International Journal of Molecular Sciences

29 pages, 2607 KiB

Open AccessReview

Synthesis, Properties, and Biological Applications of Metallic Alloy Nanoparticles

by Kim-Hung Huynh, Xuan-Hung Pham, Jaehi Kim, Sang Hun Lee, Hyejin Chang, Won-Yeop Rho and Bong-Hyun Jun

Int. J. Mol. Sci. 2020, 21(14), 5174; https://doi.org/10.3390/ijms21145174 - 21 Jul 2020

Cited by 110 | Viewed by 12492

Abstract

Metallic alloy nanoparticles are synthesized by combining two or more different metals. Bimetallic or trimetallic nanoparticles are considered more effective than monometallic nanoparticles because of their synergistic characteristics. In this review, we outline the structure, synthesis method, properties, and biological applications of metallic [...] Read more.

Metallic alloy nanoparticles are synthesized by combining two or more different metals. Bimetallic or trimetallic nanoparticles are considered more effective than monometallic nanoparticles because of their synergistic characteristics. In this review, we outline the structure, synthesis method, properties, and biological applications of metallic alloy nanoparticles based on their plasmonic, catalytic, and magnetic characteristics. Full article

(This article belongs to the Special Issue Metal Nano/Microparticles for Bioapplications)

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17 pages, 423 KiB

Open AccessReview

Salivary Biomarkers and Their Application in the Diagnosis and Monitoring of the Most Common Oral Pathologies

by Lucía Melguizo-Rodríguez, Victor J. Costela-Ruiz, Francisco Javier Manzano-Moreno, Concepción Ruiz and Rebeca Illescas-Montes

Int. J. Mol. Sci. 2020, 21(14), 5173; https://doi.org/10.3390/ijms21145173 - 21 Jul 2020

Cited by 59 | Viewed by 7569

Abstract

Saliva is a highly versatile biological fluid that is easy to gather in a non-invasive manner—and the results of its analysis complement clinical and histopathological findings in the diagnosis of multiple diseases. The objective of this review was to offer an update on [...] Read more.

Saliva is a highly versatile biological fluid that is easy to gather in a non-invasive manner—and the results of its analysis complement clinical and histopathological findings in the diagnosis of multiple diseases. The objective of this review was to offer an update on the contribution of salivary biomarkers to the diagnosis and prognosis of diseases of the oral cavity, including oral lichen planus, periodontitis, Sjögren’s syndrome, oral leukoplakia, peri-implantitis, and medication-related osteonecrosis of the jaw. Salivary biomarkers such as interleukins, growth factors, enzymes, and other biomolecules have proven useful in the diagnosis and follow-up of these diseases, facilitating the early evaluation of malignization risk and the monitoring of disease progression and response to treatment. However, further studies are required to identify new biomarkers and verify their reported role in the diagnosis and/or prognosis of oral diseases. Full article

(This article belongs to the Special Issue Salivary Biomarkers and Their Application to Diagnosis and Monitoring Human Diseases)

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16 pages, 3380 KiB

Open AccessArticle

Parity Attenuates Intraepithelial Corneal Sensory Nerve Loss in Female Mice

by Mary Ann Stepp, Sonali Pal-Ghosh, Gauri Tadvalkar and Cintia S. de Paiva

Int. J. Mol. Sci. 2020, 21(14), 5172; https://doi.org/10.3390/ijms21145172 - 21 Jul 2020

Cited by 4 | Viewed by 2506

Abstract

Aging impacts the ocular surface and reduces intraepithelial corneal nerve (ICN) density in male and female mice. Many researchers use retired breeders to study naturally aged female mice. Yet, the impact of parity and the length of time since breeders were retired on [...] Read more.

Aging impacts the ocular surface and reduces intraepithelial corneal nerve (ICN) density in male and female mice. Many researchers use retired breeders to study naturally aged female mice. Yet, the impact of parity and the length of time since breeders were retired on age-related changes in the intraepithelial corneal nerves is not known. Here we study 2 month (M) nulliparous (NP) females as well as 9M, 10M, and 11M NP and multiparous (MP) female mice to determine whether parity impacts the age-related decline seen in corneal axon density; 9M male mice are also included in these assessments. After showing that parity attenuates age-related loss in axon density, we also assess the impact of parity on corneal epithelial cell proliferation and find that it impacts cell proliferation and axon density normalized by cell proliferation. Stromal nerve arborization is also impacted by aging with parity enhancing stromal nerves in older mice. qPCR was performed on 20 genes implicated in ICN density using corneal epithelial RNA isolated from 10M NP and MP mice and showed that NGF expression was significantly elevated in MP corneal epithelium. Corneal sensitivity was significantly higher in 9M MP mice compared to NP mice and increased sensitivity in MP mice was accompanied by increased nerve terminals in the apical and middle cell layers. Together, these data show that parity in mice attenuates several aspects of the age-related decline seen on the ocular surface by retaining sensory axons and corneal sensitivity as mice age. Full article

(This article belongs to the Special Issue Mechanisms of Dry Eye Diseases)

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20 pages, 821 KiB

Open AccessReview

Protective Effect of Epigallocatechin-3-Gallate (EGCG) in Diseases with Uncontrolled Immune Activation: Could Such a Scenario Be Helpful to Counteract COVID-19?

by Marta Menegazzi, Rachele Campagnari, Mariarita Bertoldi, Rosalia Crupi, Rosanna Di Paola and Salvatore Cuzzocrea

Int. J. Mol. Sci. 2020, 21(14), 5171; https://doi.org/10.3390/ijms21145171 - 21 Jul 2020

Cited by 67 | Viewed by 12080

Abstract

Some coronavirus disease 2019 (COVID-19) patients develop acute pneumonia which can result in a cytokine storm syndrome in response to Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection. The most effective anti-inflammatory drugs employed so far in severe COVID-19 belong to the cytokine-directed [...] Read more.

Some coronavirus disease 2019 (COVID-19) patients develop acute pneumonia which can result in a cytokine storm syndrome in response to Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection. The most effective anti-inflammatory drugs employed so far in severe COVID-19 belong to the cytokine-directed biological agents, widely used in the management of many autoimmune diseases. In this paper we analyze the efficacy of epigallocatechin 3-gallate (EGCG), the most abundant ingredient in green tea leaves and a well-known antioxidant, in counteracting autoimmune diseases, which are dominated by a massive cytokines production. Indeed, many studies registered that EGCG inhibits signal transducer and activator of transcription (STAT)1/3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factors, whose activities are crucial in a multiplicity of downstream pro-inflammatory signaling pathways. Importantly, the safety of EGCG/green tea extract supplementation is well documented in many clinical trials, as discussed in this review. Since EGCG can restore the natural immunological homeostasis in many different autoimmune diseases, we propose here a supplementation therapy with EGCG in COVID-19 patients. Besides some antiviral and anti-sepsis actions, the major EGCG benefits lie in its anti-fibrotic effect and in the ability to simultaneously downregulate expression and signaling of many inflammatory mediators. In conclusion, EGCG can be considered a potential safe natural supplement to counteract hyper-inflammation growing in COVID-19. Full article

(This article belongs to the Special Issue Natural Antioxidants)

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19 pages, 1247 KiB

Open AccessReview

Trans-Axonal Signaling in Neural Circuit Wiring

by Olivia Spead and Fabienne E. Poulain

Int. J. Mol. Sci. 2020, 21(14), 5170; https://doi.org/10.3390/ijms21145170 - 21 Jul 2020

Cited by 17 | Viewed by 4692

Abstract

The development of neural circuits is a complex process that relies on the proper navigation of axons through their environment to their appropriate targets. While axon–environment and axon–target interactions have long been known as essential for circuit formation, communication between axons themselves has [...] Read more.

