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A Commemorative Issue in Honour of Rudolf Virchow: From Cell Morphology to Molecular Pathology-Volume 2

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 21835

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Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza Giulio Cesare 11, 70124 Bari, Italy
Interests: diagnostics; molecular oncology and pathology; precision medicine
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Special Issue Information

Dear Colleagues,

“Chemistry brings the clarification of living processes nearer than does anatomy. Each anatomical change must have been preceded by a chemical one.”

After 120 years after Virchow’s death, his words sound like a prophecy in front of the outstanding achievements of molecular research. Indeed, “chemical changes” at the subcellular and molecular level, like point mutations and single nucleotide polymorphisms, are currently exploited in several medical fields, ranging from oncohematology to prenatal diagnosis of genetic diseases. Furthermore, other research areas also benefit from progress in molecular medicine (e.g. forensic science, pharmacogenomics). In this respect, the 21st century has seen an impressive evolution of molecular methods, mainly based on PCR and mass spectrometry techniques, gradually moving from the academic context to diagnostics laboratories. This transition is supported by massive instrumental automation, combined with the development of algorithms for pattern recognition and management of complex information. Therefore, in the era of big data, the modern pathologist is expected to handle more frequently data mining challenges, rather than perform manual tasks. More than a century after Rudolf Virchow’s death, molecular approaches are reshaping research laboratories, speeding up turn-around times, and improving the sensitivity and specificity of analyses.

This new special issue, dedicated to the Father of modern pathology, will honor his memory, providing the latest insights into molecular techniques for medicine. Original research papers, reviews, and case studies reporting innovative molecular assays for pathology studies, diagnostic purposes, as well as for adjustment of therapy and follow-up, are herein welcome. The same applies to manuscripts dealing with new applications of molecular techniques, original strategies to solve technical issues, enhance standardization and improve sensitivity. Furthermore, systematic reviews and critical analyses, describing the advantages and current drawbacks of molecular approaches in a research context, will be considered.

Prof. Dr. Maria Addolorata Mariggiò
Dr. Maria Addolorata Bonifacio
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

 

Keywords

  • molecular methods
  • biomarkers
  • biochemical mechanisms
  • bioinformatics
  • omics
  • data mining
  • laboratory medicine
  • translational research
  • clinical pathology
  • evidence-based medicine

Published Papers (13 papers)

