Biomolecules

17 pages, 3675 KiB

Open AccessArticle

Identification and Characterization of Circular RNAs in Mammary Tissue from Holstein Cows at Early Lactation and Non-Lactation

by Yan Liang, Qisong Gao, Haiyang Wang, Mengling Guo, Abdelaziz Adam Idriss Arbab, Mudasir Nazar, Mingxun Li, Zhangping Yang, Niel A. Karrow and Yongjiang Mao

Biomolecules 2022, 12(3), 478; https://doi.org/10.3390/biom12030478 - 21 Mar 2022

Cited by 5 | Viewed by 2169

Abstract

In this study, circular RNAs (circRNAs) from Holstein cow mammary tissues were identified and compared between early lactation and non-lactation. After analysis, 10,684 circRNAs were identified, ranging from 48 to 99,406 bp, and the average size was 882 bp. The circRNAs were mainly [...] Read more.

In this study, circular RNAs (circRNAs) from Holstein cow mammary tissues were identified and compared between early lactation and non-lactation. After analysis, 10,684 circRNAs were identified, ranging from 48 to 99,406 bp, and the average size was 882 bp. The circRNAs were mainly distributed on chromosomes 1 to 11, and 89.89% of the circRNAs belonged to sense-overlapping circRNA. The exons contained with circRNAs ranged from 1 to 47 and were concentrated from 1 to 5. Compared with the non-lactating cows, 87 circRNAs were significantly differentially expressed in the peak lactation cows. There were 68 upregulated circRNAs and 19 downregulated circRNAs. Enrichment analysis of circRNAs showed that GO analysis mainly focused on immune response, triglyceride transport, T cell receptor signaling pathway, etc. Pathway analysis mainly focused on cytokine-cytokine receptor interaction, T helper 17 cell differentiation, fatty acid biosynthesis, the JAK-STAT signaling pathway, etc. Specific primers were designed for two proximal ends of the circRNA junction sites to allow for PCR validation of four randomly selected circRNAs and carry out circRNA-miRNA interaction research. This study revealed the expression profile and characteristics of circRNAs in mammary tissue from Holstein cows at early lactation and non-lactation, thus providing rich information for the study of circRNA functions and mechanisms, as well as potential candidate miRNA genes for studying lactation in Holstein cows. Full article

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18 pages, 7882 KiB

Open AccessArticle

Effects of the Leptin-Mediated MAPK/ERK Signaling Pathway on Collagen II Expression in Knee Cartilage of Newborn Male Mice from Obese Maternal Offspring

by Wenji Wang, Jialing Zhang, Yu Huo, Yuanzheng Zheng and Yonghao Gui

Biomolecules 2022, 12(3), 477; https://doi.org/10.3390/biom12030477 - 21 Mar 2022

Cited by 7 | Viewed by 2371

Abstract

Epidemiological data suggest that various noncommunicable diseases develop as a result of altered maternal metabolic and physiological status due to exposure to several adverse factors during pregnancy. However, evidence for intrauterine exposure factors and mechanisms underlying the origin of early cartilage disease in [...] Read more.

Epidemiological data suggest that various noncommunicable diseases develop as a result of altered maternal metabolic and physiological status due to exposure to several adverse factors during pregnancy. However, evidence for intrauterine exposure factors and mechanisms underlying the origin of early cartilage disease in chronic osteoarthritic disease is still lacking. In this study, we found that persistent overnutrition during pregnancy in obese mothers led to cartilage damage in neonatal male mice. This was mainly characterized by increased apoptosis with decreased expression of chondrocyte collagen II and low expression of Runx family transcription factor 2 (RUNX2) and SRY-box transcription factor 9 (SOX9). This reduction was also found to be associated with high leptin expression in newborn male mice of obese maternal offspring. Furthermore, the administration of leptin and mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) inhibitors in primary chondrocytes showed that leptin mediated MAPK/ERK signaling activation and thus affected the key regulators of cartilage matrix metallopeptidase 1 (MMP1) and tissue inhibitor of metalloproteinase 1 (TIMP1), thereby altering the expression of collagen II in mouse cartilage. Altogether, this study provided insights into the molecular mechanisms of cartilage-related disease development and also new clues and evidence for the fetogenetic origin of cartilage diseases. Full article

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2 pages, 178 KiB

Open AccessEditorial

Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease

by Liang-Jun Yan

Biomolecules 2022, 12(3), 476; https://doi.org/10.3390/biom12030476 - 21 Mar 2022

Cited by 1 | Viewed by 2019

Abstract

The kidneys carry out fundamental life-sustaining functions by removing waste substances, controlling salt and water balance, retaining substances vital to the body such as glucose and proteins, and maintaining blood pH balance [...] Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)

14 pages, 2170 KiB

Open AccessArticle

Defining the Protease and Protease Inhibitor (P/PI) Proteomes of Healthy and Diseased Human Skin by Modified Systematic Review

by Callum Stewart-McGuinness, Christopher I. Platt, Matiss Ozols, Brian Goh, Tamara W. Griffiths and Michael J. Sherratt

Biomolecules 2022, 12(3), 475; https://doi.org/10.3390/biom12030475 - 20 Mar 2022

Cited by 3 | Viewed by 3130

Abstract

Proteases and protease inhibitors (P/PIs) are involved in many biological processes in human skin, yet often only specific families or related groups of P/PIs are investigated. Proteomics approaches, such as mass spectrometry, can define proteome signatures (including P/PIs) in tissues; however, they struggle [...] Read more.

Proteases and protease inhibitors (P/PIs) are involved in many biological processes in human skin, yet often only specific families or related groups of P/PIs are investigated. Proteomics approaches, such as mass spectrometry, can define proteome signatures (including P/PIs) in tissues; however, they struggle to detect low-abundance proteins. To overcome these issues, we aimed to produce a comprehensive proteome of all P/PIs present in normal and diseased human skin, in vivo, by carrying out a modified systematic review using a list of P/PIs from MEROPS and combining this with key search terms in Web of Science. Resulting articles were manually reviewed against inclusion/exclusion criteria and a dataset constructed. This study identified 111 proteases and 77 protease inhibitors in human skin, comprising the serine, metallo-, cysteine and aspartic acid catalytic families of proteases. P/PIs showing no evidence of catalytic activity or protease inhibition, were designated non-peptidase homologs (NPH), and no reported protease inhibitory activity (NRPIA), respectively. MMP9 and TIMP1 were the most frequently published P/PIs and were reported in normal skin and most skin disease groups. Normal skin and diseased skin showed significant overlap with respect to P/PI profile; however, MMP23 was identified in several skin disease groups, but was absent in normal skin. The catalytic profile of P/PIs in wounds, scars and solar elastosis was distinct from normal skin, suggesting that a different group of P/PIs is responsible for disease progression. In conclusion, this study uses a novel approach to provide a comprehensive inventory of P/PIs in normal and diseased human skin reported in our database. The database may be used to determine either which P/PIs are present in specific diseases or which diseases individual P/PIs may influence. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 2.0)

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12 pages, 1759 KiB

Open AccessEditor’s ChoiceArticle

Identification of Regions Involved in the Physical Interaction between Melanocortin Receptor Accessory Protein 2 and Prokineticin Receptor 2

by Maria Rosaria Fullone, Daniela Maftei, Martina Vincenzi, Roberta Lattanzi and Rossella Miele

Biomolecules 2022, 12(3), 474; https://doi.org/10.3390/biom12030474 - 20 Mar 2022

Cited by 9 | Viewed by 1948

Abstract

Melanocortin Receptor Accessory Protein 2 (MRAP2) modulates the trafficking and signal transduction of several G-protein-coupled receptors (GPCRs) involved in the control of energy homeostasis, such as Prokineticin receptors (PKRs). They bind the endogenous ligand prokineticin 2 (PK2), a novel adipokine that has an [...] Read more.

