International Journal of Molecular Sciences

27 pages, 6703 KiB

Open AccessArticle

Development of a Bispecific Antibody-Based Platform for Retargeting of Capsid Modified AAV Vectors

by Juliane Kuklik, Stefan Michelfelder, Felix Schiele, Sebastian Kreuz, Thorsten Lamla, Philipp Müller and John E. Park

Int. J. Mol. Sci. 2021, 22(15), 8355; https://doi.org/10.3390/ijms22158355 - 3 Aug 2021

Cited by 6 | Viewed by 5886

Abstract

A major limiting factor for systemically delivered gene therapies is the lack of novel tissue specific AAV (Adeno-associated virus) derived vectors. Bispecific antibodies can be used to redirect AAVs to specific target receptors. Here, we demonstrate that the insertion of a short linear [...] Read more.

A major limiting factor for systemically delivered gene therapies is the lack of novel tissue specific AAV (Adeno-associated virus) derived vectors. Bispecific antibodies can be used to redirect AAVs to specific target receptors. Here, we demonstrate that the insertion of a short linear epitope “2E3” derived from human proprotein-convertase subtilisin/kexin type 9 (PCSK9) into different surface loops of the VP capsid proteins can be used for AAV de-targeting from its natural receptor(s), combined with a bispecific antibody-mediated retargeting. We chose to target a set of distinct disease relevant membrane proteins—fibroblast activation protein (FAP), which is upregulated on activated fibroblasts within the tumor stroma and in fibrotic tissues, as well as programmed death-ligand 1 (PD-L1), which is strongly upregulated in many cancers. Upon incubation with a bispecific antibody recognizing the 2E3 epitope and FAP or PD-L1, the bispecific antibody/rAAV complex was able to selectively transduce receptor positive cells. In summary, we developed a novel, rationally designed vector retargeting platform that can target AAVs to a new set of cellular receptors in a modular fashion. This versatile platform may serve as a valuable tool to investigate the role of disease relevant cell types and basis for novel gene therapy approaches. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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21 pages, 2408 KiB

Open AccessArticle

Activation of Local and Systemic Defence Responses by Flg22 Is Dependent on Daytime and Ethylene in Intact Tomato Plants

by Zalán Czékus, András Kukri, Kamirán Áron Hamow, Gabriella Szalai, Irma Tari, Attila Ördög and Péter Poór

Int. J. Mol. Sci. 2021, 22(15), 8354; https://doi.org/10.3390/ijms22158354 - 3 Aug 2021

Cited by 18 | Viewed by 4277

Abstract

The first line of plant defence responses against pathogens can be induced by the bacterial flg22 and can be dependent on various external and internal factors. Here, we firstly studied the effects of daytime and ethylene (ET) using Never ripe (Nr) [...] Read more.

The first line of plant defence responses against pathogens can be induced by the bacterial flg22 and can be dependent on various external and internal factors. Here, we firstly studied the effects of daytime and ethylene (ET) using Never ripe (Nr) mutants in the local and systemic defence responses of intact tomato plants after flg22 treatments. Flg22 was applied in the afternoon and at night and rapid reactions were detected. The production of hydrogen peroxide and nitric oxide was induced by flg22 locally, while superoxide was induced systemically, in wild type plants in the light period, but all remained lower at night and in Nr leaves. Flg22 elevated, locally, the ET, jasmonic acid (JA) and salicylic acid (SA) levels in the light period; these levels did not change significantly at night. Expression of Pathogenesis-related 1 (PR1), Ethylene response factor 1 (ERF1) and Defensin (DEF) showed also daytime- and ET-dependent changes. Enhanced ERF1 and DEF expression and stomatal closure were also observable in systemic leaves of wild type plants in the light. These data demonstrate that early biotic signalling in flg22-treated leaves and distal ones is an ET-dependent process and it is also determined by the time of day and inhibited in the early night phase. Full article

(This article belongs to the Special Issue Plant Innate Immunity 4.0)

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40 pages, 2164 KiB

Open AccessReview

Molecular Drivers of Developmental Arrest in the Human Preimplantation Embryo: A Systematic Review and Critical Analysis Leading to Mapping Future Research

by Konstantinos Sfakianoudis, Evangelos Maziotis, Eleni Karantzali, Georgia Kokkini, Sokratis Grigoriadis, Amelia Pantou, Polina Giannelou, Konstantina Petroutsou, Christina Markomichali, Maria Fakiridou, Michael Koutsilieris, Byron Asimakopoulos, Konstantinos Pantos and Mara Simopoulou

Int. J. Mol. Sci. 2021, 22(15), 8353; https://doi.org/10.3390/ijms22158353 - 3 Aug 2021

Cited by 24 | Viewed by 6280

Abstract

Developmental arrest of the preimplantation embryo is a multifactorial condition, characterized by lack of cellular division for at least 24 hours, hindering the in vitro fertilization cycle outcome. This systematic review aims to present the molecular drivers of developmental arrest, focusing on embryonic [...] Read more.

Developmental arrest of the preimplantation embryo is a multifactorial condition, characterized by lack of cellular division for at least 24 hours, hindering the in vitro fertilization cycle outcome. This systematic review aims to present the molecular drivers of developmental arrest, focusing on embryonic and parental factors. A systematic search in PubMed/Medline, Embase and Cochrane-Central-Database was performed in January 2021. A total of 76 studies were included. The identified embryonic factors associated with arrest included gene variations, mitochondrial DNA copy number, methylation patterns, chromosomal abnormalities, metabolic profile and morphological features. Parental factors included, gene variation, protein expression levels and infertility etiology. A valuable conclusion emerging through critical analysis indicated that genetic origins of developmental arrest analyzed from the perspective of parental infertility etiology and the embryo itself, share common ground. This is a unique and long-overdue contribution to literature that for the first time presents an all-inclusive methodological report on the molecular drivers leading to preimplantation embryos’ arrested development. The variety and heterogeneity of developmental arrest drivers, along with their inevitable intertwining relationships does not allow for prioritization on the factors playing a more definitive role in arrested development. This systematic review provides the basis for further research in the field. Full article

(This article belongs to the Special Issue Novel Molecular Mechanisms and Pathophysiology of Human Embryos)

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15 pages, 3845 KiB

Open AccessArticle

Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity

by Magdi E. A. Zaki, Sami A. Al-Hussain, Vijay H. Masand, Manoj K. Sabnani and Abdul Samad

Int. J. Mol. Sci. 2021, 22(15), 8352; https://doi.org/10.3390/ijms22158352 - 3 Aug 2021

Cited by 5 | Viewed by 2625

Abstract

Thrombosis is a life-threatening disease with a high mortality rate in many countries. Even though anti-thrombotic drugs are available, their serious side effects compel the search for safer drugs. In search of a safer anti-thrombotic drug, Quantitative Structure-Activity Relationship (QSAR) could be useful [...] Read more.

