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Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0
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Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 36945

Special Issue Editors

Prof. Dr. Mariarosaria Santillo

E-Mail Website
Guest Editor
Dipartimento di Medicina Clinica e Chirurgia, Universita degli Studi di Napoli Federico II, Naples, Italy
Interests: obesity; DNA methylation
Special Issues, Collections and Topics in MDPI journals
Dr. Simona Damiano

E-Mail Website
Guest Editor
Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli “Federico II”, Via Pansini, 5, 80131 Napoli, Italy
Interests: obesity; DNA methylation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Control of the peripheral organ metabolism and the whole-body energy homeostasis are realized through a tight integration among hormonal, dietary, and  nervous physiological mechanisms. Topics of special interest are the mechanisms by which  dietary nutrients and drugs, acting on peripheral targets directly or indirectly at various levels of the microbiota–gut–brain axis,  affect metabolism and  inflammatory processes which, in turn, influence eating behavior and impact the course of many diseases; similarly interesting are the molecular mechanisms linking cell metabolism and growth for the understanding of metabolic alteration in cancer cells.  Despite growing progress in this area, many questions remain unresolved, with particular regard to the mechanisms of metabolism control at a molecular level. Indeed, a better understanding of how the metabolism is dysregulated in disease state can lead to the potential development of new drugs targeting metabolic pathways.  To contribute to a greater knowledge in this field, the aim of this Special Issue is to collect original papers and reviews dealing with central and peripheral molecular mechanisms underlying metabolism regulation and their disruption in diseases with significant metabolic implications, including cardiovascular diseases, obesity, neurodegenerative diseases, and cancer. Papers addressing dietary and hormone molecular mechanisms of control of adipose tissue, muscle, bone or liver metabolism  as well as central molecular mechanisms of metabolism control and energy balance are welcome.

Prof. Dr. Mariarosaria Santillo
Dr. Simona Damiano
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • cell metabolism
  • diet
  • energy homeostasis
  • hypothalamus
  • metabolic diseases
  • adipose tissue
  • muscle metabolism
  • bone metabolism
  • liver metabolism
  • inflammation
  • obesity
  • hormones
  • neurodegenerative diseases
  • cancer metabolism

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Published Papers (17 papers)

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19 pages, 2241 KiB  
Article
The Dynamic and Crucial Role of the Arginine Methylproteome in Myoblast Cell Differentiation
by Nikolaos A. Papanikolaou, Marios Nikolaidis, Grigorios D. Amoutzias, Ariadni Fouza, Maria Papaioannou, Akhilesh Pandey and Athanasios G. Papavassiliou
Int. J. Mol. Sci. 2023, 24(3), 2124; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032124 - 20 Jan 2023
Viewed by 1681
Abstract
Protein arginine methylation is an extensive and functionally significant post-translational modification. However, little is known about its role in differentiation at the systems level. Using stable isotope labeling by amino acids in cell culture (SILAC) proteomics of whole proteome analysis in proliferating or [...] Read more.
Protein arginine methylation is an extensive and functionally significant post-translational modification. However, little is known about its role in differentiation at the systems level. Using stable isotope labeling by amino acids in cell culture (SILAC) proteomics of whole proteome analysis in proliferating or five-day differentiated mouse C2C12 myoblasts, followed by high-resolution mass spectrometry, biochemical assays, and specific immunoprecipitation of mono- or dimethylated arginine peptides, we identified several protein families that were differentially methylated on arginine. Our study is the first to reveal global changes in the arginine mono- or dimethylation of proteins in proliferating myoblasts and differentiated myocytes and to identify enriched protein domains and novel short linear motifs (SLiMs). Our data may be crucial for dissecting the links between differentiation and cancer growth. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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20 pages, 2400 KiB  
Article
Characterisation of the Paternal Influence on Intergenerational Offspring Cardiac and Brain Lipid Homeostasis in Mice
by Samuel Furse, Hannah L. Morgan, Albert Koulman and Adam J. Watkins
Int. J. Mol. Sci. 2023, 24(3), 1814; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24031814 - 17 Jan 2023
Cited by 2 | Viewed by 1401
Abstract
There is growing evidence that poor paternal diet at the time of conception increase the risk of offspring developing a range of non-communicable metabolic diseases, such as obesity, diabetes and cardiovascular disease, in adulthood. We hypothesise that a paternal low protein–high carbohydrate diet [...] Read more.