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Research

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14 pages, 3850 KiB  
Article
Obesity Enhances Non-Th2 Airway Inflammation in a Murine Model of Allergic Asthma
by Marwa M. E. Mohamed and Yassine Amrani
Int. J. Mol. Sci. 2024, 25(11), 6170; https://doi.org/10.3390/ijms25116170 - 4 Jun 2024
Viewed by 125
Abstract
Obese patients with asthma present with aggravated symptoms that are also harder to treat. Here, we used a mouse model of allergic asthma sensitised and challenged to house dust mite (HDM) extracts to determine whether high-fat-diet consumption would exacerbate the key features of [...] Read more.
Obese patients with asthma present with aggravated symptoms that are also harder to treat. Here, we used a mouse model of allergic asthma sensitised and challenged to house dust mite (HDM) extracts to determine whether high-fat-diet consumption would exacerbate the key features of allergic airway inflammation. C57BL/6 mice were intranasally sensitised and challenged with HDM extracts over a duration of 3 weeks. The impact of high-fat-diet (HFD) vs. normal diet (ND) chow was studied on HDM-induced lung inflammation and inflammatory cell infiltration as well as cytokine production. HFD-fed mice had greater inflammatory cell infiltration around airways and blood vessels, and an overall more severe degree of inflammation than in the ND-fed mice (semiquantitative blinded evaluation). Quantitative assessment of HDM-associated Th2 responses (numbers of lung CD4+ T cells, eosinophils, serum levels of allergen-specific IgE as well as the expression of Th2 cytokines (Il5 and Il13)) did not show significant changes between the HFD and ND groups. Interestingly, the HFD group exhibited a more pronounced neutrophilic infiltration within their lung tissues and an increase in non-Th2 cytokines (Il17, Tnfa, Tgf-b, Il-1b). These findings provide additional evidence that obesity triggered by a high-fat-diet regimen may exacerbate asthma by involving non-Th2 and neutrophilic pathways. Full article
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22 pages, 5854 KiB  
Article
ApoE Isoforms Inhibit Amyloid Aggregation of Proinflammatory Protein S100A9
by Shamasree Ghosh, Shanmugam Tamilselvi, Chloe Williams, Sanduni W. Jayaweera, Igor A. Iashchishyn, Darius Šulskis, Jonathan D. Gilthorpe, Anders Olofsson, Vytautas Smirnovas, Željko M. Svedružić and Ludmilla A. Morozova-Roche
Int. J. Mol. Sci. 2024, 25(4), 2114; https://doi.org/10.3390/ijms25042114 - 9 Feb 2024
Viewed by 967
Abstract
Increasing evidence suggests that the calcium-binding and proinflammatory protein S100A9 is an important player in neuroinflammation-mediated Alzheimer’s disease (AD). The amyloid co-aggregation of S100A9 with amyloid-β (Aβ) is an important hallmark of this pathology. Apolipoprotein E (ApoE) is also known to be one [...] Read more.
Increasing evidence suggests that the calcium-binding and proinflammatory protein S100A9 is an important player in neuroinflammation-mediated Alzheimer’s disease (AD). The amyloid co-aggregation of S100A9 with amyloid-β (Aβ) is an important hallmark of this pathology. Apolipoprotein E (ApoE) is also known to be one of the important genetic risk factors of AD. ApoE primarily exists in three isoforms, ApoE2 (Cys112/Cys158), ApoE3 (Cys112/Arg158), and ApoE4 (Arg112/Arg158). Even though the difference lies in just two amino acid residues, ApoE isoforms produce differential effects on the neuroinflammation and activation of the microglial state in AD. Here, we aim to understand the effect of the ApoE isoforms on the amyloid aggregation of S100A9. We found that both ApoE3 and ApoE4 suppress the aggregation of S100A9 in a concentration-dependent manner, even at sub-stoichiometric ratios compared to S100A9. These interactions lead to a reduction in the quantity and length of S100A9 fibrils. The inhibitory effect is more pronounced if ApoE isoforms are added in the lipid-free state versus lipidated ApoE. We found that, upon prolonged incubation, S100A9 and ApoE form low molecular weight complexes with stochiometric ratios of 1:1 and 2:1, which remain stable under SDS-gel conditions. These complexes self-assemble also under the native conditions; however, their interactions are transient, as revealed by glutaraldehyde cross-linking experiments and molecular dynamics (MD) simulation. MD simulation demonstrated that the lipid-binding C-terminal domain of ApoE and the second EF-hand calcium-binding motif of S100A9 are involved in these interactions. We found that amyloids of S100A9 are cytotoxic to neuroblastoma cells, and the presence of either ApoE isoforms does not change the level of their cytotoxicity. A significant inhibitory effect produced by both ApoE isoforms on S100A9 amyloid aggregation can modulate the amyloid-neuroinflammatory cascade in AD. Full article
