Biomolecules

2024

Jump to: 2023, 2022, 2021

16 pages, 1695 KiB

Open AccessArticle

Mouse Exploratory Behaviour in the Open Field with and without NAT-1 EEG Device: Effects of MK801 and Scopolamine

by Charmaine J. M. Lim, Jack Bray, Sanna K. Janhunen, Bettina Platt and Gernot Riedel

Biomolecules 2024, 14(8), 1008; https://doi.org/10.3390/biom14081008 - 15 Aug 2024

Viewed by 873

Abstract

One aspect of reproducibility in preclinical research that is frequently overlooked is the physical condition in which physiological, pharmacological, or behavioural recordings are conducted. In this study, the physical conditions of mice were altered through the attachments of wireless electrophysiological recording devices (Neural [...] Read more.

One aspect of reproducibility in preclinical research that is frequently overlooked is the physical condition in which physiological, pharmacological, or behavioural recordings are conducted. In this study, the physical conditions of mice were altered through the attachments of wireless electrophysiological recording devices (Neural Activity Tracker-1, NAT-1). NAT-1 devices are miniaturised multichannel devices with onboard memory for direct high-resolution recording of brain activity for >48 h. Such devices may limit the mobility of animals and affect their behavioural performance due to the added weight (total weight of approximately 3.4 g). The mice were additionally treated with saline (control), N-methyl-D-aspartate (NMDA) receptor antagonist MK801 (0.85 mg/kg), or the muscarinic acetylcholine receptor blocker scopolamine (0.65 mg/kg) to allow exploration of the effect of NAT-1 attachments in pharmacologically treated mice. We found only minimal differences in behavioural outcomes with NAT-1 attachments in standard parameters of locomotor activity widely reported for the open field test between the drug treatments. Hypoactivity was globally observed as a consistent outcome in the MK801-treated mice and hyperactivity in scopolamine groups regardless of NAT-1 attachments. These data collectively confirm the reproducibility for combined behavioural, pharmacological, and physiological endpoints even in the presence of lightweight wireless data loggers. The NAT-1 therefore constitutes a pertinent tool for investigating brain activity in, e.g., drug discovery and models of neuropsychiatric and/or neurodegenerative diseases with minimal effects on pharmacological and behavioural outcomes. Full article

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2023

Jump to: 2024, 2022, 2021

21 pages, 1519 KiB

Open AccessReview

Nociceptor–Macrophage Interactions in Apical Periodontitis: How Biomolecules Link Inflammation with Pain

by Nandita Menon and Anil Kishen

Biomolecules 2023, 13(8), 1193; https://doi.org/10.3390/biom13081193 - 31 Jul 2023

Cited by 2 | Viewed by 3370

Abstract

Periradicular tissues have a rich supply of peripheral afferent neurons, also known as nociceptive neurons, originating from the trigeminal nerve. While their primary function is to relay pain signals to the brain, these are known to be involved in modulating innate and adaptive [...] Read more.

Periradicular tissues have a rich supply of peripheral afferent neurons, also known as nociceptive neurons, originating from the trigeminal nerve. While their primary function is to relay pain signals to the brain, these are known to be involved in modulating innate and adaptive immunity by initiating neurogenic inflammation (NI). Studies have investigated neuroanatomy and measured the levels of biomolecules such as cytokines and neuropeptides in human saliva, gingival crevicular fluid, or blood/serum samples in apical periodontitis (AP) to validate the possible role of trigeminal nociceptors in inflammation and tissue regeneration. However, the contributions of nociceptors and the mechanisms involved in the neuro-immune interactions in AP are not fully understood. This narrative review addresses the complex biomolecular interactions of trigeminal nociceptors with macrophages, the effector cells of the innate immune system, in the clinical manifestations of AP. Full article

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14 pages, 2183 KiB

Open AccessFeature PaperArticle

HIV-1 Transcriptional Activator Tat Inhibits IL2 Expression by Preventing the Presence of Pol II on the IL2 Promoter

by Spyridoula Anastasopoulou, Tassos Georgakopoulos and Athanasia Mouzaki

Biomolecules 2023, 13(6), 881; https://doi.org/10.3390/biom13060881 - 24 May 2023

Cited by 2 | Viewed by 1768

Abstract

HIV-1 infection leads to a gradual loss of T helper cells, chronic immune activation, and eventual immune system breakdown. HIV-1 causes deregulation of the expression of IL-2, a cytokine important for T helper cell growth and survival, which is downregulated in HIV-1 patients. [...] Read more.

