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Essential Molecules in Life: Regulation, Defense, and Longevity

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

Deadline for manuscript submissions: closed (20 November 2024) | Viewed by 22555

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Prof. Dr. José Antonio Lupiáñez

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Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Avenida Fuentenueva 1, 18071 Granada, Spain
Interests: study of the anticancer potential of natural and derivatives products derived from the olive grove; molecular pathways involved in anticancer processes; glucose metabolism and its regulation; enzimology and kinetics; biochemical characterization of anti-inflammatory and anti-oxidant properties; proteomics and metabolomics associated with cancer; cell growth processes: protein synthesis and degradation
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Dr. Amalia Pérez-Jiménez

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Department of Zoology, University of Granada, Granada, Spain
Interests: animal welfare; aquatic toxicology; functional molecules; natural compounds; oxidative stress and immunology
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Dr. Eva E. Rufino Palomares

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Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Granada, Spain
Interests: anticancer bioactivities of natural products; functional proteomics; gene regulation by microRNAs; molecular characterization during inflammation and oxidative stress
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Special Issue Information

Dear Colleagues,

During the reproduction, development, longevity and evolution of the different living beings that make up the extraordinary biodiversity of animal and plant species in their environment, there have been, are and will be chemical molecules that have played a crucial role in assisting these biological processes.

Many are the examples we can give, such as amino acids, monosaccharides, disaccharides and polysaccharides, nucleotides, essential fatty acids, significant lipids, primary metabolites, secondary metabolites, peptides, low molecular weight proteins, high molecular weight proteins, different types of nucleic acids.

Different amino acids, such as aromatic, branched, sulfur-containing and simple ones like glycine, have been authentic precursors of molecules indispensable for life, among them we must mention regulators of enzymatic and metabolic activity, hormones, neurotransmitters, coenzymes, proteins like collagen, etc.

Among the nucleotides that, in addition to being the constituents of the different nucleic acids, such as DNA and RNA, single-, di- and triphosphorylated nucleosides, are presented as true regulators of metabolic activity, as a store of chemical energy or as biosynthetic precursors; cyclic nucleotides, such as cyclic AMP and cyclic GMP as cellular and physiological regulators. In this section, we should also include the different types of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) because of their relevant role in most cellular, physiological and pathological processes, which have been highlighted in recent years.

Essential fatty acids (n3 and n6 series), simple lipids such as cholesterol and its derivatives, or complex lipids such as cephalins, lecithins, inositols, cardiolipins, etc., which also behave as authentic and indispensable in the regulation and development of numerous cellular processes.

Primary metabolites such as pyruvate, acetyl-CoA, etc. that behave as metabolic crossroads; or secondary metabolites such as the different classes of phytochemicals that are key to understanding not only the defense of the organisms that generate them, but also behave as authentic regulators of immune, inflammatory, anticancer, antioxidant, etc. activity, all of these bioactivities being key to understanding the role in biological longevity.

The rest of the key molecules, peptides, low molecular weight proteins, high molecular weight proteins, different types of nucleic acids, are equally essential to understand the behavior, development and evolution of living beings.

Therefore, this special issue aims to publish the most recent and innovative advances of all the molecules and macromolecules defined above, as well as others not mentioned, both the original ones and different chemical derivatives of them, to help us understand their role in the prevention, defense, development, longevity and evolution of all living beings.

Prof. Dr. José Antonio Lupiáñez
Dr. Amalia Pérez-Jiménez
Dr. Eva E. Rufino Palomares
Guest Editors

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Keywords

glucose metabolism and its regulation
enzimology and kinetics
metabolism and evolution
cell growth
protein synthesis and degradation
cell proliferation and apoptosis
cancer
metastasis and angiogenesis
oxidative stress
genomic
proteomic and metab

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Published Papers (10 papers)

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Research

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18 pages, 9015 KiB

Open AccessArticle

Hesperetin Increases Lifespan and Antioxidant Ability Correlating with IIS, HSP, mtUPR, and JNK Pathways of Chronic Oxidative Stress in Caenorhabditis elegans

by Run-Jia Wang, Ya-Jing Ni and Yan-Qiang Liu

Int. J. Mol. Sci. 2024, 25(23), 13148; https://doi.org/10.3390/ijms252313148 - 6 Dec 2024