There is growing evidence that poor paternal diet at the time of conception increase the risk of offspring developing a range of non-communicable metabolic diseases, such as obesity, diabetes and cardiovascular disease, in adulthood. We hypothesise that a paternal low protein–high carbohydrate diet perturbs offspring tissue lipid abundance through both sperm and seminal plasma-mediated mechanisms. To test our hypothesis, we fed male C57BL/6 mice either a control normal protein diet (NPD; 18% protein) or an isocaloric low protein diet (LPD; 9% protein) for a minimum of 8 weeks. We generated offspring through artificial insemination, in combination with vasectomised male mating. Using this approach, we derived offspring from either NPD or LPD sperm but in the presence of NPD or LPD seminal plasma. Using high resolution mass-spectrometry, we found that offspring derived from either LPD sperm or seminal fluid displayed perturbed cardiac and brain lipid abundance from just three weeks of age, typically associated with the altered abundance of tissue triglycerides. We also observed the differential sex-specific patterns of lipids between the control and experimental offspring’s hearts and brains. These observations indicate that poor paternal diet at the time of conception affects offspring cardiac and brain lipid profiles in an age-, sex- and generation-specific manner. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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11 pages, 10913 KiB  
Communication
Impacts of Subchronic and Mild Social Defeat Stress on Plasma Putrefactive Metabolites and Cardiovascular Structure in Male Mice
by Atsushi Toyoda, Kina Kawakami, Yuto Amano, Hideaki Nishizawa, Shin-ichi Nakamura, Takahiro Kawase, Yuta Yoshida, Hodaka Suzuki and Takamitsu Tsukahara
Int. J. Mol. Sci. 2023, 24(2), 1237; https://doi.org/10.3390/ijms24021237 - 08 Jan 2023
Viewed by 1625
Abstract
Psychosocial stress precipitates mental illnesses, such as depression, and increases the risk of other health problems, including cardiovascular diseases. In this study, we observed the effects of psychosocial stress on the histopathological features of systemic organs and tissues in a mouse psychosocial stress [...] Read more.
Psychosocial stress precipitates mental illnesses, such as depression, and increases the risk of other health problems, including cardiovascular diseases. In this study, we observed the effects of psychosocial stress on the histopathological features of systemic organs and tissues in a mouse psychosocial stress model, namely the subchronic and mild social defeat stress (sCSDS) model. There were several pathological findings in the tissues of both sCSDS and control mice. Mild fibrosis of the heart was observed in sCSDS mice but not in control mice. Extramedullary hematopoiesis in the spleen and hemorrhage in the lungs were observed in both the control and sCSDS mice. Focal necrosis of the liver was seen only in control mice. Furthermore, putrefactive substances in the blood plasma were analyzed because these metabolites originating from intestinal fermentation might be linked to heart fibrosis. Among them, plasma p-cresyl glucuronide and p-cresyl sulfate concentrations significantly increased owing to subchronic social defeat stress, which might influence cardiac fibrosis in sCSDS mice. In conclusion, several pathological features such as increased cardiac fibrosis and elevated plasma putrefactive substances were found in sCSDS mice. Thus, sCSDS mice are a potential model for elucidating the pathophysiology of psychosocial stress and heart failure. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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18 pages, 3444 KiB  
Article
A Low-Fat/Sucrose Diet Rich in Complex Carbohydrates Reverses High-Fat/Sucrose Diet-Induced Corneal Dysregulation
by Prince K. Akowuah, Carolina Lema, Rolando E. Rumbaut and Alan R. Burns
Int. J. Mol. Sci. 2023, 24(2), 931; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24020931 - 04 Jan 2023
Cited by 1 | Viewed by 1551
Abstract
High-fat/sucrose diet feeding in mice causes loss of corneal nerve function and impairs corneal wound healing. While changing to a diet with a low fat/sugar composition and enrichments in complex carbohydrates mitigates the reduction in nerve function, it remains to be determined if [...] Read more.