The development of neural circuits is a complex process that relies on the proper navigation of axons through their environment to their appropriate targets. While axon–environment and axon–target interactions have long been known as essential for circuit formation, communication between axons themselves has only more recently emerged as another crucial mechanism. Trans-axonal signaling governs many axonal behaviors, including fasciculation for proper guidance to targets, defasciculation for pathfinding at important choice points, repulsion along and within tracts for pre-target sorting and target selection, repulsion at the target for precise synaptic connectivity, and potentially selective degeneration for circuit refinement. This review outlines the recent advances in identifying the molecular mechanisms of trans-axonal signaling and discusses the role of axon–axon interactions during the different steps of neural circuit formation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neural Circuit Development and Regeneration)

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25 pages, 1586 KiB

Open AccessReview

Osteocyte-Related Cytokines Regulate Osteoclast Formation and Bone Resorption

by Hideki Kitaura, Aseel Marahleh, Fumitoshi Ohori, Takahiro Noguchi, Wei-Ren Shen, Jiawei Qi, Yasuhiko Nara, Adya Pramusita, Ria Kinjo and Itaru Mizoguchi

Int. J. Mol. Sci. 2020, 21(14), 5169; https://doi.org/10.3390/ijms21145169 - 21 Jul 2020

Cited by 157 | Viewed by 10883

Abstract

The process of bone remodeling is the result of the regulated balance between bone cell populations, namely bone-forming osteoblasts, bone-resorbing osteoclasts, and the osteocyte, the mechanosensory cell type. Osteoclasts derived from the hematopoietic stem cell lineage are the principal cells involved in bone [...] Read more.

The process of bone remodeling is the result of the regulated balance between bone cell populations, namely bone-forming osteoblasts, bone-resorbing osteoclasts, and the osteocyte, the mechanosensory cell type. Osteoclasts derived from the hematopoietic stem cell lineage are the principal cells involved in bone resorption. In osteolytic diseases such as rheumatoid arthritis, periodontitis, and osteoporosis, the balance is lost and changes in favor of bone resorption. Therefore, it is vital to elucidate the mechanisms of osteoclast formation and bone resorption. It has been reported that osteocytes express Receptor activator of nuclear factor κΒ ligand (RANKL), an essential factor for osteoclast formation. RANKL secreted by osteocytes is the most important factor for physiologically supported osteoclast formation in the developing skeleton and in pathological bone resorption such as experimental periodontal bone loss. TNF-α directly enhances RANKL expression in osteocytes and promotes osteoclast formation. Moreover, TNF-α enhances sclerostin expression in osteocytes, which also increases osteoclast formation. These findings suggest that osteocyte-related cytokines act directly to enhance osteoclast formation and bone resorption. In this review, we outline the most recent knowledge concerning bone resorption-related cytokines and discuss the osteocyte as the master regulator of bone resorption and effector in osteoclast formation. Full article

(This article belongs to the Special Issue Molecular Mechanisms Regulating Osteoclastogenesis)

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25 pages, 9083 KiB

Open AccessReview

Covid-19: The Rollercoaster of Fibrin(Ogen), D-Dimer, Von Willebrand Factor, P-Selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes

by Corlia Grobler, Siphosethu C. Maphumulo, L. Mireille Grobbelaar, Jhade C. Bredenkamp, Gert J. Laubscher, Petrus J. Lourens, Janami Steenkamp, Douglas B. Kell and Etheresia Pretorius

Int. J. Mol. Sci. 2020, 21(14), 5168; https://doi.org/10.3390/ijms21145168 - 21 Jul 2020

Cited by 114 | Viewed by 19796

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), also known as coronavirus disease 2019 (COVID-19)-induced infection, is strongly associated with various coagulopathies that may result in either bleeding and thrombocytopenia or hypercoagulation and thrombosis. Thrombotic and bleeding or thrombotic pathologies are significant accompaniments to [...] Read more.

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), also known as coronavirus disease 2019 (COVID-19)-induced infection, is strongly associated with various coagulopathies that may result in either bleeding and thrombocytopenia or hypercoagulation and thrombosis. Thrombotic and bleeding or thrombotic pathologies are significant accompaniments to acute respiratory syndrome and lung complications in COVID-19. Thrombotic events and bleeding often occur in subjects with weak constitutions, multiple risk factors and comorbidities. Of particular interest are the various circulating inflammatory coagulation biomarkers involved directly in clotting, with specific focus on fibrin(ogen), D-dimer, P-selectin and von Willebrand Factor (VWF). Central to the activity of these biomarkers are their receptors and signalling pathways on endothelial cells, platelets and erythrocytes. In this review, we discuss vascular implications of COVID-19 and relate this to circulating biomarker, endothelial, erythrocyte and platelet dysfunction. During the progression of the disease, these markers may either be within healthy levels, upregulated or eventually depleted. Most significant is that patients need to be treated early in the disease progression, when high levels of VWF, P-selectin and fibrinogen are present, with normal or slightly increased levels of D-dimer (however, D-dimer levels will rapidly increase as the disease progresses). Progression to VWF and fibrinogen depletion with high D-dimer levels and even higher P-selectin levels, followed by the cytokine storm, will be indicative of a poor prognosis. We conclude by looking at point-of-care devices and methodologies in COVID-19 management and suggest that a personalized medicine approach should be considered in the treatment of patients. Full article

(This article belongs to the Special Issue Advances in Biological Function of Fibrinogen and Fibrin)

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18 pages, 2293 KiB

Open AccessArticle

Different Mechanisms Underlie the Metabolic Response of GBM Stem-Like Cells to Ionizing Radiation: Biological and MRS Studies on Effects of Photons and Carbon Ions

by Alessandra Palma, Sveva Grande, Lucia Ricci-Vitiani, Anna Maria Luciani, Mariachiara Buccarelli, Mauro Biffoni, Valentina Dini, Giuseppe A. P. Cirrone, Mario Ciocca, Laura Guidoni, Roberto Pallini, Vincenza Viti and Antonella Rosi

Int. J. Mol. Sci. 2020, 21(14), 5167; https://doi.org/10.3390/ijms21145167 - 21 Jul 2020

Cited by 9 | Viewed by 2884

Abstract

Glioblastoma multiforme (GBM) is a malignant primary brain tumor with very poor prognosis, high recurrence rate, and failure of chemo-radiotherapy, mainly due to a small fraction of cells with stem-like properties (GSCs). To study the mechanisms of GSCs resistance to radiation, two GSC [...] Read more.