Viewed by 1089

Abstract

Hesperetin (Hst) is a common citrus fruit flavonoid with antioxidant, anti-inflammatory, and anti-neurodegenerative effects. To explore the antioxidant and anti-aging effects and mechanisms of Hst, we induced chronic oxidative stress in Caenorhabditis elegans (C. elegans) using low-concentration H₂O₂ and examined its effects on lifespan, healthy life index, reactive oxygen species (ROS), antioxidant enzymes, and transcriptomic metrics. Hst significantly prolonged lifespan, increased body bending and pharyngeal pumping frequency, decreased ROS accumulation, and increased antioxidant enzyme activity in normal and stressed C. elegans. Hst significantly upregulated daf-18, daf-16, gst-2, gst-3, gst-4, gst-39, hsp-16.11, sip-1, clpp-1, and dve-1 and downregulated ist-1 and kgb-1 mRNAs in stressed C. elegans. These genes are involved in the insulin/insulin-like growth factor-1 signaling (IIS), heat shock protein (HSP), mitochondrial unfolded protein response (mtUPR), and c-Jun N-terminal kinase (JNK) pathways. In summary, Hst increases lifespan and antioxidant ability, correlating with these pathways, during chronic oxidative stress in C. elegans. Full article

(This article belongs to the Special Issue Essential Molecules in Life: Regulation, Defense, and Longevity)

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14 pages, 2047 KiB

Open AccessArticle

Phenylalanine Regulates Milk Protein Synthesis via LAT1–mTOR Signaling Pathways in Bovine Mammary Epithelial Cells

by Long Guo, Chen Zheng, Jiao Chen, Ruifang Du and Fei Li

Int. J. Mol. Sci. 2024, 25(23), 13135; https://doi.org/10.3390/ijms252313135 - 6 Dec 2024

Cited by 2 | Viewed by 1051

Abstract

Phenylalanine (Phe) is a potentially limiting amino acid for lactating cows. The mechanism by which Phe regulates milk protein synthesis remains unclear. The present study elucidates the mechanisms by which phenylalanine affects milk protein synthesis, amino acid utilization, and related signaling pathways in bovine mammary epithelial cells (BMECs). The BMECs were treated with five concentrations (0, 0.22, 0.44, 0.88, 1.76 mM, and serum free). Rapamycin inhibitors and RNA interference (RNAi) were used to inhibit the phosphorylation of the mammalian target of rapamycin (mTOR) signaling pathway and the expression of relevant amino acid transporters, respectively. The results showed that 4×Phe (0.88 mM) significantly increased (p < 0.05) both the mRNA and protein expression of α-casein (CSN1S1), β-casein (CSN2), and κ-casein (CSN3), as well as L-type amino acid transporter-1 (LAT1) mRNA expression. Protein expression and modification assays of mTOR-related proteins showed that 4×Phe could increase (p < 0.05) the expression of α-casein and eukaryotic initiation factor 4E-binding protein-1 (4EBP1) and tended to increase the expression of ribosomal protein S6 protein kinase (S6K1, p = 0.054). The general control nonderepressible 2 (GCN2) signaling pathway factor, eukaryotic initiation factor 2 (eIF2α), was downregulated by 4×Phe treatment (p < 0.05). The rapamycin inhibition test showed that Phe regulated casein synthesis via the mTOR signaling pathway. RNAi experiments showed that LAT1 mediated the entry of Phe into cells. Moreover, 4×Phe treatment tended to decrease (0.05 < p < 0.10) the consumption of valine, leucine, histidine, tyrosine, cysteine, alanine, asparagine, and serine in the medium. Collectively, phenylalanine enhanced α-casein synthesis by regulating the phosphorylation of 4EBP1 and eIF2α and promoting the formation of the mTOR-centered casein translation initiation complex. Full article

(This article belongs to the Special Issue Essential Molecules in Life: Regulation, Defense, and Longevity)

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17 pages, 60081 KiB

Open AccessArticle

Molecules That Have Rarely Been Studied in Lymphatic Endothelial Cells

by Jürgen Becker and Jörg Wilting

Int. J. Mol. Sci. 2024, 25(22), 12226; https://doi.org/10.3390/ijms252212226 - 14 Nov 2024

Viewed by 1246

Abstract

A number of standard molecules are used for the molecular and histological characterization of lymphatic endothelial cells (LECs), including lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), Podoplanin (D2-40), VEGFR3, Prospero homeobox protein 1 (PROX1), and CD31. The number of molecules whose mutations cause lymphatic malformations or primary congenital lymphedema is considerable, but the majority of these diseases have not yet been characterized at the molecular level. Therefore, there is still considerable scope for molecular and functional studies of the lymphatic vasculature. Using RNASeq, we have previously characterized lymphatic endothelial cells (LECs) under normoxic and hypoxic conditions. We used this information to compare it with immunohistochemical data. We carried out some of the immunohistology ourselves, and systematically studied the Human Protein Atlas, a cell and tissue database based in Sweden. Here we describe molecules that are expressed at RNA and protein levels in LECs, hoping to stimulate future functional studies of these molecules. Full article