HIV-1 infection leads to a gradual loss of T helper cells, chronic immune activation, and eventual immune system breakdown. HIV-1 causes deregulation of the expression of IL-2, a cytokine important for T helper cell growth and survival, which is downregulated in HIV-1 patients. The present study addresses the regulation of IL2 expression via HIV-1 Tat transcriptional activator. We used J-LAT cells, a T cell line that serves as a latency model for studies of HIV-1 expression in T cells, and as controls a T cell line lacking HIV-1 elements and a T cell line with a stably integrated copy of the HIV-1-LTR promoter. We show that endogenously expressed Tat inhibits IL2 transcription in J-Lat cells via its presence in the ARRE-1/2 elements of the IL2 promoter and that the inhibition of IL2 expression is mediated by Tat inhibiting Pol II activity at the IL2 promoter, which is mediated by preventing the presence of Pol II at the ARRE-1/2 elements. Overall, Tat is present at the IL2 promoter, apart from its cognate HIV-1 LTR target. This supports our current knowledge of how HIV-1 affects the host transcriptional machinery and reflects the potential of Tat to disrupt transcriptional regulation of host genes to manipulate cell responses. Full article

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21 pages, 2741 KiB

Open AccessReview

Biological Catalysis and Information Storage Have Relied on N-Glycosyl Derivatives of β-D-Ribofuranose since the Origins of Life

by Katarzyna Wozniak and Krzysztof Brzezinski

Biomolecules 2023, 13(5), 782; https://doi.org/10.3390/biom13050782 - 30 Apr 2023

Viewed by 2302

Abstract

Most naturally occurring nucleotides and nucleosides are N-glycosyl derivatives of β-d-ribose. These N-ribosides are involved in most metabolic processes that occur in cells. They are essential components of nucleic acids, forming the basis for genetic information storage and flow. [...] Read more.

Most naturally occurring nucleotides and nucleosides are N-glycosyl derivatives of β-d-ribose. These N-ribosides are involved in most metabolic processes that occur in cells. They are essential components of nucleic acids, forming the basis for genetic information storage and flow. Moreover, these compounds are involved in numerous catalytic processes, including chemical energy production and storage, in which they serve as cofactors or coribozymes. From a chemical point of view, the overall structure of nucleotides and nucleosides is very similar and simple. However, their unique chemical and structural features render these compounds versatile building blocks that are crucial for life processes in all known organisms. Notably, the universal function of these compounds in encoding genetic information and cellular catalysis strongly suggests their essential role in the origins of life. In this review, we summarize major issues related to the role of N-ribosides in biological systems, especially in the context of the origin of life and its further evolution, through the RNA-based World(s), toward the life we observe today. We also discuss possible reasons why life has arisen from derivatives of β-d-ribofuranose instead of compounds based on other sugar moieties. Full article

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24 pages, 6204 KiB

Open AccessArticle

nWASP Inhibition Increases Wound Healing via TrKb/PLCγ Signalling

by Bethan A. Frugtniet, Fiona Ruge, Andrew J. Sanders, Sioned Owen, Keith G. Harding, Wen G. Jiang and Tracey A. Martin

Biomolecules 2023, 13(2), 379; https://doi.org/10.3390/biom13020379 - 17 Feb 2023

Viewed by 2337

Abstract

(1) Background: Chronic wounds represent a major burden to patients and healthcare systems and identifying new therapeutic targets to encourage wound healing is a significant challenge. This study evaluated nWASP as a new therapeutic target in human wound healing and determined how this [...] Read more.

(1) Background: Chronic wounds represent a major burden to patients and healthcare systems and identifying new therapeutic targets to encourage wound healing is a significant challenge. This study evaluated nWASP as a new therapeutic target in human wound healing and determined how this can be regulated. (2) Methods: Clinical cohorts from patients with chronic wounds were tested for the expression of nWASP and cell models were employed to evaluate the influence of nWASP on cellular functions that are key to the healing process following knockdown and/or the use of nWASP-specific inhibitors. (3) Results: nWASP was significantly elevated at transcript levels in human non-healing chronic wounds versus healing tissues. nWASP inhibitors, wiskostatin and 187-1, along with the knockdown of nWASP, modified both HaCaT and HECV cell behaviour. We then identified two signalling pathways affected by nWASP inhibition: TrkB signalling and downstream PLCγ1 phosphorylation were impaired by nWASP inhibition in HaCaT cells. The healing of wounds in a diabetic murine model was significantly improved with an nWASP inhibitor treatment. (4) Conclusions: This study showed that nWASP activity was related to the non-healing behaviour of chronic wounds and together with the findings in the in vivo models, it strongly suggested nWASP as a therapeutic target in non-healing wounds that are regulated via TrkB and PLCγ1 signalling. Full article

