Editorial

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Open AccessEditorial

Advances in Molecular and Translational Medicine

by Mariarosaria Boccellino

Int. J. Mol. Sci. 2023, 24(9), 7726; https://doi.org/10.3390/ijms24097726 - 23 Apr 2023

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Translational medicine is an interdisciplinary field that combines basic research findings with clinical practice to accelerate the development of new diagnostic tools, therapies, and preventive strategies for human diseases [...] Full article

(This article belongs to the Special Issue Advances in Molecular and Translational Medicine)

Research

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16 pages, 3378 KiB

Open AccessArticle

Co-Expression of Podoplanin and CD44 in Proliferative Vitreoretinopathy Epiretinal Membranes

by Denise Bonente, Laura Bianchi, Rossana De Salvo, Claudio Nicoletti, Elena De Benedetto, Tommaso Bacci, Luca Bini, Giovanni Inzalaco, Lorenzo Franci, Mario Chiariello, Gian Marco Tosi, Eugenio Bertelli and Virginia Barone

Int. J. Mol. Sci. 2023, 24(11), 9728; https://doi.org/10.3390/ijms24119728 - 04 Jun 2023

Cited by 2 | Viewed by 1563

Abstract

Epiretinal membranes (ERMs) are sheets of tissue that pathologically develop in the vitreoretinal interface leading to progressive vision loss. They are formed by different cell types and by an exuberant deposition of extracellular matrix proteins. Recently, we reviewed ERMs’ extracellular matrix components to [...] Read more.

Epiretinal membranes (ERMs) are sheets of tissue that pathologically develop in the vitreoretinal interface leading to progressive vision loss. They are formed by different cell types and by an exuberant deposition of extracellular matrix proteins. Recently, we reviewed ERMs’ extracellular matrix components to better understand molecular dysfunctions that trigger and fuel the onset and development of this disease. The bioinformatics approach we applied delineated a comprehensive overview on this fibrocellular tissue and on critical proteins that could really impact ERM physiopathology. Our interactomic analysis proposed the hyaluronic-acid-receptor cluster of differentiation 44 (CD44) as a central regulator of ERM aberrant dynamics and progression. Interestingly, the interaction between CD44 and podoplanin (PDPN) was shown to promote directional migration in epithelial cells. PDPN is a glycoprotein overexpressed in various cancers and a growing body of evidence indicates its relevant function in several fibrotic and inflammatory pathologies. The binding of PDPN to partner proteins and/or its ligand results in the modulation of signaling pathways regulating proliferation, contractility, migration, epithelial–mesenchymal transition, and extracellular matrix remodeling, all processes that are vital in ERM formation. In this context, the understanding of the PDPN role can help to modulate signaling during fibrosis, hence opening a new line of therapy. Full article

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22 pages, 4753 KiB

Open AccessArticle

Adaptive and Innate Cytotoxic Effectors in Chronic Lymphocytic Leukaemia (CLL) Subjects with Stable Disease

by Valentina Rubino, Flavia Carriero, Anna Teresa Palatucci, Angela Giovazzino, Stefania Leone, Valerio Nicolella, Martina Calabrò, Rosangela Montanaro, Vincenzo Brancaleone, Fabrizio Pane, Federico Chiurazzi, Giuseppina Ruggiero and Giuseppe Terrazzano

Int. J. Mol. Sci. 2023, 24(11), 9596; https://doi.org/10.3390/ijms24119596 - 31 May 2023

Cited by 1 | Viewed by 1228

Abstract

Chronic lymphocytic leukaemia (CLL) is characterised by the expansion of a neoplastic mature B cell clone. CLL clinical outcome is very heterogeneous, with some subjects never requiring therapy and some showing an aggressive disease. Genetic and epigenetic alterations and pro-inflammatory microenvironment influence CLL [...] Read more.