Glioblastoma multiforme (GBM) is a malignant primary brain tumor with very poor prognosis, high recurrence rate, and failure of chemo-radiotherapy, mainly due to a small fraction of cells with stem-like properties (GSCs). To study the mechanisms of GSCs resistance to radiation, two GSC lines, named line #1 and line #83, with different metabolic patterns and clinical outcome, were irradiated with photon beams and carbon ions and assessed by ¹H Magnetic Resonance Spectroscopy (MRS). Both irradiation modalities induced early cytotoxic effects in line #1 with small effects on cell cycle, whereas a proliferative G2/M cytostatic block was observed in line #83. MR spectroscopy signals from mobile lipids (ML) increased in spectra of line #1 after photon and C-ion irradiation with effects on lipid unsaturation level, whereas no effects were detected in line #83 spectra. Gamma-Aminobutyric Acid (GABA), glutamic acid (glu) and Phosphocreatine (pCr) signals showed a significant variation only for line #1 after carbon ion irradiation. Glucose (glc) level and lactate (Lac) extrusion behaved differently in the two lines. Our findings suggest that the differences in irradiation response of GSCs #1 and #83 lines are likely attributable to their different metabolic fingerprint rather than to the different radiation types. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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14 pages, 2338 KiB

Open AccessArticle

Resolution-Associated Lactoferrin Peptides Limit LPS Signaling and Cytokine Secretion from Human Macrophages

by Aviv Lutaty, Soaad Soboh, Sagie Schif-Zuck and Amiram Ariel

Int. J. Mol. Sci. 2020, 21(14), 5166; https://doi.org/10.3390/ijms21145166 - 21 Jul 2020

Cited by 9 | Viewed by 2723

Abstract

The neutrophil granule protein lactoferrin is cleaved and accumulates in efferocytic macrophages as inflammation is resolved. Two peptides present within a resolution-associated 17 kDa fragment of lactoferrin promote the termination of inflammation in vivo by enhancing murine macrophage reprogramming. Here, we report that [...] Read more.

The neutrophil granule protein lactoferrin is cleaved and accumulates in efferocytic macrophages as inflammation is resolved. Two peptides present within a resolution-associated 17 kDa fragment of lactoferrin promote the termination of inflammation in vivo by enhancing murine macrophage reprogramming. Here, we report that these two bioactive tripeptides, phenylalanine-lysine-aspartic acid and phenylalanine-lysine-glutamic acid (FKD and FKE, respectively), inhibit ERK and cJun activation following human macrophage exposure to LPS. In addition, these peptides at low concentrations (1–10 μM) modulate human macrophage reprogramming to an anti-inflammatory/pro-resolving phenotype. This was reflected by inhibition of LPS-induced TNF-α and IL-6 secretion and increased IL-10 levels. Moreover, we found naturally occurring FKE analogs (FKECH and FKECHLA) can recapitulate the activity of the short peptide in regulating macrophage cytokine secretion, whereas a reversed EKF peptide was inert in this respect. Curiously, FKD and FKE also regulated cytokine production by bone marrow-derived mouse macrophages, but in a very different fashion than their effect on human macrophages. Thus, lactoferrin peptides limit pro-inflammatory signaling and cytokine production by LPS-activated human macrophages and thereby enhance the resolution of inflammation. Full article

(This article belongs to the Special Issue Peptides for Health Benefits 2020)

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16 pages, 4065 KiB

Open AccessArticle

Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

by Mara Bonelli, Rita Terenziani, Silvia Zoppi, Claudia Fumarola, Silvia La Monica, Daniele Cretella, Roberta Alfieri, Andrea Cavazzoni, Graziana Digiacomo, Maricla Galetti and Pier Giorgio Petronini

Int. J. Mol. Sci. 2020, 21(14), 5165; https://doi.org/10.3390/ijms21145165 - 21 Jul 2020

Cited by 22 | Viewed by 3579

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated to asbestos exposure. One of the most frequent genetic alteration in MPM patients is CDKN2A/ARF loss, leading to aberrant activation of the Rb pathway. In MPM cells, we previously demonstrated the therapeutic [...] Read more.

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated to asbestos exposure. One of the most frequent genetic alteration in MPM patients is CDKN2A/ARF loss, leading to aberrant activation of the Rb pathway. In MPM cells, we previously demonstrated the therapeutic efficacy of targeting this signaling with the CDK4/6 inhibitor palbociclib in combination with PI3K/mTOR inhibitors. Here, we investigated whether such combination may have an impact on cell energy metabolism. Methods: The study was performed in MPM cells of different histotypes; metabolic analyses were conducted by measuring GLUT-1 expression and glucose uptake/consumption, and by SeaHorse technologies. Results: MPM cell models differed for their ability to adapt to metabolic stress conditions, such as glucose starvation and hypoxia. Independently of these differences, combined treatments with palbociclib and PI3K/mTOR inhibitors inhibited cell proliferation more efficaciously than single agents. The drugs alone reduced glucose uptake/consumption as well as glycolysis, and their combination further enhanced these effects under both normoxic and hypoxic conditions. Moreover, the drug combinations significantly impaired mitochondrial respiration as compared with individual treatments. These metabolic effects were mediated by the concomitant inhibition of Rb/E2F/c-myc and PI3K/AKT/mTOR signaling. Conclusions: Dual blockade of glycolysis and respiration contributes to the anti-tumor efficacy of palbociclib-PI3K/mTOR inhibitors combination. Full article

(This article belongs to the Special Issue Molecular Players in Diagnostics and Therapeutics of Malignant Pleural Mesothelioma)

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43 pages, 2318 KiB

Open AccessReview

Small Molecule NF-κB Pathway Inhibitors in Clinic

by Venkataramanan Ramadass, Thamilselvan Vaiyapuri and Vinay Tergaonkar

Int. J. Mol. Sci. 2020, 21(14), 5164; https://doi.org/10.3390/ijms21145164 - 21 Jul 2020

Cited by 109 | Viewed by 12788

Abstract

Nuclear factor kappa B (NF-κB) signaling is implicated in all major human chronic diseases, with its role in transcription of hundreds of gene well established in the literature. This has propelled research into targeting the NF-κB pathways for modulating expression of those genes [...] Read more.

Nuclear factor kappa B (NF-κB) signaling is implicated in all major human chronic diseases, with its role in transcription of hundreds of gene well established in the literature. This has propelled research into targeting the NF-κB pathways for modulating expression of those genes and the diseases mediated by them. In-spite of the critical, but often promiscuous role played by this pathway and the inhibition causing adverse drug reaction, currently many biologics, macromolecules, and small molecules that modulate this pathway are in the market or in clinical trials. Furthermore, many marketed drugs that were later found to also have NF-κB targeting activity were repurposed for new therapeutic interventions. Despite the rising importance of biologics in drug discovery, small molecules got around 76% of US-FDA (Food and Drug Administration-US) approval in the last decade. This encouraged us to review information regarding clinically relevant small molecule inhibitors of the NF-κB pathway from cell surface receptor stimulation to nuclear signaling. We have also highlighted the underexplored targets in this pathway that have potential to succeed in clinic. Full article

(This article belongs to the Special Issue NF-κB and Disease)

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24 pages, 4907 KiB

Open AccessReview

Therapeutic Potentials of Extracellular Vesicles for the Treatment of Diabetes and Diabetic Complications

by Wei Hu, Xiang Song, Haibo Yu, Jingyu Sun and Yong Zhao

Int. J. Mol. Sci. 2020, 21(14), 5163; https://doi.org/10.3390/ijms21145163 - 21 Jul 2020

Cited by 25 | Viewed by 4683

Abstract

Extracellular vesicles (EVs), including exosomes and microvesicles, are nano-to-micrometer vesicles released from nearly all cellular types. EVs comprise a mixture of bioactive molecules (e.g., mRNAs, miRNAs, lipids, and proteins) that can be transported to the targeted cells/tissues via the blood or lymph circulation. [...] Read more.