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13 pages, 2210 KiB

Open AccessArticle

The Role of a Cytokinin Antagonist in the Progression of Clubroot Disease

by Jana Bíbová, Veronika Kábrtová, Veronika Večeřová, Zuzana Kučerová, Martin Hudeček, Lenka Plačková, Ondřej Novák, Miroslav Strnad and Ondřej Plíhal

Biomolecules 2023, 13(2), 299; https://doi.org/10.3390/biom13020299 - 5 Feb 2023

Cited by 1 | Viewed by 2596

Abstract

Plasmodiophora brassicae is an obligate biotrophic pathogen causing clubroot disease in cruciferous plants. Infected plant organs are subject to profound morphological changes, the roots form characteristic galls, and the leaves are chlorotic and abscise. The process of gall formation is governed by timely [...] Read more.

Plasmodiophora brassicae is an obligate biotrophic pathogen causing clubroot disease in cruciferous plants. Infected plant organs are subject to profound morphological changes, the roots form characteristic galls, and the leaves are chlorotic and abscise. The process of gall formation is governed by timely changes in the levels of endogenous plant hormones that occur throughout the entire life cycle of the clubroot pathogen. The homeostasis of two plant hormones, cytokinin and auxin, appears to be crucial for club development. To investigate the role of cytokinin and auxin in gall formation, we used metabolomic and transcriptomic profiling of Arabidopsis thaliana infected with clubroot, focusing on the late stages of the disease, where symptoms were more pronounced. Loss-of-function mutants of three cytokinin receptors, AHK2, AHK3, and CRE1/AHK4, were employed to further study the homeostasis of cytokinin in response to disease progression; ahk double mutants developed characteristic symptoms of the disease, albeit with varying intensity. The most susceptible to clubroot disease was the ahk3 ahk4 double mutant, as revealed by measuring its photosynthetic performance. Quantification of phytohormone levels and pharmacological treatment with the cytokinin antagonist PI-55 showed significant changes in the levels of endogenous cytokinin and auxin, which was manifested by both enhanced and reduced development of disease symptoms in different genotypes. Full article

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11 pages, 1378 KiB

Open AccessArticle

Heparin-Induced Changes of Vascular Endothelial Growth Factor (VEGF₁₆₅) Structure

by Ekaterina L. Nemashkalova, Marina P. Shevelyova, Andrey V. Machulin, Dmitry D. Lykoshin, Roman S. Esipov and Evgenia I. Deryusheva

Biomolecules 2023, 13(1), 98; https://doi.org/10.3390/biom13010098 - 3 Jan 2023

Cited by 3 | Viewed by 2307

Abstract

Vascular endothelial growth factor-A (VEGF-A), a secreted homodimeric glycoprotein, is a critical regulator of angiogenesis in normal and pathological states. The binding of heparin (HE) to VEGF₁₆₅ (the major form of VEGF-A) modulates the angiogenesis-related cascade, but the mechanism of the observed [...] Read more.

Vascular endothelial growth factor-A (VEGF-A), a secreted homodimeric glycoprotein, is a critical regulator of angiogenesis in normal and pathological states. The binding of heparin (HE) to VEGF₁₆₅ (the major form of VEGF-A) modulates the angiogenesis-related cascade, but the mechanism of the observed changes at the structural level is still insufficiently explored. In the present study, we examined the effect of HE on the structural and physicochemical properties of recombinant human VEGF₁₆₅ (rhVEGF₁₆₅). The HE binding results in an increase of hydrophobic surface exposure in rhVEGF₁₆₅ without changes in its secondary structure. Differential scanning calorimetry measurements for intact and HE-bound rhVEGF₁₆₅ reveals the absence of any pronounced thermally induced transitions in the protein in the temperature range from 20 to 100 °C. The apolar area increase during the heparin binding explains the pronounced HE-induced oligomerization/aggregation of rhVEGF₁₆₅, as studied by chemical glutaraldehyde cross-linking and dynamic light scattering. Molecular modeling and docking techniques were used to model the full structure of dimeric VEGF₁₆₅ and to reveal putative molecular mechanisms underlying the function of the VEGF₁₆₅/HE system. In general, the results obtained can be a basis for explaining the modulating effect of HE on the biological activity of VEGF-A. Full article

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2022

Jump to: 2024, 2023, 2021

21 pages, 1760 KiB

Open AccessArticle

Proteome Profile Changes Induced by Heterologous Overexpression of Mycobacterium tuberculosis-Derived Antigens PstS-1 (Rv0934) and Ag85B (Rv1886c) in Mycobacterium microti

by Viridiana García-Ruiz, Patricia Orduña, Antonia I. Castillo-Rodal, Teresa J. Flores-Rodríguez and Yolanda López-Vidal

Biomolecules 2022, 12(12), 1836; https://doi.org/10.3390/biom12121836 - 8 Dec 2022

Viewed by 2054

Abstract

The development of new tuberculosis vaccines remains a global priority, and recombinant vaccines are a frequently investigated option. These vaccines follow a molecular strategy that may enhance protective efficacy. However, their functional differences, particularly with respect to glycosylation, remain unknown. Recent studies have [...] Read more.