(This article belongs to the Special Issue Essential Molecules in Life: Regulation, Defense, and Longevity)

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22 pages, 5490 KiB

Open AccessArticle

Fem-1 Gene of Chinese White Pine Beetle (Dendroctonus armandi): Function and Response to Environmental Treatments

by Jiajin Wang, Songkai Liao, Haoyu Lin, Hongjian Wei, Xinjie Mao, Qi Wang and Hui Chen

Int. J. Mol. Sci. 2024, 25(19), 10349; https://doi.org/10.3390/ijms251910349 - 26 Sep 2024

Viewed by 999

Abstract

Dendroctonus armandi (Tsai and Li) (Coleoptera: Curculionidae: Scolytinae) is regarded as the most destructive forest pest in the Qinling and Bashan Mountains of China. The sex determination of Dendroctonus armandi plays a significant role in the reproduction of its population. In recent years, the role of the fem-1 gene in sex determination in other insects has been reported. However, the function and expression of the fem-1 gene in Dendroctonus armandi remain uncertain. In this study, three fem-1 genes were cloned and characterized. These were named Dafem-1A, Dafem-1B, and Dafem-1C, respectively. The expression levels of these three Dafem-1 genes vary at different stages of development and between the sexes. In response to different environmental treatments, including temperature, nutrients, terpenoids, and feeding duration, significant differences were observed between the three Dafem-1 genes at different developmental stages and between males and females. Furthermore, injection of double-stranded RNA (dsRNA) targeting the expressions of the Dafem-1A, Dafem-1B, and Dafem-1C genes resulted in increased mortality, deformity, and decreased emergence rates, as well as an imbalance in the sex ratio. Following the interference with Dafem-1A and Dafem-1C, no notable difference was observed in the expression of the Dafem-1B gene. Similarly, after the interference with the Dafem-1B gene, no significant difference was evident in the expression levels of the Dafem-1A and Dafem-1C genes. However, the interference of either the Dafem-1A or Dafem-1C gene results in the downregulation of the other gene. The aforementioned results demonstrate that the Dafem-1A, Dafem-1B, and Dafem-1C genes play a pivotal role in the regulation of life development and sex determination. Furthermore, it can be concluded that external factors such as temperature, nutrition, terpenoids, and feeding have a significant impact on the expression levels of the Dafem-1A, Dafem-1B, and Dafem-1C genes. This provides a crucial theoretical foundation for further elucidating the sex determination mechanism of Dendroctonus armandi. Full article

(This article belongs to the Special Issue Essential Molecules in Life: Regulation, Defense, and Longevity)

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17 pages, 338 KiB

Open AccessArticle

Effect of Nutraceutical Factors on Hepatic Intermediary Metabolism in Wistar Rats with Induced Tendinopathy

by Marta Ramos-Barbero, Eva E. Rufino-Palomares, Sergio Serrano-Carmona, Manuel Hernández-Yera, Leticia García-Salguero, José Antonio Lupiáñez and Amalia Pérez-Jiménez

Int. J. Mol. Sci. 2024, 25(1), 629; https://doi.org/10.3390/ijms25010629 - 3 Jan 2024

Cited by 1 | Viewed by 1801

Abstract

Tendinopathy (TP) is a complex clinical syndrome characterized by local inflammation, pain in the affected area, and loss of performance, preceded by tendon injury. The disease develops in three phases: Inflammatory phase, proliferative phase, and remodeling phase. There are currently no proven treatments for early reversal of this type of injury. However, the metabolic pathways of the transition metabolism, which are necessary for the proper functioning of the organism, are known. These metabolic pathways can be modified by a number of external factors, such as nutritional supplements. In this study, the modulatory effect of four dietary supplements, maslinic acid (MA), hydroxytyrosol (HT), glycine, and aspartate (AA), on hepatic intermediary metabolism was observed in Wistar rats with induced tendinopathy at different stages of the disease. Induced tendinopathy in rats produces alterations in the liver intermediary metabolism. Nutraceutical treatments modify the intermediary metabolism in the different phases of tendinopathy, so AA treatment produced a decrease in carbohydrate metabolism. In lipid metabolism, MA and AA caused a decrease in lipogenesis at the tendinopathy and increased fatty acid oxidation. In protein metabolism, MA treatment increased GDH and AST activity; HT decreased ALT activity; and the AA treatment does not cause any alteration. Use of nutritional supplements of diet could help to regulate the intermediary metabolism in the TP. Full article