Chronic lymphocytic leukaemia (CLL) is characterised by the expansion of a neoplastic mature B cell clone. CLL clinical outcome is very heterogeneous, with some subjects never requiring therapy and some showing an aggressive disease. Genetic and epigenetic alterations and pro-inflammatory microenvironment influence CLL progression and prognosis. The involvement of immune-mediated mechanisms in CLL control needs to be investigated. We analyse the activation profile of innate and adaptive cytotoxic immune effectors in a cohort of 26 CLL patients with stable disease, as key elements for immune-mediated control of cancer progression. We observed an increase in CD54 expression and interferon (IFN)-γ production by cytotoxic T cells (CTL). CTL ability to recognise tumour-targets depends on human leukocyte antigens (HLA)-class I expression. We observed a decreased expression of HLA-A and HLA-BC on B cells of CLL subjects, associated with a significant reduction in intracellular calnexin that is relevant for HLA surface expression. Natural killer (NK) cells and CTL from CLL subjects show an increased expression of the activating receptor KIR2DS2 and a reduction of 3DL1 and NKG2A inhibiting molecules. Therefore, an activation profile characterises CTL and NK cells of CLL subjects with stable disease. This profile is conceivable with the functional involvement of cytotoxic effectors in CLL control. Full article

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25 pages, 14711 KiB

Open AccessArticle

Local Concentrations of TGF-β1 and IGF-1 Appear Determinant in Regulating Bone Regeneration in Human Postextraction Tooth Sockets

by Maria B. Asparuhova, Dominic Riedwyl, Ryo Aizawa, Clemens Raabe, Emilio Couso-Queiruga and Vivianne Chappuis

Int. J. Mol. Sci. 2023, 24(9), 8239; https://doi.org/10.3390/ijms24098239 - 04 May 2023

Cited by 3 | Viewed by 1607

Abstract

Healing after tooth extraction involves a series of reparative processes affecting both alveolar bone and soft tissues. The aim of the present study was to investigate whether activation of molecular signals during the healing process confers a regenerative advantage to the extraction socket [...] Read more.

Healing after tooth extraction involves a series of reparative processes affecting both alveolar bone and soft tissues. The aim of the present study was to investigate whether activation of molecular signals during the healing process confers a regenerative advantage to the extraction socket soft tissue (ESsT) at 8 weeks of healing. Compared to subepithelial connective tissue graft (CTG), qRT-PCR analyses revealed a dramatic enrichment of the ESsT in osteogenic differentiation markers. However, ESsT and CTG shared characteristics of nonspecialized soft connective tissue by expressing comparable levels of genes encoding abundant extracellular matrix (ECM) proteins. Genes encoding the transforming growth factor-β1 (TGF-β1) and its receptors were strongly enriched in the CTG, whereas the transcript for the insulin-like growth factor-1 (IGF-1) showed significantly high and comparable expression in both tissues. Mechanical stimulation, by the means of cyclic strain or matrix stiffness applied to primary ESsT cells (ESsT-C) and CTG fibroblasts (CTG-F) extracted from the tissue samples, revealed that stress-induced TGF-β1 not exceeding 2.3 ng/mL, as measured by ELISA, in combination with IGF-1 up to 2.5 ng/mL was able to induce the osteogenic potential of ESsT-Cs. However, stiff matrices (50 kPa), upregulating the TGF-β1 expression up to 6.6 ng/mL, caused downregulation of osteogenic gene expression in the ESsT-Cs. In CTG-Fs, endogenous or stress-induced TGF-β1 ≥ 4.6 ng/mL was likely responsible for the complete lack of osteogenesis. Treatment of ESsT-Cs with TGF-β1 and IGF-1 proved that, at specific concentrations, the two growth factors exhibited either an inductive-synergistic or a suppressive activity, thus determining the osteogenic and mineralization potential of ESsT-Cs. Taken together, our data strongly warrant the clinical exploration of ESsT as a graft in augmentative procedures during dental implant placement surgeries. Full article

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16 pages, 1560 KiB

Open AccessArticle

A Method for Increasing the Robustness of Stable Feature Selection for Biomarker Discovery in Molecular Medicine Developed Using Serum Small Extracellular Vesicle Associated miRNAs and the Barrett’s Oesophagus Disease Spectrum

by George C. Mayne, Richard J. Woodman, David I. Watson, Tim Bright, Susan Gan, Reginald V. Lord, Michael J. Bourke, Angelique Levert-Mignon, Isabell Bastian, Tanya Irvine, Ann Schloithe, Marian Martin, Lorraine Sheehan-Hennessy and Damian J. Hussey

Int. J. Mol. Sci. 2023, 24(8), 7068; https://doi.org/10.3390/ijms24087068 - 11 Apr 2023

Cited by 1 | Viewed by 1275

Abstract

The biomarker development field within molecular medicine remains limited by the methods that are available for building predictive models. We developed an efficient method for conservatively estimating confidence intervals for the cross validation-derived prediction errors of biomarker models. This new method was investigated [...] Read more.