Thrombosis is a life-threatening disease with a high mortality rate in many countries. Even though anti-thrombotic drugs are available, their serious side effects compel the search for safer drugs. In search of a safer anti-thrombotic drug, Quantitative Structure-Activity Relationship (QSAR) could be useful to identify crucial pharmacophoric features. The present work is based on a larger data set comprising 1121 diverse compounds to develop a QSAR model having a balance of acceptable predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The developed six parametric model fulfils the recommended values for internal and external validation along with Y-randomization parameters such as R²_tr = 0.831, Q²_LMO = 0.828, R²_ex = 0.783. The present analysis reveals that anti-thrombotic activity is found to be correlated with concealed structural traits such as positively charged ring carbon atoms, specific combination of aromatic Nitrogen and sp2-hybridized carbon atoms, etc. Thus, the model captured reported as well as novel pharmacophoric features. The results of QSAR analysis are further vindicated by reported crystal structures of compounds with factor Xa. The analysis led to the identification of useful novel pharmacophoric features, which could be used for future optimization of lead compounds. Full article

(This article belongs to the Special Issue Drug Design and Virtual Screening)

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13 pages, 28055 KiB

Open AccessArticle

Extracellular Vesicles as Biological Indicators and Potential Sources of Autologous Therapeutics in Osteoarthritis

by Xin Zhang, Janet L. Huebner and Virginia Byers Kraus

Int. J. Mol. Sci. 2021, 22(15), 8351; https://doi.org/10.3390/ijms22158351 - 3 Aug 2021

Cited by 15 | Viewed by 2955

Abstract

Along with cytokines, extracellular vesicles (EVs) released by immune cells in the joint contribute to osteoarthritis (OA) pathogenesis. By high-resolution flow cytometry, we characterized 18 surface markers and 4 proinflammatory cytokines carried by EVs of various sizes in plasma and synovial fluid (SF) [...] Read more.

Along with cytokines, extracellular vesicles (EVs) released by immune cells in the joint contribute to osteoarthritis (OA) pathogenesis. By high-resolution flow cytometry, we characterized 18 surface markers and 4 proinflammatory cytokines carried by EVs of various sizes in plasma and synovial fluid (SF) from individuals with knee OA, with a primary focus on immune cells that play a major role in OA pathogenesis. By multiplex immunoassay, we also measured concentrations of cytokines within (endo) and outside (exo) EVs. EVs carrying HLA-DR, -DP and -DQ were the most enriched subpopulations in SF relative to plasma (25–50-fold higher depending on size), suggesting a major contribution to the SF EV pool from infiltrating immune cells in OA joints. In contrast, the CD34⁺ medium and small EVs, reflecting hematopoietic stem cells, progenitor cells, and endothelial cells, were the most significantly enriched subpopulations in plasma relative to SF (7.3- and 7.7-fold higher). Ratios of EVs derived from neutrophils and lymphocytes were highly correlated between SF and plasma, indicating that plasma EVs could reflect OA severity and serve as systemic biomarkers of OA joint pathogenesis. Select subsets of plasma EVs might also provide next generation autologous biological products for intra-articular therapy of OA joints. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)

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21 pages, 5989 KiB

Open AccessArticle

Cardiolipin-Containing Lipid Membranes Attract the Bacterial Cell Division Protein DivIVA

by Naďa Labajová, Natalia Baranova, Miroslav Jurásek, Robert Vácha, Martin Loose and Imrich Barák

Int. J. Mol. Sci. 2021, 22(15), 8350; https://doi.org/10.3390/ijms22158350 - 3 Aug 2021

Cited by 5 | Viewed by 4131

Abstract

DivIVA is a protein initially identified as a spatial regulator of cell division in the model organism Bacillus subtilis, but its homologues are present in many other Gram-positive bacteria, including Clostridia species. Besides its role as topological regulator of the Min system [...] Read more.

DivIVA is a protein initially identified as a spatial regulator of cell division in the model organism Bacillus subtilis, but its homologues are present in many other Gram-positive bacteria, including Clostridia species. Besides its role as topological regulator of the Min system during bacterial cell division, DivIVA is involved in chromosome segregation during sporulation, genetic competence, and cell wall synthesis. DivIVA localizes to regions of high membrane curvature, such as the cell poles and cell division site, where it recruits distinct binding partners. Previously, it was suggested that negative curvature sensing is the main mechanism by which DivIVA binds to these specific regions. Here, we show that Clostridioides difficile DivIVA binds preferably to membranes containing negatively charged phospholipids, especially cardiolipin. Strikingly, we observed that upon binding, DivIVA modifies the lipid distribution and induces changes to lipid bilayers containing cardiolipin. Our observations indicate that DivIVA might play a more complex and so far unknown active role during the formation of the cell division septal membrane. Full article

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

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16 pages, 4467 KiB

Open AccessArticle

Quercetin Administration Suppresses the Cytokine Storm in Myeloid and Plasmacytoid Dendritic Cells

by Giulio Verna, Marina Liso, Elisabetta Cavalcanti, Giusy Bianco, Veronica Di Sarno, Angelo Santino, Pietro Campiglia and Marcello Chieppa

Int. J. Mol. Sci. 2021, 22(15), 8349; https://doi.org/10.3390/ijms22158349 - 3 Aug 2021

Cited by 14 | Viewed by 3186

Abstract

Dendritic cells (DCs) can be divided by lineage into myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs). They both are present in mucosal tissues and regulate the immune response by secreting chemokines and cytokines. Inflammatory bowel diseases (IBDs) are characterized by a [...] Read more.

Dendritic cells (DCs) can be divided by lineage into myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs). They both are present in mucosal tissues and regulate the immune response by secreting chemokines and cytokines. Inflammatory bowel diseases (IBDs) are characterized by a leaky intestinal barrier and the consequent translocation of bacterial lipopolysaccharide (LPS) to the basolateral side. This results in DCs activation, but the response of pDCs is still poorly characterized. In the present study, we compared mDCs and pDCs responses to LPS administration. We present a broad panel of DCs secreted factors, including cytokines, chemokines, and growth factors. Our recent studies demonstrated the anti-inflammatory effects of quercetin administration, but to date, there is no evidence about quercetin’s effects on pDCs. The results of the present study demonstrate that pDCs can respond to LPS and that quercetin exposure modulates soluble factors release through the same molecular pathway used by mDCs (Slpi, Hmox1, and AP-1). Full article

(This article belongs to the Special Issue Role of Dendritic Cells in Inflammation 2.0)

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12 pages, 4279 KiB

Open AccessArticle

Preparation and Size Control of Efficient and Safe Nanopesticides by Anodic Aluminum Oxide Templates-Assisted Method

by Chunxin Wang, Bo Cui, Yan Wang, Mengjie Wang, Zhanghua Zeng, Fei Gao, Changjiao Sun, Liang Guo, Xiang Zhao and Haixin Cui

Int. J. Mol. Sci. 2021, 22(15), 8348; https://doi.org/10.3390/ijms22158348 - 3 Aug 2021

Cited by 9 | Viewed by 2400

Abstract

Efficient and safe nanopesticides play an important role in pest control due to enhancing target efficiency and reducing undesirable side effects, which has become a hot spot in pesticide formulation research. However, the preparation methods of nanopesticides are facing critical challenges including low [...] Read more.