(This article belongs to the Special Issue Essential Molecules in Life: Regulation, Defense, and Longevity)

18 pages, 5483 KiB

Open AccessArticle

Multi-Omics Analysis Reveals the Pathogenesis of Growth-Disordered Raccoon Dog

by Danyang Chen, Xiaolan Guo, Kaiying Wang, Weigang Zhao, Zhongjuan Chang, Quankai Wang and Chao Xu

Int. J. Mol. Sci. 2023, 24(18), 14237; https://doi.org/10.3390/ijms241814237 - 18 Sep 2023

Viewed by 1761

Abstract

Microorganisms of the genus Eperythrozoon are a zoonotic chronic infectious disease with wide distribution. We found that raccoons infected with Eperythrozoon showed obvious stunting, which seriously affected the economic benefits of raccoon dogs. To investigate the pathogenesis of the raccoon dog, we used transcriptome and proteome sequencing to analyze the changes in mRNA, miRNA, and protein expression in raccoon dogs infected with Eperythrozoon and normal raccoons. The results showed that the expression levels of genes related to immunity, metabolism, and enzyme activity were significantly changed. Among these, ERLIN1, IGF1R, CREB3L1, TNS1, TENC1, and mTOR play key roles. Additionally, the miR-1268, miR-125b, miR-10-5p, and miR-10 as central miRNAs regulate the expression of these genes. Integrated transcriptomic and proteomic analyses revealed consistent trends in mRNA and protein changes in MYH9, FKBP1A, PRKCA, and CYP11B2. These results suggest that Eperythrozoon may contribute to the slow development of raccoons by affecting the expression of mRNAs and miRNAs, reducing their immunity and causing metabolic abnormalities. Full article

(This article belongs to the Special Issue Essential Molecules in Life: Regulation, Defense, and Longevity)

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20 pages, 12763 KiB

Open AccessArticle

In Silico Identification and Analysis of Proteins Containing the Phox Homology Phosphoinositide-Binding Domain in Kinetoplastea Protists: Evolutionary Conservation and Uniqueness of Phox-Homology-Domain-Containing Protein Architectures

by Marina Petsana, Ahmed F. Roumia, Pantelis G. Bagos, Haralabia Boleti and Georgia G. Braliou

Int. J. Mol. Sci. 2023, 24(14), 11521; https://doi.org/10.3390/ijms241411521 - 15 Jul 2023

Cited by 1 | Viewed by 1973

Abstract

Kinetoplastea are free living and parasitic protists with unique features among Eukaryota. Pathogenic Kinetoplastea parasites (i.e., Trypanosoma and Leishmania spp.) undergo several developmental transitions essential for survival in their hosts. These transitions require membrane and cytoskeleton reorganizations that involve phosphoinositides (PIs). Phospholipids like PIs are key regulators of vital functions in all eukaryotes including signal transduction, protein transport and sorting, membrane trafficking, and cytoskeleton and membrane remodeling. A large repertoire of PI-metabolizing enzymes and PI-binding proteins/effectors carrying distinct PI-binding modules like the PX (phox homology) module could play significant roles in the life and virulence of pathogenic Kinetoplastea. The aim of this study was to retrieve the entire spectrum of Kinetoplastea protein sequences containing the PX module (PX-proteins), predict their structures, and identify in them evolutionary conserved and unique traits. Using a large array of bioinformatics tools, protein IDs from two searches (based on PFam’s pHMM for PX domain (PF00787)) were combined, aligned, and utilized for the construction of a new Kinetoplastea_PX pHMM. This three-step search retrieved 170 PX-protein sequences. Structural domain configuration analysis identified PX, Pkinase, Lipocalin_5, and Vps5/BAR3-WASP domains and clustered them into five distinct subfamilies. Phylogenetic tree and domain architecture analysis showed that some domain architectures exist in proteomes of all Kinetoplastea spp., while others are genus-specific. Finally, amino acid conservation logos of the Kinetoplastea spp. and Homo sapiens PX domains revealed high evolutionary conservation in residues forming the critical structural motifs for PtdIns3P recognition. This study highlights the PX-Pkinase domain architecture as unique within Trypanosoma spp. and forms the basis for a targeted functional analysis of Kinetoplastea PX-proteins as putative targets for a rational design of anti-parasitic drugs. Full article

(This article belongs to the Special Issue Essential Molecules in Life: Regulation, Defense, and Longevity)

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17 pages, 3174 KiB

Open AccessArticle

Transcriptome Profiling of Prostate Cancer, Considering Risk Groups and the TMPRSS2-ERG Molecular Subtype

by Anastasiya A. Kobelyatskaya, Elena A. Pudova, Irina V. Katunina, Anastasiya V. Snezhkina, Maria S. Fedorova, Vladislav S. Pavlov, Anastasiya O. Kotelnikova, Kirill M. Nyushko, Boris Y. Alekseev, George S. Krasnov and Anna V. Kudryavtseva