High-fat/sucrose diet feeding in mice causes loss of corneal nerve function and impairs corneal wound healing. While changing to a diet with a low fat/sugar composition and enrichments in complex carbohydrates mitigates the reduction in nerve function, it remains to be determined if it has an effect on corneal wound healing. In this study, 6-week-old C57BL/6 male mice were fed either a normal diet or a high-fat/sucrose diet for 20 weeks. A third group (diet reversal) was placed on a high-fat/sucrose diet for 10 weeks followed by a normal diet for an additional 10 weeks. A central corneal epithelial abrasion wound was created, and wound closure was monitored. Neutrophil and platelet recruitment was assessed by immunofluorescence microscopy. Mice fed the high-fat/sucrose diet-only had greater adiposity (p < 0.005) than normal diet-only fed mice; diet reversal markedly reduced adiposity. Following corneal abrasion, wound closure was delayed by ~6 h (p ≤ 0.01) and, at 30 h post-wounding, fewer neutrophils reached the wound center and fewer extravascular platelets were present at the limbus (p < 0.05). Diet restored normal wound closure and neutrophil and platelet influx in the injured cornea. These data suggest compositional changes to the diet may be an effective diet-based therapeutic strategy for maintaining or restoring corneal health. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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23 pages, 5287 KiB  
Article
Protective Effects of Human Pericyte-like Adipose-Derived Mesenchymal Stem Cells on Human Retinal Endothelial Cells in an In Vitro Model of Diabetic Retinopathy: Evidence for Autologous Cell Therapy
by Gabriella Lupo, Aleksandra Agafonova, Alessia Cosentino, Giovanni Giurdanella, Giuliana Mannino, Debora Lo Furno, Ivana Roberta Romano, Rosario Giuffrida, Floriana D’Angeli and Carmelina Daniela Anfuso
Int. J. Mol. Sci. 2023, 24(2), 913; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24020913 - 04 Jan 2023
Cited by 8 | Viewed by 2422
Abstract
Diabetic retinopathy (DR) is characterized by morphologic and metabolic alterations in endothelial cells (ECs) and pericytes (PCs) of the blood–retinal barrier (BRB). The loss of interendothelial junctions, increased vascular permeability, microaneurysms, and finally, EC detachment are the main features of DR. In this [...] Read more.
Diabetic retinopathy (DR) is characterized by morphologic and metabolic alterations in endothelial cells (ECs) and pericytes (PCs) of the blood–retinal barrier (BRB). The loss of interendothelial junctions, increased vascular permeability, microaneurysms, and finally, EC detachment are the main features of DR. In this scenario, a pivotal role is played by the extensive loss of PCs. Based on previous results, the aim of this study was to assess possible beneficial effects exerted by adipose mesenchymal stem cells (ASCs) and their pericyte-like differentiated phenotype (P-ASCs) on human retinal endothelial cells (HRECs) in high glucose conditions (25 mM glucose, HG). P-ASCs were more able to preserve BRB integrity than ASCs in terms of (a) increased transendothelial electrical resistance (TEER); (b) increased expression of adherens junction and tight junction proteins (VE-cadherin and ZO-1); (c) reduction in mRNA levels of inflammatory cytokines TNF-α, IL-1β, and MMP-9; (d) reduction in the angiogenic factor VEGF and in fibrotic TGF-β1. Moreover, P-ASCs counteracted the HG-induced activation of the pro-inflammatory phospho-ERK1/2/phospho-cPLA2/COX-2 pathway. Finally, crosstalk between HRECs and ASCs or P-ASCs based on the PDGF-B/PDGFR-β axis at the mRNA level is described herein. Thus, P-ASCs might be considered valuable candidates for therapeutic approaches aimed at countering BRB disruption in DR. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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15 pages, 3727 KiB  
Article
Amelioration of Cyclosporine A-Induced Acute Nephrotoxicity by Cordyceps cicadae Mycelia via Mg+2 Reabsorption and the Inhibition of GRP78-IRE1-CHOP Pathway: In Vivo and In Vitro
by Zong-Han Wu, Chun-Hung Chiu, Chin-Chu Chen, Charng-Cherng Chyau and Chi-Hung Cheng
Int. J. Mol. Sci. 2023, 24(1), 772; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010772 - 01 Jan 2023
Cited by 2 | Viewed by 1613
Abstract
Fruiting bodies of Cordyceps cicadae (CC) have been reported to have a therapeutic effect in chronic kidney disease. Due to the rare and expensive resources from natural habitats, artificially cultivated mycelia using submerged liquid cultivation of CC (CCM) have been recently developed as [...] Read more.