The biomarker development field within molecular medicine remains limited by the methods that are available for building predictive models. We developed an efficient method for conservatively estimating confidence intervals for the cross validation-derived prediction errors of biomarker models. This new method was investigated for its ability to improve the capacity of our previously developed method, StaVarSel, for selecting stable biomarkers. Compared with the standard cross validation method, StaVarSel markedly improved the estimated generalisable predictive capacity of serum miRNA biomarkers for the detection of disease states that are at increased risk of progressing to oesophageal adenocarcinoma. The incorporation of our new method for conservatively estimating confidence intervals into StaVarSel resulted in the selection of less complex models with increased stability and improved or similar predictive capacities. The methods developed in this study have the potential to improve progress from biomarker discovery to biomarker driven translational research. Full article

(This article belongs to the Special Issue Advances in Molecular and Translational Medicine)

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26 pages, 4346 KiB

Open AccessArticle

Lacrimal Gland Epithelial Cells Shape Immune Responses through the Modulation of Inflammasomes and Lipid Metabolism

by Vanessa Delcroix, Olivier Mauduit, Menglu Yang, Amrita Srivastava, Takeshi Umazume, Cintia S. de Paiva, Valery I. Shestopalov, Darlene A. Dartt and Helen P. Makarenkova

Int. J. Mol. Sci. 2023, 24(5), 4309; https://doi.org/10.3390/ijms24054309 - 21 Feb 2023

Cited by 8 | Viewed by 2001

Abstract

Lacrimal gland inflammation triggers dry eye disease through impaired tear secretion by the epithelium. As aberrant inflammasome activation occurs in autoimmune disorders including Sjögren’s syndrome, we analyzed the inflammasome pathway during acute and chronic inflammation and investigated its potential regulators. Bacterial infection was [...] Read more.

Lacrimal gland inflammation triggers dry eye disease through impaired tear secretion by the epithelium. As aberrant inflammasome activation occurs in autoimmune disorders including Sjögren’s syndrome, we analyzed the inflammasome pathway during acute and chronic inflammation and investigated its potential regulators. Bacterial infection was mimicked by the intraglandular injection of lipopolysaccharide (LPS) and nigericin, known to activate the NLRP3 inflammasome. Acute injury of the lacrimal gland was induced by interleukin (IL)-1α injection. Chronic inflammation was studied using two Sjögren’s syndrome models: diseased NOD.H2^b compared to healthy BALBc mice and Thrombospondin-1-null (TSP-1^-/-) compared to TSP-1^WT C57BL/6J mice. Inflammasome activation was investigated by immunostaining using the R26^ASC-citrine reporter mouse, by Western blotting, and by RNAseq. LPS/Nigericin, IL-1α and chronic inflammation induced inflammasomes in lacrimal gland epithelial cells. Acute and chronic inflammation of the lacrimal gland upregulated multiple inflammasome sensors, caspases 1/4, and interleukins Il1b and Il18. We also found increased IL-1β maturation in Sjögren’s syndrome models compared with healthy control lacrimal glands. Using RNA-seq data of regenerating lacrimal glands, we found that lipogenic genes were upregulated during the resolution of inflammation following acute injury. In chronically inflamed NOD.H2^b lacrimal glands, an altered lipid metabolism was associated with disease progression: genes for cholesterol metabolism were upregulated, while genes involved in mitochondrial metabolism and fatty acid synthesis were downregulated, including peroxisome proliferator-activated receptor alpha (PPARα)/sterol regulatory element-binding 1 (SREBP-1)-dependent signaling. We conclude that epithelial cells can promote immune responses by forming inflammasomes, and that sustained inflammasome activation, together with an altered lipid metabolism, are key players of Sjögren’s syndrome-like pathogenesis in the NOD.H2^b mouse lacrimal gland by promoting epithelial dysfunction and inflammation. Full article

(This article belongs to the Special Issue Advances in Molecular and Translational Medicine)

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11 pages, 1716 KiB

Open AccessArticle

The rs368698783 (G>A) Polymorphism Affecting LYAR Binding to the Aγ-Globin Gene Is Associated with High Fetal Hemoglobin (HbF) in β-Thalassemia Erythroid Precursor Cells Treated with HbF Inducers

by Cristina Zuccato, Lucia Carmela Cosenza, Matteo Zurlo, Giulia Breveglieri, Nicoletta Bianchi, Ilaria Lampronti, Jessica Gasparello, Chiara Scapoli, Monica Borgatti, Alessia Finotti and Roberto Gambari

Int. J. Mol. Sci. 2023, 24(1), 776; https://doi.org/10.3390/ijms24010776 - 01 Jan 2023

Cited by 4 | Viewed by 2140

Abstract

The human homologue of mouse Ly-1 antibody reactive clone protein (LYAR) is a putative novel regulator of γ-globin gene transcription. The LYAR DNA-binding motif (5′-GGTTAT-3′) is located within the 5′-UTR of the Aγ-globin gene. The LYAR rs368698783 (G>A) polymorphism is present in β-thalassemia [...] Read more.