Efficient and safe nanopesticides play an important role in pest control due to enhancing target efficiency and reducing undesirable side effects, which has become a hot spot in pesticide formulation research. However, the preparation methods of nanopesticides are facing critical challenges including low productivity, uneven particle size and batch differences. Here, we successfully developed a novel, versatile and tunable strategy for preparing buprofezin nanoparticles with tunable size via anodic aluminum oxide (AAO) template-assisted method, which exhibited better reproducibility and homogeneity comparing with the traditional method. The storage stability of nanoparticles at different temperatures was evaluated, and the release properties were also determined to evaluate the performance of nanoparticles. Moreover, the present method is further demonstrated to be easily applicable for insoluble drugs and be extended for the study of the physicochemical properties of drug particles with different sizes. Full article

(This article belongs to the Special Issue Multifunctional Nanomaterials: Synthesis, Properties and Applications)

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20 pages, 4067 KiB

Open AccessReview

Importance of Surface Topography in Both Biological Activity and Catalysis of Nanomaterials: Can Catalysis by Design Guide Safe by Design?

by Mary Gulumian, Charlene Andraos, Antreas Afantitis, Tomasz Puzyn and Neil J. Coville

Int. J. Mol. Sci. 2021, 22(15), 8347; https://doi.org/10.3390/ijms22158347 - 3 Aug 2021

Cited by 17 | Viewed by 4066

Abstract

It is acknowledged that the physicochemical properties of nanomaterials (NMs) have an impact on their toxicity and, eventually, their pathogenicity. These properties may include the NMs’ surface chemical composition, size, shape, surface charge, surface area, and surface coating with ligands (which can carry [...] Read more.

It is acknowledged that the physicochemical properties of nanomaterials (NMs) have an impact on their toxicity and, eventually, their pathogenicity. These properties may include the NMs’ surface chemical composition, size, shape, surface charge, surface area, and surface coating with ligands (which can carry different functional groups as well as proteins). Nanotopography, defined as the specific surface features at the nanoscopic scale, is not widely acknowledged as an important physicochemical property. It is known that the size and shape of NMs determine their nanotopography which, in turn, determines their surface area and their active sites. Nanotopography may also influence the extent of dissolution of NMs and their ability to adsorb atoms and molecules such as proteins. Consequently, the surface atoms (due to their nanotopography) can influence the orientation of proteins as well as their denaturation. However, although it is of great importance, the role of surface topography (nanotopography) in nanotoxicity is not much considered. Many of the issues that relate to nanotopography have much in common with the fundamental principles underlying classic catalysis. Although these were developed over many decades, there have been recent important and remarkable improvements in the development and study of catalysts. These have been brought about by new techniques that have allowed for study at the nanoscopic scale. Furthermore, the issue of quantum confinement by nanosized particles is now seen as an important issue in studying nanoparticles (NPs). In catalysis, the manipulation of a surface to create active surface sites that enhance interactions with external molecules and atoms has much in common with the interaction of NP surfaces with proteins, viruses, and bacteria with the same active surface sites of NMs. By reviewing the role that surface nanotopography plays in defining many of the NMs’ surface properties, it reveals the need for its consideration as an important physicochemical property in descriptive and predictive toxicology. Through the manipulation of surface topography, and by using principles developed in catalysis, it may also be possible to make safe-by-design NMs with a reduction of the surface properties which contribute to their toxicity. Full article

(This article belongs to the Special Issue Advances in Cheminformatics and Nanoinformatics: From Materials Modelling to Precision Toxicology, Medicine and Agriculture)

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51 pages, 997 KiB

Open AccessReview

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

by Valeria Pietropaolo, Carla Prezioso and Ugo Moens

Int. J. Mol. Sci. 2021, 22(15), 8346; https://doi.org/10.3390/ijms22158346 - 3 Aug 2021

Cited by 39 | Viewed by 6142

Abstract

The tumor viruses human T-lymphotropic virus 1 (HTLV-1), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), high-risk human papillomaviruses (HR-HPVs), Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV) and hepatitis B virus (HBV) account for approximately 15% of all human cancers. Although the [...] Read more.

The tumor viruses human T-lymphotropic virus 1 (HTLV-1), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), high-risk human papillomaviruses (HR-HPVs), Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV) and hepatitis B virus (HBV) account for approximately 15% of all human cancers. Although the oncoproteins of these tumor viruses display no sequence similarity to one another, they use the same mechanisms to convey cancer hallmarks on the infected cell. Perturbed gene expression is one of the underlying mechanisms to induce cancer hallmarks. Epigenetic processes, including DNA methylation, histone modification and chromatin remodeling, microRNA, long noncoding RNA, and circular RNA affect gene expression without introducing changes in the DNA sequence. Increasing evidence demonstrates that oncoviruses cause epigenetic modifications, which play a pivotal role in carcinogenesis. In this review, recent advances in the role of host cell epigenetic changes in virus-induced cancers are summarized. Full article

(This article belongs to the Special Issue Genetics and Epigenetics in Complex Diseases)

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15 pages, 2608 KiB

Open AccessArticle

Cigarette Smoke Condensate Exposure Induces Receptor for Advanced Glycation End-Products (RAGE)-Dependent Sterile Inflammation in Amniotic Epithelial Cells

by Helena Choltus, Régine Minet-Quinard, Corinne Belville, Julie Durif, Denis Gallot, Loic Blanchon and Vincent Sapin

Int. J. Mol. Sci. 2021, 22(15), 8345; https://doi.org/10.3390/ijms22158345 - 3 Aug 2021

Cited by 8 | Viewed by 4273

Abstract

Maternal smoking is a risk factor of preterm prelabor rupture of the fetal membranes (pPROM), which is responsible for 30% of preterm births worldwide. Cigarettes induce oxidative stress and inflammation, mechanisms both implicated in fetal membranes (FM) weakening. We hypothesized that the receptor [...] Read more.

Maternal smoking is a risk factor of preterm prelabor rupture of the fetal membranes (pPROM), which is responsible for 30% of preterm births worldwide. Cigarettes induce oxidative stress and inflammation, mechanisms both implicated in fetal membranes (FM) weakening. We hypothesized that the receptor for advanced glycation end-products (RAGE) and its ligands can result in cigarette-dependent inflammation. FM explants and amniotic epithelial cells (AECs) were treated with cigarette smoke condensate (CSC), combined or not with RAGE antagonist peptide (RAP), an inhibitor of RAGE. Cell suffering was evaluated by measuring lactate dehydrogenase (LDH) medium-release. Extracellular HMGB1 (a RAGE ligand) release by amnion and choriodecidua explants were checked by western blot. NF-κB pathway induction was determined by a luciferase gene reporter assay, and inflammation was evaluated by cytokine RT-qPCR and protein quantification. Gelatinase activity was assessed using a specific assay. CSC induced cell suffering and HMGB1 secretion only in the amnion, which is directly associated with a RAGE-dependent response. CSC also affected AECs by inducing inflammation (cytokine release and NFκB activation) and gelatinase activity through RAGE engagement, which was linked to an increase in extracellular matrix degradation. This RAGE dependent CSC-induced inflammation associated with an increase of gelatinase activity could explain a pathological FM weakening directly linked to pPROM. Full article

(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)

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32 pages, 2286 KiB

Open AccessReview

Unraveling Axon Guidance during Axotomy and Regeneration

by Miguel E. Domínguez-Romero and Paula G. Slater

Int. J. Mol. Sci. 2021, 22(15), 8344; https://doi.org/10.3390/ijms22158344 - 3 Aug 2021

Cited by 18 | Viewed by 6786

Abstract

During neuronal development and regeneration axons extend a cytoskeletal-rich structure known as the growth cone, which detects and integrates signals to reach its final destination. The guidance cues “signals” bind their receptors, activating signaling cascades that result in the regulation of the growth [...] Read more.

