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

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 (20 January 2023) | Viewed by 99358

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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 from 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 a massive instrumental automation, combined to 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 to 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 sensitivity and specificity of analyses.

This special issue, dedicated to the Father of modern pathology, will honour 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, 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 research context, will be considered.

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

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Keywords

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

Published Papers (33 papers)

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Editorial

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7 pages, 643 KiB  
Editorial
New Trends in Pathology: From Cell Morphology to Molecular Medicine
by Maria Addolorata Bonifacio and Maria Addolorata Mariggiò
Int. J. Mol. Sci. 2023, 24(14), 11743; https://doi.org/10.3390/ijms241411743 - 21 Jul 2023
Viewed by 1042
Abstract
After Rudolf Virchow’s pioneering works, technological advances boosted the scientific interest in this research field, which nowadays is still far from extinguished [...] Full article
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Research

Jump to: Editorial, Review, Other

19 pages, 6807 KiB  
Article
Statins as Potential Preventative Treatment of ETX and Multiple Pore-Forming Toxin-Induced Diseases
by Jing Huang, Baohua Zhao, Tingting Liu, Lin Kang, Jiaxin Li, Zishuo Guo, Ming Chen, Shan Gao, Jing Wang, Yanwei Li, Jinglin Wang and Wenwen Xin
Int. J. Mol. Sci. 2023, 24(6), 5414; https://doi.org/10.3390/ijms24065414 - 12 Mar 2023
Cited by 1 | Viewed by 1265
Abstract
Epsilon toxin (ETX), produced by type B and D strains of Clostridium perfringens, can cause fatal enterotoxaemia in ruminant animals, particularly sheep, cattle, and goats. Previous studies show that the cytotoxicity of ETX is dependent on the integrity of lipid rafts, the [...] Read more.
Epsilon toxin (ETX), produced by type B and D strains of Clostridium perfringens, can cause fatal enterotoxaemia in ruminant animals, particularly sheep, cattle, and goats. Previous studies show that the cytotoxicity of ETX is dependent on the integrity of lipid rafts, the maintenance of which is ensured by cholesterol. Zaragozic acid (ZA) is a statin drug that reduces the synthesis of squalene, which is responsible for cholesterol synthesis. In this study, ZA significantly reduced the toxicity of ETX in Madin–Darby canine kidney (MDCK) cells. We show that ZA does not affect the binding of ETX to MDCK cells, but propidium iodide staining (PI) and Western blotting confirmed that ZA significantly disrupts the ability of ETX to form pores or oligomers in MDCK cells. Additionally, ZA decreased the phosphatidylserine exposure on the plasma membrane and increased the Ca2+ influx of the cells. Results of density gradient centrifugation suggest that ZA decreased the number of lipid rafts in MDCK membranes, which probably contributed to the attenuation of pore-formation. Moreover, ZA protected mice against ETX in vivo. All mice pre-treated with ZA for 48 h before exposure to an absolute lethal dose of ETX (6400 ng/kg) survived. In summary, these findings provide an innovative method to prevent ETX intoxication. Considering many pore-forming toxins require lipid rafts, we tested and found ZA also inhibited the toxicity of other toxins such as Clostridium perfringens Net B and β-toxin (CPB) and Staphylococcus aureus α-hemolysin (Hla). We expect ZA can thus be developed as a broad-spectrum medicine for the treatment of multiple toxins. In addition, other statins, such as lovastatin (LO), also reduced the toxicity of ETX. These findings indicate that statin medicines are potential candidates for preventing and treating multiple toxin-induced diseases. Full article
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17 pages, 3269 KiB  
Article
The Potential Chemopreventive Effect of Andrographis paniculata on 1,2-Dimethylhydrazine and High-Fat-Diet-Induced Colorectal Cancer in Sprague Dawley Rats
by Tharani Subarmaniam, Rusydatul Nabila Mahmad Rusli, Kokila Vani Perumal, Yoke Keong Yong, Siti Hadizah, Fezah Othman, Khaled Salem, Nurul Husna Shafie, Rosnani Hasham, Khoo Boon Yin, Khairul Kamilah Abdul Kadir, Hasnah Bahari and Zainul Amiruddin Zakaria
Int. J. Mol. Sci. 2023, 24(6), 5224; https://doi.org/10.3390/ijms24065224 - 9 Mar 2023
Cited by 1 | Viewed by 2354
Abstract
Colorectal cancer (CRC) is responsible for a notable rise in the overall mortality rate. Obesity is found to be one of the main factors behind CRC development. Andrographis paniculata is a herbaceous plant famous for its medicinal properties, particularly in Southeast Asia for [...] Read more.