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17 pages, 17464 KiB  
Article
Associations between Host Genetic Variants and Subgingival Microbiota in Patients with the Metabolic Syndrome
by Luigi Nibali, Abish S. Stephen, Robert P. Allaker, Antonino Di Pino, Valentina Terranova, Marcella Pisano, Salvatore Di Marca, Viviana Ferrara, Roberto Scicali, Francesco Purrello, Nikolaos Donos, Matteo Regolo and Lorenzo Malatino
Int. J. Mol. Sci. 2023, 24(23), 16649; https://doi.org/10.3390/ijms242316649 - 23 Nov 2023
Viewed by 1067
Abstract
Host genetic variants may affect oral biofilms, playing a role in the periodontitis–systemic disease axis. This is the first study to assess the associations between host genetic variants and subgingival microbiota in patients with metabolic syndrome (MetS); 103 patients with MetS underwent medical [...] Read more.
Host genetic variants may affect oral biofilms, playing a role in the periodontitis–systemic disease axis. This is the first study to assess the associations between host genetic variants and subgingival microbiota in patients with metabolic syndrome (MetS); 103 patients with MetS underwent medical and periodontal examinations and had blood and subgingival plaque samples taken. DNA was extracted and processed, assessing a panel of selected single nucleotide polymorphisms (SNPs) first (hypothesis testing) and then expanding to a discovery phase. The subgingival plaque microbiome from these patients was profiled. Analysis of associations between host genetic and microbial factors was performed and stratified for periodontal diagnosis. Specific SNPs within RUNX2, CAMTA1 and VDR genes were associated with diversity metrics with no genome-wide associations detected for periodontitis severity or Mets components at p < 10−7. Severe periodontitis was associated with pathogenic genera and species. Some SNPs correlated with specific bacterial genera as well as with microbial taxa, notably VDR (rs12717991) with Streptococcus mutans and RUNX2 (rs3749863) with Porphyromonas gingivalis. In conclusion, variation in host genotypes may play a role in the dysregulated immune responses characterizing periodontitis and thus the oral microbiome, suggesting that systemic health-associated host traits further interact with oral health and the microbiome. Full article
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24 pages, 29108 KiB  
Article
The Dual Luminescence Lifetime pH/Oxygen Sensor: Evaluation of Applicability for Intravital Analysis of 2D- and 3D-Cultivated Human Endometrial Mesenchymal Stromal Cells
by Ilia K. Litvinov, Tatiana N. Belyaeva, Anna V. Salova, Nikolay D. Aksenov, Pavel S. Chelushkin, Anastasia I. Solomatina, Sergey P. Tunik and Elena S. Kornilova
Int. J. Mol. Sci. 2023, 24(21), 15606; https://doi.org/10.3390/ijms242115606 - 26 Oct 2023
Viewed by 1047
Abstract
The oxygenation of cells and tissues and acidification of the cellular endolysosomal system are among the major factors that ensure normal functioning of an organism and are violated in various pathologies. Recording of these parameters and their changes under various conditions is an [...] Read more.
The oxygenation of cells and tissues and acidification of the cellular endolysosomal system are among the major factors that ensure normal functioning of an organism and are violated in various pathologies. Recording of these parameters and their changes under various conditions is an important task for both basic research and clinical applications. In the present work, we utilized internalizable dual pH/O2 lifetime sensor (Ir-HSA-FITC) based on the covalent conjugation of human serum albumin (HSA) with fluorescein isothiocyanate (FITC) as pH sensor and an orthometalated iridium complex as O2 sensor. The probe was tested for simultaneous detection of acidification level and oxygen concentration in endolysosomes of endometrial mesenchymal stem/stromal cells (enMSCs) cultivated as 2D monolayers and 3D spheroids. Using a combined FLIM/PLIM approach, we found that due to high autofluorescence of enMSCs FITC lifetime signal in control cells was insufficient to estimate pH changes. However, using flow cytometry and confocal microscopy, we managed to detect the FITC signal response to inhibition of endolysosomal acidification by Bafilomycin A1. The iridium chromophore phosphorescence was detected reliably by all methods used. It was demonstrated that the sensor, accumulated in endolysosomes for 24 h, disappeared from proliferating 2D enMSCs by 72 h, but can still be recorded in non-proliferating spheroids. PLIM showed high sensitivity and responsiveness of iridium chromophore phosphorescence to experimental hypoxia both in 2D and 3D cultures. In spheroids, the phosphorescence signal was detected at a depth of up to 60 μm using PLIM and showed a gradient in the intracellular O2 level towards their center. Full article