During neuronal development and regeneration axons extend a cytoskeletal-rich structure known as the growth cone, which detects and integrates signals to reach its final destination. The guidance cues “signals” bind their receptors, activating signaling cascades that result in the regulation of the growth cone cytoskeleton, defining growth cone advance, pausing, turning, or collapse. Even though much is known about guidance cues and their isolated mechanisms during nervous system development, there is still a gap in the understanding of the crosstalk between them, and about what happens after nervous system injuries. After neuronal injuries in mammals, only axons in the peripheral nervous system are able to regenerate, while the ones from the central nervous system fail to do so. Therefore, untangling the guidance cues mechanisms, as well as their behavior and characterization after axotomy and regeneration, are of special interest for understanding and treating neuronal injuries. In this review, we present findings on growth cone guidance and canonical guidance cues mechanisms, followed by a description and comparison of growth cone pathfinding mechanisms after axotomy, in regenerative and non-regenerative animal models. Full article

(This article belongs to the Special Issue Role of Neuronal Guidance Cues in Inflammation and Vascular Biology)

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22 pages, 1119 KiB

Open AccessReview

Purinergic Signalling in Allogeneic Haematopoietic Stem Cell Transplantation and Graft-versus-Host Disease

by Peter Cuthbertson, Nicholas J. Geraghty, Sam R. Adhikary, Katrina M. Bird, Stephen J. Fuller, Debbie Watson and Ronald Sluyter

Int. J. Mol. Sci. 2021, 22(15), 8343; https://doi.org/10.3390/ijms22158343 - 3 Aug 2021

Cited by 9 | Viewed by 3999

Abstract

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for blood cancers and other haematological disorders. However, allo-HSCT leads to graft-versus-host disease (GVHD), a severe and often lethal immunological response, in the majority of transplant recipients. Current therapies for GVHD are limited [...] Read more.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for blood cancers and other haematological disorders. However, allo-HSCT leads to graft-versus-host disease (GVHD), a severe and often lethal immunological response, in the majority of transplant recipients. Current therapies for GVHD are limited and often reduce the effectiveness of allo-HSCT. Therefore, pro- and anti-inflammatory factors contributing to disease need to be explored in order to identify new treatment targets. Purinergic signalling plays important roles in haematopoiesis, inflammation and immunity, and recent evidence suggests that it can also affect haematopoietic stem cell transplantation and GVHD development. This review provides a detailed assessment of the emerging roles of purinergic receptors, most notably P2X7, P2Y₂ and A_2A receptors, and ectoenzymes, CD39 and CD73, in GVHD. Full article

(This article belongs to the Special Issue Transplant Immunology in Allogeneic Hematopoietic Stem Cell Transplantation)

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13 pages, 33620 KiB

Open AccessArticle

alfaNET: A Database of Alfalfa-Bacterial Stem Blight Protein–Protein Interactions Revealing the Molecular Features of the Disease-causing Bacteria

by Raghav Kataria and Rakesh Kaundal

Int. J. Mol. Sci. 2021, 22(15), 8342; https://doi.org/10.3390/ijms22158342 - 3 Aug 2021

Cited by 7 | Viewed by 3182

Abstract

Alfalfa has emerged as one of the most important forage crops, owing to its wide adaptation and high biomass production worldwide. In the last decade, the emergence of bacterial stem blight (caused by Pseudomonas syringae pv. syringae ALF3) in alfalfa has caused around [...] Read more.

Alfalfa has emerged as one of the most important forage crops, owing to its wide adaptation and high biomass production worldwide. In the last decade, the emergence of bacterial stem blight (caused by Pseudomonas syringae pv. syringae ALF3) in alfalfa has caused around 50% yield losses in the United States. Studies are being conducted to decipher the roles of the key genes and pathways regulating the disease, but due to the sparse knowledge about the infection mechanisms of Pseudomonas, the development of resistant cultivars is hampered. The database alfaNET is an attempt to assist researchers by providing comprehensive Pseudomonas proteome annotations, as well as a host–pathogen interactome tool, which predicts the interactions between host and pathogen based on orthology. alfaNET is a user-friendly and efficient tool and includes other features such as subcellular localization annotations of pathogen proteins, gene ontology (GO) annotations, network visualization, and effector protein prediction. Users can also browse and search the database using particular keywords or proteins with a specific length. Additionally, the BLAST search tool enables the user to perform a homology sequence search against the alfalfa and Pseudomonas proteomes. With the successful implementation of these attributes, alfaNET will be a beneficial resource to the research community engaged in implementing molecular strategies to mitigate the disease. alfaNET is freely available for public use at http://bioinfo.usu.edu/alfanet/. Full article

(This article belongs to the Special Issue Genomics: Infectious Disease and Host-Pathogen Interaction)

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15 pages, 1773 KiB

Open AccessReview

Application of Carbon Nanoparticles in Oncology and Regenerative Medicine

by Katarzyna Lisik and Anita Krokosz

Int. J. Mol. Sci. 2021, 22(15), 8341; https://doi.org/10.3390/ijms22158341 - 3 Aug 2021

Cited by 29 | Viewed by 4006

Abstract

Currently, carbon nanoparticles play a large role as carriers of various types of drugs, and also have applications in other fields of medicine, e.g., in tissue engineering, where they are used to reconstruct bone tissue. They also contribute to the early detection of [...] Read more.

Currently, carbon nanoparticles play a large role as carriers of various types of drugs, and also have applications in other fields of medicine, e.g., in tissue engineering, where they are used to reconstruct bone tissue. They also contribute to the early detection of cancer cells, and can act as markers in imaging diagnostics. Their antibacterial and anti-inflammatory properties are also known. This feature is particularly important in dental implantology, where various types of bacterial infections and implant rejection often occur. The search for newer and more effective treatments may lead to future use of nanoparticles on a large scale. In this work, the current state of knowledge on the possible use of nanotubes, nanodiamonds, and fullerenes in therapy is reviewed. Both advantages and disadvantages of the use of carbon nanoparticles in therapy and diagnostics have been indicated. Full article

(This article belongs to the Special Issue Biologically Synthesized Nanomaterials and Their Nanocomposites for Biomedical Applications)

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24 pages, 40798 KiB

Open AccessReview

Dendritic Cells and CCR7 Expression: An Important Factor for Autoimmune Diseases, Chronic Inflammation, and Cancer

by Emma Probst Brandum, Astrid Sissel Jørgensen, Mette Marie Rosenkilde and Gertrud Malene Hjortø

Int. J. Mol. Sci. 2021, 22(15), 8340; https://doi.org/10.3390/ijms22158340 - 3 Aug 2021

Cited by 69 | Viewed by 11614

Abstract

Chemotactic cytokines—chemokines—control immune cell migration in the process of initiation and resolution of inflammatory conditions as part of the body’s defense system. Many chemokines also participate in pathological processes leading up to and exacerbating the inflammatory state characterizing chronic inflammatory diseases. In this [...] Read more.