Melanocortin Receptor Accessory Protein 2 (MRAP2) modulates the trafficking and signal transduction of several G-protein-coupled receptors (GPCRs) involved in the control of energy homeostasis, such as Prokineticin receptors (PKRs). They bind the endogenous ligand prokineticin 2 (PK2), a novel adipokine that has an anorexic effect and modulates thermoregulation and energy homeostasis. In the present work, we used biochemical techniques to analyze the mechanism of interaction of MRAP2 with PKR2 and we identified the specific amino acid regions involved in the complex formation. Our results indicate that MRAP2 likely binds to the N-terminal region of PKR2, preventing glycosylation and consequently the correct receptor localization. We also identified a C-terminal region of MRAP2 that is critical for the interaction with PKR2. Consequently, we analyzed the role of the prokineticin transduction system in the regulation of MRAP2 expression in tissues involved in the control of food intake: at the central level, in hypothalamic explants, and at the peripheral level, in adipocytes. We demonstrated the modulation of MRAP2 expression by the prokineticin transduction system. Full article

(This article belongs to the Collection Feature Papers in Section Molecular Medicine)

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9 pages, 318 KiB

Open AccessReview

Evaluation of Adipose Cell-Based Therapies for the Treatment of Thumb Carpometacarpal Joint Osteoarthritis

by Eleni Karagergou, Theodora Ligomenou, Byron Chalidis, Dimitrios Kitridis, Sophia Papadopoulou and Panagiotis Givissis

Biomolecules 2022, 12(3), 473; https://doi.org/10.3390/biom12030473 - 20 Mar 2022

Cited by 4 | Viewed by 4024

Abstract

Adipose tissue and its regenerative products which are isolated with enzymatic or mechanical processing of the harvested fat have been studied in a wide range of degenerative diseases, including osteoarthritis of the knee and hip. Intra-articular injection of these products can provide symptomatic [...] Read more.

Adipose tissue and its regenerative products which are isolated with enzymatic or mechanical processing of the harvested fat have been studied in a wide range of degenerative diseases, including osteoarthritis of the knee and hip. Intra-articular injection of these products can provide symptomatic relief of pain and postpone surgery. However, their use in the treatment of thumb carpometacarpal joint (CMCJ) osteoarthritis is limited and just a few studies have been published on that topic. For this reason, a review of the literature was performed by a thorough search of eight terms using the Pubmed database. In total, seven human studies met the selection criteria, including case-control studies, case-series and one case report. In all studies, intra-articular injection of autologous fat in osteoarthritic thumb CMCJ provided reduction in pain and improvement in hand function. Grip and pinch strength showed variable results, from no change to significant improvement. Fat-processing techniques were based on centrifugation and mechanical homogenization but biological characterization of the injected cells was not performed in any study. Although the results are encouraging, a uniformly standardized method of fat processing and the conduction of randomized controlled trials in the future could better evaluate the effectiveness of this procedure for thumb CMCJ osteoarthritis. Full article

(This article belongs to the Special Issue Core of Biomolecules Affecting Degenerative Disorders)

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25 pages, 7004 KiB

Open AccessEditor’s ChoiceReview

Glucose Oxidase, an Enzyme “Ferrari”: Its Structure, Function, Production and Properties in the Light of Various Industrial and Biotechnological Applications

by Jacob A. Bauer, Monika Zámocká, Juraj Majtán and Vladena Bauerová-Hlinková

Biomolecules 2022, 12(3), 472; https://doi.org/10.3390/biom12030472 - 19 Mar 2022

Cited by 61 | Viewed by 12820

Abstract

Glucose oxidase (GOx) is an important oxidoreductase enzyme with many important roles in biological processes. It is considered an “ideal enzyme” and is often called an oxidase “Ferrari” because of its fast mechanism of action, high stability and specificity. Glucose oxidase catalyzes the [...] Read more.

Glucose oxidase (GOx) is an important oxidoreductase enzyme with many important roles in biological processes. It is considered an “ideal enzyme” and is often called an oxidase “Ferrari” because of its fast mechanism of action, high stability and specificity. Glucose oxidase catalyzes the oxidation of

β

-d-glucose to d-glucono-

δ

-lactone and hydrogen peroxide in the presence of molecular oxygen. d-glucono-

δ

-lactone is sequentially hydrolyzed by lactonase to d-gluconic acid, and the resulting hydrogen peroxide is hydrolyzed by catalase to oxygen and water. GOx is presently known to be produced only by fungi and insects. The current main industrial producers of glucose oxidase are Aspergillus and Penicillium. An important property of GOx is its antimicrobial effect against various pathogens and its use in many industrial and medical areas. The aim of this review is to summarize the structure, function, production strains and biophysical and biochemical properties of GOx in light of its various industrial, biotechnological and medical applications. Full article

(This article belongs to the Special Issue Recombinant Enzymes/Proteins in Biotechnology)

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18 pages, 2616 KiB

Open AccessArticle

Structural Comparative Modeling of Multi-Domain F508del CFTR

by Eli Fritz McDonald, Hope Woods, Shannon T. Smith, Minsoo Kim, Clara T. Schoeder, Lars Plate and Jens Meiler

Biomolecules 2022, 12(3), 471; https://doi.org/10.3390/biom12030471 - 18 Mar 2022

Cited by 9 | Viewed by 3296

Abstract

Cystic fibrosis (CF) is a rare genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial anion channel expressed in several vital organs. Absence of functional CFTR results in imbalanced osmotic equilibrium and subsequent mucus build up in [...] Read more.

Cystic fibrosis (CF) is a rare genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial anion channel expressed in several vital organs. Absence of functional CFTR results in imbalanced osmotic equilibrium and subsequent mucus build up in the lungs-which increases the risk of infection and eventually causes death. CFTR is an ATP-binding cassette (ABC) transporter family protein composed of two transmembrane domains (TMDs), two nucleotide binding domains (NBDs), and an unstructured regulatory domain. The most prevalent patient mutation is the deletion of F508 (F508del), making F508del CFTR the primary target for current FDA approved CF therapies. However, no experimental multi-domain F508del CFTR structure has been determined and few studies have modeled F508del using multi-domain WT CFTR structures. Here, we used cryo-EM density data and Rosetta comparative modeling (RosettaCM) to compare a F508del model with published experimental data on CFTR NBD1 thermodynamics. We then apply this modeling method to generate multi-domain WT and F508del CFTR structural models. These models demonstrate the destabilizing effects of F508del on NBD1 and the NBD1/TMD interface in both the inactive and active conformation of CFTR. Furthermore, we modeled F508del/R1070W and F508del bound to the CFTR corrector VX-809. Our models reveal the stabilizing effects of VX-809 on multi-domain models of F508del CFTR and pave the way for rational design of additional drugs that target F508del CFTR for treatment of CF. Full article

(This article belongs to the Section Molecular Structure and Dynamics)

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12 pages, 2370 KiB

Open AccessArticle

PD-L1 Silencing in Liver Using siRNAs Enhances Efficacy of Therapeutic Vaccination for Chronic Hepatitis B

by Till Bunse, Anna D. Kosinska, Thomas Michler and Ulrike Protzer

Biomolecules 2022, 12(3), 470; https://doi.org/10.3390/biom12030470 - 18 Mar 2022

Cited by 10 | Viewed by 3788

Abstract

In chronic hepatitis B virus (HBV) infection, virus-specific T cells are scarce and partially dysfunctional. Therapeutic vaccination is a promising strategy to induce and activate new virus-specific T cells. In long-term or high-level HBV carriers, however, therapeutic vaccination by itself may not suffice [...] Read more.