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20 pages, 16170 KiB  
Article
Effect of Fetal Bovine Serum or Basic Fibroblast Growth Factor on Cell Survival and the Proliferation of Neural Stem Cells: The Influence of Homocysteine Treatment
by Dražen Juraj Petrović, Denis Jagečić, Jure Krasić, Nino Sinčić and Dinko Mitrečić
Int. J. Mol. Sci. 2023, 24(18), 14161; https://doi.org/10.3390/ijms241814161 - 15 Sep 2023
Cited by 1 | Viewed by 1430
Abstract
In vitro cell culture is a routinely used method which is also applied for in vitro modeling of various neurological diseases. On the other hand, media used for cell culture are often not strictly standardized between laboratories, which hinders the comparison of the [...] Read more.
In vitro cell culture is a routinely used method which is also applied for in vitro modeling of various neurological diseases. On the other hand, media used for cell culture are often not strictly standardized between laboratories, which hinders the comparison of the obtained results. Here, we compared the effects of homocysteine (Hcy), a molecule involved in neurodegeneration, on immature cells of the nervous system cultivated in basal medium or media supplemented by either fetal bovine serum or basic fibroblast growth factor. The number of cells in basal media supplemented with basic fibroblast growth factor (bFGF) was 2.5 times higher in comparison to the number of cells in basal media supplemented with fetal bovine serum (FBS). We also found that the neuron-specific β-3-tubulin protein expression dose dependently decreased with increasing Hcy exposure. Interestingly, bFGF exerts a protective effect on β-3-tubulin protein expression at a concentration of 1000 µM Hcy compared to FBS-treated neural stem cells on Day 7. Supplementation with bFGF increased SOX2 protein expression two-fold compared to FBS supplementation. GFAP protein expression increased five-fold on Day 3 in FBS-treated neural stem cells, whereas on Day 7, bFGF increased GFAP expression two-fold compared to FBS-treated neural stem cells. Here, we have clearly shown that the selection of culturing media significantly influences various cellular parameters, which, in turn, can lead to different conclusions in experiments based on in vitro models of pathological conditions. Full article
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14 pages, 1873 KiB  
Article
Underfeeding Alters Brain Tissue Synthesis Rate in a Rat Brain Injury Model
by Casey C. Curl, Robert G. Leija, Jose A. Arevalo, Adam D. Osmond, Justin J. Duong, Daniela Kaufer, Michael A. Horning and George A. Brooks
Int. J. Mol. Sci. 2023, 24(17), 13195; https://doi.org/10.3390/ijms241713195 - 25 Aug 2023
Viewed by 803
Abstract
Brain injuries (BI) are highly disruptive, often having long lasting effects. Inadequate standard of care (SOC) energy support in the hospital leads to dietary energy deficiencies in BI patients. However, it is unclear how underfeeding (UF) affects protein synthesis post-BI. Therefore, in a [...] Read more.
Brain injuries (BI) are highly disruptive, often having long lasting effects. Inadequate standard of care (SOC) energy support in the hospital leads to dietary energy deficiencies in BI patients. However, it is unclear how underfeeding (UF) affects protein synthesis post-BI. Therefore, in a rat model, we addressed the issue of UF on the protein fractional synthesis rate (fSR) post-BI. Compared to ad libitum (AL)-fed animals, we found that UF decreased protein synthesis in hind-limb skeletal muscle and cortical mitochondrial and structural proteins (p ≤ 0.05). BI significantly increased protein synthesis in the left and right cortices (p ≤ 0.05), but suppressed protein synthesis in the cerebellum (p ≤ 0.05) as compared to non-injured sham animals. Compared to underfeeding alone, UF in conjunction with BI (UF+BI) caused increased protein synthesis rates in mitochondrial, cytosolic, and whole-tissue proteins of the cortical brain regions. The increased rates of protein synthesis found in the UF+BI group were mitigated by AL feeding, demonstrating that caloric adequacy alleviates the effects of BI on protein dynamics in cortical and cerebellar brain regions. This research provides evidence that underfeeding has a negative impact on brain healing post-BI and that protein reserves in uninjured tissues are mobilized to support cortical tissue repair following BI. Full article