Fruiting bodies of Cordyceps cicadae (CC) have been reported to have a therapeutic effect in chronic kidney disease. Due to the rare and expensive resources from natural habitats, artificially cultivated mycelia using submerged liquid cultivation of CC (CCM) have been recently developed as an alternative to scarce sources of CC. However, little is known regarding potential protective effects of CCM against cyclosporine A (CsA)-induced acute nephrotoxicity in vivo and in vitro. In this study, male Sprague-Dawley rats were divided into six groups: control, CCM (40 mg and 400 mg/kg, orally), CsA (10 mg/kg, oral gavage), and CsA + CCM (40 mg and 400 mg/kg, orally). At the end of the study on day 8, all rats were sacrificed, and the blood and kidneys retrieved. CsA-induced acute nephrotoxicity was evident by increased levels of blood urea nitrogen (BUN). Levels of the endoplasmic reticulum (ER) resident chaperone glucose regulated protein 78 (GRP 78) were increased significantly in rats with acute nephrotoxicity. BUN and GRP 78 were significantly ameliorated in synchronous oral groups of CCM (40 or 400 mg/kg) plus CsA. Examination of hematoxylin and eosin stained kidney tissues revealed that the combined treatment of CCM slightly improved vacuolization in renal tubules upon CsA-induced damage. CsA-induced down-regulation of protein expression of magnesium ion channel proteins and transient receptor potential melastatin 6 and 7 were abolished by the combined treatment of CCM. CCM has the potential to protect the kidney against CsA-induced nephrotoxicity by reducing magnesium ion wasting, tubular cell damage, and ER stress demonstrated further by human renal proximal tubular epithelial cell line HK-2. Our results contribute to the in-depth understanding of the role of polysaccharides and nucleobases as the main secondary metabolites of CCM in the defense system of renal functions in CsA-induced acute nephrotoxicity. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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16 pages, 1401 KiB  
Article
Unbalance between Pyridine Nucleotide Cofactors in The SOD1 Deficient Yeast Saccharomyces cerevisiae Causes Hypersensitivity to Alcohols and Aldehydes
by Magdalena Kwolek-Mirek, Sabina Bednarska, Aleksandra Dubicka-Lisowska, Roman Maslanka, Renata Zadrag-Tecza and Pawel Kaszycki
Int. J. Mol. Sci. 2023, 24(1), 659; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010659 - 30 Dec 2022
Cited by 2 | Viewed by 1531
Abstract
Alcohol and aldehyde dehydrogenases are especially relevant enzymes involved in metabolic and detoxification reactions that occur in living cells. The comparison between the gene expression, protein content, and enzymatic activities of cytosolic alcohol and aldehyde dehydrogenases of the wild-type strain and the Δ [...] Read more.
Alcohol and aldehyde dehydrogenases are especially relevant enzymes involved in metabolic and detoxification reactions that occur in living cells. The comparison between the gene expression, protein content, and enzymatic activities of cytosolic alcohol and aldehyde dehydrogenases of the wild-type strain and the Δsod1 mutant lacking superoxide dismutase 1, which is hypersensitive to alcohols and aldehydes, shows that the activity of these enzymes is significantly higher in the Δsod1 mutant, but this is not a mere consequence of differences in the enzymatic protein content nor in the expression levels of genes. The analysis of the NAD(H) and NADP(H) content showed that the higher activity of alcohol and aldehyde dehydrogenases in the Δsod1 mutant could be a result of the increased availability of pyridine nucleotide cofactors. The higher level of NAD+ in the Δsod1 mutant is not related to the higher level of tryptophan; in turn, a higher generation of NADPH is associated with the upregulation of the pentose phosphate pathway. It is concluded that the increased sensitivity of the Δsod1 mutant to alcohols and aldehydes is not only a result of the disorder of redox homeostasis caused by the induction of oxidative stress but also a consequence of the unbalance between pyridine nucleotide cofactors. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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20 pages, 4231 KiB  
Article
Murine Fibroblasts and Primary Hepatocytes as Tools When Studying the Efficacy of Potential Therapies for Mucopolysaccharidosis Type I
by Magdalena Węsierska, Wioletta Nowicka, Anna Kloska, Joanna Jakóbkiewicz-Banecka and Marcelina Malinowska
Int. J. Mol. Sci. 2023, 24(1), 534; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010534 - 28 Dec 2022
Viewed by 1282
Abstract
Mucopolysaccharidosis type I (MPS I) is a metabolic genetic disease caused by the deficiency of a lysosomal enzyme involved in glycosaminoglycans (GAGs) degradation. MPS I cells have a constant level of GAG synthesis, but disturbed degradation means that GAGs accumulate progressively, impairing cell [...] Read more.