Colorectal cancer (CRC) is responsible for a notable rise in the overall mortality rate. Obesity is found to be one of the main factors behind CRC development. Andrographis paniculata is a herbaceous plant famous for its medicinal properties, particularly in Southeast Asia for its anti-cancer properties. This study examines the chemopreventive impact of A. paniculata ethanolic extract (APEE) against a high-fat diet and 1,2-dimethylhydrazine-induced colon cancer in Sprague Dawley rats. Sprague Dawley rats were administered 1,2-dimethylhydrazine (40 mg/kg, i.p. once a week for 10 weeks) and a high-fat diet (HFD) for 20 weeks to induce colorectal cancer. APEE was administered at 125 mg/kg, 250 mg/kg, and 500 mg/kg for 20 weeks. At the end of the experiment, blood serum and organs were collected. DMH/HFD-induced rats had abnormal crypts and more aberrant crypt foci (ACF). APEE at a dose of 500 mg/kg improved the dysplastic state of the colon tissue and caused a 32% reduction in the total ACF. HFD increased adipocyte cell size, while 500 mg/kg APEE reduced it. HFD and DMH/HFD rats had elevated serum insulin and leptin levels. Moreover, UHPLC-QTOF-MS analysis revealed that APEE was rich in anti-cancer phytochemicals. This finding suggests that APEE has anti-cancer potential against HFD/DMH-induced CRC and anti-adipogenic and anti-obesity properties. Full article
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12 pages, 2072 KiB  
Article
A Proof of Principle Proteomic Study Detects Dystrophin in Human Plasma: Implications in DMD Diagnosis and Clinical Monitoring
by Rachele Rossi, Camilla Johansson, Wendy Heywood, Heloise Vinette, Gabriella Jensen, Hanna Tegel, Albert Jiménez-Requena, Silvia Torelli, Cristina Al-Khalili Szigyarto and Alessandra Ferlini
Int. J. Mol. Sci. 2023, 24(6), 5215; https://doi.org/10.3390/ijms24065215 - 8 Mar 2023
Cited by 2 | Viewed by 1794
Abstract
Duchenne muscular dystrophy (DMD) is a rare neuromuscular disease caused by pathogenic variations in the DMD gene. There is a need for robust DMD biomarkers for diagnostic screening and to aid therapy monitoring. Creatine kinase, to date, is the only routinely used blood [...] Read more.