Chemotactic cytokines—chemokines—control immune cell migration in the process of initiation and resolution of inflammatory conditions as part of the body’s defense system. Many chemokines also participate in pathological processes leading up to and exacerbating the inflammatory state characterizing chronic inflammatory diseases. In this review, we discuss the role of dendritic cells (DCs) and the central chemokine receptor CCR7 in the initiation and sustainment of selected chronic inflammatory diseases: multiple sclerosis (MS), rheumatoid arthritis (RA), and psoriasis. We revisit the binary role that CCR7 plays in combatting and progressing cancer, and we discuss how CCR7 and DCs can be harnessed for the treatment of cancer. To provide the necessary background, we review the differential roles of the natural ligands of CCR7, CCL19, and CCL21 and how they direct the mobilization of activated DCs to lymphoid organs and control the formation of associated lymphoid tissues (ALTs). We provide an overview of DC subsets and, briefly, elaborate on the different T-cell effector types generated upon DC–T cell priming. In the conclusion, we promote CCR7 as a possible target of future drugs with an antagonistic effect to reduce inflammation in chronic inflammatory diseases and an agonistic effect for boosting the reactivation of the immune system against cancer in cell-based and/or immune checkpoint inhibitor (ICI)-based anti-cancer therapy. Full article

(This article belongs to the Special Issue Role of Dendritic Cells in Inflammation 2.0)

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12 pages, 3618 KiB

Open AccessArticle

Hierarchical Structure of Protein Sequence

by Alexei N. Nekrasov, Yuri P. Kozmin, Sergey V. Kozyrev, Rustam H. Ziganshin, Alexandre G. de Brevern and Anastasia A. Anashkina

Int. J. Mol. Sci. 2021, 22(15), 8339; https://doi.org/10.3390/ijms22158339 - 3 Aug 2021

Cited by 7 | Viewed by 3074

Abstract

Most non-communicable diseases are associated with dysfunction of proteins or protein complexes. The relationship between sequence and structure has been analyzed for a long time, and the analysis of the sequences organization in domains and motifs remains an actual research area. Here, we [...] Read more.

Most non-communicable diseases are associated with dysfunction of proteins or protein complexes. The relationship between sequence and structure has been analyzed for a long time, and the analysis of the sequences organization in domains and motifs remains an actual research area. Here, we propose a mathematical method for revealing the hierarchical organization of protein sequences. The method is based on the pentapeptide as a unit of protein sequences. Employing the frequency of occurrence of pentapeptides in sequences of natural proteins and a special mathematical approach, this method revealed a hierarchical structure in the protein sequence. The method was applied to 24,647 non-homologous protein sequences with sizes ranging from 50 to 400 residues from the NRDB90 database. Statistical analysis of the branching points of the graphs revealed 11 characteristic values of y (the width of the inscribed function), showing the relationship of these multiple fragments of the sequences. Several examples illustrate how fragments of the protein spatial structure correspond to the elements of the hierarchical structure of the protein sequence. This methodology provides a promising basis for a mathematically-based classification of the elements of the spatial organization of proteins. Elements of the hierarchical structure of different levels of the hierarchy can be used to solve biotechnological and medical problems. Full article

(This article belongs to the Special Issue Medical Genetics, Genomics and Bioinformatics – 2021)

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23 pages, 1235 KiB

Open AccessReview

The Prion-Like Spreading of Alpha-Synuclein in Parkinson’s Disease: Update on Models and Hypotheses

by Asad Jan, Nádia Pereira Gonçalves, Christian Bjerggaard Vaegter, Poul Henning Jensen and Nelson Ferreira

Int. J. Mol. Sci. 2021, 22(15), 8338; https://doi.org/10.3390/ijms22158338 - 3 Aug 2021

Cited by 58 | Viewed by 10631

Abstract

The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson’s disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn [...] Read more.

The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson’s disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn accumulation in the CNS are not fully understood, growing evidence suggests that de novo α-syn misfolding and/or neuronal internalization of aggregated α-syn facilitates conformational templating of endogenous α-syn monomers in a mechanism reminiscent of prions. A refined understanding of the biochemical and cellular factors mediating the pathological neuron-to-neuron propagation of misfolded α-syn will potentially elucidate the etiology of PD and unravel novel targets for therapeutic intervention. Here, we discuss recent developments on the hypothesis regarding trans-synaptic propagation of α-syn pathology in the context of neuronal vulnerability and highlight the potential utility of novel experimental models of synucleinopathies. Full article

(This article belongs to the Special Issue Alpha-Synuclein in Neurodegeneration)

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13 pages, 2683 KiB

Open AccessArticle

Regulation Network of Colorectal-Cancer-Specific Enhancers in the Progression of Colorectal Cancer

by Bohan Chen, Yiping Ma, Jinfang Bi, Wenbin Wang, Anshun He, Guangsong Su, Zhongfang Zhao, Jiandang Shi and Lei Zhang

Int. J. Mol. Sci. 2021, 22(15), 8337; https://doi.org/10.3390/ijms22158337 - 3 Aug 2021

Cited by 5 | Viewed by 3726

Abstract

Enhancers regulate multiple genes via higher-order chromatin structures, and they further affect cancer progression. Epigenetic changes in cancer cells activate several cancer-specific enhancers that are silenced in normal cells. These cancer-specific enhancers are potential therapeutic targets of cancer. However, the functions and regulation [...] Read more.

Enhancers regulate multiple genes via higher-order chromatin structures, and they further affect cancer progression. Epigenetic changes in cancer cells activate several cancer-specific enhancers that are silenced in normal cells. These cancer-specific enhancers are potential therapeutic targets of cancer. However, the functions and regulation networks of colorectal-cancer-specific enhancers are still unknown. In this study, we profile colorectal-cancer-specific enhancers and reveal their regulation network through the analysis of HiChIP data that were derived from a colorectal cancer cell line and Hi-C and RNA-seq data that were derived from tissue samples by in silico analysis and in vitro experiments. Enhancer–promoter loops in colorectal cancer cells containing colorectal-cancer-specific enhancers are involved in more than 50% of the topological associated domains (TADs) changed in colorectal cancer cells compared to normal colon cells. In addition, colorectal-cancer-specific enhancers interact with 152 genes that are significantly and highly expressed in colorectal cancer cells. These colorectal-cancer-specific enhancer target genes include ITGB4, RECQL4, MSLN, and GDF15. We propose that the regulation network of colorectal-cancer-specific enhancers plays an important role in the progression of colorectal cancer. Full article

(This article belongs to the Section Molecular Oncology)

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16 pages, 2039 KiB

Open AccessArticle

Inflammasome Signaling Regulates the Microbial–Neuroimmune Axis and Visceral Pain in Mice

by Mònica Aguilera, Valerio Rossini, Ana Hickey, Donjete Simnica, Fiona Grady, Valeria D. Felice, Amy Moloney, Lauren Pawley, Aine Fanning, Lorraine McCarthy, Siobhan M. O’Mahony, John F. Cryan, Ken Nally, Fergus Shanahan and Silvia Melgar

Int. J. Mol. Sci. 2021, 22(15), 8336; https://doi.org/10.3390/ijms22158336 - 3 Aug 2021

Cited by 13 | Viewed by 3787

Abstract

Interactions between the intestinal microbiota, immune system and nervous system are essential for homeostasis in the gut. Inflammasomes contribute to innate immunity and brain–gut interactions, but their role in microbiota–neuro–immune interactions is not clear. Therefore, we investigated the effect of the inflammasome on [...] Read more.