Extracellular vesicles (EVs), including exosomes and microvesicles, are nano-to-micrometer vesicles released from nearly all cellular types. EVs comprise a mixture of bioactive molecules (e.g., mRNAs, miRNAs, lipids, and proteins) that can be transported to the targeted cells/tissues via the blood or lymph circulation. Recently, EVs have received increased attention, owing to their emerging roles in cell-to-cell communication, or as biomarkers with the therapeutic potential to replace cell-based therapy. Diabetes comprises a group of metabolic disorders characterized by hyperglycemia that cause the development of life-threatening complications. The impacts of conventional clinical treatment are generally limited and are followed by many side effects, including hypoglycemia, obesity, and damage to the liver and kidney. Recently, several studies have shown that EVs released by stem cells and immune cells can regulate gene expression in the recipient cells, thus providing a strategy to treat diabetes and its complications. In this review, we summarize the results from currently available studies, demonstrating the therapeutic potentials of EVs in diabetes and diabetic complications. Additionally, we highlight recommendations for future research. Full article

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

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15 pages, 905 KiB

Open AccessArticle

Identification of Subclinical Lung Involvement in ACPA-Positive Subjects through Functional Assessment and Serum Biomarkers

by Bruno Lucchino, Marcello Di Paolo, Chiara Gioia, Marta Vomero, Davide Diacinti, Cristina Mollica, Cristiano Alessandri, Daniele Diacinti, Paolo Palange and Manuela Di Franco

Int. J. Mol. Sci. 2020, 21(14), 5162; https://doi.org/10.3390/ijms21145162 - 21 Jul 2020

Cited by 10 | Viewed by 2315

Abstract

Lung involvement is related to the natural history of anti-citrullinated proteins antibodies (ACPA)-positive rheumatoid arthritis (RA), both during the pathogenesis of the disease and as a site of disease-related injury. Increasing evidence suggests that there is a subclinical, early lung involvement during the [...] Read more.

Lung involvement is related to the natural history of anti-citrullinated proteins antibodies (ACPA)-positive rheumatoid arthritis (RA), both during the pathogenesis of the disease and as a site of disease-related injury. Increasing evidence suggests that there is a subclinical, early lung involvement during the course of the disease, even before the onset of articular manifestations, which can potentially progress to a symptomatic interstitial lung disease. To date, reliable, non-invasive markers of subclinical lung involvement are still lacking in clinical practice. The aim of this study is to evaluate the diagnostic potential of functional assessment and serum biomarkers in the identification of subclinical lung involvement in ACPA-positive subjects. Fifty ACPA-positive subjects with or without confirmed diagnosis of RA (2010 ARC-EULAR criteria) were consecutively enrolled. Each subject underwent clinical evaluation, pulmonary function testing (PFT) with assessment of diffusion lung capacity for carbon monoxide (DL_CO), cardiopulmonary exercise testing (CPET), surfactant protein D (SPD) serum levels dosage and high-resolution computed tomography (HRCT) of the chest. The cohort was composed of 21 ACPA-positive subjects without arthritis (ND), 10 early (disease duration < 6 months, treatment-naïve) RA (ERA) and 17 long-standing (disease duration < 36 months, on treatment) RA (LSRA). LSRA patients had a significantly higher frequency of overall HRCT abnormalities compared to the other groups (p = 0.001). SPD serum levels were significantly higher in ACPA-positive subjects compared with healthy controls (158.5 ± 132.3 ng/mL vs 61.27 ± 34.11 ng/mL; p < 0.0001) and showed an increasing trend from ND subjects to LSRD patients (p = 0.004). Patients with HRCT abnormalities showed significantly lower values of DL_CO (74.19 ± 13.2% pred. vs 131.7 ± 93% pred.; p = 0.009), evidence of ventilatory inefficiency at CPET and significantly higher SPD serum levels compared with subjects with no HRCT abnormalities (213.5 ± 157.2 ng/mL vs 117.7 ± 157.3 ng/mL; p = 0.018). Abnormal CPET responses and higher SPD levels were also associated with specific radiological findings. Impaired DL_CO and increased SPD serum levels were independently associated with the presence of HRCT abnormalities. Subclinical lung abnormalities occur early in RA-associated autoimmunity. The presence of subclinical HRCT abnormalities is associated with several functional abnormalities and increased SPD serum levels of SPD. Functional evaluation through PFT and CPET, together with SPD assessment, may have a diagnostic potential in ACPA-positive subjects, contributing to the identification of those patients to be referred to HRCT scan. Full article

(This article belongs to the Special Issue Research of Pathogenesis and Novel Therapeutics in Arthritis 2.0)

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35 pages, 1437 KiB

Open AccessReview

Intrinsic Regulatory Role of RNA Structural Arrangement in Alternative Splicing Control

by Katarzyna Taylor and Krzysztof Sobczak

Int. J. Mol. Sci. 2020, 21(14), 5161; https://doi.org/10.3390/ijms21145161 - 21 Jul 2020

Cited by 16 | Viewed by 4489

Abstract

Alternative splicing is a highly sophisticated process, playing a significant role in posttranscriptional gene expression and underlying the diversity and complexity of organisms. Its regulation is multilayered, including an intrinsic role of RNA structural arrangement which undergoes time- and tissue-specific alterations. In this [...] Read more.

Alternative splicing is a highly sophisticated process, playing a significant role in posttranscriptional gene expression and underlying the diversity and complexity of organisms. Its regulation is multilayered, including an intrinsic role of RNA structural arrangement which undergoes time- and tissue-specific alterations. In this review, we describe the principles of RNA structural arrangement and briefly decipher its cis- and trans-acting cellular modulators which serve as crucial determinants of biological functionality of the RNA structure. Subsequently, we engage in a discussion about the RNA structure-mediated mechanisms of alternative splicing regulation. On one hand, the impairment of formation of optimal RNA structures may have critical consequences for the splicing outcome and further contribute to understanding the pathomechanism of severe disorders. On the other hand, the structural aspects of RNA became significant features taken into consideration in the endeavor of finding potential therapeutic treatments. Both aspects have been addressed by us emphasizing the importance of ongoing studies in both fields. Full article

(This article belongs to the Special Issue Interplay between Pre-mRNA Splicing and Other Gene Expression Steps in Eukaryotes 2.0)

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14 pages, 2484 KiB

Open AccessReview

EPAC in Vascular Smooth Muscle Cells

by Nadine Wehbe, Suzanne Awni Nasser, Yusra Al-Dhaheri, Rabah Iratni, Alessandra Bitto, Ahmed F. El-Yazbi, Adnan Badran, Firas Kobeissy, Elias Baydoun and Ali H. Eid

Int. J. Mol. Sci. 2020, 21(14), 5160; https://doi.org/10.3390/ijms21145160 - 21 Jul 2020

Cited by 13 | Viewed by 5971

Abstract

Vascular smooth muscle cells (VSMCs) are major components of blood vessels. They regulate physiological functions, such as vascular tone and blood flow. Under pathological conditions, VSMCs undergo a remodeling process known as phenotypic switching. During this process, VSMCs lose their contractility and acquire [...] Read more.