The human homologue of mouse Ly-1 antibody reactive clone protein (LYAR) is a putative novel regulator of γ-globin gene transcription. The LYAR DNA-binding motif (5′-GGTTAT-3′) is located within the 5′-UTR of the Aγ-globin gene. The LYAR rs368698783 (G>A) polymorphism is present in β-thalassemia patients and decreases the LYAR binding efficiency to the Aγ-globin gene. The objective of this study was to stratify β-thalassemia patients with respect to the rs368698783 (G>A) polymorphism and to verify whether their erythroid precursor cells (ErPCs) differentially respond in vitro to selected fetal hemoglobin (HbF) inducers. The rs368698783 (G>A) polymorphism was detected by DNA sequencing, hemoglobin production by HPLC, and accumulation of globin mRNAs by RT-qPCR. We found that the LYAR rs368698783 (G>A) polymorphism is associated with high basal and induced production of fetal hemoglobin in β-thalassemia patients. The most striking association was found using rapamycin as an HbF inducer. The results presented here could be considered important not only for basic biomedicine but also in applied translational research for precision medicine in personalized therapy of β-thalassemia. Accordingly, our data suggest that the rs368698783 polymorphism might be considered among the parameters useful to recruit patients with the highest probability of responding to in vivo hydroxyurea (HU) treatment. Full article

(This article belongs to the Special Issue Advances in Molecular and Translational Medicine)

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13 pages, 963 KiB

Open AccessArticle

Influence of Short and Long Hyperglycemia on Cardioprotection by Remote Ischemic Preconditioning—A Translational Approach

by Katharina Feige, Sebastian Roth, René M’Pembele, Anna Galow, Sarah Koenig, Martin Stroethoff, Annika Raupach, Giovanna Lurati Buse, Alexander M. Mathes, Markus W. Hollmann, Ragnar Huhn and Carolin Torregroza

Int. J. Mol. Sci. 2022, 23(23), 14557; https://doi.org/10.3390/ijms232314557 - 22 Nov 2022

Cited by 1 | Viewed by 1224

Abstract

The adverse impact of common diseases like diabetes mellitus and acute hyperglycemia on morbidity and mortality from myocardial infarction (MI) has been well documented over the past years of research. In the clinical setting, the relationship between blood glucose and mortality appears linear, [...] Read more.

The adverse impact of common diseases like diabetes mellitus and acute hyperglycemia on morbidity and mortality from myocardial infarction (MI) has been well documented over the past years of research. In the clinical setting, the relationship between blood glucose and mortality appears linear, with amplifying risk associated with increasing blood glucose levels. Further, this seems to be independent of a diagnosis of diabetes. In the experimental setting, various comorbidities seem to impact ischemic and pharmacological conditioning strategies, protecting the heart against ischemia and reperfusion injury. In this translational experimental approach from bedside to bench, we set out to determine whether acute and/or prolonged hyperglycemia have an influence on the protective effect of transferred human RIPC-plasma and, therefore, might obstruct translation into the clinical setting. Control and RIPC plasma of young healthy men were transferred to isolated hearts of young male Wistar rats in vitro. Plasma was administered before global ischemia under either short hyperglycemic (HGs Con, HGs RIPC) conditions, prolonged hyperglycemia (HGl Con, HGl RIPC), or under normoglycemia (Con, RIPC). Infarct sizes were determined by TTC staining. Control hearts showed an infarct size of 55 ± 7%. Preconditioning with transferred RIPC plasma under normoglycemia significantly reduced infarct size to 25 ± 4% (p < 0.05 vs. Con). Under acute hyperglycemia, control hearts showed an infarct size of 63 ± 5%. Applying RIPC plasma under short hyperglycemic conditions led to a significant infarct size reduction of 41 ± 4% (p < 0.05 vs. HGs Con). However, the cardioprotective effect of RIPC plasma under normoglycemia was significantly stronger compared with acute hyperglycemic conditions (RIPC vs. HGs RIPC; p < 0.05). Prolonged hyperglycemia (HGl RIPC) completely abolished the cardioprotective effect of RIPC plasma (infarct size 60 ± 7%; p < 0.05 vs. HGl Con; HGl Con 59 ± 5%). Full article