Interactions between the intestinal microbiota, immune system and nervous system are essential for homeostasis in the gut. Inflammasomes contribute to innate immunity and brain–gut interactions, but their role in microbiota–neuro–immune interactions is not clear. Therefore, we investigated the effect of the inflammasome on visceral pain and local and systemic neuroimmune responses after antibiotic-induced changes to the microbiota. Wild-type (WT) and caspase-1/11 deficient (Casp1 KO) mice were orally treated for 2 weeks with an antibiotic cocktail (Abx, Bacitracin A and Neomycin), followed by quantification of representative fecal commensals (by qPCR), cecal short chain fatty acids (by HPLC), pathways implicated in the gut–neuro-immune axis (by RT-qPCR, immunofluorescence staining, and flow cytometry) in addition to capsaicin-induced visceral pain responses. Abx-treatment in WT-mice resulted in an increase in colonic macrophages, central neuro-immune interactions, colonic inflammasome and nociceptive receptor gene expression and a reduction in capsaicin-induced visceral pain. In contrast, these responses were attenuated in Abx-treated Casp1 KO mice. Collectively, the data indicate an important role for the inflammasome pathway in functional and inflammatory gastrointestinal conditions where pain and alterations in microbiota composition are prominent. Full article

(This article belongs to the Special Issue Diet-Microbiota and Host Interactions in Intestinal Health and Inflammation)

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15 pages, 6595 KiB

Open AccessReview

Hypoxia in Cancer and Fibrosis: Part of the Problem and Part of the Solution

by Yair Romero and Arnoldo Aquino-Gálvez

Int. J. Mol. Sci. 2021, 22(15), 8335; https://doi.org/10.3390/ijms22158335 - 3 Aug 2021

Cited by 17 | Viewed by 4521

Abstract

Adaptive responses to hypoxia are involved in the progression of lung cancer and pulmonary fibrosis. However, it has not been pointed out that hypoxia may be the link between these diseases. As tumors or scars expand, a lack of oxygen results in the [...] Read more.

Adaptive responses to hypoxia are involved in the progression of lung cancer and pulmonary fibrosis. However, it has not been pointed out that hypoxia may be the link between these diseases. As tumors or scars expand, a lack of oxygen results in the activation of the hypoxia response, promoting cell survival even during chronic conditions. The role of hypoxia-inducible factors (HIFs) as master regulators of this adaptation is crucial in both lung cancer and idiopathic pulmonary fibrosis, which have shown the active transcriptional signature of this pathway. Emerging evidence suggests that interconnected feedback loops such as metabolic changes, fibroblast differentiation or extracellular matrix remodeling contribute to HIF overactivation, making it an irreversible phenomenon. This review will focus on the role of HIF signaling and its possible overlapping in order to identify new opportunities in therapy and regeneration. Full article

(This article belongs to the Special Issue Hypoxia Signaling in Human Diseases)

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21 pages, 841 KiB

Open AccessReview

The Role of the IL-6 Cytokine Family in Epithelial–Mesenchymal Plasticity in Cancer Progression

by Andrea Abaurrea, Angela M. Araujo and Maria M. Caffarel

Int. J. Mol. Sci. 2021, 22(15), 8334; https://doi.org/10.3390/ijms22158334 - 3 Aug 2021

Cited by 54 | Viewed by 6556

Abstract

Epithelial–mesenchymal plasticity (EMP) plays critical roles during embryonic development, wound repair, fibrosis, inflammation and cancer. During cancer progression, EMP results in heterogeneous and dynamic populations of cells with mixed epithelial and mesenchymal characteristics, which are required for local invasion and metastatic dissemination. Cancer [...] Read more.

Epithelial–mesenchymal plasticity (EMP) plays critical roles during embryonic development, wound repair, fibrosis, inflammation and cancer. During cancer progression, EMP results in heterogeneous and dynamic populations of cells with mixed epithelial and mesenchymal characteristics, which are required for local invasion and metastatic dissemination. Cancer development is associated with an inflammatory microenvironment characterized by the accumulation of multiple immune cells and pro-inflammatory mediators, such as cytokines and chemokines. Cytokines from the interleukin 6 (IL-6) family play fundamental roles in mediating tumour-promoting inflammation within the tumour microenvironment, and have been associated with chronic inflammation, autoimmunity, infectious diseases and cancer, where some members often act as diagnostic or prognostic biomarkers. All IL-6 family members signal through the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway and are able to activate a wide array of signalling pathways and transcription factors. In general, IL-6 cytokines activate EMP processes, fostering the acquisition of mesenchymal features in cancer cells. However, this effect may be highly context dependent. This review will summarise all the relevant literature related to all members of the IL-6 family and EMP, although it is mainly focused on IL-6 and oncostatin M (OSM), the family members that have been more extensively studied. Full article

(This article belongs to the Special Issue The Epithelial-to-Mesenchymal Transition (EMT) in Cancers)

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19 pages, 18705 KiB

Open AccessArticle

Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease

by Carsten Esselun, Ellen Theyssen and Gunter P. Eckert

Int. J. Mol. Sci. 2021, 22(15), 8333; https://doi.org/10.3390/ijms22158333 - 3 Aug 2021

Cited by 32 | Viewed by 6122

Abstract

(1) Background: Ellagitannins are natural products occurring in pomegranate and walnuts. They are hydrolyzed in the gut to release ellagic acid, which is further metabolized by the microflora into urolithins, such as urolithin A (UA). Accumulation of damaged mitochondria is a hallmark of [...] Read more.

(1) Background: Ellagitannins are natural products occurring in pomegranate and walnuts. They are hydrolyzed in the gut to release ellagic acid, which is further metabolized by the microflora into urolithins, such as urolithin A (UA). Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegenerative diseases. In this study, we investigated the neuroprotective activity of the metabolite UA against mitochondrial dysfunction in a cellular model of early Alzheimer disease (AD). (2) Methods: In the present study we used SH-SY5Y-APP695 cells and its corresponding controls (SH-SY5Ymock) to assess UA’s effect on mitochondrial function. Using these cells we investigated mitochondrial respiration (OXPHOS), mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, autophagy and levels of reactive oxygen species (ROS) in cells treated with UA. Furthermore, we assessed UA’s effect on the expression of genes related to mitochondrial bioenergetics, mitochondrial biogenesis, and autophagy via quantitative real-time PCR (qRT-PCR). (3) Results: Treatment of SH-SY5Y-APP695 cells suggests changes to autophagy corresponding with qRT-PCR results. However, LC3B-I, LC3B-II, and p62 levels were unchanged. UA (10 µM) reduced MMP, and ATP-levels. Treatment of cells with UA (1 µM) for 24 h did not affect ROS production or levels of Aβ, but significantly increased expression of genes for mitochondrial biogenesis and OXPHOS. Mitochondrial Transcription Factor A (TFAM) expression was specifically increased in SH-SY5Y-APP695. Both cell lines showed unaltered levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which is commonly associated with mitochondrial biogenesis. Results imply that biogenesis might be facilitated by estrogen-related receptor (ESRR) genes. (4) Conclusion: Urolithin A shows no effect on autophagy in SH-SY5Y-APP695 cells and its effect on mitochondrial function is limited. Instead, data suggests that UA treatment induces hormetic effects as it induces transcription of several genes related to mitochondrial biogenesis. Full article

(This article belongs to the Special Issue Natural Products and Neuroprotection 3.0)

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15 pages, 779 KiB

Open AccessReview

Dual Nature of Relationship between Mycobacteria and Cancer

by Marek Fol, Piotr Koziński, Jakub Kulesza, Piotr Białecki and Magdalena Druszczyńska

Int. J. Mol. Sci. 2021, 22(15), 8332; https://doi.org/10.3390/ijms22158332 - 3 Aug 2021

Cited by 13 | Viewed by 4056

Abstract

Although the therapeutic effect of mycobacteria as antitumor agents has been known for decades, recent epidemiological and experimental studies have revealed that mycobacterium-related chronic inflammation may be a possible mechanism of cancer pathogenesis. Mycobacterium tuberculosis and non-tuberculous Mycobacterium avium complex infections have been [...] Read more.