Vascular smooth muscle cells (VSMCs) are major components of blood vessels. They regulate physiological functions, such as vascular tone and blood flow. Under pathological conditions, VSMCs undergo a remodeling process known as phenotypic switching. During this process, VSMCs lose their contractility and acquire a synthetic phenotype, where they over-proliferate and migrate from the tunica media to the tunica interna, contributing to the occlusion of blood vessels. Since their discovery as effector proteins of cyclic adenosine 3′,5′-monophosphate (cAMP), exchange proteins activated by cAMP (EPACs) have been shown to play vital roles in a plethora of pathways in different cell systems. While extensive research to identify the role of EPAC in the vasculature has been conducted, much remains to be explored to resolve the reported discordance in EPAC’s effects. In this paper, we review the role of EPAC in VSMCs, namely its regulation of the vascular tone and phenotypic switching, with the likely involvement of reactive oxygen species (ROS) in the interplay between EPAC and its targets/effectors. Full article

(This article belongs to the Special Issue Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease)

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5 pages, 812 KiB

Open AccessCorrection

Correction: Sato, K., et al. Identification of a Novel Oligosaccharide in Maple Syrup as a Potential Alternative Saccharide for Diabetes Mellitus Patients. Int. J. Mol. Sci. 2019, 20, 5041

by Kanta Sato, Noriaki Nagai, Tetsushi Yamamoto, Kuniko Mitamura and Atsushi Taga

Int. J. Mol. Sci. 2020, 21(14), 5159; https://doi.org/10.3390/ijms21145159 - 21 Jul 2020

Cited by 1 | Viewed by 2074

Abstract

The authors wish to make the following corrections to this paper [...] Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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15 pages, 3580 KiB

Open AccessArticle

Arming Oncolytic Adenoviruses: Effect of Insertion Site and Splice Acceptor on Transgene Expression and Viral Fitness

by Martí Farrera-Sal, Jana de Sostoa, Estela Nuñez-Manchón, Rafael Moreno, Cristina Fillat, Miriam Bazan-Peregrino and Ramon Alemany

Int. J. Mol. Sci. 2020, 21(14), 5158; https://doi.org/10.3390/ijms21145158 - 21 Jul 2020

Cited by 5 | Viewed by 2543

Abstract

Oncolytic adenoviruses (OAds) present limited efficacy in clinics. The insertion of therapeutic transgenes into OAds genomes, known as “arming OAds”, has been the main strategy to improve their therapeutic potential. Different approaches were published in the decade of the 2000s, but with few [...] Read more.

Oncolytic adenoviruses (OAds) present limited efficacy in clinics. The insertion of therapeutic transgenes into OAds genomes, known as “arming OAds”, has been the main strategy to improve their therapeutic potential. Different approaches were published in the decade of the 2000s, but with few comparisons. Most armed OAds have complete or partial E3 deletions, leading to a shorter half-life in vivo. We generated E3+ OAds using two insertion sites, After-fiber and After-E4, and two different splice acceptors linked to the major late promoter, either the Ad5 protein IIIa acceptor (IIIaSA) or the Ad40 long fiber acceptor (40SA). The highest transgene levels were obtained with the After-fiber location and 40SA. However, the set of codons of the transgene affected viral fitness, highlighting the relevance of transgene codon usage when arming OAds using the major late promoter. Full article

(This article belongs to the Special Issue Adenovirus: Enduring Toolbox for Basic and Applied Research)

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16 pages, 2874 KiB

Open AccessArticle

Rapid Regulation of Human Multidrug and Extrusion Transporters hMATE1 and hMATE2K

by Marta Kantauskaitė, Anna Hucke, Moritz Reike, Sara Ahmed Eltayeb, Chuyan Xiao, Vivien Barz and Giuliano Ciarimboli

Int. J. Mol. Sci. 2020, 21(14), 5157; https://doi.org/10.3390/ijms21145157 - 21 Jul 2020

Cited by 9 | Viewed by 2197

Abstract

Vectorial transport of organic cations (OCs) in renal proximal tubules is mediated by sequential action of human OC transporter 2 (hOCT2) and human multidrug and toxic extrusion protein 1 and 2K (hMATE1 and hMATE2K), expressed in the basolateral (hOCT2) and luminal (hMATE1 and [...] Read more.

Vectorial transport of organic cations (OCs) in renal proximal tubules is mediated by sequential action of human OC transporter 2 (hOCT2) and human multidrug and toxic extrusion protein 1 and 2K (hMATE1 and hMATE2K), expressed in the basolateral (hOCT2) and luminal (hMATE1 and hMATE2K) plasma membranes, respectively. It is well known that hOCT2 activity is subjected to rapid regulation by several signaling pathways, suggesting that renal OC secretion may be acutely adapted to physiological requirements. Therefore, in this work, the acute regulation of hMATEs stably expressed in human embryonic kidney cells was characterized using the fluorescent substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP⁺) as a marker. A specific regulation of ASP⁺ transport by hMATE1 and hMATE2K measured in uptake and efflux configurations was observed. In the example of hMATE1 efflux reduction by inhibition of casein kinase II, it was also shown that this regulation is able to modify transcellular transport of ASP⁺ in Madin–Darby canine kidney II cells expressing hOCT2 and hMATE1 on the basolateral and apical membrane domains, respectively. The activity of hMATEs can be rapidly regulated by some intracellular pathways, which sometimes are common to those found for hOCTs. Interference with these pathways may be important to regulate renal secretion of OCs. Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations)

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23 pages, 1054 KiB

Open AccessReview

Clinical Role of Extraoral Bitter Taste Receptors

by Joanna Jeruzal-Świątecka, Wojciech Fendler and Wioletta Pietruszewska

Int. J. Mol. Sci. 2020, 21(14), 5156; https://doi.org/10.3390/ijms21145156 - 21 Jul 2020

Cited by 42 | Viewed by 9537

Abstract

Humans can recognise five basic tastes: sweet, sour, salty, bitter and umami. Sour and salty substances are linked to ion channels, while sweet, bitter and umami flavours are transmitted through receptors linked to the G protein (G protein-coupled receptors; GPCRs). There are two [...] Read more.

Humans can recognise five basic tastes: sweet, sour, salty, bitter and umami. Sour and salty substances are linked to ion channels, while sweet, bitter and umami flavours are transmitted through receptors linked to the G protein (G protein-coupled receptors; GPCRs). There are two main types of GPCRs that transmit information about sweet, umami and bitter tastes—the Tas1r and TAS2R families. There are about 25 functional TAS2R genes coding bitter taste receptor proteins. They are found not only in the mouth and throat, but also in the intestines, brain, bladder and lower and upper respiratory tract. The determination of their purpose in these locations has become an inspiration for much research. Their presence has also been confirmed in breast cancer cells, ovarian cancer cells and neuroblastoma, revealing a promising new oncological marker. Polymorphisms of TAS2R38 have been proven to have an influence on the course of chronic rhinosinusitis and upper airway defensive mechanisms. TAS2R receptors mediate the bronchodilatory effect in human airway smooth muscle, which may lead to the creation of another medicine group used in asthma or chronic obstructive pulmonary disease. The discovery that functionally compromised TAS2R receptors negatively impact glucose homeostasis has produced a new area of diabetes research. In this article, we would like to focus on what facts have been already established in the matter of extraoral TAS2R receptors in humans. Full article

(This article belongs to the Special Issue Antioxidants and Obesity)

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18 pages, 1499 KiB

Open AccessReview

The Application of Molecular Spectroscopy in Combination with Chemometrics for Halal Authentication Analysis: A Review

by Abdul Rohman and Anjar Windarsih

Int. J. Mol. Sci. 2020, 21(14), 5155; https://doi.org/10.3390/ijms21145155 - 21 Jul 2020

Cited by 37 | Viewed by 6125

Abstract

Halal is an Arabic term used to describe any components allowed to be used in any products by Muslim communities. Halal food and halal pharmaceuticals are any food and pharmaceuticals which are safe and allowed to be consumed according to Islamic law (Shariah). [...] Read more.