In chronic hepatitis B virus (HBV) infection, virus-specific T cells are scarce and partially dysfunctional. Therapeutic vaccination is a promising strategy to induce and activate new virus-specific T cells. In long-term or high-level HBV carriers, however, therapeutic vaccination by itself may not suffice to cure HBV. One reason is the impairment of antiviral T cells by immune checkpoints. In this study, we used small-interfering RNA (siRNA) in combination with a heterologous prime-boost therapeutic vaccination scheme (TherVacB) to interfere with a major immune checkpoint, the interaction of programmed death protein-1 (PD-1) and its ligand (PDL-1). In mice persistently replicating HBV after infection with an adeno-associated virus harboring the HBV genome, siRNA targeting PD-L1 resulted in a higher functionality of HBV-specific CD8+ T cells after therapeutic vaccination, and allowed for a more sustained antiviral effect and control of HBV in peripheral blood and in the liver. The antiviral effect was more pronounced if PD-L1 was down-regulated during prime than during boost vaccination. Thus, targeting PD-L1 using siRNA is a promising approach to enhance the efficacy of therapeutic vaccination and finally cure HBV. Full article

(This article belongs to the Topic Novel Biomolecules Modulating Innate Immune Responses against Virus Infection)

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14 pages, 1810 KiB

Open AccessEditor’s ChoiceArticle

Alpha-Synuclein-Specific Naturally Occurring Antibodies Inhibit Aggregation In Vitro and In Vivo

by Anne K. Braczynski, Marc Sevenich, Ian Gering, Tatsiana Kupreichyk, Emil D. Agerschou, Yannick Kronimus, Pardes Habib, Matthias Stoldt, Dieter Willbold, Jörg B. Schulz, Jan-Philipp Bach, Björn H. Falkenburger and Wolfgang Hoyer

Biomolecules 2022, 12(3), 469; https://doi.org/10.3390/biom12030469 - 18 Mar 2022

Cited by 9 | Viewed by 2761

Abstract

Parkinson’s disease (PD) is associated with motor and non-motor symptoms and characterized by aggregates of alpha-synuclein (αSyn). Naturally occurring antibodies (nAbs) are part of the innate immune system, produced without prior contact to their specific antigen, and polyreactive. The abundance of nAbs against [...] Read more.

Parkinson’s disease (PD) is associated with motor and non-motor symptoms and characterized by aggregates of alpha-synuclein (αSyn). Naturally occurring antibodies (nAbs) are part of the innate immune system, produced without prior contact to their specific antigen, and polyreactive. The abundance of nAbs against αSyn is altered in patients with PD. In this work, we biophysically characterized nAbs against αSyn (nAbs-αSyn) and determined their biological effects. nAbs-αSyn were isolated from commercial intravenous immunoglobulins using column affinity purification. Biophysical properties were characterized using a battery of established in vitro assays. Biological effects were characterized in HEK293T cells transiently transfected with fluorescently tagged αSyn. Specific binding of nAbs-αSyn to monomeric αSyn was demonstrated by Dot blot, ELISA, and Surface Plasmon Resonance. nAbs-αSyn did not affect viability of HEK293T cells as reported by Cell Titer Blue and LDH Assays. nAbs-αSyn inhibited fibrillation of αSyn reported by the Thioflavin T aggregation assay. Altered fibril formation was confirmed with atomic force microscopy. In cells transfected with EGFP-tagged αSyn we observed reduced formation of aggresomes, perinuclear accumulations of αSyn aggregates. The results demonstrate that serum of healthy individuals contains nAbs that specifically bind αSyn and inhibit aggregation of αSyn in vitro. The addition of nAbs-αSyn to cultured cells affects intracellular αSyn aggregates. These findings help understanding the role of the innate immune systems for the pathogenesis of PD and suggest that systemic αSyn binding agents could potentially affect neuronal αSyn pathology. Full article

(This article belongs to the Special Issue Synuclein Proteins)

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15 pages, 2483 KiB

Open AccessEditor’s ChoiceArticle

Impact of Molecule Concentration, Diffusion Rates and Surface Passivation on Single-Molecule Fluorescence Studies in Solution

by Olessya Yukhnovets, Henning Höfig, Nuno Bustorff, Alexandros Katranidis and Jörg Fitter

Biomolecules 2022, 12(3), 468; https://doi.org/10.3390/biom12030468 - 18 Mar 2022

Cited by 2 | Viewed by 2267

Abstract

For single-molecule studies in solution, very small concentrations of dye-labelled molecules are employed in order to achieve single-molecule sensitivity. In typical studies with confocal microscopes, often concentrations in the pico-molar regime are required. For various applications that make use of single-molecule Förster resonance [...] Read more.

For single-molecule studies in solution, very small concentrations of dye-labelled molecules are employed in order to achieve single-molecule sensitivity. In typical studies with confocal microscopes, often concentrations in the pico-molar regime are required. For various applications that make use of single-molecule Förster resonance energy transfer (smFRET) or two-color coincidence detection (TCCD), the molecule concentration must be set explicitly to targeted values and furthermore needs to be stable over a period of several hours. As a consequence, specific demands must be imposed on the surface passivation of the cover slides during the measurements. The aim of having only one molecule in the detection volume at the time is not only affected by the absolute molecule concentration, but also by the rate of diffusion. Therefore, we discuss approaches to control and to measure absolute molecule concentrations. Furthermore, we introduce an approach to calculate the probability of chance coincidence events and demonstrate that measurements with challenging smFRET samples require a strict limit of maximal sample concentrations in order to produce meaningful results. Full article

(This article belongs to the Special Issue Single-Molecule Protein Dynamics)

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24 pages, 2520 KiB

Open AccessEditor’s ChoiceReview

Acetylation, Phosphorylation, Ubiquitination (Oh My!): Following Post-Translational Modifications on the Ubiquitin Road

by Rachel E. Lacoursiere, Dania Hadi and Gary S. Shaw

Biomolecules 2022, 12(3), 467; https://doi.org/10.3390/biom12030467 - 18 Mar 2022

Cited by 15 | Viewed by 4872

Abstract

Ubiquitination is controlled by a series of E1, E2, and E3 enzymes that can ligate ubiquitin to cellular proteins and dictate the turnover of a substrate and the outcome of signalling events such as DNA damage repair and cell cycle. This process is [...] Read more.

Ubiquitination is controlled by a series of E1, E2, and E3 enzymes that can ligate ubiquitin to cellular proteins and dictate the turnover of a substrate and the outcome of signalling events such as DNA damage repair and cell cycle. This process is complex due to the combinatorial power of ~35 E2 and ~1000 E3 enzymes involved and the multiple lysine residues on ubiquitin that can be used to assemble polyubiquitin chains. Recently, mass spectrometric methods have identified that most enzymes in the ubiquitination cascade can be further modified through acetylation or phosphorylation under particular cellular conditions and altered modifications have been noted in different cancers and neurodegenerative diseases. This review provides a cohesive summary of ubiquitination, acetylation, and phosphorylation sites in ubiquitin, the human E1 enzyme UBA1, all E2 enzymes, and some representative E3 enzymes. The potential impacts these post-translational modifications might have on each protein function are highlighted, as well as the observations from human disease. Full article

(This article belongs to the Special Issue The Ubiquitin Proteasome System (UPS) in Pathogenesis and Diseases)

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8 pages, 658 KiB

Open AccessFeature PaperArticle

Assessment of Two Different Glucagon Assays in Healthy Individuals and Type 1 and Type 2 Diabetes Patients

by Martina Brunner, Othmar Moser, Reingard Raml, Maximilian Haberlander, Beate Boulgaropoulos, Barbara Obermayer-Pietsch, Eva Svehlikova, Thomas R. Pieber and Harald Sourij

Biomolecules 2022, 12(3), 466; https://doi.org/10.3390/biom12030466 - 18 Mar 2022

Cited by 2 | Viewed by 2181

Abstract

Methods for glucagon analysis suffered in the past from lack of specificity and a narrow sensitivity range, which has led to inaccurate results and to the suggestion that type 1 diabetes (T1D) and type 2 diabetes (T2D) patients have elevated fasting glucagon levels. [...] Read more.