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18 pages, 3126 KiB  
Article
Distinct Molecular Signatures of Amyloid-Beta and Tau in Alzheimer’s Disease Associated with Down Syndrome
by Shojiro Ichimata, Ivan Martinez-Valbuena, Seojin Lee, Jun Li, Ali M. Karakani and Gabor G. Kovacs
Int. J. Mol. Sci. 2023, 24(14), 11596; https://doi.org/10.3390/ijms241411596 - 18 Jul 2023
Cited by 5 | Viewed by 1911
Abstract
Limited comparative data exist on the molecular spectrum of amyloid-beta (Aβ) and tau deposition in individuals with Down syndrome (DS) and sporadic Alzheimer’s disease (sAD). We assessed Aβ and tau deposition severity in the temporal lobe and cerebellum of ten DS and ten [...] Read more.
Limited comparative data exist on the molecular spectrum of amyloid-beta (Aβ) and tau deposition in individuals with Down syndrome (DS) and sporadic Alzheimer’s disease (sAD). We assessed Aβ and tau deposition severity in the temporal lobe and cerebellum of ten DS and ten sAD cases. Immunohistochemistry was performed using antibodies against eight different Aβ epitopes (6F/3D, Aβ38, Aβ39, Aβ40, Aβ42, Aβ43, pyroglutamate Aβ at third glutamic acid (AβNp3E), phosphorylated- (p-)Aβ at 8th serine (AβpSer8)), and six different pathological tau epitopes (p-Ser202/Thr205, p-Thr231, p-Ser396, Alz50, MC1, GT38). Findings were evaluated semi-quantitatively and quantitatively using digital pathology. DS cases had significantly higher neocortical parenchymal deposition (Aβ38, Aβ42, and AβpSer8), and cerebellar parenchymal deposition (Aβ40, Aβ42, AβNp3E, and AβpSer8) than sAD cases. Furthermore, DS cases had a significantly larger mean plaque size (6F/3D, Aβ42, AβNp3E) in the temporal lobe, and significantly greater deposition of cerebral and cerebellar Aβ42 than sAD cases in the quantitative analysis. Western blotting corroborated these findings. Regarding tau pathology, DS cases had significantly more severe cerebral tau deposition than sAD cases, especially in the white matter (p-Ser202/Thr205, p-Thr231, Alz50, and MC1). Greater total tau deposition in the white matter (p-Ser202/Thr205, p-Thr231, and Alz50) of DS cases was confirmed by quantitative analysis. Our data suggest that the Aβ and tau molecular signatures in DS are distinct from those in sAD. Full article
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17 pages, 3106 KiB  
Article
Gut Region-Specific Interleukin 1β Induction in Different Myenteric Neuronal Subpopulations of Type 1 Diabetic Rats
by Afnan AL Doghmi, Bence Pál Barta, Abigél Egyed-Kolumbán, Benita Onhausz, Szilvia Kiss, János Balázs, Zita Szalai, Mária Bagyánszki and Nikolett Bódi
Int. J. Mol. Sci. 2023, 24(6), 5804; https://doi.org/10.3390/ijms24065804 - 18 Mar 2023
Viewed by 1701
Abstract
Interleukin 1β (IL1β) is a pro-inflammatory cytokine that may play a crucial role in enteric neuroinflammation in type 1 diabetes. Therefore, our goal is to evaluate the effects of chronic hyperglycemia and insulin treatment on IL1β immunoreactivity in myenteric neurons and their different [...] Read more.
Interleukin 1β (IL1β) is a pro-inflammatory cytokine that may play a crucial role in enteric neuroinflammation in type 1 diabetes. Therefore, our goal is to evaluate the effects of chronic hyperglycemia and insulin treatment on IL1β immunoreactivity in myenteric neurons and their different subpopulations along the duodenum–ileum–colon axis. Fluorescent immunohistochemistry was used to count IL1β expressing neurons as well as the neuronal nitric oxide synthase (nNOS)- and calcitonin gene-related peptide (CGRP)-immunoreactive myenteric neurons within this group. Tissue IL1β level was measured by ELISA in muscle/myenteric plexus-containing homogenates. IL1β mRNA was detected by RNAscope in different intestinal layers. The proportion of IL1β-immunoreactive myenteric neurons was significantly higher in the colon than in the small intestine of controls. In diabetics, this proportion significantly increased in all gut segments, which was prevented by insulin treatment. The proportion of IL1β-nNOS-immunoreactive neurons only increased in the diabetic colon, while the proportion of IL1β-CGRP-immunoreactive neurons only increased in the diabetic ileum. Elevated IL1β levels were also confirmed in tissue homogenates. IL1β mRNA induction was detected in the myenteric ganglia, smooth muscle and intestinal mucosa of diabetics. These findings support that diabetes-related IL1β induction is specific for the different myenteric neuronal subpopulations, which may contribute to diabetic motility disturbances. Full article
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Review