(This article belongs to the Special Issue Advances in Molecular and Translational Medicine)

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14 pages, 2618 KiB

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Spatial and Quantitative Analysis of Tumor-Associated Macrophages: Intratumoral CD163-/PD-L1+ TAMs as a Marker of Favorable Clinical Outcomes in Triple-Negative Breast Cancer

by Hajime Shinohara, Maki Kobayashi, Kumiko Hayashi, Daichi Nogawa, Ayaka Asakawa, Yae Ohata, Kazuishi Kubota, Hisashi Takahashi, Miyuki Yamada, Masanori Tokunaga, Yusuke Kinugasa, Goshi Oda, Tsuyoshi Nakagawa, Iichiroh Onishi, Yuko Kinowaki, Morito Kurata, Kenichi Ohashi, Masanobu Kitagawa and Kouhei Yamamoto

Int. J. Mol. Sci. 2022, 23(21), 13235; https://doi.org/10.3390/ijms232113235 - 31 Oct 2022

Cited by 7 | Viewed by 2429

Abstract

Tumor-associated macrophages (TAMs) and abnormalities in cancer cells affect cancer progression and response to therapy. TAMs are a major component of the tumor microenvironment (TME) in breast cancer, with their invasion affecting clinical outcomes. Programmed death-ligand 1 (PD-L1), a target of immune checkpoint [...] Read more.

Tumor-associated macrophages (TAMs) and abnormalities in cancer cells affect cancer progression and response to therapy. TAMs are a major component of the tumor microenvironment (TME) in breast cancer, with their invasion affecting clinical outcomes. Programmed death-ligand 1 (PD-L1), a target of immune checkpoint inhibitors, acts as a suppressive signal for the surrounding immune system; however, its expression and effect on TAMs and the clinical outcome in breast cancer are unknown. In this study, we used high-throughput multiple immunohistochemistry to spatially and quantitatively analyze TAMs. We subjected 81 breast cancer specimens to immunostaining for CD68, CD163, PD-1, PD-L1, CD20, and pan-CK. In both stromal and intratumoral areas, the triple-negative subtype had significantly more CD68/CD163, CD68/PD-L1, and CD163/PD-L1 double-positive cells than the estrogen receptor (ER)/progesterone receptor (PR) subtype. Interestingly, a higher number of CD68+/PD-L1+/CK-/CD163- TAMs in the intratumoral area was correlated with a favorable recurrence rate (p = 0.048). These findings indicated that the specific subpopulation and localization of TAMs in the TME affect clinical outcomes in breast cancer. Full article

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20 pages, 3346 KiB

Open AccessArticle

Therapeutic Intervention with Anti-Complement Component 5 Antibody Does Not Reduce NASH but Does Attenuate Atherosclerosis and MIF Concentrations in Ldlr-/-.Leiden Mice

by Florine Seidel, Robert Kleemann, Wim van Duyvenvoorde, Nikki van Trigt, Nanda Keijzer, Sandra van der Kooij, Cees van Kooten, Lars Verschuren, Aswin Menke, Amanda J. Kiliaan, Johnathan Winter, Timothy R. Hughes, B. Paul Morgan, Frank Baas, Kees Fluiter and Martine C. Morrison

Int. J. Mol. Sci. 2022, 23(18), 10736; https://doi.org/10.3390/ijms231810736 - 14 Sep 2022

Cited by 7 | Viewed by 2314

Abstract

Background: Chronic inflammation is an important driver in the progression of non-alcoholic steatohepatitis (NASH) and atherosclerosis. The complement system, one of the first lines of defense in innate immunity, has been implicated in both diseases. However, the potential therapeutic value of complement inhibition [...] Read more.