Halal is an Arabic term used to describe any components allowed to be used in any products by Muslim communities. Halal food and halal pharmaceuticals are any food and pharmaceuticals which are safe and allowed to be consumed according to Islamic law (Shariah). Currently, in line with halal awareness, some Muslim countries such as Indonesia, Malaysia, and Middle East regions have developed some standards and regulations on halal products and halal certification. Among non-halal components, the presence of pig derivatives (lard, pork, and porcine gelatin) along with other non-halal meats (rat meat, wild boar meat, and dog meat) is typically found in food and pharmaceutical products. This review updates the recent application of molecular spectroscopy, including ultraviolet-visible, infrared, Raman, and nuclear magnetic resonance (NMR) spectroscopies, in combination with chemometrics of multivariate analysis, for analysis of non-halal components in food and pharmaceutical products. The combination of molecular spectroscopic-based techniques and chemometrics offers fast and reliable methods for screening the presence of non-halal components of pig derivatives and non-halal meats in food and pharmaceutical products. Full article

(This article belongs to the Section Molecular Biophysics)

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18 pages, 1926 KiB

Open AccessReview

Emerging Roles for Neuropilin-2 in Cardiovascular Disease

by Jennifer L. Harman, Jacob Sayers, Chey Chapman and Caroline Pellet-Many

Int. J. Mol. Sci. 2020, 21(14), 5154; https://doi.org/10.3390/ijms21145154 - 21 Jul 2020

Cited by 14 | Viewed by 5182

Abstract

Cardiovascular disease, the leading cause of death worldwide, is predominantly associated with atherosclerosis. Atherosclerosis is a chronic inflammatory disease characterised by the narrowing of large to medium-sized arteries due to a build-up of plaque. Atherosclerotic plaque is comprised of lipids, extracellular matrix, and [...] Read more.

Cardiovascular disease, the leading cause of death worldwide, is predominantly associated with atherosclerosis. Atherosclerosis is a chronic inflammatory disease characterised by the narrowing of large to medium-sized arteries due to a build-up of plaque. Atherosclerotic plaque is comprised of lipids, extracellular matrix, and several cell types, including endothelial, immune, and vascular smooth muscle cells. Such narrowing of the blood vessels can itself restrict blood flow to vital organs but most severe clinical complications, including heart attacks and strokes, occur when lesions rupture, triggering the blood to clot and obstructing blood flow further down the vascular tree. To circumvent such obstructions, percutaneous coronary intervention or bypass grafts are often required; however, re-occlusion of the treated artery frequently occurs. Neuropilins (NRPs), a multifunctional family of cell surface co-receptors, are expressed by endothelial, immune, and vascular smooth muscle cells and are regulators of numerous signalling pathways within the vasculature. Here, we review recent studies implicating NRP2 in the development of occlusive vascular diseases and discuss how NRP2 could be targeted for therapeutic intervention. Full article

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

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12 pages, 2803 KiB

Open AccessArticle

Red and Yellow Injectable Platelet-Rich Fibrin Demonstrated Differential Effects on Periodontal Ligament Stem Cell Proliferation, Migration, and Osteogenic Differentiation

by Prakan Thanasrisuebwong, Sirichai Kiattavorncharoen, Rudee Surarit, Chareerut Phruksaniyom and Nisarat Ruangsawasdi

Int. J. Mol. Sci. 2020, 21(14), 5153; https://doi.org/10.3390/ijms21145153 - 21 Jul 2020

Cited by 27 | Viewed by 2723

Abstract

The biological benefits of using two fractions derived from injectable platelet-rich fibrin (i-PRF) in bone regeneration remain unclear. Thus, the current study examined two fractionation protocols producing yellow i-PRF and red i-PRF on periodontal ligament stem cells (PDLSCs). The i-PRF samples from five [...] Read more.

The biological benefits of using two fractions derived from injectable platelet-rich fibrin (i-PRF) in bone regeneration remain unclear. Thus, the current study examined two fractionation protocols producing yellow i-PRF and red i-PRF on periodontal ligament stem cells (PDLSCs). The i-PRF samples from five donors were harvested from two different levels, with and without a buffy coat layer, to obtain red and yellow i-PRF, respectively. The PDLSCs were isolated and characterized before their experimental use. The culture medium in each assay was loaded with 20% of the conditioned medium containing the factors released from the red and yellow i-PRF. Cell proliferation and cell migration were determined with an MTT and trans-well assay, respectively. Osteogenic differentiation was investigated using alkaline phosphatase and Alizarin red staining. The efficiency of both i-PRFs was statistically compared. We found that the factors released from the red i-PRF had a greater effect on cell proliferation and cell migration. Moreover, the factors released from the yellow i-PRF stimulated PDLSC osteogenic differentiation earlier compared with the red i-PRF. These data suggest that the red i-PRF might be suitable for using in bone regeneration because it induced the mobilization and growth of bone regenerative cells without inducing premature mineralization. Full article

(This article belongs to the Special Issue Recent Advances in Dental Materials and Biomaterials)

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17 pages, 1925 KiB

Open AccessArticle

A Comprehensive Mapping of the Druggable Cavities within the SARS-CoV-2 Therapeutically Relevant Proteins by Combining Pocket and Docking Searches as Implemented in Pockets 2.0

by Silvia Gervasoni, Giulio Vistoli, Carmine Talarico, Candida Manelfi, Andrea R. Beccari, Gabriel Studer, Gerardo Tauriello, Andrew Mark Waterhouse, Torsten Schwede and Alessandro Pedretti

Int. J. Mol. Sci. 2020, 21(14), 5152; https://doi.org/10.3390/ijms21145152 - 21 Jul 2020

Cited by 28 | Viewed by 5326

Abstract

(1) Background: Virtual screening studies on the therapeutically relevant proteins of the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) require a detailed characterization of their druggable binding sites, and, more generally, a convenient pocket mapping represents a key step for structure-based in silico [...] Read more.