Duchenne muscular dystrophy (DMD) is a rare neuromuscular disease caused by pathogenic variations in the DMD gene. There is a need for robust DMD biomarkers for diagnostic screening and to aid therapy monitoring. Creatine kinase, to date, is the only routinely used blood biomarker for DMD, although it lacks specificity and does not correlate with disease severity. To fill this critical gap, we present here novel data about dystrophin protein fragments detected in human plasma by a suspension bead immunoassay using two validated anti-dystrophin-specific antibodies. Using both antibodies, a reduction of the dystrophin signal is detected in a small cohort of plasma samples from DMD patients when compared to healthy controls, female carriers, and other neuromuscular diseases. We also demonstrate the detection of dystrophin protein by an antibody-independent method using targeted liquid chromatography mass spectrometry. This last assay detects three different dystrophin peptides in all healthy individuals analysed and supports our finding that dystrophin protein is detectable in plasma. The results of our proof-of-concept study encourage further studies in larger sample cohorts to investigate the value of dystrophin protein as a low invasive blood biomarker for diagnostic screening and clinical monitoring of DMD. Full article
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16 pages, 6208 KiB  
Article
Organizational Principles of the Centrifugal Projections to the Olfactory Bulb
by Li Wang, Xiangning Li, Fengming Chen, Qing Liu and Fuqiang Xu
Int. J. Mol. Sci. 2023, 24(5), 4579; https://doi.org/10.3390/ijms24054579 - 26 Feb 2023
Cited by 4 | Viewed by 2045
Abstract
Centrifugal projections in the olfactory system are critical to both olfactory processing and behavior. The olfactory bulb (OB), the first relay station in odor processing, receives a substantial number of centrifugal inputs from the central brain regions. However, the anatomical organization of these [...] Read more.
Centrifugal projections in the olfactory system are critical to both olfactory processing and behavior. The olfactory bulb (OB), the first relay station in odor processing, receives a substantial number of centrifugal inputs from the central brain regions. However, the anatomical organization of these centrifugal connections has not been fully elucidated, especially for the excitatory projection neurons of the OB, the mitral/tufted cells (M/TCs). Using rabies virus-mediated retrograde monosynaptic tracing in Thy1-Cre mice, we identified that the three most prominent inputs of the M/TCs came from the anterior olfactory nucleus (AON), the piriform cortex (PC), and the basal forebrain (BF), similar to the granule cells (GCs), the most abundant population of inhibitory interneurons in the OB. However, M/TCs received proportionally less input from the primary olfactory cortical areas, including the AON and PC, but more input from the BF and contralateral brain regions than GCs. Unlike organizationally distinct inputs from the primary olfactory cortical areas to these two types of OB neurons, inputs from the BF were organized similarly. Furthermore, individual BF cholinergic neurons innervated multiple layers of the OB, forming synapses on both M/TCs and GCs. Taken together, our results indicate that the centrifugal projections to different types of OB neurons may provide complementary and coordinated strategies in olfactory processing and behavior. Full article
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13 pages, 5047 KiB  
Article
Potent Therapeutic Strategies for COVID-19 with Single-Domain Antibody Immunoliposomes Neutralizing SARS-CoV-2 and Lip/cGAMP Enhancing Protective Immunity
by Yajun Zhou, Xing Lu, Xiaoqing Wang, Tianlei Ying and Xiangshi Tan
Int. J. Mol. Sci. 2023, 24(4), 4068; https://doi.org/10.3390/ijms24044068 - 17 Feb 2023
Cited by 7 | Viewed by 1825
Abstract
The worldwide spread of COVID-19 continues to impact our lives and has led to unprecedented damage to global health and the economy. This highlights the need for an efficient approach to rapidly develop therapeutics and prophylactics against SARS-CoV-2. We modified a single-domain antibody, [...] Read more.
The worldwide spread of COVID-19 continues to impact our lives and has led to unprecedented damage to global health and the economy. This highlights the need for an efficient approach to rapidly develop therapeutics and prophylactics against SARS-CoV-2. We modified a single-domain antibody, SARS-CoV-2 VHH, to the surface of the liposomes. These immunoliposomes demonstrated a good neutralizing ability, but could also carry therapeutic compounds. Furthermore, we used the 2019-nCoV RBD-SD1 protein as an antigen with Lip/cGAMP as the adjuvant to immunize mice. Lip/cGAMP enhanced the immunity well. It was demonstrated that the combination of RBD-SD1 and Lip/cGAMP was an effective preventive vaccine. This work presented potent therapeutic anti-SARS-CoV-2 drugs and an effective vaccine to prevent the spread of COVID-19. Full article
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11 pages, 952 KiB  
Article
Evaluation of New Potential Inflammatory Markers in Patients with Nonvalvular Atrial Fibrillation
by Gabriela Lopes Martins, Rita Carolina Figueiredo Duarte, Érica Leandro Marciano Vieira, Natália Pessoa Rocha, Estêvão Lanna Figueiredo, Francisco Rezende Silveira, José Raymundo Sollero Caiaffa, Rodrigo Pinheiro Lanna, Maria das Graças Carvalho, András Palotás, Cláudia Natália Ferreira and Helton José Reis
Int. J. Mol. Sci. 2023, 24(4), 3326; https://doi.org/10.3390/ijms24043326 - 7 Feb 2023
Cited by 4 | Viewed by 1698
Abstract
Atrial fibrillation (AF), the most common arrhythmia in clinical practice, is associated with an increase in mortality and morbidity due to its high potential to cause stroke and systemic thromboembolism. Inflammatory mechanisms may play a role in the pathogenesis of AF and its [...] Read more.