The development of new tuberculosis vaccines remains a global priority, and recombinant vaccines are a frequently investigated option. These vaccines follow a molecular strategy that may enhance protective efficacy. However, their functional differences, particularly with respect to glycosylation, remain unknown. Recent studies have shown that glycosylation plays a key role in the host-pathogen interactions during immune recognition. The aim of this study was to determine the differences in the glycosylation profiles of two recombinant strains of Mycobacterium microti, overexpressing Ag85B (Rv1886c) and PstS-1 (Rv0934) antigens of M. tuberculosis. For each strain, the glycosylation profile was determined by Western blotting with lectins. The results showed the presence of mannosylated proteins and evidence of linked sialic acid proteins. Interestingly, different proteome and glycoproteome profiles were observed between the two recombinant strains and the wild-type strain. We have shown here that the construction of the recombinant strains of M. microti has altered the proteome and glycosylation profiles of these strains, leading us to ask what impact these changes might have on the immune response. Full article

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11 pages, 2322 KiB

Open AccessBrief Report

Lack of Ecto-5′-Nucleotidase Protects Sensitized Mice against Allergen Challenge

by Elisabetta Caiazzo, Ida Cerqua, Roberta Turiello, Maria Antonietta Riemma, Giacomo De Palma, Armando Ialenti, Fiorentina Roviezzo, Silvana Morello and Carla Cicala

Biomolecules 2022, 12(5), 697; https://doi.org/10.3390/biom12050697 - 13 May 2022

Cited by 4 | Viewed by 3147

Abstract

Ecto-5′-nucleotidase (CD73), the ectoenzyme that together with CD39 is responsible for extracellular ATP hydrolysis and adenosine accumulation, regulates immune/inflammatory processes by controlling innate and acquired immunity cell functions. We previously demonstrated that CD73 is required for the assessment of a controlled allergic sensitization, [...] Read more.

Ecto-5′-nucleotidase (CD73), the ectoenzyme that together with CD39 is responsible for extracellular ATP hydrolysis and adenosine accumulation, regulates immune/inflammatory processes by controlling innate and acquired immunity cell functions. We previously demonstrated that CD73 is required for the assessment of a controlled allergic sensitization, in mice. Here, we evaluated the response to aerosolized allergen of female-sensitized mice lacking CD73 in comparison with their wild type counterpart. Results obtained show, in mice lacking CD73, the absence of airway hyperreactivity in response to an allergen challenge, paralleled by reduced airway CD23⁺B cells and IL4⁺T cells pulmonary accumulation together with reduced mast cells accumulation and degranulation. Our findings indicate CD73 as a potential therapeutic target for allergic asthma. Full article

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2021

Jump to: 2024, 2023, 2022

22 pages, 2795 KiB

Open AccessArticle

Deepening into Intracellular Signaling Landscape through Integrative Spatial Proteomics and Transcriptomics in a Lymphoma Model

by Alicia Landeira-Viñuela, Paula Díez, Pablo Juanes-Velasco, Quentin Lécrevisse, Alberto Orfao, Javier De Las Rivas and Manuel Fuentes

Biomolecules 2021, 11(12), 1776; https://doi.org/10.3390/biom11121776 - 26 Nov 2021

Cited by 11 | Viewed by 2848

Abstract

Human Proteome Project (HPP) presents a systematic characterization of the protein landscape under different conditions using several complementary-omic techniques (LC-MS/MS proteomics, affinity proteomics, transcriptomics, etc.). In the present study, using a B-cell lymphoma cell line as a model, comprehensive integration of RNA-Seq transcriptomics, [...] Read more.

