beatrice Guiso, Federico Suprani, Vittoria Pulcinelli, Maria Novella Iaselli, Ilaria Pinna, Giulia Somaini, Laura Arru, Carolina Corrias, Federica Pinna, Bernardo Carpiniello, Stefano Comai and Mirko Manchia Show full author list Hide full author list

Metabolites 2022, 12(11), 1127; https://doi.org/10.3390/metabo12111127 - 17 Nov 2022

Cited by 2 | Viewed by 1611

Abstract

The kynurenine pathway (KP) may play a role in the pathophysiology of bipolar disorder (BD). We conducted a genome-wide association study (GWAS) to identify genetic variants associated with the plasma levels of the metabolites of tryptophan (TRP) via the serotonin (5-HT) and kynurenine [...] Read more.

The kynurenine pathway (KP) may play a role in the pathophysiology of bipolar disorder (BD). We conducted a genome-wide association study (GWAS) to identify genetic variants associated with the plasma levels of the metabolites of tryptophan (TRP) via the serotonin (5-HT) and kynurenine (KYN) pathways in 44 patients with BD and 45 healthy controls. We assessed whether variants that were differentially associated with metabolite levels based on the diagnostic status improved the prediction accuracy of BD using penalized regression approaches. We identified several genetic variants that were significantly associated with metabolites (5-HT, 5-hydroxytryptophan (5-HTP), TRP, and quinolinic acid (QA) or metabolite ratios (5-HTP/TRP and KYN/TRP) and for which the diagnostic status exerted a significant effect. The inclusion of genetic variants led to increased accuracy in the prediction of the BD diagnostic status. Specifically, we obtained an accuracy of 0.77 using Least Absolute Shrinkage and Selection Operator (LASSO) regression. The predictors retained as informative in this model included body mass index (BMI), the levels of TRP, QA, and 5-HT, the 5-HTP/TRP ratio, and genetic variants associated with the levels of QA (rs6827515, rs715692, rs425094, rs4645874, and rs77048355) and TRP (rs292212) or the 5-HTP/TRP ratio (rs7902231). In conclusion, our study identified statistically significant associations between metabolites of TRP via the 5-HT and KYN pathways and genetic variants at the genome-wide level. The discriminative performance of penalized regression models incorporating clinical, genetic, and metabolic predictors warrants a follow-up analysis of this panel of determinants. Full article

(This article belongs to the Special Issue Effect of Tryptophan Metabolism on Neuropsychiatry and Cancer Immunotherapy)

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