Atrial fibrillation (AF), the most common arrhythmia in clinical practice, is associated with an increase in mortality and morbidity due to its high potential to cause stroke and systemic thromboembolism. Inflammatory mechanisms may play a role in the pathogenesis of AF and its maintenance. We aimed to evaluate a range of inflammatory markers as potentially involved in the pathophysiology of individuals with nonvalvular AF (NVAF). A total of 105 subjects were enrolled and divided into two groups: patients with NVAF (n = 55, mean age 72 ± 8 years) and a control group of individuals in sinus rhythm (n = 50, mean age 71 ± 8 years). Inflammatory-related mediators were quantified in plasma samples by using Cytometric Bead Array and Multiplex immunoassay. Subjects with NVAF presented significantly elevated values of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF), interferon-gamma, growth differentiation factor-15, myeloperoxidase, as well as IL-4, interferon-gamma-induced protein (IP-10), monokine induced by interferon-gamma, neutrophil gelatinase-associated lipocalin, and serum amyloid A in comparison with controls. However, after multivariate regression analysis adjusting for confounding factors, only IL-6, IL-10, TNF, and IP-10 remained significantly associated with AF. We provided a basis for the study of inflammatory markers whose association with AF has not been addressed before, such as IP-10, in addition to supporting evidence about molecules that had previously been associated with the disease. We expect to contribute to the discovery of markers that can be implemented in clinical practice hereafter. Full article
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16 pages, 1611 KiB  
Article
Concentration of Selected Adipokines and Factors Regulating Carbohydrate Metabolism in Patients with Head and Neck Cancer in Respect to Their Body Mass Index
by Jarosław Nuszkiewicz, Jolanta Czuczejko, Wiktor Dróżdż, Alina Woźniak, Bogdan Małkowski and Karolina Szewczyk-Golec
Int. J. Mol. Sci. 2023, 24(4), 3283; https://doi.org/10.3390/ijms24043283 - 7 Feb 2023
Cited by 5 | Viewed by 1946
Abstract
Head and neck cancers (HNCs) are a group of tumors not common in European populations. So far, not much is known about the role of obesity, adipokines, glucose metabolism, and inflammation in the pathogenesis of HNC. The aim of the study was to [...] Read more.