Methods for glucagon analysis suffered in the past from lack of specificity and a narrow sensitivity range, which has led to inaccurate results and to the suggestion that type 1 diabetes (T1D) and type 2 diabetes (T2D) patients have elevated fasting glucagon levels. However, the availability of more specific and more sensitive methods to detect intact glucagon has shown that actual glucagon levels are lower than previously assumed. This study aimed to characterize fasting plasma glucagon levels in healthy individuals and T1D and T2D patients with two different glucagon assays. The study included 20 healthy individuals, 20 T1D and 20 T2D patients. Blood was collected under fasting conditions. A double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) and a conventional radioimmunoassay (RIA) were used. A significant difference in fasting glucagon levels between healthy individuals and T2D was observed by ELISA, but not by RIA. ELISA also yielded lower glucagon levels in healthy individuals than in T1D and T2D patients which RIA did not. RIA produced significantly (p = 0.0001) higher overall median glucagon values than ELISA in a pooled analysis. These results underline the notion that the choice of selective laboratory methods is highly relevant for mechanistic endocrine research. Full article

(This article belongs to the Special Issue Diabetes: From Molecular Mechanisms to Therapies Strategies)

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19 pages, 11149 KiB

Open AccessReview

A Systematic Review of Common and Brain-Disease-Specific RNA Editing Alterations Providing Novel Insights into Neurological and Neurodegenerative Disease Manifestations

by Korina Karagianni, Spyros Pettas, Georgia Christoforidou, Eirini Kanata, Nikolaos Bekas, Konstantinos Xanthopoulos, Dimitra Dafou and Theodoros Sklaviadis

Biomolecules 2022, 12(3), 465; https://doi.org/10.3390/biom12030465 - 17 Mar 2022

Cited by 9 | Viewed by 3768

Abstract

RNA editing contributes to transcriptome diversification through RNA modifications in relation to genome-encoded information (RNA–DNA differences, RDDs). The deamination of Adenosine (A) to Inosine (I) or Cytidine (C) to Uridine (U) is the most common type of mammalian RNA editing. It occurs as [...] Read more.

RNA editing contributes to transcriptome diversification through RNA modifications in relation to genome-encoded information (RNA–DNA differences, RDDs). The deamination of Adenosine (A) to Inosine (I) or Cytidine (C) to Uridine (U) is the most common type of mammalian RNA editing. It occurs as a nuclear co- and/or post-transcriptional event catalyzed by ADARs (Adenosine deaminases acting on RNA) and APOBECs (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like genes). RNA editing may modify the structure, stability, and processing of a transcript. This review focuses on RNA editing in psychiatric, neurological, neurodegenerative (NDs), and autoimmune brain disorders in humans and rodent models. We discuss targeted studies that focus on RNA editing in specific neuron-enriched transcripts with well-established functions in neuronal activity, and transcriptome-wide studies, enabled by recent technological advances. We provide comparative editome analyses between human disease and corresponding animal models. Data suggest RNA editing to be an emerging mechanism in disease development, displaying common and disease-specific patterns. Commonly edited RNAs represent potential disease-associated targets for therapeutic and diagnostic values. Currently available data are primarily descriptive, calling for additional research to expand global editing profiles and to provide disease mechanistic insights. The potential use of RNA editing events as disease biomarkers and available tools for RNA editing identification, classification, ranking, and functional characterization that are being developed will enable comprehensive analyses for a better understanding of disease(s) pathogenesis and potential cures. Full article

(This article belongs to the Topic Cell Signaling Pathways)

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13 pages, 2489 KiB

Open AccessArticle

Transcriptomic Biomarker Signatures for Discrimination of Oral Cancer Surgical Margins

by Simon A. Fox, Michael Vacher and Camile S. Farah

Biomolecules 2022, 12(3), 464; https://doi.org/10.3390/biom12030464 - 17 Mar 2022

Cited by 7 | Viewed by 2509

Abstract

Relapse after surgery for oral squamous cell carcinoma (OSCC) contributes significantly to morbidity, mortality and poor outcomes. The current histopathological diagnostic techniques are insufficiently sensitive for the detection of oral cancer and minimal residual disease in surgical margins. We used whole-transcriptome gene expression [...] Read more.

Relapse after surgery for oral squamous cell carcinoma (OSCC) contributes significantly to morbidity, mortality and poor outcomes. The current histopathological diagnostic techniques are insufficiently sensitive for the detection of oral cancer and minimal residual disease in surgical margins. We used whole-transcriptome gene expression and small noncoding RNA profiles from tumour, close margin and distant margin biopsies from 18 patients undergoing surgical resection for OSCC. By applying multivariate regression algorithms (sPLS-DA) suitable for higher dimension data, we objectively identified biomarker signatures for tumour and marginal tissue zones. We were able to define molecular signatures that discriminated tumours from the marginal zones and between the close and distant margins. These signatures included genes not previously associated with OSCC, such as MAMDC2, SYNPO2 and ARMH4. For discrimination of the normal and tumour sampling zones, we were able to derive an effective gene-based classifying model for molecular abnormality based on a panel of eight genes (MMP1, MMP12, MYO1B, TNFRSF12A, WDR66, LAMC2, SLC16A1 and PLAU). We demonstrated the classification performance of these gene signatures in an independent validation dataset of OSCC tumour and marginal gene expression profiles. These biomarker signatures may contribute to the earlier detection of tumour cells and complement existing surgical and histopathological techniques used to determine clear surgical margins. Full article

(This article belongs to the Special Issue Biomolecules and Biomarkers in Head and Neck Medicine)

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22 pages, 767 KiB

Open AccessFeature PaperReview

Is Autophagy Always a Barrier to Cisplatin Therapy?

by Jingwen Xu and David A. Gewirtz

Biomolecules 2022, 12(3), 463; https://doi.org/10.3390/biom12030463 - 17 Mar 2022

Cited by 23 | Viewed by 4275

Abstract

Cisplatin has long been a first-line chemotherapeutic agent in the treatment of cancer, largely for solid tumors. During the course of the past two decades, autophagy has been identified in response to cancer treatments and almost uniformly detected in studies involving cisplatin. There [...] Read more.

Cisplatin has long been a first-line chemotherapeutic agent in the treatment of cancer, largely for solid tumors. During the course of the past two decades, autophagy has been identified in response to cancer treatments and almost uniformly detected in studies involving cisplatin. There has been increasing recognition of autophagy as a critical factor affecting tumor cell death and tumor chemoresistance. In this review and commentary, we introduce four mechanisms of resistance to cisplatin followed by a discussion of the factors that affect the role of autophagy in cisplatin-sensitive and resistant cells and explore the two-sided outcomes that occur when autophagy inhibitors are combined with cisplatin. Our goal is to analyze the potential for the combinatorial use of cisplatin and autophagy inhibitors in the clinic. Full article

(This article belongs to the Special Issue Cisplatin in Diseases: Molecular Mechanisms of Action)

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21 pages, 1459 KiB

Open AccessReview

The Role of LSD1 and LSD2 in Cancers of the Gastrointestinal System: An Update

by Gianluca Malagraba, Mahdieh Yarmohammadi, Aadil Javed, Carles Barceló and Teresa Rubio-Tomás

Biomolecules 2022, 12(3), 462; https://doi.org/10.3390/biom12030462 - 17 Mar 2022

Cited by 14 | Viewed by 5232

Abstract

Epigenetic mechanisms are known to play a key role in cancer progression. Specifically, histone methylation involves reversible post-translational modification of histones that govern chromatin structure remodelling, genomic imprinting, gene expression, DNA damage repair, and meiotic crossover recombination, among other chromatin-based activities. Demethylases are [...] Read more.