Background: Chronic inflammation is an important driver in the progression of non-alcoholic steatohepatitis (NASH) and atherosclerosis. The complement system, one of the first lines of defense in innate immunity, has been implicated in both diseases. However, the potential therapeutic value of complement inhibition in the ongoing disease remains unclear. Methods: After 20 weeks of high-fat diet (HFD) feeding, obese Ldlr-/-.Leiden mice were treated twice a week with an established anti-C5 antibody (BB5.1) or vehicle control. A separate group of mice was kept on a chow diet as a healthy reference. After 12 weeks of treatment, NASH was analyzed histopathologically, and genome-wide hepatic gene expression was analyzed by next-generation sequencing and pathway analysis. Atherosclerotic lesion area and severity were quantified histopathologically in the aortic roots. Results: Anti-C5 treatment considerably reduced complement system activity in plasma and MAC deposition in the liver but did not affect NASH. Anti-C5 did, however, reduce the development of atherosclerosis, limiting the total lesion size and severity independently of an effect on plasma cholesterol but with reductions in oxidized LDL (oxLDL) and macrophage migration inhibitory factor (MIF). Conclusion: We show, for the first time, that treatment with an anti-C5 antibody in advanced stages of NASH is not sufficient to reduce the disease, while therapeutic intervention against established atherosclerosis is beneficial to limit further progression. Full article

(This article belongs to the Special Issue Advances in Molecular and Translational Medicine)

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17 pages, 6354 KiB

Open AccessArticle

Smoking Cessation in Mice Does Not Switch off Persistent Lung Inflammation and Does Not Restore the Expression of HDAC2 and SIRT1

by Giovanna De Cunto, Simone De Meo, Barbara Bartalesi, Eleonora Cavarra, Giuseppe Lungarella and Monica Lucattelli

Int. J. Mol. Sci. 2022, 23(16), 9104; https://doi.org/10.3390/ijms23169104 - 14 Aug 2022

Cited by 5 | Viewed by 1785

Abstract

Once COPD is established, pulmonary lesions can only progress and smoking cessation by itself is not sufficient to switch off persistent lung inflammation. Similarly, in former-smoker mice, neutrophil inflammation persists and lung lesions undergo progressive deterioration. The molecular mechanisms underlying disease progression and [...] Read more.

Once COPD is established, pulmonary lesions can only progress and smoking cessation by itself is not sufficient to switch off persistent lung inflammation. Similarly, in former-smoker mice, neutrophil inflammation persists and lung lesions undergo progressive deterioration. The molecular mechanisms underlying disease progression and the inefficiency of smoking cessation in quenching neutrophilic inflammation were studied in male C57 Bl/6 mice after 6 months of rest from smoking cessation. As compared with the mice that continued to smoke, the former-smoker mice showed reduced expression of histone deacetylases HDAC2 and SIRT1 and marked expression of p-p38 MAPK and p-Ser10. All these factors are involved in corticosteroid insensitivity and in perpetuating inflammation. Former-smoker mice do show persistent lung neutrophilic influx and a high number of macrophages which account for the intense staining in the alveolar structures of neutrophil elastase and MMP-9 (capable of destroying lung scaffolding) and 8-OHdG (marker of oxidative stress). “Alarmins” released from necrotic cells together with these factors can sustain and perpetuate inflammation after smoking cessation. Several factors and mechanisms all together are involved in sustaining and perpetuating inflammation in former-smoker mice. This study suggests that a better control of COPD in humans may be achieved by precise targeting of the various molecular mechanisms associated with different phenotypes of disease by using a cocktail of drug active toward specific molecules. Full article

(This article belongs to the Special Issue Advances in Molecular and Translational Medicine)

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Review

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20 pages, 1120 KiB

Open AccessReview

Novel Molecular Mechanisms Involved in the Medical Treatment of Pulmonary Arterial Hypertension

by Irene Martin de Miguel, Alejandro Cruz-Utrilla, Eduardo Oliver and Pilar Escribano-Subias

Int. J. Mol. Sci. 2023, 24(4), 4147; https://doi.org/10.3390/ijms24044147 - 19 Feb 2023

Cited by 5 | Viewed by 3099

Abstract

Pulmonary arterial hypertension (PAH) is a severe condition with a high mortality rate despite advances in diagnostic and therapeutic strategies. In recent years, significant scientific progress has been made in the understanding of the underlying pathobiological mechanisms. Since current available treatments mainly target [...] Read more.