Although the therapeutic effect of mycobacteria as antitumor agents has been known for decades, recent epidemiological and experimental studies have revealed that mycobacterium-related chronic inflammation may be a possible mechanism of cancer pathogenesis. Mycobacterium tuberculosis and non-tuberculous Mycobacterium avium complex infections have been implicated as potentially contributing to the etiology of lung cancer, whereas Mycobacterium ulcerans has been correlated with skin carcinogenesis. The risk of tumor development with chronic mycobacterial infections is thought to be a result of many host effector mechanisms acting at different stages of oncogenesis. In this paper, we focus on the nature of the relationship between mycobacteria and cancer, describing the clinical significance of mycobacteria-based cancer therapy as well as epidemiological evidence on the contribution of chronic mycobacterial infections to the increased lung cancer risk. Full article

(This article belongs to the Special Issue The Consequences of Infections on the Host Immune Microenvironment)

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17 pages, 2983 KiB

Open AccessCase Report

A Novel Germline Mutation of ADA2 Gene in Two “Discordant” Homozygous Female Twins Affected by Adenosine Deaminase 2 Deficiency: Description of the Bone-Related Phenotype

by Silvia Vai, Erika Marin, Roberta Cosso, Francesco Saettini, Sonia Bonanomi, Alessandro Cattoni, Iacopo Chiodini, Luca Persani and Alberto Falchetti

Int. J. Mol. Sci. 2021, 22(15), 8331; https://doi.org/10.3390/ijms22158331 - 3 Aug 2021

Cited by 1 | Viewed by 2623

Abstract

Adenosine Deaminase 2 Deficiency (DADA2) syndrome is a rare monogenic disorder prevalently linked to recessive inherited loss of function mutations in the ADA2/CECR1 gene. It consists of an immune systemic disease including autoinflammatory vasculopathies, with a frequent onset at infancy/early childhood age. DADA2 [...] Read more.

Adenosine Deaminase 2 Deficiency (DADA2) syndrome is a rare monogenic disorder prevalently linked to recessive inherited loss of function mutations in the ADA2/CECR1 gene. It consists of an immune systemic disease including autoinflammatory vasculopathies, with a frequent onset at infancy/early childhood age. DADA2 syndrome encompasses pleiotropic manifestations such as stroke, systemic vasculitis, hematologic alterations, and immunodeficiency. Although skeletal abnormalities have been reported in patients with this disease, clear information about skeletal health, with appropriate biochemical-clinical characterization/management, its evolution over time and any appropriate clinical management is still insufficient. In this paper, after a general introduction shortly reviewing the pathophysiology of Ada2 enzymatic protein, its potential role in bone health, we describe a case study of two 27 year-old DADA2 monozygotic female twins exhibiting bone mineral density and bone turnover rate abnormalities over the years of their clinical follow-up. Full article

(This article belongs to the Special Issue Osteoporosis)

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21 pages, 3423 KiB

Open AccessArticle

Synthesis and Characterization of New Biodegradable Injectable Thermosensitive Smart Hydrogels for 5-Fluorouracil Delivery

by Adam Kasiński, Monika Zielińska-Pisklak, Sebastian Kowalczyk, Andrzej Plichta, Anna Zgadzaj, Ewa Oledzka and Marcin Sobczak

Int. J. Mol. Sci. 2021, 22(15), 8330; https://doi.org/10.3390/ijms22158330 - 3 Aug 2021

Cited by 13 | Viewed by 3585

Abstract

In this paper, injectable, thermosensitive smart hydrogel local drug delivery systems (LDDSs) releasing the model antitumour drug 5-fluorouracil (5-FU) were developed. The systems were based on biodegradable triblock copolymers synthesized via ring opening polymerization (ROP) of ε-caprolactone (CL) in the presence of poly(ethylene [...] Read more.

In this paper, injectable, thermosensitive smart hydrogel local drug delivery systems (LDDSs) releasing the model antitumour drug 5-fluorouracil (5-FU) were developed. The systems were based on biodegradable triblock copolymers synthesized via ring opening polymerization (ROP) of ε-caprolactone (CL) in the presence of poly(ethylene glycol) (PEG) and zirconium(IV) acetylacetonate (Zr(acac)₄), as co-initiator and catalyst, respectively. The structure, molecular weight (M_n) and molecular weight distribution (Đ) of the synthesized materials was studied in detail using nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC) techniques; the optimal synthesis conditions were determined. The structure corresponded well to the theoretical assumptions. The produced hydrogels demonstrated a sharp sol–gel transition at temperature close to physiological value, forming a stable gel with good mechanical properties at 37 °C. The kinetics and mechanism of in vitro 5-FU release were characterized by zero order, first order, Higuchi and Korsmeyer–Peppas mathematical models. The obtained results indicate good release control; the kinetics were generally defined as first order according to the predominant diffusion mechanism; and the total drug release time was approximately 12 h. The copolymers were considered to be biodegradable and non-toxic; the resulting hydrogels appear to be promising as short-term LDDSs, potentially useful in antitumor therapy. Full article

(This article belongs to the Special Issue Challenges, Opportunities, and Innovation in Local Drug Delivery)

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27 pages, 2917 KiB

Open AccessReview

Cannabinoids Drugs and Oral Health—From Recreational Side-Effects to Medicinal Purposes: A Systematic Review

by Luigi Bellocchio, Alessio Danilo Inchingolo, Angelo Michele Inchingolo, Felice Lorusso, Giuseppina Malcangi, Luigi Santacroce, Antonio Scarano, Ioana Roxana Bordea, Denisa Hazballa, Maria Teresa D’Oria, Ciro Gargiulo Isacco, Ludovica Nucci, Rosario Serpico, Gianluca Martino Tartaglia, Delia Giovanniello, Maria Contaldo, Marco Farronato, Gianna Dipalma and Francesco Inchingolo

Int. J. Mol. Sci. 2021, 22(15), 8329; https://doi.org/10.3390/ijms22158329 - 3 Aug 2021

Cited by 15 | Viewed by 8733

Abstract

Background: marijuana, the common name for cannabis sativa preparations, is one of the most consumed drug all over the world, both at therapeutical and recreational levels. With the legalization of medical uses of cannabis in many countries, and even its recreational use in [...] Read more.