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17 pages, 1388 KiB  
Review
Lymphatic System and the Kidney: From Lymphangiogenesis to Renal Inflammation and Fibrosis Development
by Elodie Stasi, Savino Sciascia, Carla Naretto, Simone Baldovino and Dario Roccatello
Int. J. Mol. Sci. 2024, 25(5), 2853; https://doi.org/10.3390/ijms25052853 - 1 Mar 2024
Viewed by 1722
Abstract
The lymphatic kidney system plays a crucial role in managing interstitial fluid removal, regulating fluid balance, and tuning immune response. It also assists in the reabsorption of proteins, electrolytes, cytokines, growth factors, and immune cells. Pathological conditions, including tissue damage, excessive interstitial fluid, [...] Read more.
The lymphatic kidney system plays a crucial role in managing interstitial fluid removal, regulating fluid balance, and tuning immune response. It also assists in the reabsorption of proteins, electrolytes, cytokines, growth factors, and immune cells. Pathological conditions, including tissue damage, excessive interstitial fluid, high blood glucose levels, and inflammation, can initiate lymphangiogenesis—the formation of new lymphatic vessels. This process is associated with various kidney diseases, including polycystic kidney disease, hypertension, ultrafiltration challenges, and complications post-organ transplantation. Although lymphangiogenesis has beneficial effects in removing excess fluid and immune cells, it may also contribute to inflammation and fibrosis within the kidneys. In this review, we aim to discuss the biology of the lymphatic system, from its development and function to its response to disease stimuli, with an emphasis on renal pathophysiology. Furthermore, we explore how innovative treatments targeting the lymphatic system could potentially enhance the management of kidney diseases. Full article
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14 pages, 1063 KiB  
Review
Mitochondrial Quantity and Quality in Age-Related Sarcopenia
by Emanuele Marzetti, Riccardo Calvani, Hélio José Coelho-Júnior, Francesco Landi and Anna Picca
Int. J. Mol. Sci. 2024, 25(4), 2052; https://doi.org/10.3390/ijms25042052 - 8 Feb 2024
Cited by 1 | Viewed by 1990
Abstract
Sarcopenia, the age-associated decline in skeletal muscle mass and strength, is a condition with a complex pathophysiology. Among the factors underlying the development of sarcopenia are the progressive demise of motor neurons, the transition from fast to slow myosin isoform (type II to [...] Read more.
Sarcopenia, the age-associated decline in skeletal muscle mass and strength, is a condition with a complex pathophysiology. Among the factors underlying the development of sarcopenia are the progressive demise of motor neurons, the transition from fast to slow myosin isoform (type II to type I fiber switch), and the decrease in satellite cell number and function. Mitochondrial dysfunction has been indicated as a key contributor to skeletal myocyte decline and loss of physical performance with aging. Several systems have been implicated in the regulation of muscle plasticity and trophism such as the fine-tuned and complex regulation between the stimulator of protein synthesis, mechanistic target of rapamycin (mTOR), and the inhibitor of mTOR, AMP-activated protein kinase (AMPK), that promotes muscle catabolism. Here, we provide an overview of the molecular mechanisms linking mitochondrial signaling and quality with muscle homeostasis and performance and discuss the main pathways elicited by their imbalance during age-related muscle wasting. We also discuss lifestyle interventions (i.e., physical exercise and nutrition) that may be exploited to preserve mitochondrial function in the aged muscle. Finally, we illustrate the emerging possibility of rescuing muscle tissue homeostasis through mitochondrial transplantation. Full article
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16 pages, 847 KiB  
Review
Splanchnic Vein Thrombosis in Myelofibrosis—An Underappreciated Hallmark of Disease Phenotype
by Elina A. Beleva
Int. J. Mol. Sci. 2023, 24(21), 15717; https://doi.org/10.3390/ijms242115717 - 29 Oct 2023
Viewed by 1225
Abstract
Splanchnic vein thrombosis (SVT) encompasses thrombosis in the vessels of the splanchnic basin and has a relatively rare occurrence with a reported frequency in the general population of 1–2%. An episode of seemingly unprovoked SVT almost always triggers a diagnostic work-up for a [...] Read more.
Splanchnic vein thrombosis (SVT) encompasses thrombosis in the vessels of the splanchnic basin and has a relatively rare occurrence with a reported frequency in the general population of 1–2%. An episode of seemingly unprovoked SVT almost always triggers a diagnostic work-up for a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN), since atypical site thrombosis is a hallmark of MPN-associated thrombophilia. Primary myelofibrosis (PMF) is a rare MPN with an estimated incidence between 0.1 and 1/100,000 per year. Although prothrombotic tendency in PMF is not envisioned as a subject of specific therapeutic management, unlike other MPNs, such as polycythemia vera (PV) and essential thrombocythemia (ET), thrombotic risk and SVT prevalence in PMF may be comparably high. Additionally, unlike PV and ET, SVT development in PMF may depend more on procoagulant mechanisms involving endothelium than on blood cell activation. Emerging results from registry data also suggest that PMF patients with SVT may exhibit lower risk and better prognosis, thus highlighting the need for better thrombotic risk stratification and identifying a subset of patients with potential benefit from antithrombotic prophylaxis. This review highlights specific epidemiological, pathogenetic, and clinical features pertinent to SVT in myelofibrosis. Full article