Head and neck cancers (HNCs) are a group of tumors not common in European populations. So far, not much is known about the role of obesity, adipokines, glucose metabolism, and inflammation in the pathogenesis of HNC. The aim of the study was to determine the concentrations of ghrelin, omentin-1, adipsin, adiponectin, leptin, resistin, visfatin, glucagon, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), plasminogen activator inhibitor-1 (PAI-1), and gastric inhibitory peptide (GIP) in the blood serum of HNC patients depending on their body mass index (BMI). The study included 46 patients divided into two groups according to their BMI values: the normal BMI group (nBMI) included 23 patients with BMI < 25 kg/m2 and the increased BMI group (iBMI) included patients with BMI ≥ 25 kg/m2. A control group (CG) included 23 healthy people (BMI < 25 kg/m2). Statistically significant differences in the levels of adipsin, ghrelin, glucagon, PAI-1, and visfatin were shown between nBMI and CG. In the case of nBMI and iBMI, statistically significant differences were observed in the concentrations of adiponectin, C-peptide, ghrelin, GLP-1, insulin, leptin, omentin-1, PAI-1, resistin, and visfatin. The obtained results indicate a disruption of endocrine function of adipose tissue and impaired glucose metabolism in HNC. Obesity, which is not a typical risk factor for HNC, may aggravate the negative metabolic changes associated with this type of neoplasm. Ghrelin, visfatin, PAI-1, adipsin, and glucagon might be related to head and neck carcinogenesis. They seem to be promising directions for further research. Full article
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23 pages, 4881 KiB  
Article
Metabolic and Molecular Response to High-Fat Diet Differs between Rats with Constitutionally High and Low Serotonin Tone
by Petra Baković, Maja Kesić, Darko Kolarić, Jasminka Štefulj and Lipa Čičin-Šain
Int. J. Mol. Sci. 2023, 24(3), 2169; https://doi.org/10.3390/ijms24032169 - 21 Jan 2023
Cited by 4 | Viewed by 2069
Abstract
Maintaining energy balance is a complex physiological function whose dysregulation can lead to obesity and associated metabolic disorders. The bioamine serotonin (5HT) is an important regulator of energy homeostasis, with its central and peripheral pools influencing energy status in opposing ways. Using sublines [...] Read more.
Maintaining energy balance is a complex physiological function whose dysregulation can lead to obesity and associated metabolic disorders. The bioamine serotonin (5HT) is an important regulator of energy homeostasis, with its central and peripheral pools influencing energy status in opposing ways. Using sublines of rats with constitutionally increased (high-5HT) or decreased (low-5HT) whole-body 5HT tone, we have previously shown that under standard diet constitutionally higher 5HT activity is associated with increased body weight, adiposity, and impaired glucose homeostasis. Here, we investigated the response of 5HT sublines to an obesogenic diet. Consistent with previous findings, high-5HT animals fed a standard diet had poorer metabolic health. However, in response to a high-fat diet, only low-5HT animals increased body weight and insulin resistance. They also showed more pronounced changes in blood metabolic parameters and the expression of various metabolic genes in hypothalamus and adipose tissue. On the other hand, high-5HT animals appeared to be protected from major metabolic disturbances of the obesogenic diet. The results suggest that constitutionally low 5HT activity is associated with higher susceptibility to harmful effects of a high-energy diet. High-5HT subline, which developed less adverse metabolic outcomes on hypercaloric diets, may prove useful in understanding metabolically healthy obesity in humans. Full article
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11 pages, 3783 KiB  
Article
Dimethyl Fumarate Treatment Reduces the Amount but Not the Avidity of the Epstein–Barr Virus Capsid-Antigen-Specific Antibody Response in Multiple Sclerosis: A Pilot Study
by Massimiliano Castellazzi, Caterina Ferri, Alice Piola, Samantha Permunian, Gaia Buscemi, Michele Laudisi, Eleonora Baldi and Maura Pugliatti
Int. J. Mol. Sci. 2023, 24(2), 1500; https://doi.org/10.3390/ijms24021500 - 12 Jan 2023
Cited by 3 | Viewed by 1749
Abstract
(1) Multiple sclerosis (MS) is a chronic inflammatory disease of autoimmune origin. The Epstein–Barr virus (EBV) is associated with the onset of MS, as almost all patients have high levels of EBV-specific antibodies as a result of a previous infection. We evaluated longitudinally [...] Read more.