Human Proteome Project (HPP) presents a systematic characterization of the protein landscape under different conditions using several complementary-omic techniques (LC-MS/MS proteomics, affinity proteomics, transcriptomics, etc.). In the present study, using a B-cell lymphoma cell line as a model, comprehensive integration of RNA-Seq transcriptomics, MS/MS, and antibody-based affinity proteomics (combined with size-exclusion chromatography) (SEC-MAP) were performed to uncover correlations that could provide insights into protein dynamics at the intracellular level. Here, 5672 unique proteins were systematically identified by MS/MS analysis and subcellular protein extraction strategies (neXtProt release 2020-21, MS/MS data are available via ProteomeXchange with identifier PXD003939). Moreover, RNA deep sequencing analysis of this lymphoma B-cell line identified 19,518 expressed genes and 5707 protein coding genes (mapped to neXtProt). Among these data sets, 162 relevant proteins (targeted by 206 antibodies) were systematically analyzed by the SEC-MAP approach, providing information about PTMs, isoforms, protein complexes, and subcellular localization. Finally, a bioinformatic pipeline has been designed and developed for orthogonal integration of these high-content proteomics and transcriptomics datasets, which might be useful for comprehensive and global characterization of intracellular protein profiles. Full article

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11 pages, 2184 KiB

Open AccessFeature PaperArticle

Attenuation of PITPNM1 Signaling Cascade Can Inhibit Breast Cancer Progression

by Zihao Liu, Yu Shi, Qun Lin, Wenqian Yang, Qing Luo, Yinghuan Cen, Juanmei Li, Xiaolin Fang, Wen G. Jiang and Chang Gong

Biomolecules 2021, 11(9), 1265; https://doi.org/10.3390/biom11091265 - 25 Aug 2021

Cited by 3 | Viewed by 2751

Abstract

Phosphatidylinositol transfer protein membrane-associated 1 (PITPNM1) contains a highly conserved phosphatidylinositol transfer domain which is involved in phosphoinositide trafficking and signaling transduction under physiological conditions. However, the functional role of PITPNM1 in cancer progression remains unknown. Here, by integrating datasets of The Cancer [...] Read more.

Phosphatidylinositol transfer protein membrane-associated 1 (PITPNM1) contains a highly conserved phosphatidylinositol transfer domain which is involved in phosphoinositide trafficking and signaling transduction under physiological conditions. However, the functional role of PITPNM1 in cancer progression remains unknown. Here, by integrating datasets of The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer (METABRIC), we found that the expression of PITPNM1 is much higher in breast cancer tissues than in normal breast tissues, and a high expression of PITPNM1 predicts a poor prognosis for breast cancer patients. Through gene set variation analysis (GSEA) and gene ontology (GO) analysis, we found PITPNM1 is mainly associated with carcinogenesis and cell-to-cell signaling ontology. Silencing of PITPNM1, in vitro, significantly abrogates proliferation and colony formation of breast cancer cells. Collectively, PITPNM1 is an important prognostic indicator and a potential therapeutic target for breast cancer. Full article

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14 pages, 2420 KiB

Open AccessArticle

A Thermodynamic Analysis of the Binding Specificity between Four Human PDZ Domains and Eight Host, Viral and Designed Ligands

by Eva S. Cobos, Ignacio E. Sánchez, Lucía B. Chemes, Jose C. Martinez and Javier Murciano-Calles

Biomolecules 2021, 11(8), 1071; https://doi.org/10.3390/biom11081071 - 21 Jul 2021

Cited by 2 | Viewed by 2418

Abstract

PDZ domains are binding modules mostly involved in cell signaling and cell–cell junctions. These domains are able to recognize a wide variety of natural targets and, among the PDZ partners, viruses have been discovered to interact with their host via a PDZ domain. [...] Read more.

PDZ domains are binding modules mostly involved in cell signaling and cell–cell junctions. These domains are able to recognize a wide variety of natural targets and, among the PDZ partners, viruses have been discovered to interact with their host via a PDZ domain. With such an array of relevant and diverse interactions, PDZ binding specificity has been thoroughly studied and a traditional classification has grouped PDZ domains in three major specificity classes. In this work, we have selected four human PDZ domains covering the three canonical specificity-class binding mode and a set of their corresponding binders, including host/natural, viral and designed PDZ motifs. Through calorimetric techniques, we have covered the entire cross interactions between the selected PDZ domains and partners. The results indicate a rather basic specificity in each PDZ domain, with two of the domains that bind their cognate and some non-cognate ligands and the two other domains that basically bind their cognate partners. On the other hand, the host partners mostly bind their corresponding PDZ domain and, interestingly, the viral ligands are able to bind most of the studied PDZ domains, even those not previously described. Some viruses may have evolved to use of the ability of the PDZ fold to bind multiple targets, with resulting affinities for the virus–host interactions that are, in some cases, higher than for host–host interactions. Full article

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