Int. J. Mol. Sci. 2023, 24(11), 9282; https://doi.org/10.3390/ijms24119282 - 25 May 2023

Cited by 6 | Viewed by 2316

Abstract

Molecular heterogeneity in prostate cancer (PCa) is one of the key reasons underlying the differing likelihoods of recurrence after surgical treatment in individual patients of the same clinical category. In this study, we performed RNA-Seq profiling of 58 localized PCa and 43 locally advanced PCa tissue samples obtained as a result of radical prostatectomy on a cohort of Russian patients. Based on bioinformatics analysis, we examined features of the transcriptome profiles within the high-risk group, including within the most commonly represented molecular subtype, TMPRSS2-ERG. The most significantly affected biological processes in the samples were also identified, so that they may be further studied in the search for new potential therapeutic targets for the categories of PCa under consideration. The highest predictive potential was found with the EEF1A1P5, RPLP0P6, ZNF483, CIBAR1, HECTD2, OGN, and CLIC4 genes. We also reviewed the main transcriptome changes in the groups at intermediate risk of PCa—Gleason Score 7 (groups 2 and 3 according to the ISUP classification)—on the basis of which the LPL, MYC, and TWIST1 genes were identified as promising additional prognostic markers, the statistical significance of which was confirmed using qPCR validation. Full article

(This article belongs to the Special Issue Essential Molecules in Life: Regulation, Defense, and Longevity)

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Review

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15 pages, 1535 KiB

Open AccessReview

Relationship between Hypoxia and Hypercapnia Tolerance and Life Expectancy

by Pavel P. Tregub, Yulia K. Komleva, Vladimir P. Kulikov, Pavel A. Chekulaev, Oksana F. Tregub, Larisa D. Maltseva, Zaripat Sh. Manasova, Inga A. Popova, Natalia S. Andriutsa, Natalia V. Samburova, Alla B. Salmina and Peter F. Litvitskiy

Int. J. Mol. Sci. 2024, 25(12), 6512; https://doi.org/10.3390/ijms25126512 - 13 Jun 2024

Cited by 1 | Viewed by 2259

Abstract

The review discusses the potential relationship between hypoxia resistance and longevity, the influence of carbon dioxide on the mechanisms of aging of the mammalian organism, and intermittent hypercapnic–hypoxic effects on the signaling pathways of aging mechanisms. In the article, we focused on the potential mechanisms of the gero-protective efficacy of carbon dioxide when combined with hypoxia. The review summarizes the possible influence of intermittent hypoxia and hypercapnia on aging processes in the nervous system. We considered the perspective variants of the application of hypercapnic–hypoxic influences for achieving active longevity and the prospects for the possibilities of developing hypercapnic–hypoxic training methods. Full article

(This article belongs to the Special Issue Essential Molecules in Life: Regulation, Defense, and Longevity)

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25 pages, 6919 KiB

Open AccessReview

Aestivation in Nature: Physiological Strategies and Evolutionary Adaptations in Hypometabolic States

by Chunxi Jiang, Kenneth B. Storey, Hongsheng Yang and Lina Sun

Int. J. Mol. Sci. 2023, 24(18), 14093; https://doi.org/10.3390/ijms241814093 - 14 Sep 2023

Cited by 11 | Viewed by 6561

Abstract

Aestivation is considered to be one of the “purest” hypometabolic states in nature, as it involves aerobic dormancy that can be induced and sustained without complex factors. Animals that undergo aestivation to protect themselves from environmental stressors such as high temperatures, droughts, and food shortages. However, this shift in body metabolism presents new challenges for survival, including oxidative stress upon awakening from aestivation, accumulation of toxic metabolites, changes in energy sources, adjustments to immune status, muscle atrophy due to prolonged immobility, and degeneration of internal organs due to prolonged food deprivation. In this review, we summarize the physiological and metabolic strategies, key regulatory factors, and networks utilized by aestivating animals to address the aforementioned components of aestivation. Furthermore, we present a comprehensive overview of the advancements made in aestivation research across major species, including amphibians, fish, reptiles, annelids, mollusks, and echinoderms, categorized according to their respective evolutionary positions. This approach offers a distinct perspective for comparative analysis, facilitating an understanding of the shared traits and unique features of aestivation across different groups of organisms. Full article

(This article belongs to the Special Issue Essential Molecules in Life: Regulation, Defense, and Longevity)

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