Pulmonary arterial hypertension (PAH) is a severe condition with a high mortality rate despite advances in diagnostic and therapeutic strategies. In recent years, significant scientific progress has been made in the understanding of the underlying pathobiological mechanisms. Since current available treatments mainly target pulmonary vasodilation, but lack an effect on the pathological changes that develop in the pulmonary vasculature, there is need to develop novel therapeutic compounds aimed at antagonizing the pulmonary vascular remodeling. This review presents the main molecular mechanisms involved in the pathobiology of PAH, discusses the new molecular compounds currently being developed for the medical treatment of PAH and assesses their potential future role in the therapeutic algorithms of PAH. Full article

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16 pages, 1126 KiB

Open AccessReview

Autoantibodies in Atrial Fibrillation—State of the Art

by Joanna Zygadło, Grzegorz Procyk, Paweł Balsam, Piotr Lodziński, Marcin Grabowski and Aleksandra Gąsecka

Int. J. Mol. Sci. 2023, 24(3), 1852; https://doi.org/10.3390/ijms24031852 - 17 Jan 2023

Cited by 4 | Viewed by 1902

Abstract

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. To date, a lot of research has been conducted to investigate the underlying mechanisms of this disease at both molecular and cellular levels. There is increasing evidence suggesting that autoimmunity is an [...] Read more.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. To date, a lot of research has been conducted to investigate the underlying mechanisms of this disease at both molecular and cellular levels. There is increasing evidence suggesting that autoimmunity is an important factor in the initiation and perpetuation of AF. Autoantibodies are thought to play a pivotal role in the regulation of heart rhythm and the conduction system and, therefore, are associated with AF development. In this review, we have summarized current knowledge concerning the role of autoantibodies in AF development as well as their prognostic and predictive value in this disease. The establishment of the autoantibody profile of separate AF patient groups may appear to be crucial in terms of developing novel treatment approaches for those patients; however, the exact role of various autoantibodies in AF is still a matter of ongoing debate. Full article

(This article belongs to the Special Issue Advances in Molecular and Translational Medicine)

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11 pages, 614 KiB

Open AccessReview

Involvement of Atopic Dermatitis in the Development of Systemic Inflammatory Diseases

by Misa Itamura and Yu Sawada

Int. J. Mol. Sci. 2022, 23(21), 13445; https://doi.org/10.3390/ijms232113445 - 03 Nov 2022

Cited by 10 | Viewed by 3216

Abstract

The skin is recognized as a peripheral lymphoid organ that plays an essential defensive action against external environmental stimuli. However, continuous stimulation of these factors causes chronic inflammation at the local site and occasionally causes tissue damage. Chronic inflammation is recognized as a [...] Read more.

The skin is recognized as a peripheral lymphoid organ that plays an essential defensive action against external environmental stimuli. However, continuous stimulation of these factors causes chronic inflammation at the local site and occasionally causes tissue damage. Chronic inflammation is recognized as a trigger for systemic organ inflammation. Atopic dermatitis (AD) is a chronic inflammatory skin disease that is influenced by various external environmental factors, such as dry conditions, chemical exposure, and microorganisms. The pathogenesis of AD involves various Th2 and proinflammatory cytokines. Recently updated studies have shown that atopic skin-derived cytokines influence systemic organ function and oncogenesis. In this review, we focus on AD’s influence on the development of systemic inflammatory diseases and malignancies. Full article

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15 pages, 349 KiB

Open AccessReview

Biomarkers of Bladder Cancer: Cell-Free DNA, Epigenetic Modifications and Non-Coding RNAs

by Stefan Harsanyi, Zuzana Varchulova Novakova, Katarina Bevizova, Lubos Danisovic and Stanislav Ziaran

Int. J. Mol. Sci. 2022, 23(21), 13206; https://doi.org/10.3390/ijms232113206 - 30 Oct 2022

Cited by 8 | Viewed by 2148

Abstract

Bladder cancer (BC) is the 10th most frequent cancer in the world. The initial diagnosis and surveillance of BC require a combination of invasive and non-invasive methods, which are costly and suffer from several limitations. Cystoscopy with urine cytology and histological examination presents [...] Read more.

Bladder cancer (BC) is the 10th most frequent cancer in the world. The initial diagnosis and surveillance of BC require a combination of invasive and non-invasive methods, which are costly and suffer from several limitations. Cystoscopy with urine cytology and histological examination presents the standard diagnostic approach. Various biomarkers (e.g., proteins, genes, and RNAs) have been extensively studied in relation to BC. However, the new trend of liquid biopsy slowly proves to be almost equally effective. Cell-free DNA, non-coding RNA, and other subcellular structures are now being tested for the best predictive and diagnostic value. In this review, we focused on published gene mutations, especially in DNA fragments, but also epigenetic modifications, and non-coding RNA (ncRNA) molecules acquired by liquid biopsy. We performed an online search in PubMed/Medline, Scopus, and Web of Science databases using the terms “bladder cancer”, in combination with “markers” or “biomarkers” published until August 2022. If applicable, we set the sensitivity and specificity threshold to 80%. In the era of precision medicine, the development of complex laboratory techniques fuels the search and development of more sensitive and specific biomarkers for diagnosis, follow-up, and screening of BC. Future efforts will be focused on the validation of their sensitivity, specificity, predictive value, and their utility in everyday clinical practice. Full article