Background: marijuana, the common name for cannabis sativa preparations, is one of the most consumed drug all over the world, both at therapeutical and recreational levels. With the legalization of medical uses of cannabis in many countries, and even its recreational use in most of these, the prevalence of marijuana use has markedly risen over the last decade. At the same time, there is also a higher prevalence in the health concerns related to cannabis use and abuse. Thus, it is mandatory for oral healthcare operators to know and deal with the consequences and effects of cannabis use on oral cavity health. This review will briefly summarize the components of cannabis and the endocannabinoid system, as well as the cellular and molecular mechanisms of biological cannabis action in human cells and biologic activities on tissues. We will also look into oropharyngeal tissue expression of cannabinoid receptors, together with a putative association of cannabis to several oral diseases. Therefore, this review will elaborate the basic biology and physiology of cannabinoids in human oral tissues with the aim of providing a better comprehension of the effects of its use and abuse on oral health, in order to include cannabinoid usage into dental patient health records as well as good medicinal practice. Methods: the paper selection was performed by PubMed/Medline and EMBASE electronic databases, and reported according to the PRISMA guidelines. The scientific products were included for qualitative analysis. Results: the paper search screened a total of 276 papers. After the initial screening and the eligibility assessment, a total of 32 articles were considered for the qualitative analysis. Conclusions: today, cannabis consumption has been correlated to a higher risk of gingival and periodontal disease, oral infection and cancer of the oral cavity, while the physico-chemical activity has not been completely clarified. Further investigations are necessary to evaluate a therapeutic efficacy of this class of drugs for the promising treatment of several different diseases of the salivary glands and oral diseases. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 4.0)

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16 pages, 32655 KiB

Open AccessArticle

Evidence for Protein–Protein Interaction between Dopamine Receptors and the G Protein-Coupled Receptor 143

by Beatriz Bueschbell, Prashiela Manga, Erika Penner and Anke C. Schiedel

Int. J. Mol. Sci. 2021, 22(15), 8328; https://doi.org/10.3390/ijms22158328 - 3 Aug 2021

Cited by 8 | Viewed by 4422

Abstract

Protein-protein interactions between G protein-coupled receptors (GPCRs) can augment their functionality and increase the repertoire of signaling pathways they regulate. New therapeutics designed to modulate such interactions may allow for targeting of a specific GPCR activity, thus reducing potential for side effects. Dopamine [...] Read more.

Protein-protein interactions between G protein-coupled receptors (GPCRs) can augment their functionality and increase the repertoire of signaling pathways they regulate. New therapeutics designed to modulate such interactions may allow for targeting of a specific GPCR activity, thus reducing potential for side effects. Dopamine receptor (DR) heteromers are promising candidates for targeted therapy of neurological conditions such as Parkinson’s disease since current treatments can have severe side effects. To facilitate development of such therapies, it is necessary to identify the various DR binding partners. We report here a new interaction partner for DRD₂ and DRD₃, the orphan receptor G protein-coupled receptor 143 (GPR143), an atypical GPCR that plays multiple roles in pigment cells and is expressed in several regions of the brain. We previously demonstrated that the DRD₂/ DRD₃ antagonist pimozide also modulates GPR143 activity. Using confocal microscopy and two FRET methods, we observed that the DRs and GPR143 colocalize and interact at intracellular membranes. Furthermore, co-expression of wildtype GPR143 resulted in a 57% and 67% decrease in DRD₂ and DRD₃ activity, respectively, as determined by β-Arrestin recruitment assay. GPR143-DR dimerization may negatively modulate DR activity by changing affinity for dopamine or delaying delivery of the DRs to the plasma membrane. Full article

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

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20 pages, 775 KiB

Open AccessReview

The Roles of CCCH Zinc-Finger Proteins in Plant Abiotic Stress Tolerance

by Guoliang Han, Ziqi Qiao, Yuxia Li, Chengfeng Wang and Baoshan Wang

Int. J. Mol. Sci. 2021, 22(15), 8327; https://doi.org/10.3390/ijms22158327 - 3 Aug 2021

Cited by 75 | Viewed by 6922

Abstract

Zinc-finger proteins, a superfamily of proteins with a typical structural domain that coordinates a zinc ion and binds nucleic acids, participate in the regulation of growth, development, and stress adaptation in plants. Most zinc fingers are C2H2-type or CCCC-type, named after the configuration [...] Read more.

Zinc-finger proteins, a superfamily of proteins with a typical structural domain that coordinates a zinc ion and binds nucleic acids, participate in the regulation of growth, development, and stress adaptation in plants. Most zinc fingers are C2H2-type or CCCC-type, named after the configuration of cysteine (C) and histidine (H); the less-common CCCH zinc-finger proteins are important in the regulation of plant stress responses. In this review, we introduce the domain structures, classification, and subcellular localization of CCCH zinc-finger proteins in plants and discuss their functions in transcriptional and post-transcriptional regulation via interactions with DNA, RNA, and other proteins. We describe the functions of CCCH zinc-finger proteins in plant development and tolerance to abiotic stresses such as salt, drought, flooding, cold temperatures and oxidative stress. Finally, we summarize the signal transduction pathways and regulatory networks of CCCH zinc-finger proteins in their responses to abiotic stress. CCCH zinc-finger proteins regulate the adaptation of plants to abiotic stress in various ways, but the specific molecular mechanisms need to be further explored, along with other mechanisms such as cytoplasm-to-nucleus shuttling and post-transcriptional regulation. Unraveling the molecular mechanisms by which CCCH zinc-finger proteins improve stress tolerance will facilitate the breeding and genetic engineering of crops with improved traits. Full article

(This article belongs to the Collection Feature Papers in Molecular Plant Sciences)

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13 pages, 9399 KiB

Open AccessReview

Renal and Red Marrow Dosimetry in Peptide Receptor Radionuclide Therapy: 20 Years of History and Ahead

by Stephan Walrand and François Jamar

Int. J. Mol. Sci. 2021, 22(15), 8326; https://doi.org/10.3390/ijms22158326 - 3 Aug 2021

Cited by 14 | Viewed by 3022

Abstract

The development of dosimetry and studies in peptide receptor radionuclide therapy (PRRT) over the past two decades are reviewed. Differences in kidney and bone marrow toxicity reported between ⁹⁰Y, ¹⁷⁷Lu and external beam radiotherapy (EBRT) are discussed with regard to the [...] Read more.

The development of dosimetry and studies in peptide receptor radionuclide therapy (PRRT) over the past two decades are reviewed. Differences in kidney and bone marrow toxicity reported between ⁹⁰Y, ¹⁷⁷Lu and external beam radiotherapy (EBRT) are discussed with regard to the physical properties of these beta emitter radionuclides. The impact of these properties on the response to small and large tumors is also considered. Capacities of the imaging modalities to assess the dosimetry to target tissues are evaluated. Studies published in the past two years that confirm a red marrow uptake in ¹⁷⁷Lu-DOTATATE therapy, as already observed 20 years ago in ⁸⁶Y-DOTATOC PET studies, are analyzed in light of the recent developments in the transferrin transport mechanism. The review enlightens the importance (i) of using state-of-the-art imaging modalities, (ii) of individualizing the activity to be injected with regard to the huge tissue uptake variability observed between patients, (iii) of challenging the currently used but inappropriate blood-based red marrow dosimetry and (iv) of considering individual tandem therapy. Last, a smart individually optimized tandem therapy taking benefit of the bi-orthogonal toxicity-response pattern of ¹⁷⁷Lu-DOTATATE and of ⁹⁰Y-DOTATOC is proposed. Full article

(This article belongs to the Special Issue Somatostatin 2.0)

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