Mucopolysaccharidosis type I (MPS I) is a metabolic genetic disease caused by the deficiency of a lysosomal enzyme involved in glycosaminoglycans (GAGs) degradation. MPS I cells have a constant level of GAG synthesis, but disturbed degradation means that GAGs accumulate progressively, impairing cell metabolism. GAG metabolism can be modulated by flavonoids, and these are being studied as therapeutics for MPS. We have optimised the protocol for obtaining fibroblasts and hepatocytes from the MPS I murine model and characterised the cells for their suitability as an in vitro model for testing compounds with therapeutic potential. Methods: Murine primary hepatocytes and fibroblasts were used as a cellular model to study the effect of genistein, biochanin A, and kaempferol on the modulation of the GAG synthesis process. Flavonoids were used individually as well as in two-component mixtures. There were no statistically significant differences in GAG synthesis levels from cell types obtained from either wild-type or MPS I mice. We also showed that MPS I fibroblasts and hepatocytes store GAGs, which makes them useful in vitro models for testing the effectiveness of substrate reduction therapies. Furthermore, tested flavonoids had a different impact on GAG synthesis depending on cell type and whether they were used alone or in a mixture. The tested flavonoids reduce GAG synthesis more effectively in fibroblasts than in hepatocytes, regardless of whether they are used individually or in a mixture. Flavonoids modulate the level of GAG synthesis differently depending on cell types, therefore in vitro experiments performed to assess the effectiveness of potential therapies for metabolic diseases should be carried out using more than one cell model, and only such an approach will allow for full answering scientific questions. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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17 pages, 3031 KiB  
Article
Investigation of MicroRNA Biomarkers in Equine Distal Interphalangeal Joint Osteoarthritis
by Melissa E. Baker, Seungmee Lee, Michael Clinton, Matthias Hackl, Catarina Castanheira, Mandy J. Peffers and Sarah E. Taylor
Int. J. Mol. Sci. 2022, 23(24), 15526; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415526 - 08 Dec 2022
Cited by 3 | Viewed by 2001
Abstract
Osteoarthritis of the equine distal interphalangeal joint is a common cause of lameness. MicroRNAs from biofluids are promising biomarkers and therapeutic candidates. Synovial fluid samples from horses with mild and severe equine distal interphalangeal joint osteoarthritis were submitted for small RNA sequencing. The [...] Read more.
Osteoarthritis of the equine distal interphalangeal joint is a common cause of lameness. MicroRNAs from biofluids are promising biomarkers and therapeutic candidates. Synovial fluid samples from horses with mild and severe equine distal interphalangeal joint osteoarthritis were submitted for small RNA sequencing. The results demonstrated that miR-92a was downregulated in equine synovial fluid from horses with severe osteoarthritis and there was a significant increase in COMP, COL1A2, RUNX2 and SOX9 following miR-92a mimic treatment of equine chondrocytes in monolayer culture. This is the first equine study to evaluate the role of miR-92a in osteoarthritic chondrocytes in vitro. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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14 pages, 1728 KiB  
Article
IL-1b in the Secretomes of MSCs Seeded on Human Decellularized Allogeneic Bone Promotes Angiogenesis
by Yi-Chun Chen, Yu-Show Fu, Shang-Wen Tsai, Po-Kuei Wu, Chao-Ming Chen, Wei-Ming Chen and Cheng-Fong Chen
Int. J. Mol. Sci. 2022, 23(23), 15301; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315301 - 04 Dec 2022
Cited by 2 | Viewed by 1498
Abstract
Angiogenesis plays an important role in the development of bone and bone regeneration to provide the required molecules. Mesenchymal stem cells (MSCs) are pluripotent, self-renewing, and spindle-shaped cells, which can differentiate into multiple lineages such as chondrocytes, osteocytes, and adipocytes. MSCs derived from [...] Read more.
Angiogenesis plays an important role in the development of bone and bone regeneration to provide the required molecules. Mesenchymal stem cells (MSCs) are pluripotent, self-renewing, and spindle-shaped cells, which can differentiate into multiple lineages such as chondrocytes, osteocytes, and adipocytes. MSCs derived from bone marrow (BMMSCs), adipose tissue (ADMSCs), and Wharton’s jelly (UCMSCs) are popular in the field of tissue regeneration. MSCs have been proposed that can promote bone regeneration by enhancing vascularization. In this study, the angiogenic potential of secretomes of undifferentiated and osteo-differentiated BMMSCs, ADMSCs, and UCMSCs seeded on human decellularized allogeneic bone were compared. Human umbilical vein endothelial cells (HUVECs) were treated with MSC secretomes. Cell growth, cell migration, and angiogenesis of HUVECs were analyzed by MTT, wound healing, and tube formation assays. Angiogenic gene expression levels of MSCs were evaluated using real-time quantitative PCR. Antibody neutralization was performed to validate the candidate target. Our study demonstrates that the angiogenic gene expression profile is tissue-dependent and the angiogenic ability of secretomes is independent of the state of differentiation. We also explore that IL-1b is important for MSC angiogenic potential. Taken together, this study proves that IL-1b in the secretomes plays a vital role in angiogenesis. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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17 pages, 2410 KiB  
Article
Pleiotropic Effects of APOB Variants on Lipid Profiles, Metabolic Syndrome, and the Risk of Diabetes Mellitus
by Shih-Jung Jang, Wei-Lun Tuan, Lung-An Hsu, Leay-Kiaw Er, Ming-Sheng Teng, Semon Wu and Yu-Lin Ko
Int. J. Mol. Sci. 2022, 23(23), 14963; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314963 - 29 Nov 2022
Cited by 4 | Viewed by 1919
Abstract
Apolipoprotein B (ApoB) plays a crucial role in lipid and lipoprotein metabolism. The effects of APOB locus variants on lipid profiles, metabolic syndrome, and the risk of diabetes mellitus (DM) in Asian populations are unclear. We included 1478 Taiwan Biobank participants with whole-genome [...] Read more.