Epigenetic mechanisms are known to play a key role in cancer progression. Specifically, histone methylation involves reversible post-translational modification of histones that govern chromatin structure remodelling, genomic imprinting, gene expression, DNA damage repair, and meiotic crossover recombination, among other chromatin-based activities. Demethylases are enzymes that catalyse the demethylation of their substrate using a flavin adenine dinucleotide-dependent amine oxidation process. Lysine-specific demethylase 1 (LSD1) and its homolog, lysine-specific demethylase 2 (LSD2), are overexpressed in a variety of human cancer types and, thus, regulate tumour progression. In this review, we focus on the literature from the last 5 years concerning the role of LSD1 and LSD2 in the main gastrointestinal cancers (i.e., gastric cancer, liver cancer, pancreatic cancer, and colorectal cancer). Full article

(This article belongs to the Special Issue Jumonji Domain-Containing Proteins in Cancer Progression)

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13 pages, 1495 KiB

Open AccessCommunication

The Impact of NRF2 Inhibition on Drug-Induced Colon Cancer Cell Death and p53 Activity: A Pilot Study

by Alessia Garufi, Giuseppa Pistritto, Valerio D’Orazi, Mara Cirone and Gabriella D’Orazi

Biomolecules 2022, 12(3), 461; https://doi.org/10.3390/biom12030461 - 17 Mar 2022

Cited by 16 | Viewed by 2566

Abstract

Nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) protein is the master regulator of oxidative stress, which is at the basis of various chronic diseases including cancer. Hyperactivation of NRF2 in already established cancers can promote cell proliferation and resistance to therapies, [...] Read more.

Nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) protein is the master regulator of oxidative stress, which is at the basis of various chronic diseases including cancer. Hyperactivation of NRF2 in already established cancers can promote cell proliferation and resistance to therapies, such as in colorectal cancer (CRC), one of the most lethal and prevalent malignancies in industrialized countries with limited patient overall survival due to its escape mechanisms in both chemo- and targeted therapies. In this study, we generated stable NRF2 knockout colon cancer cells (NRF2-Cas9) to investigate the cell response to chemotherapeutic drugs with regard to p53 oncosuppressor, whose inhibition we previously showed to correlate with NRF2 pathway activation. Here, we found that NRF2 activation by sulforaphane (SFN) reduced cisplatin (CDDP)-induced cell death only in NRF2-proficient cells (NRF2-ctr) compared to NRF2-Cas9 cells. Mechanistically, we found that NRF2 activation protected NRF2-ctr cells from the drug-induced DNA damage and the apoptotic function of the unfolded protein response (UPR), in correlation with reduction of p53 activity, effects that were not observed in NRF2-Cas9 cells. Finally, we found that ZnCl₂ supplementation rescued the cisplatin cytotoxic effects, as it impaired NRF2 activation, restoring p53 activity. These findings highlight NRF2′s key role in neutralizing the cytotoxic effects of chemotherapeutic drugs in correlation with reduced DNA damage and p53 activity. They also suggest that NRF2 inhibition could be a useful strategy for efficient anticancer chemotherapy and support the use of ZnCl₂ to inhibit NRF2 pathway in combination therapies. Full article

(This article belongs to the Collection p53 Function and Dysfunction in Human Health and Diseases)

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25 pages, 6038 KiB

Open AccessEditor’s ChoiceArticle

Calystegines Improve the Metabolic Activity of Human Adipose Derived Stromal Stem Cells (ASCs) under Hyperglycaemic Condition through the Reduction of Oxidative/ER Stress, Inflammation, and the Promotion of the AKT/PI3K/mTOR Pathway

by Anna Kowalczuk, Nabila Bourebaba, Juliia Panchuk, Krzysztof Marycz and Lynda Bourebaba

Biomolecules 2022, 12(3), 460; https://doi.org/10.3390/biom12030460 - 16 Mar 2022

Cited by 6 | Viewed by 2364

Abstract

Hyperglycaemia and its resulting glucotoxicity are among the most prominent hallmarks of diabetes mellitus (DM) development. Persistent hyperglycaemia further leads to oxidative stress via mitochondrial dysfunction and subsequent ER stress onset, while associated hyperlipidaemia triggers the adipose tissue to secrete pro-inflammatory cytokines. In [...] Read more.

Hyperglycaemia and its resulting glucotoxicity are among the most prominent hallmarks of diabetes mellitus (DM) development. Persistent hyperglycaemia further leads to oxidative stress via mitochondrial dysfunction and subsequent ER stress onset, while associated hyperlipidaemia triggers the adipose tissue to secrete pro-inflammatory cytokines. In this study, the effect of calystegines has been investigated in an experimental model of hyperglycaemia induced on human ASCs cells. Different cellular pathways including apoptosis, oxidative and ER stress, inflammation as well as Pi3K/AKT/mTOR metabolic-associated axis have been evaluated by means on RT-qPCR, western blot, and flow cytometry techniques. Treatment of HuASCs cells with calystegines strongly promoted the hyperglycaemic cells survival and significantly diminished oxidative stress, mitochondrial dynamics failure and ER stress, while improving the endogenous cellular antioxidant defenses. Interestingly, nortropane alkaloids efficiently prevented the hyperglycaemia-mediated inflammatory response, as evidenced by the regulation of the pro- and anti-inflammatory response in HuASCs cells. Finally, we evidenced that calystegines may exert their protective effect on HuASCs cells metabolic functions through the restoration of the defective PI3K/AKT/mTOR pathway. Overall, the present investigation demonstrated that calystegines possess important abilities to protect HuASCs against hyperglycaemia-induced cellular dysfunction, and it evidenced that the observed effects are associated to the promotion of PI3K/AKT/mTOR pathway. Full article

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33 pages, 2773 KiB

Open AccessFeature PaperReview

Bifurcations and Proarrhythmic Behaviors in Cardiac Electrical Excitations

by Kunichika Tsumoto and Yasutaka Kurata

Biomolecules 2022, 12(3), 459; https://doi.org/10.3390/biom12030459 - 16 Mar 2022

Cited by 3 | Viewed by 4241

Abstract

The heart is a hierarchical dynamic system consisting of molecules, cells, and tissues, and acts as a pump for blood circulation. The pumping function depends critically on the preceding electrical activity, and disturbances in the pattern of excitation propagation lead to cardiac arrhythmia [...] Read more.