(1) Multiple sclerosis (MS) is a chronic inflammatory disease of autoimmune origin. The Epstein–Barr virus (EBV) is associated with the onset of MS, as almost all patients have high levels of EBV-specific antibodies as a result of a previous infection. We evaluated longitudinally the effects of dimethyl fumarate (DMF), a first-line treatment of MS, on the quantity and quality of EBV-specific IgG in MS patients. (2) Serum samples from 17 MS patients receiving DMF were taken before therapy (T0) and after 1 week (T1) and 1 (T2), 3 (T3) and 6 (T4) months of treatment. Anti-EBV nuclear antigen (EBNA)-1 and capsid antigen (CA) IgG levels and anti-CA IgG avidity were measured in all samples. (3) Serum levels of anti-CA IgG were lower at T1 (p = 0.0341), T2 (p = 0.0034), T3 (p < 0.0001) and T4 (p = 0.0023) than T0. These differences were partially confirmed also in anti-EBNA-1 IgG levels (T3 vs. T0, p = 0.0034). All patients had high-avidity anti-CA IgG at T0, and no changes were observed during therapy. (4): DMF can reduce the amount but not the avidity of the anti-EBV humoral immune response in MS patients from the very early stages of treatment. Full article
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25 pages, 10680 KiB  
Article
Emerging Perspectives on the Rare Tubulopathy Dent Disease: Is Glomerular Damage a Direct Consequence of ClC-5 Dysfunction?
by Giovanna Priante, Monica Ceol, Lisa Gianesello, Dario Bizzotto, Paola Braghetta, Lorenzo Arcangelo Calò, Dorella Del Prete and Franca Anglani
Int. J. Mol. Sci. 2023, 24(2), 1313; https://doi.org/10.3390/ijms24021313 - 9 Jan 2023
Cited by 4 | Viewed by 1825
Abstract
Dent disease (DD1) is a rare tubulopathy caused by mutations in the CLCN5 gene. Glomerulosclerosis was recently reported in DD1 patients and ClC-5 protein was shown to be expressed in human podocytes. Nephrin and actin cytoskeleton play a key role for podocyte functions [...] Read more.
Dent disease (DD1) is a rare tubulopathy caused by mutations in the CLCN5 gene. Glomerulosclerosis was recently reported in DD1 patients and ClC-5 protein was shown to be expressed in human podocytes. Nephrin and actin cytoskeleton play a key role for podocyte functions and podocyte endocytosis seems to be crucial for slit diaphragm regulation. The aim of this study was to analyze whether ClC-5 loss in podocytes might be a direct consequence of the glomerular damage in DD1 patients. Three DD1 kidney biopsies presenting focal global glomerulosclerosis and four control biopsies were analyzed by immunofluorescence (IF) for nephrin and podocalyxin, and by immunohistochemistry (IHC) for ClC-5. ClC-5 resulted as down-regulated in DD1 vs. control (CTRL) biopsies in both tubular and glomerular compartments (p < 0.01). A significant down-regulation of nephrin (p < 0.01) in DD1 vs. CTRL was demonstrated. CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/Caspase9) gene editing of CLCN5 in conditionally immortalized human podocytes was used to obtain clones with the stop codon mutation p.(R34Efs*14). We showed that ClC-5 and nephrin expression, analyzed by quantitative Reverse Transcription/Polymerase Chain Reaction (qRT/PCR) and In-Cell Western (ICW), was significantly downregulated in mutant clones compared to the wild type ones. In addition, F-actin staining with fluorescent phalloidin revealed actin derangements. Our results indicate that ClC-5 loss might alter podocyte function either through cytoskeleton disorganization or through impairment of nephrin recycling. Full article
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12 pages, 2110 KiB  
Article
Label-Free Characterization of Macrophage Polarization Using Raman Spectroscopy
by Max Naumann, Natalie Arend, Rustam R. Guliev, Christian Kretzer, Ignacio Rubio, Oliver Werz and Ute Neugebauer
Int. J. Mol. Sci. 2023, 24(1), 824; https://doi.org/10.3390/ijms24010824 - 3 Jan 2023
Cited by 6 | Viewed by 2887
Abstract
Macrophages are important cells of the innate immune system that play many different roles in host defense, a fact that is reflected by their polarization into many distinct subtypes. Depending on their function and phenotype, macrophages can be grossly classified into classically activated [...] Read more.