Apolipoprotein B (ApoB) plays a crucial role in lipid and lipoprotein metabolism. The effects of APOB locus variants on lipid profiles, metabolic syndrome, and the risk of diabetes mellitus (DM) in Asian populations are unclear. We included 1478 Taiwan Biobank participants with whole-genome sequence (WGS) data and 115,088 TWB participants with Axiom genome-wide CHB array data and subjected them to genotype–phenotype analyses using APOB locus variants. Five APOB nonsynonymous mutations, including Asian-specific rs144467873 and rs13306194 variants, were selected from participants with the WGS data. Using a combination of regional association studies, a linkage disequilibrium map, and multivariate analysis, we revealed that the APOB locus variants rs144467873, rs13306194, and rs1367117 were independently associated with total, low-density lipoprotein (LDL), and non-high-density lipoprotein (non-HDL) cholesterol levels; rs1318006 was associated with HDL cholesterol levels; rs13306194 and rs35131127 were associated with serum triglyceride levels; rs144467873, rs13306194, rs56213756, and rs679899 were associated with remnant cholesterol levels; and rs144467873 and rs4665709 were associated with metabolic syndrome. Mendelian randomization (MR) analyses conducted using weighted genetic risk scores from three or two LDL-cholesterol-level-associated APOB variants revealed significant association with prevalent DM (p = 0.0029 and 8.2 × 10−5, respectively), which became insignificant after adjustment for LDL-C levels. In conclusion, these results indicate that common and rare APOB variants are independently associated with various lipid levels and metabolic syndrome in Taiwanese individuals. MR analyses supported APOB variants associated with the risk of DM through their associations with LDL cholesterol levels. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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12 pages, 1588 KiB  
Article
DGCR8 Microprocessor Subunit Mutation and Expression Deregulation in Thyroid Lesions
by Lia Rodrigues, Sule Canberk, Sofia Macedo, Paula Soares and João Vinagre
Int. J. Mol. Sci. 2022, 23(23), 14812; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314812 - 26 Nov 2022
Cited by 4 | Viewed by 1477
Abstract
DGCR8 emerged recently as miRNAs biogenesis pathway protein with a highlighted role in thyroid disease. This study aimed to characterize this miRNA biogenesis component, in particular the p.(E518K) mutation and DGCR8 expression in a series of thyroid lesions. The series of thyroid lesions [...] Read more.
DGCR8 emerged recently as miRNAs biogenesis pathway protein with a highlighted role in thyroid disease. This study aimed to characterize this miRNA biogenesis component, in particular the p.(E518K) mutation and DGCR8 expression in a series of thyroid lesions. The series of thyroid lesions was genotyped for the c.1552G>A p.(E518K) mutation. When frozen tissue was available, DGCR8 mRNA expression was analysed by qPCR. Formalin-fixed paraffin-embedded tissues were studied for DGCR8 immunoexpression. We present for the first time the p.(E518K) mutation in a case of poorly differentiated thyroid carcinoma and present the deregulation of DGCR8 expression at mRNA level in follicular-patterned tumours. The obtained data solidify DGCR8 as another important player of miRNA-related gene mutations in thyroid tumorigenesis, particularly in follicular-patterned thyroid tumours. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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19 pages, 3755 KiB  
Article
SOCS3 Ablation in Leptin Receptor-Expressing Cells Causes Autonomic and Cardiac Dysfunctions in Middle-Aged Mice despite Improving Energy and Glucose Metabolism
by João A. B. Pedroso, Ivson B. da Silva, Thais T. Zampieri, Leonardo T. Totola, Thiago S. Moreira, Ana P. T. Taniguti, Gabriela P. Diniz, Maria Luiza M. Barreto-Chaves and Jose Donato, Jr.
Int. J. Mol. Sci. 2022, 23(12), 6484; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126484 - 10 Jun 2022
Cited by 5 | Viewed by 1885
Abstract
Leptin resistance is a hallmark of obesity. Treatments aiming to improve leptin sensitivity are considered a promising therapeutical approach against obesity. However, leptin receptor (LepR) signaling also modulates several neurovegetative aspects, such as the cardiovascular system and hepatic gluconeogenesis. Thus, we investigated the [...] Read more.