The heart is a hierarchical dynamic system consisting of molecules, cells, and tissues, and acts as a pump for blood circulation. The pumping function depends critically on the preceding electrical activity, and disturbances in the pattern of excitation propagation lead to cardiac arrhythmia and pump failure. Excitation phenomena in cardiomyocytes have been modeled as a nonlinear dynamical system. Because of the nonlinearity of excitation phenomena, the system dynamics could be complex, and various analyses have been performed to understand the complex dynamics. Understanding the mechanisms underlying proarrhythmic responses in the heart is crucial for developing new ways to prevent and control cardiac arrhythmias and resulting contractile dysfunction. When the heart changes to a pathological state over time, the action potential (AP) in cardiomyocytes may also change to a different state in shape and duration, often undergoing a qualitative change in behavior. Such a dynamic change is called bifurcation. In this review, we first summarize the contribution of ion channels and transporters to AP formation and our knowledge of ion-transport molecules, then briefly describe bifurcation theory for nonlinear dynamical systems, and finally detail its recent progress, focusing on the research that attempts to understand the developing mechanisms of abnormal excitations in cardiomyocytes from the perspective of bifurcation phenomena. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

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10 pages, 5464 KiB

Open AccessArticle

Multicenter ¹⁸F-PI-2620 PET for In Vivo Braak Staging of Tau Pathology in Alzheimer’s Disease

by Michael Rullmann, Matthias Brendel, Matthias L. Schroeter, Dorothee Saur, Johannes Levin, Robert G. Perneczky, Solveig Tiepolt, Marianne Patt, Andre Mueller, Victor L. Villemagne, Joseph Classen, Andrew W. Stephens, Osama Sabri, Henryk Barthel and on behalf of the German Imaging Initiative for Tauopathies (GII4T)

Biomolecules 2022, 12(3), 458; https://doi.org/10.3390/biom12030458 - 16 Mar 2022

Cited by 9 | Viewed by 3266

Abstract

Tau aggregates accumulate in the Alzheimer’s disease (AD) brain according to the established Braak staging scheme and spread from transentorhinal over limbic regions to the neocortex. To impact the management of AD patients, an in vivo tool for tau Braak staging is needed. [...] Read more.

Tau aggregates accumulate in the Alzheimer’s disease (AD) brain according to the established Braak staging scheme and spread from transentorhinal over limbic regions to the neocortex. To impact the management of AD patients, an in vivo tool for tau Braak staging is needed. First-generation tau tracers have limited performance in detecting early stages of tau. Therefore, we tested the corresponding capability of the next-generation tau tracer, ¹⁸F-PI-2620. We analyzed ¹⁸F-PI-2620 multicenter PET data from 37 beta-amyloid-positive AD dementia patients and those from 26 healthy controls. We applied kinetic modeling of the 0–60 min p.i. PET data using MRTM2 with the lower cerebellum as the reference region to extract Braak stage-dependent distribution volume ratios, whereas controls were used to define Braak stage PET positivity thresholds. Stage-dependent PET positivity widely followed the Braak scheme (except Braak stage III) presenting descending frequency of PET positivity from Braak I (43%), II (38%), III (49%), IV (35%), V (30%) to VI (14%). A strictly hierarchical model was met by 64% of AD dementia cases. Nineteen percent showed a hippocampal sparing tauopathy pattern. Thus, we could assign 87% to the six-stage hierarchical Braak model including tauopathy variants. ¹⁸F-PI-2620 PET appears to be able to perform Braak tau staging of AD in vivo. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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16 pages, 1581 KiB

Open AccessArticle

The Vasoactive Effect of Perivascular Adipose Tissue and Hydrogen Sulfide in Thoracic Aortas of Normotensive and Spontaneously Hypertensive Rats

by Samuel Golas, Andrea Berenyiova, Miroslava Majzunova, Magdalena Drobna, Muobarak J. Tuorkey and Sona Cacanyiova

Biomolecules 2022, 12(3), 457; https://doi.org/10.3390/biom12030457 - 16 Mar 2022

Cited by 4 | Viewed by 2045

Abstract

The objective of this study was to investigate the vasoregulatory role of perivascular adipose tissue (PVAT) and its mutual interaction with endogenous and exogenous H₂S in the thoracic aorta (TA) of adult normotensive Wistar rats and spontaneously hypertensive rats (SHRs). In [...] Read more.

The objective of this study was to investigate the vasoregulatory role of perivascular adipose tissue (PVAT) and its mutual interaction with endogenous and exogenous H₂S in the thoracic aorta (TA) of adult normotensive Wistar rats and spontaneously hypertensive rats (SHRs). In SHRs, hypertension was associated with cardiac hypertrophy and increased contractility. Regardless of the strain, PVAT revealed an anticontractile effect; however, PVAT worsened endothelial-dependent vasorelaxation. Since H₂S produced by both the vascular wall and PVAT had a pro-contractile effect in SHRs, H₂S decreased the sensitivity of adrenergic receptors to noradrenaline in Wistar rats. While H₂S had no contribution to endothelium-dependent relaxation in Wistar rats, in SHRs, H₂S produced by the vascular wall had a pro-relaxant effect. We observed a larger vasorelaxation induced by exogenous H₂S donor in SHRs than in Wistar rats. Additionally, in the presence of PVAT, this effect was potentiated. We demonstrated that PVAT of the TA aggravated endothelial function in SHRs. However, H₂S produced by the TA vascular wall had a pro-relaxation effect, and PVAT revealed anti-contractile activity mediated by the release of an unknown factor and potentiated the vasorelaxation induced by exogenous H₂S. All these actions could represent a form of compensatory mechanism to balance impaired vascular tone regulation. Full article

(This article belongs to the Special Issue Gaseous Transmitters and Cardiovascular System)

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23 pages, 2204 KiB

Open AccessArticle

Colocalization Analysis of Peripheral Myelin Protein-22 and Lamin-B1 in the Schwann Cell Nuclei of Wt and TrJ Mice

by María Vittoria Di Tomaso, Lucía Vázquez Alberdi, Daniela Olsson, Saira Cancela, Anabel Fernández, Juan Carlos Rosillo, Ana Laura Reyes Ábalos, Magdalena Álvarez Zabaleta, Miguel Calero and Alejandra Kun

Biomolecules 2022, 12(3), 456; https://doi.org/10.3390/biom12030456 - 16 Mar 2022

Cited by 5 | Viewed by 4990

Abstract

Myelination of the peripheral nervous system requires Schwann cells (SC) differentiation into the myelinating phenotype. The peripheral myelin protein-22 (PMP22) is an integral membrane glycoprotein, expressed in SC. It was initially described as a growth arrest-specific (gas3) gene product, up-regulated by [...] Read more.

Myelination of the peripheral nervous system requires Schwann cells (SC) differentiation into the myelinating phenotype. The peripheral myelin protein-22 (PMP22) is an integral membrane glycoprotein, expressed in SC. It was initially described as a growth arrest-specific (gas3) gene product, up-regulated by serum starvation. PMP22 mutations were pathognomonic for human hereditary peripheral neuropathies, including the Charcot-Marie-Tooth disease (CMT). Trembler-J (TrJ) is a heterozygous mouse model carrying the same pmp22 point mutation as a CMT1E variant. Mutations in lamina genes have been related to a type of peripheral (CMT2B1) or central (autosomal dominant leukodystrophy) neuropathy. We explore the presence of PMP22 and Lamin B1 in Wt and TrJ SC nuclei of sciatic nerves and the colocalization of PMP22 concerning the silent heterochromatin (HC: DAPI-dark counterstaining), the transcriptionally active euchromatin (EC), and the nuclear lamina (H3K4m3 and Lamin B1 immunostaining, respectively). The results revealed that the number of TrJ SC nuclei in sciatic nerves was greater, and the SC volumes were smaller than those of Wt. The myelin protein PMP22 and Lamin B1 were detected in Wt and TrJ SC nuclei and predominantly in peripheral nuclear regions. The level of PMP22 was higher, and those of Lamin B1 lower in TrJ than in Wt mice. The level of PMP22 was higher, and those of Lamin B1 lower in TrJ than in Wt mice. PMP22 colocalized more with Lamin B1 and with the transcriptionally competent EC, than the silent HC with differences between Wt and TrJ genotypes. The results are discussed regarding the probable nuclear role of PMP22 and the relationship with TrJ neuropathy. Full article

(This article belongs to the Special Issue Recent Advances in Schwann Cells)

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21 pages, 5089 KiB

Open AccessArticle

Inherited Retinal Degeneration: PARP-Dependent Activation of Calpain Requires CNG Channel Activity

by Jie Yan, Alexander Günter, Soumyaparna Das, Regine Mühlfriedel, Stylianos Michalakis, Kangwei Jiao, Mathias W. Seeliger and François Paquet-Durand

Biomolecules 2022, 12(3), 455; https://doi.org/10.3390/biom12030455 - 15 Mar 2022

Cited by 6 | Viewed by 2564

Abstract

Inherited retinal degenerations (IRDs) are a group of blinding diseases, typically involving a progressive loss of photoreceptors. The IRD pathology is often based on an accumulation of cGMP in photoreceptors and associated with the excessive activation of calpain and poly (ADP-ribose) polymerase (PARP). [...] Read more.