(1) Background: Virtual screening studies on the therapeutically relevant proteins of the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) require a detailed characterization of their druggable binding sites, and, more generally, a convenient pocket mapping represents a key step for structure-based in silico studies; (2) Methods: Along with a careful literature search on SARS-CoV-2 protein targets, the study presents a novel strategy for pocket mapping based on the combination of pocket (as performed by the well-known FPocket tool) and docking searches (as performed by PLANTS or AutoDock/Vina engines); such an approach is implemented by the Pockets 2.0 plug-in for the VEGA ZZ suite of programs; (3) Results: The literature analysis allowed the identification of 16 promising binding cavities within the SARS-CoV-2 proteins and the here proposed approach was able to recognize them showing performances clearly better than those reached by the sole pocket detection; and (4) Conclusions: Even though the presented strategy should require more extended validations, this proved successful in precisely characterizing a set of SARS-CoV-2 druggable binding pockets including both orthosteric and allosteric sites, which are clearly amenable for virtual screening campaigns and drug repurposing studies. All results generated by the study and the Pockets 2.0 plug-in are available for download. Full article

(This article belongs to the Special Issue Exscalate4CoV: Innovative High Performing Computing (HPC) Strategies to Tackle Pandemic Crisis)

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12 pages, 2732 KiB

Open AccessArticle

The Role of miR-375-3p and miR-200b-3p in Gastrointestinal Stromal Tumors

by Ugne Gyvyte, Rokas Lukosevicius, Ruta Inciuraite, Greta Streleckiene, Greta Gudoityte, Justina Bekampyte, Serena Valentini, Violeta Salteniene, Paulius Ruzgys, Saulius Satkauskas, Kristina Zviniene, Juozas Kupcinskas and Jurgita Skieceviciene

Int. J. Mol. Sci. 2020, 21(14), 5151; https://doi.org/10.3390/ijms21145151 - 21 Jul 2020

Cited by 13 | Viewed by 3010

Abstract

Deregulated microRNA (miRNA) expression profiles and their contribution to carcinogenesis have been observed in virtually all types of human cancer. However, their role in the pathogenesis of rare mesenchymal gastrointestinal stromal tumors (GISTs) is not well defined, yet. In this study, we aimed [...] Read more.

Deregulated microRNA (miRNA) expression profiles and their contribution to carcinogenesis have been observed in virtually all types of human cancer. However, their role in the pathogenesis of rare mesenchymal gastrointestinal stromal tumors (GISTs) is not well defined, yet. In this study, we aimed to investigate the role of two miRNAs strongly downregulated in GIST—miR-375-3p and miR-200b-3p—in the pathogenesis of GIST. To achieve this, miRNA mimics were transfected into GIST-T1 cells and changes in the potential target gene mRNA and protein expression, as well as alterations in cell viability, migration, apoptotic cell counts and direct miRNA–target interaction, were evaluated. Results revealed that overexpression of miR-375-3p downregulated the expression of KIT mRNA and protein by direct binding to KIT 3′UTR, reduced GIST cell viability and migration rates. MiR-200b-3p lowered expression of ETV1 protein, directly targeted and lowered expression of EGFR mRNA and protein, and negatively affected cell migration rates. To conclude, the present study identified that miR-375-3p and miR-200b-3p have a tumor-suppressive role in GIST. Full article

(This article belongs to the Special Issue Non-Coding RNA Biogenesis and Function 2020)

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31 pages, 2599 KiB

Open AccessReview

Herpes Simplex Virus Type 1 Interactions with the Interferon System

by Kevin Danastas, Monica Miranda-Saksena and Anthony L. Cunningham

Int. J. Mol. Sci. 2020, 21(14), 5150; https://doi.org/10.3390/ijms21145150 - 21 Jul 2020

Cited by 44 | Viewed by 6037

Abstract

The interferon (IFN) system is one of the first lines of defense activated against invading viral pathogens. Upon secretion, IFNs activate a signaling cascade resulting in the production of several interferon stimulated genes (ISGs), which work to limit viral replication and establish an [...] Read more.

The interferon (IFN) system is one of the first lines of defense activated against invading viral pathogens. Upon secretion, IFNs activate a signaling cascade resulting in the production of several interferon stimulated genes (ISGs), which work to limit viral replication and establish an overall anti-viral state. Herpes simplex virus type 1 is a ubiquitous human pathogen that has evolved to downregulate the IFN response and establish lifelong latent infection in sensory neurons of the host. This review will focus on the mechanisms by which the host innate immune system detects invading HSV-1 virions, the subsequent IFN response generated to limit viral infection, and the evasion strategies developed by HSV-1 to evade the immune system and establish latency in the host. Full article

(This article belongs to the Special Issue Herpes Simplex Virus: From Reactivation to Assembly)

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17 pages, 1439 KiB

Open AccessReview

Endosomal-Lysosomal Processing of Neurodegeneration-Associated Proteins in Astrocytes

by Ching-On Wong

Int. J. Mol. Sci. 2020, 21(14), 5149; https://doi.org/10.3390/ijms21145149 - 21 Jul 2020

Cited by 13 | Viewed by 4807

Abstract

Most common neurodegenerative diseases (NDs) are characterized by deposition of protein aggregates that are resulted from misfolding, dysregulated trafficking, and compromised proteolytic degradation. These proteins exert cellular toxicity to a broad range of brain cells and are found in both neurons and glia. [...] Read more.

Most common neurodegenerative diseases (NDs) are characterized by deposition of protein aggregates that are resulted from misfolding, dysregulated trafficking, and compromised proteolytic degradation. These proteins exert cellular toxicity to a broad range of brain cells and are found in both neurons and glia. Extracellular monomeric and oligomeric ND-associated proteins are taken up by astrocytes, the most abundant glial cell in the brain. Internalization, intracellular trafficking, processing, and disposal of these proteins are executed by the endosomal-lysosomal system of astrocytes. Endosomal-lysosomal organelles thus mediate the cellular impact and metabolic fate of these toxic protein species. Given the indispensable role of astrocytes in brain metabolic homeostasis, the endosomal-lysosomal processing of these proteins plays a fundamental role in altering the trajectory of neurodegeneration. This review aims at summarizing the mounting evidence that has established the essential role of astrocytic endosomal-lysosomal organelles in the processing of amyloid precursor proteins, Apolipoprotein E (ApoE), tau, alpha synuclein, and huntingtin, which are associated with NDs such as Alzheimer’s, Parkinson’s, and Huntington diseases. Full article

(This article belongs to the Special Issue Biogenesis and Functional Roles of Lysosomes: Their Implications for the Pathogenesis and Therapy of Human Diseases)

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15 pages, 4494 KiB

Open AccessArticle

The Role of Methionine Aminopeptidase 2 in Lymphangiogenesis

by Rawnaq Esa, Eliana Steinberg, Dvir Dror, Ouri Schwob, Mehrdad Khajavi, Miriam Maoz, Yael Kinarty, Adi Inbal, Aviad Zick and Ofra Benny

Int. J. Mol. Sci. 2020, 21(14), 5148; https://doi.org/10.3390/ijms21145148 - 21 Jul 2020

Cited by 13 | Viewed by 3063

Abstract

During the metastasis process, tumor cells invade the blood circulatory system directly from venous capillaries or indirectly via lymphatic vessels. Understanding the relative contribution of each pathway and identifying the molecular targets that affect both processes is critical for reducing cancer spread. Methionine [...] Read more.