Leptin resistance is a hallmark of obesity. Treatments aiming to improve leptin sensitivity are considered a promising therapeutical approach against obesity. However, leptin receptor (LepR) signaling also modulates several neurovegetative aspects, such as the cardiovascular system and hepatic gluconeogenesis. Thus, we investigated the long-term consequences of increased leptin sensitivity, considering the potential beneficial and deleterious effects. To generate a mouse model with increased leptin sensitivity, the suppressor of cytokine signaling 3 (SOCS3) was ablated in LepR-expressing cells (LepR∆SOCS3 mice). LepR∆SOCS3 mice displayed reduced food intake, body adiposity and weight gain, as well as improved glucose tolerance and insulin sensitivity, and were protected against aging-induced leptin resistance. Surprisingly, a very high mortality rate was observed in aging LepR∆SOCS3 mice. LepR∆SOCS3 mice showed cardiomyocyte hypertrophy, increased myocardial fibrosis and reduced cardiovascular capacity. LepR∆SOCS3 mice exhibited impaired post-ischemic cardiac functional recovery and middle-aged LepR∆SOCS3 mice showed substantial arhythmic events during the post-ischemic reperfusion period. Finally, LepR∆SOCS3 mice exhibited fasting-induced hypoglycemia and impaired counterregulatory response to glucopenia associated with reduced gluconeogenesis. In conclusion, although increased sensitivity to leptin improved the energy and glucose homeostasis of aging LepR∆SOCS3 mice, major autonomic/neurovegetative dysfunctions compromised the health and longevity of these animals. Consequently, these potentially negative aspects need to be considered in the therapies that increase leptin sensitivity chronically. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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20 pages, 3082 KiB  
Article
Metabolic Disturbances in Rat Sublines with Constitutionally Altered Serotonin Homeostasis
by Maja Kesić, Petra Baković, Ranko Stojković, Jasminka Štefulj and Lipa Čičin-Šain
Int. J. Mol. Sci. 2021, 22(10), 5400; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105400 - 20 May 2021
Cited by 4 | Viewed by 2685
Abstract
Central and peripheral serotonin (5HT) have opposing functions in the regulation of energy homeostasis. Both increasing 5HT signaling in the brain and decreasing 5HT signaling in the periphery have been proposed as potential treatments for obesity. This study investigates the relationship between constitutionally [...] Read more.
Central and peripheral serotonin (5HT) have opposing functions in the regulation of energy homeostasis. Both increasing 5HT signaling in the brain and decreasing 5HT signaling in the periphery have been proposed as potential treatments for obesity. This study investigates the relationship between constitutionally high or low 5HT activity and systemic net energy balance. Two sublines of rats with high and low whole-body 5HT tone, obtained by selective breeding for platelet 5HT parameters, were examined for fat accumulation in different white adipose tissue (WAT) depots, glucose/insulin tolerance, blood metabolic parameters, and expression of various metabolic genes. High-5HT animals, unlike their low-5HT counterparts, developed widespread intra-abdominal obesity associated with glucose and insulin intolerance, which worsened with age. They also had elevated blood glucose and lipid parameters but showed no significant changes in circulating leptin, resistin, and adipsin levels. Surprisingly, adiponectin levels were increased in plasma but reduced in the WAT of high-5HT rats. A limited number of metabolic genes belonging to different functional classes showed differential expression in WAT of high-5HT compared to low-5HT rats. Overall, a constitutive increase in 5HT tone is associated with a positive energy balance acting through subtle dysregulation of a broad spectrum of metabolic pathways. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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Review

Jump to: Research

30 pages, 1801 KiB  
Review
Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells
by George Anderson
Int. J. Mol. Sci. 2023, 24(4), 3300; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043300 - 07 Feb 2023
Cited by 7 | Viewed by 3404
Abstract
Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic β-cells to produce adequate insulin, usually as a consequence of extensive pancreatic β-cell destruction. T1DM is classed as an immune-mediated condition. However, the processes that drive pancreatic β-cell apoptosis remain to be [...] Read more.
Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic β-cells to produce adequate insulin, usually as a consequence of extensive pancreatic β-cell destruction. T1DM is classed as an immune-mediated condition. However, the processes that drive pancreatic β-cell apoptosis remain to be determined, resulting in a failure to prevent ongoing cellular destruction. Alteration in mitochondrial function is clearly the major pathophysiological process underpinning pancreatic β-cell loss in T1DM. As with many medical conditions, there is a growing interest in T1DM as to the role of the gut microbiome, including the interactions of gut bacteria with Candida albicans fungal infection. Gut dysbiosis and gut permeability are intimately associated with raised levels of circulating lipopolysaccharide and suppressed butyrate levels, which can act to dysregulate immune responses and systemic mitochondrial function. This manuscript reviews broad bodies of data on T1DM pathophysiology, highlighting the importance of alterations in the mitochondrial melatonergic pathway of pancreatic β-cells in driving mitochondrial dysfunction. The suppression of mitochondrial melatonin makes pancreatic β-cells susceptible to oxidative stress and dysfunctional mitophagy, partly mediated by the loss of melatonin’s induction of PTEN-induced kinase 1 (PINK1), thereby suppressing mitophagy and increasing autoimmune associated major histocompatibility complex (MHC)-1. The immediate precursor to melatonin, N-acetylserotonin (NAS), is a brain-derived neurotrophic factor (BDNF) mimic, via the activation of the BDNF receptor, TrkB. As both the full-length and truncated TrkB play powerful roles in pancreatic β-cell function and survival, NAS is another important aspect of the melatonergic pathway relevant to pancreatic β-cell destruction in T1DM. The incorporation of the mitochondrial melatonergic pathway in T1DM pathophysiology integrates wide bodies of previously disparate data on pancreatic intercellular processes. The suppression of Akkermansia muciniphila, Lactobacillus johnsonii, butyrate, and the shikimate pathway—including by bacteriophages—contributes to not only pancreatic β-cell apoptosis, but also to the bystander activation of CD8+ T cells, which increases their effector function and prevents their deselection in the thymus. The gut microbiome is therefore a significant determinant of the mitochondrial dysfunction driving pancreatic β-cell loss as well as ‘autoimmune’ effects derived from cytotoxic CD8+ T cells. This has significant future research and treatment implications. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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15 pages, 1434 KiB  
Review
Liver Brain Interactions: Focus on FGF21 a Systematic Review
by Eva Prida, Sara Álvarez-Delgado, Raquel Pérez-Lois, Mateo Soto-Tielas, Ana Estany-Gestal, Johan Fernø, Luisa María Seoane, Mar Quiñones and Omar Al-Massadi
Int. J. Mol. Sci. 2022, 23(21), 13318; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113318 - 01 Nov 2022
Cited by 10 | Viewed by 4429
Abstract
Fibroblast growth factor 21 is a pleiotropic hormone secreted mainly by the liver in response to metabolic and nutritional challenges. Physiologically, fibroblast growth factor 21 plays a key role in mediating the metabolic responses to fasting or starvation and acts as an important [...] Read more.
Fibroblast growth factor 21 is a pleiotropic hormone secreted mainly by the liver in response to metabolic and nutritional challenges. Physiologically, fibroblast growth factor 21 plays a key role in mediating the metabolic responses to fasting or starvation and acts as an important regulator of energy homeostasis, glucose and lipid metabolism, and insulin sensitivity, in part by its direct action on the central nervous system. Accordingly, pharmacological recombinant fibroblast growth factor 21 therapies have been shown to counteract obesity and its related metabolic disorders in both rodents and nonhuman primates. In this systematic review, we discuss how fibroblast growth factor 21 regulates metabolism and its interactions with the central nervous system. In addition, we also state our vision for possible therapeutic uses of this hepatic-brain axis. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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14 pages, 1297 KiB  
Review
Endothelial Cell Participation in Inflammatory Reaction
by Jean-Luc Wautier and Marie-Paule Wautier
Int. J. Mol. Sci. 2021, 22(12), 6341; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126341 - 13 Jun 2021
Cited by 15 | Viewed by 3202
Abstract
Inflammation is an old concept that has started to be considered as an important factor in infection and chronic diseases. The role of leukocytes, the plasmatic components, then of the mediators such as prostaglandins, cytokines, and, in recent decades, of the endothelium has [...] Read more.
Inflammation is an old concept that has started to be considered as an important factor in infection and chronic diseases. The role of leukocytes, the plasmatic components, then of the mediators such as prostaglandins, cytokines, and, in recent decades, of the endothelium has completed the concept of the inflammation process. The function of the endothelium appeared to be crucial as a regulator or the initiator of the inflammatory process. Culture of human endothelial cells and experimental systems made it possible to define the molecular basis of inflammation in vascular diseases, in diabetes mellitus, atherosclerosis, vasculitis and thromboembolic complications. Advanced glycation end product receptor (RAGE), present on endothelial cells (ECs) and monocytes, participates in the activation of these cells in inflammatory conditions. Inflammasome is a cytosolic multiprotein that controls the response to diverse microorganisms. It is positively regulated by stimulator of interferon response CGAMP interactor-1 (STING1). Angiogenesis and thrombotic events are dysregulated during inflammation. ECs appear to be a protector, but also a possible initiator of thrombosis. Full article
(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation 2.0)
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