Inherited retinal degenerations (IRDs) are a group of blinding diseases, typically involving a progressive loss of photoreceptors. The IRD pathology is often based on an accumulation of cGMP in photoreceptors and associated with the excessive activation of calpain and poly (ADP-ribose) polymerase (PARP). Inhibitors of calpain or PARP have shown promise in preventing photoreceptor cell death, yet the relationship between these enzymes remains unclear. To explore this further, organotypic retinal explant cultures derived from wild-type and IRD-mutant mice were treated with inhibitors specific for calpain, PARP, and voltage-gated Ca²⁺ channels (VGCCs). The outcomes were assessed using in situ activity assays for calpain and PARP and immunostaining for activated calpain-2, poly (ADP-ribose), and cGMP, as well as the TUNEL assay for cell death detection. The IRD models included the Pde6b-mutant rd1 mouse and rd1*Cngb1^−/− double-mutant mice, which lack the beta subunit of the rod cyclic nucleotide-gated (CNG) channel and are partially protected from rd1 degeneration. We confirmed that an inhibition of either calpain or PARP reduces photoreceptor cell death in rd1 retina. However, while the activity of calpain was decreased by the inhibition of PARP, calpain inhibition did not alter the PARP activity. A combination treatment with calpain and PARP inhibitors did not synergistically reduce cell death. In the slow degeneration of rd1*Cngb1^−/− double mutant, VGCC inhibition delayed photoreceptor cell death, while PARP inhibition did not. Our results indicate that PARP acts upstream of calpain and that both are part of the same degenerative pathway in Pde6b-dependent photoreceptor degeneration. While PARP activation may be associated with CNG channel activity, calpain activation is linked to VGCC opening. Overall, our data highlights PARP as a target for therapeutic interventions in IRD-type diseases. Full article

(This article belongs to the Special Issue Cell and Organ Cultures for Studying Retinal Diseases)

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18 pages, 2418 KiB

Open AccessReview

Histamine Intolerance—A Kind of Pseudoallergic Reaction

by Ying Zhao, Xiaoyan Zhang, Hengxi Jin, Lu Chen, Jiang Ji and Zhongwei Zhang

Biomolecules 2022, 12(3), 454; https://doi.org/10.3390/biom12030454 - 15 Mar 2022

Cited by 15 | Viewed by 11159

Abstract

Histamine intolerance (HIT) is a common disorder associated with impaired histamine metabolism. Notwithstanding, it is often misdiagnosed as other diseases because of its lack of specific clinical manifestations. HIT did not gain traction until the early 21st century. In this review, we will [...] Read more.

Histamine intolerance (HIT) is a common disorder associated with impaired histamine metabolism. Notwithstanding, it is often misdiagnosed as other diseases because of its lack of specific clinical manifestations. HIT did not gain traction until the early 21st century. In this review, we will focus on the latest research and elaborate on the clinical manifestations of HIT, including its manifestations in special populations such as atopic dermatitis (AD) and chronic urticaria (CU), as well as the latest understanding of its etiology and pathogenesis. In addition, we will explore the latest treatment strategies for HIT and the treatment of specific cases. Full article

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21 pages, 1585 KiB

Open AccessReview

Cross-Talk between p53 and Wnt Signaling in Cancer

by Qiyun Xiao, Johannes Werner, Nachiyappan Venkatachalam, Kim E. Boonekamp, Matthias P. Ebert and Tianzuo Zhan

Biomolecules 2022, 12(3), 453; https://doi.org/10.3390/biom12030453 - 15 Mar 2022

Cited by 13 | Viewed by 4332

Abstract

Targeting cancer hallmarks is a cardinal strategy to improve antineoplastic treatment. However, cross-talk between signaling pathways and key oncogenic processes frequently convey resistance to targeted therapies. The p53 and Wnt pathway play vital roles for the biology of many tumors, as they are [...] Read more.

Targeting cancer hallmarks is a cardinal strategy to improve antineoplastic treatment. However, cross-talk between signaling pathways and key oncogenic processes frequently convey resistance to targeted therapies. The p53 and Wnt pathway play vital roles for the biology of many tumors, as they are critically involved in cancer onset and progression. Over recent decades, a high level of interaction between the two pathways has been revealed. Here, we provide a comprehensive overview of molecular interactions between the p53 and Wnt pathway discovered in cancer, including complex feedback loops and reciprocal transactivation. The mutational landscape of genes associated with p53 and Wnt signaling is described, including mutual exclusive and co-occurring genetic alterations. Finally, we summarize the functional consequences of this cross-talk for cancer phenotypes, such as invasiveness, metastasis or drug resistance, and discuss potential strategies to pharmacologically target the p53-Wnt interaction. Full article

(This article belongs to the Collection p53 Function and Dysfunction in Human Health and Diseases)

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13 pages, 287 KiB

Open AccessEditor’s ChoiceReview

Applications of Single-Cell Sequencing Technology to the Enteric Nervous System

by Richard A. Guyer, Jessica L. Mueller and Allan M. Goldstein

Biomolecules 2022, 12(3), 452; https://doi.org/10.3390/biom12030452 - 15 Mar 2022

Cited by 3 | Viewed by 3245

Abstract

With recent technical advances and diminishing sequencing costs, single-cell sequencing modalities have become commonplace. These tools permit analysis of RNA expression, DNA sequence, chromatin structure, and cell surface antigens at single-cell resolution. Simultaneous measurement of numerous parameters can resolve populations including rare cells, [...] Read more.

With recent technical advances and diminishing sequencing costs, single-cell sequencing modalities have become commonplace. These tools permit analysis of RNA expression, DNA sequence, chromatin structure, and cell surface antigens at single-cell resolution. Simultaneous measurement of numerous parameters can resolve populations including rare cells, thus revealing cellular diversity within organs and permitting lineage reconstruction in developing tissues. Application of these methods to the enteric nervous system has yielded a wealth of data and biological insights. We review recent papers applying single-cell sequencing tools to the nascent neural crest and to the developing and mature enteric nervous system. These studies have shown significant diversity of enteric neurons and glia, suggested paradigms for neuronal specification, and revealed signaling pathways active during development. As technology evolves and multiome techniques combining two or more of transcriptomic, genomic, epigenetic, and proteomic data become prominent, we anticipate these modalities will become commonplace in ENS research and may find a role in diagnostic testing and personalized therapeutics. Full article

(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)

24 pages, 29819 KiB

Open AccessFeature PaperArticle

Network Theoretical Approach to Explore Factors Affecting Signal Propagation and Stability in Dementia’s Protein-Protein Interaction Network

by Amit Kumar Lalwani, Kushagra Krishnan, Sali Abubaker Bagabir, Mustfa F. Alkhanani, Atiah H. Almalki, Shafiul Haque, Saurabh Kumar Sharma, R. K. Brojen Singh and Md. Zubbair Malik

Biomolecules 2022, 12(3), 451; https://doi.org/10.3390/biom12030451 - 15 Mar 2022

Cited by 11 | Viewed by 3778

Abstract

Dementia—a syndrome affecting human cognition—is a major public health concern given to its rising prevalence worldwide. Though multiple research studies have analyzed disorders such as Alzheimer’s disease and Frontotemporal dementia using a systems biology approach, a similar approach to dementia syndrome as a [...] Read more.