(This article belongs to the Special Issue Advances in Molecular and Translational Medicine)

18 pages, 1657 KiB

Open AccessReview

The Challenge of Long COVID-19 Management: From Disease Molecular Hallmarks to the Proposal of Exercise as Therapy

by Raffaele Scurati, Nadia Papini, Paola Giussani, Giampietro Alberti and Cristina Tringali

Int. J. Mol. Sci. 2022, 23(20), 12311; https://doi.org/10.3390/ijms232012311 - 14 Oct 2022

Cited by 11 | Viewed by 4905

Abstract

Long coronavirus disease 19 (COVID-19) is the designation given to a novel syndrome that develops within a few months after infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and that is presenting with increasing incidence because of the numerous cases of infection. Long [...] Read more.

Long coronavirus disease 19 (COVID-19) is the designation given to a novel syndrome that develops within a few months after infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and that is presenting with increasing incidence because of the numerous cases of infection. Long COVID-19 is characterized by a sequela of clinical symptoms that concern different organs and tissues, from nervous, respiratory, gastrointestinal, and renal systems to skeletal muscle and cardiovascular apparatus. The main common molecular cause for all long COVID-19 facets appears to be related to immune dysregulations, the persistence of inflammatory status, epigenetic modifications, and alterations of neurotrophin release. The prevention and management of long COVID-19 are still inappropriate because many aspects need further clarification. Exercise is known to exert a deep action on molecular dysfunctions elicited by long COVID-19 depending on training intensity, duration, and continuity. Evidence suggests that it could improve the quality of life of long COVID-19 patients. This review explores the main clinical features and the known molecular mechanisms underlying long COVID-19 in the perspective of considering exercise as a co-medication in long COVID-19 management. Full article

(This article belongs to the Special Issue Advances in Molecular and Translational Medicine)

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Transcriptomics and RNA-Based Therapeutics as Potential Approaches to Manage SARS-CoV-2 Infection

by Cristian Arriaga-Canon, Laura Contreras-Espinosa, Rosa Rebollar-Vega, Rogelio Montiel-Manríquez, Alberto Cedro-Tanda, José Antonio García-Gordillo, Rosa María Álvarez-Gómez, Francisco Jiménez-Trejo, Clementina Castro-Hernández and Luis A. Herrera

Int. J. Mol. Sci. 2022, 23(19), 11058; https://doi.org/10.3390/ijms231911058 - 21 Sep 2022

Cited by 2 | Viewed by 2857

Abstract

SARS-CoV-2 is a coronavirus family member that appeared in China in December 2019 and caused the disease called COVID-19, which was declared a pandemic in 2020 by the World Health Organization. In recent months, great efforts have been made in the field of [...] Read more.

SARS-CoV-2 is a coronavirus family member that appeared in China in December 2019 and caused the disease called COVID-19, which was declared a pandemic in 2020 by the World Health Organization. In recent months, great efforts have been made in the field of basic and clinical research to understand the biology and infection processes of SARS-CoV-2. In particular, transcriptome analysis has contributed to generating new knowledge of the viral sequences and intracellular signaling pathways that regulate the infection and pathogenesis of SARS-CoV-2, generating new information about its biology. Furthermore, transcriptomics approaches including spatial transcriptomics, single-cell transcriptomics and direct RNA sequencing have been used for clinical applications in monitoring, detection, diagnosis, and treatment to generate new clinical predictive models for SARS-CoV-2. Consequently, RNA-based therapeutics and their relationship with SARS-CoV-2 have emerged as promising strategies to battle the SARS-CoV-2 pandemic with the assistance of novel approaches such as CRISPR-CAS, ASOs, and siRNA systems. Lastly, we discuss the importance of precision public health in the management of patients infected with SARS-CoV-2 and establish that the fusion of transcriptomics, RNA-based therapeutics, and precision public health will allow a linkage for developing health systems that facilitate the acquisition of relevant clinical strategies for rapid decision making to assist in the management and treatment of the SARS-CoV-2-infected population to combat this global public health problem. Full article

(This article belongs to the Special Issue Advances in Molecular and Translational Medicine)

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