During the metastasis process, tumor cells invade the blood circulatory system directly from venous capillaries or indirectly via lymphatic vessels. Understanding the relative contribution of each pathway and identifying the molecular targets that affect both processes is critical for reducing cancer spread. Methionine aminopeptidase 2 (MetAp2) is an intracellular enzyme known to modulate angiogenesis. In this study, we investigated the additional role of MetAp2 in lymphangiogenesis. A histological staining of tumors from human breast-cancer donors was performed in order to detect the level and the localization of MetAp2 and lymphatic capillaries. The basal enzymatic level and activity in vascular and lymphatic endothelial cells were compared, followed by loss of function studies determining the role of MetAp2 in lymphangiogenesis in vitro and in vivo. The results from the histological analyses of the tumor tissues revealed a high MetAp2 expression, with detectable sites of co-localization with lymphatic capillaries. We showed slightly reduced levels of the MetAp2 enzyme and MetAp2 mRNA expression and activity in primary lymphatic cells when compared to the vascular endothelial cells. The genetic and biochemical manipulation of MetAp2 confirmed the dual activity of the enzyme in both vascular and lymphatic remodulation in cell function assays and in a zebrafish model. We found that cancer-related lymphangiogenesis is inhibited in murine models following MetAp2 inhibition treatment. Taken together, our study provides an indication that MetAp2 is a significant contributor to lymphangiogenesis and carries a dual role in both vascular and lymphatic capillary formation. Our data suggests that MetAp2 inhibitors can be effectively used as anti-metastatic broad-spectrum drugs. Full article

(This article belongs to the Special Issue Attacking Cancer Progression and Metastasis)

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12 pages, 3346 KiB

Open AccessArticle

ATG4 Mediated Psm ES4326/AvrRpt2-Induced Autophagy Dependent on Salicylic Acid in Arabidopsis Thaliana

by Wenjun Gong, Bingcong Li, Baihong Zhang and Wenli Chen

Int. J. Mol. Sci. 2020, 21(14), 5147; https://doi.org/10.3390/ijms21145147 - 21 Jul 2020

Cited by 4 | Viewed by 3434

Abstract

Psm ES4326/AvrRpt2 (AvrRpt2) was widely used as the reaction system of hypersensitive response (HR) in Arabidopsis. The study showed that in npr1 (GFP-ATG8a), AvrRpt2 was more effective at inducing the production of autophagosome and autophagy flux than that [...] Read more.

Psm ES4326/AvrRpt2 (AvrRpt2) was widely used as the reaction system of hypersensitive response (HR) in Arabidopsis. The study showed that in npr1 (GFP-ATG8a), AvrRpt2 was more effective at inducing the production of autophagosome and autophagy flux than that in GFP-ATG8a. The mRNA expression of ATG1, ATG6 and ATG8a were more in npr1 during the early HR. Based on transcriptome data analysis, enhanced disease susceptibility 1 (EDS1) was up-regulated in wild-type (WT) but was not induced in atg4a4b (ATG4 deletion mutant) during AvrRpt2 infection. Compared with WT, atg4a4b had higher expression of salicylic acid glucosyltransferase 1 (SGT1) and isochorismate synthase 1 (ICS1); but less salicylic acid (SA) in normal condition and the same level of free SA during AvrRpt2 infection. These results suggested that the consumption of free SA should be occurred in atg4a4b. AvrRpt2 may trigger the activation of Toll/Interleukin-1 receptor (TIR)-nucleotide binding site (NB)-leucine rich repeat (LRR)—TIR-NB-LRR—to induce autophagy via EDS1, which was inhibited by nonexpressor of PR genes 1 (NPR1). Moreover, high expression of NPR3 in atg4a4b may accelerate the degradation of NPR1 during AvrRpt2 infection. Full article

(This article belongs to the Special Issue New Insight into Signaling and Autophagy in Plants)

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30 pages, 14287 KiB

Open AccessArticle

A Fish Leukocyte Immune-Type Receptor Uses a Novel Intracytoplasmic Tail Networking Mechanism to Cross-Inhibit the Phagocytic Response

by Chenjie Fei, Myron A. Zwozdesky and James L. Stafford

Int. J. Mol. Sci. 2020, 21(14), 5146; https://doi.org/10.3390/ijms21145146 - 21 Jul 2020

Cited by 5 | Viewed by 2175

Abstract

Channel catfish (Ictalurus punctatus) leukocyte immune-type receptors (IpLITRs) are a family of immunoregulatory proteins shown to regulate several innate immune cell effector responses, including phagocytosis. The precise mechanisms of IpLITR-mediated regulation of the phagocytic process are not entirely understood, but we [...] Read more.

Channel catfish (Ictalurus punctatus) leukocyte immune-type receptors (IpLITRs) are a family of immunoregulatory proteins shown to regulate several innate immune cell effector responses, including phagocytosis. The precise mechanisms of IpLITR-mediated regulation of the phagocytic process are not entirely understood, but we have previously shown that different IpLITR-types use classical as well as novel pathways for controlling immune cell-mediated target engulfment. To date, all functional assessments of IpLITR-mediated regulatory actions have focused on the independent characterization of select IpLITR-types in transfected cells. As members of the immunoglobulin superfamily, many IpLITRs share similar extracellular Ig-like domains, thus it is possible that various IpLITR actions are influenced by cross-talk mechanisms between different IpLITR-types; analogous to the paired innate receptor paradigm in mammals. Here, we describe in detail the co-expression of different IpLITR-types in the human embryonic AD293 cell line and examination of their receptor cross-talk mechanisms during the regulation of the phagocytic response using imaging flow cytometry, confocal microscopy, and immunoprecipitation protocols. Overall, our data provides interesting new insights into the integrated control of phagocytosis via the antagonistic networking of independent IpLITR-types that requires the selective recruitment of inhibitory signaling molecules for the initiation and sustained cross-inhibition of phagocytosis. Full article

(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks)

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16 pages, 593 KiB

Open AccessReview

COVID-19: A Review on Diagnosis, Treatment, and Prophylaxis

by Alessandra Fierabracci, Andrea Arena and Paolo Rossi

Int. J. Mol. Sci. 2020, 21(14), 5145; https://doi.org/10.3390/ijms21145145 - 21 Jul 2020

Cited by 22 | Viewed by 7365

Abstract

Coronavirus 2 (CoV) Severe Acute Respiratory Syndrome (SARS-CoV2) is causing a highly infectious pandemic pneumonia. Coronaviruses are positive sense single-stranded RNA viruses that infect several animal species, causing symptoms that range from those similar to the common cold to severe respiratory syndrome. The [...] Read more.

Coronavirus 2 (CoV) Severe Acute Respiratory Syndrome (SARS-CoV2) is causing a highly infectious pandemic pneumonia. Coronaviruses are positive sense single-stranded RNA viruses that infect several animal species, causing symptoms that range from those similar to the common cold to severe respiratory syndrome. The Angiotensin Converting Enzyme 2 (ACE2) is the SARS-CoV2 functional receptor. Measures are currently undertaken worldwide to control the infection to avoid disruption of the social and economic equilibrium, especially in countries with poor healthcare resources. In a guarded optimistic view, we hope that the undertaken preventive and treatment measures will at least contribute to contain viral diffusion, attenuate activity, or even eliminate SARS-CoV2. In this review, we discuss emerging perspectives for prevention/treatment of COVID-19 infection. In addition to vaccines under development, passive immunization is an open opportunity since patients develop neutralizing antibodies. A full spectrum of potential drugs for COVID-19 infections could in turn affect virus binding or enzymatic activities involved in viral replication and transcription. Furthermore, clinical trials are currently evaluating the safety and efficacy of anti-inflammatory drugs, such as tocilizumab. Bioinformatics may allow characterization of specific CD8+ and CD4+ T cell responses; thus, CoV2 T cells’ frequency can be correlated with the disease severity and outcome. Combinatorial antibody phage display may be empowered to identify the immune repertoire of CoV2-specific neutralizing antibodies. Full article

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

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