Dementia—a syndrome affecting human cognition—is a major public health concern given to its rising prevalence worldwide. Though multiple research studies have analyzed disorders such as Alzheimer’s disease and Frontotemporal dementia using a systems biology approach, a similar approach to dementia syndrome as a whole is required. In this study, we try to find the high-impact core regulating processes and factors involved in dementia’s protein–protein interaction network. We also explore various aspects related to its stability and signal propagation. Using gene interaction databases such as STRING and GeneMANIA, a principal dementia network (PDN) consisting of 881 genes and 59,085 interactions was achieved. It was assortative in nature with hierarchical, scale-free topology enriched in various gene ontology (GO) categories and KEGG pathways, such as negative and positive regulation of apoptotic processes, macroautophagy, aging, response to drug, protein binding, etc. Using a clustering algorithm (Louvain method of modularity maximization) iteratively, we found a number of communities at different levels of hierarchy in PDN consisting of 95 “motif-localized hubs”, out of which, 7 were present at deepest level and hence were key regulators (KRs) of PDN (HSP90AA1, HSP90AB1, EGFR, FYN, JUN, CELF2 and CTNNA3). In order to explore aspects of network’s resilience, a knockout (of motif-localized hubs) experiment was carried out. It changed the network’s topology from a hierarchal scale-free topology to scale-free, where independent clusters exhibited greater control. Additionally, network experiments on interaction of druggable genome and motif-localized hubs were carried out where UBC, EGFR, APP, CTNNB1, NTRK1, FN1, HSP90AA1, MDM2, VCP, CTNNA1 and GRB2 were identified as hubs in the resultant network (RN). We finally concluded that stability and resilience of PDN highly relies on motif-localized hubs (especially those present at deeper levels), making them important therapeutic intervention candidates. HSP90AA1, involved in heat shock response (and its master regulator, i.e., HSF1), and EGFR are most important genes in pathology of dementia apart from KRs, given their presence as KRs as well as hubs in RN. Full article

(This article belongs to the Topic Intelligent Computing Unlocks the Molecular Code of Complex Diseases)

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16 pages, 3083 KiB

Open AccessArticle

The Exoproteome of Staphylococcus pasteuri Isolated from Cervical Mucus during the Estrus Phase in Water Buffalo (Bubalus bubalis)

by Mahalingam Srinivasan, Subramanian Muthukumar, Durairaj Rajesh, Vinod Kumar, Rajamanickam Rajakumar, Mohammad Abdulkader Akbarsha, Balázs Gulyás, Parasuraman Padmanabhan and Govindaraju Archunan

Biomolecules 2022, 12(3), 450; https://doi.org/10.3390/biom12030450 - 15 Mar 2022

Cited by 1 | Viewed by 2605

Abstract

Bacterial extracellular proteins participate in the host cell communication by virtue of the modulation of pathogenicity, commensalism and mutualism. Studies on the microbiome of cervical mucus of the water buffalo (Bubalus bubalis) have shown the occurrence of Staphylococcus pasteuri and that [...] Read more.

Bacterial extracellular proteins participate in the host cell communication by virtue of the modulation of pathogenicity, commensalism and mutualism. Studies on the microbiome of cervical mucus of the water buffalo (Bubalus bubalis) have shown the occurrence of Staphylococcus pasteuri and that the presence of this bacterium is indicative of various physiological and reproductive states in the host. Recently, S. pasteuri has been isolated from the cervical mucus of the buffalo during the different phases of estrous cycle, and has proved to be much more pronounced during the estrus phase. The basis underlying the availability of a significantly increased S. pasteuri population, specifically during the estrus phase, is not known. Consequently, it is important to determine the significance of the specific abundance of S. pasteuri during the estrus phase of the buffalo host, particularly from the perspective of whether this bacterial species is capable of contributing to sexual communication via its extracellular proteins and volatiles. Therefore, the relevance of S. pasteuri exoproteome in the buffalo cervical mucus during the estrus phase was analyzed using LC-MS/MS. As many as 219 proteins were identified, among which elongation factor Tu (EF-Tu), 60-kDa chaperonin (Cpn60), enolase, fructose-bisphosphate aldolase class 1 (FBP aldolase), enoyl-[acyl-carrier-protein] reductase [NADPH] (ENR) and lipoprotein (Lpp) were the functionally important candidates. Most of the proteins present in the exoproteome of S. pasteuri were those involved in cellular–metabolic functions, as well as catalytic- and binding activities. Moreover, computational studies of Lpp have shown enhanced interaction with volatiles such as acetic-, butanoic-, isovaleric- and valeric acids, which were identified in the cervical mucus S. pasteuri culture supernatant. The present findings suggest that S. pasteuri extracellular proteins may play an important role in buffalo sexual communication during the estrus phase. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

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11 pages, 4223 KiB

Open AccessCommunication

Attenuation of the Counter-Regulatory Glucose Response in CVLM C1 Neurons: A Possible Explanation for Anorexia of Aging

by Hajira Ramlan and Hanafi Ahmad Damanhuri

Biomolecules 2022, 12(3), 449; https://doi.org/10.3390/biom12030449 - 14 Mar 2022

Cited by 1 | Viewed by 1701

Abstract

This study aimed to determine the effect of age on CVLM C1 neuron glucoregulatory proteins in the feeding pathway. Male Sprague Dawley rats aged 3 months and 24 months old were divided into two subgroups: the treatment group with 2-deoxy-d-glucose (2DG) [...] Read more.

This study aimed to determine the effect of age on CVLM C1 neuron glucoregulatory proteins in the feeding pathway. Male Sprague Dawley rats aged 3 months and 24 months old were divided into two subgroups: the treatment group with 2-deoxy-d-glucose (2DG) and the control group. Rat brains were dissected to obtain the CVLM region of the brainstem. Western blot was used to determine protein expression of tyrosine hydroxylase (TH), phosphorylated TH at Serine40 (pSer40TH), AMP-activated protein kinase (AMPK), phosphorylated AMPK (phospho AMPK), and neuropeptide Y Y5 receptors (NPY5R) in CVLM samples. Immunofluorescence was used to determine TH-, AMPK-, and NPY5R-like immunoreactivities among other brain coronal sections. Results obtained denote a decrease in basal TH phosphorylation levels and AMPK proteins and an increase in TH proteins among aged CVLM neurons. Increases in the basal immunoreactivity of TH+, AMPK+, NPY5R+, TH+/AMPK+, and TH+/NPY5R+ were also observed among old rats. Young treatment-group rats saw a decrease in TH phosphorylation and AMPK proteins following 2DG administration, while an increase in AMPK phosphorylation and a decrease in TH proteins were found among the old-treatment-group rats. These findings suggest the participation of CVLM C1 neurons in counter-regulatory responses among young and old rats. Altering protein changes in aged CVLM C1 neurons may attenuate responses to glucoprivation, thus explaining the decline in food intake among the elderly. Full article

(This article belongs to the Special Issue Aging and Aging-Associated Diseases: From Molecular Mechanisms to Therapies Strategies)

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