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19 pages, 2273 KiB  
Review
Endogenous Biological Drivers in Diabetic Lower Limb Wounds Recurrence: Hypothetical Reflections
by Jorge Berlanga-Acosta, Ariana Garcia-Ojalvo, Gerardo Guillen-Nieto and Marta Ayala-Avila
Int. J. Mol. Sci. 2023, 24(12), 10170; https://doi.org/10.3390/ijms241210170 - 15 Jun 2023
Cited by 1 | Viewed by 1312
Abstract
An impaired healing response underlies diabetic foot wound chronicity, frequently translating to amputation, disability, and mortality. Diabetics suffer from underappreciated episodes of post-epithelization ulcer recurrence. Recurrence epidemiological data are alarmingly high, so the ulcer is considered in “remission” and not healed from the [...] Read more.
An impaired healing response underlies diabetic foot wound chronicity, frequently translating to amputation, disability, and mortality. Diabetics suffer from underappreciated episodes of post-epithelization ulcer recurrence. Recurrence epidemiological data are alarmingly high, so the ulcer is considered in “remission” and not healed from the time it remains epithelialized. Recurrence may result from the combined effects of behavioral and endogenous biological factors. Although the damaging role of behavioral, clinical predisposing factors is undebatable, it still remains elusive in the identification of endogenous biological culprits that may prime the residual scar tissue for recurrence. Furthermore, the event of ulcer recurrence still waits for the identification of a molecular predictor. We propose that ulcer recurrence is deeply impinged by chronic hyperglycemia and its downstream biological effectors, which originate epigenetic drivers that enforce abnormal pathologic phenotypes to dermal fibroblasts and keratinocytes as memory cells. Hyperglycemia-derived cytotoxic reactants accumulate and modify dermal proteins, reduce scar tissue mechanical tolerance, and disrupt fibroblast-secretory activity. Accordingly, the combination of epigenetic and local and systemic cytotoxic signalers induce the onset of “at-risk phenotypes” such as premature skin cell aging, dysmetabolism, inflammatory, pro-degradative, and oxidative programs that may ultimately converge to scar cell demise. Post-epithelialization recurrence rate data are missing in clinical studies of reputed ulcer healing therapies during follow-up periods. Intra-ulcer infiltration of epidermal growth factor exhibits the most consistent remission data with the lowest recurrences during 12-month follow-up. Recurrence data should be regarded as a valuable clinical endpoint during the investigational period for each emergent healing candidate. Full article
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20 pages, 743 KiB  
Review
Glutamine Deficiency Promotes Immune and Endothelial Cell Dysfunction in COVID-19
by William Durante
Int. J. Mol. Sci. 2023, 24(8), 7593; https://doi.org/10.3390/ijms24087593 - 20 Apr 2023
Cited by 4 | Viewed by 5623
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has caused the death of almost 7 million people worldwide. While vaccinations and new antiviral drugs have greatly reduced the number of COVID-19 cases, there remains a need for additional therapeutic strategies to combat this deadly disease. [...] Read more.
The coronavirus disease 2019 (COVID-19) pandemic has caused the death of almost 7 million people worldwide. While vaccinations and new antiviral drugs have greatly reduced the number of COVID-19 cases, there remains a need for additional therapeutic strategies to combat this deadly disease. Accumulating clinical data have discovered a deficiency of circulating glutamine in patients with COVID-19 that associates with disease severity. Glutamine is a semi-essential amino acid that is metabolized to a plethora of metabolites that serve as central modulators of immune and endothelial cell function. A majority of glutamine is metabolized to glutamate and ammonia by the mitochondrial enzyme glutaminase (GLS). Notably, GLS activity is upregulated in COVID-19, favoring the catabolism of glutamine. This disturbance in glutamine metabolism may provoke immune and endothelial cell dysfunction that contributes to the development of severe infection, inflammation, oxidative stress, vasospasm, and coagulopathy, which leads to vascular occlusion, multi-organ failure, and death. Strategies that restore the plasma concentration of glutamine, its metabolites, and/or its downstream effectors, in conjunction with antiviral drugs, represent a promising therapeutic approach that may restore immune and endothelial cell function and prevent the development of occlusive vascular disease in patients stricken with COVID-19. Full article
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