Macrophages are important cells of the innate immune system that play many different roles in host defense, a fact that is reflected by their polarization into many distinct subtypes. Depending on their function and phenotype, macrophages can be grossly classified into classically activated macrophages (pro-inflammatory M1 cells), alternatively activated macrophages (anti-inflammatory M2 cells), and non-activated cells (resting M0 cells). A fast, label-free and non-destructive characterization of macrophage phenotypes could be of importance for studying the contribution of the various subtypes to numerous pathologies. In this work, single cell Raman spectroscopic imaging was applied to visualize the characteristic phenotype as well as to discriminate between different human macrophage phenotypes without any label and in a non-destructive manner. Macrophages were derived by differentiation of peripheral blood monocytes of human healthy donors and differently treated to yield M0, M1 and M2 phenotypes, as confirmed by marker analysis using flow cytometry and fluorescence imaging. Raman images of chemically fixed cells of those three macrophage phenotypes were processed using chemometric methods of unmixing (N-FINDR) and discrimination (PCA-LDA). The discrimination models were validated using leave-one donor-out cross-validation. The results show that Raman imaging is able to discriminate between pro- and anti-inflammatory macrophage phenotypes with high accuracy in a non-invasive, non-destructive and label-free manner. The spectral differences observed can be explained by the biochemical characteristics of the different phenotypes. Full article
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10 pages, 1646 KiB  
Article
Atractylodin Ameliorates Colitis via PPARα Agonism
by Gwangbeom Heo, Yuju Kim, Eun-La Kim, Soyeong Park, Sang Hoon Rhee, Jee H. Jung and Eunok Im
Int. J. Mol. Sci. 2023, 24(1), 802; https://doi.org/10.3390/ijms24010802 - 2 Jan 2023
Cited by 5 | Viewed by 1964
Abstract
Atractylodin is a major compound in the rhizome of Atractylodes lancea, an oriental herbal medicine used for the treatment of gastrointestinal diseases, including dyspepsia, nausea, and diarrhea. Recent studies have shown that atractylodin exerts anti-inflammatory effects in various inflammatory diseases. Herein, we investigated [...] Read more.
Atractylodin is a major compound in the rhizome of Atractylodes lancea, an oriental herbal medicine used for the treatment of gastrointestinal diseases, including dyspepsia, nausea, and diarrhea. Recent studies have shown that atractylodin exerts anti-inflammatory effects in various inflammatory diseases. Herein, we investigated the anti-colitis effects of atractylodin and its molecular targets. We determined the non-cytotoxic concentration of atractylodin (50 μM) using a cell proliferation assay in colonic epithelial cells. We found that pretreatment with atractylodin significantly inhibits tumor necrosis factor-α-induced phosphorylation of nuclear factor-κ-light-chain-enhancer of activated B in HCT116 cells. Through docking simulation analysis, luciferase assays, and in vitro binding assays, we found that atractylodin has an affinity for peroxisome proliferator-activated receptor alpha (PPARα). Daily administration of atractylodin (40 mg/kg) increased the survival rate of mice in a dextran sodium sulfate-induced colitis mouse model. Thus, atractylodin can be a good strategy for colitis therapy through inducing PPARα-dependent pathways. Full article
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19 pages, 3487 KiB  
Article
Near-Infrared 810 nm Light Affects Porifera Chondrosia reniformis (Nardo, 1847) Regeneration: Molecular Implications and Evolutionary Considerations of Photobiomodulation–Animal Cell Interaction
by Andrea Amaroli, Eleonora Tassara, Sara Ferrando, Stefano Aicardi, Claudio Pasquale, Marco Giovine, Marco Bertolino, Angelina Zekiy and Marina Pozzolini
Int. J. Mol. Sci. 2023, 24(1), 226; https://doi.org/10.3390/ijms24010226 - 23 Dec 2022
Cited by 3 | Viewed by 1610
Abstract
Chemotrophic choice as a metabolic source of energy has characterised animal cell evolution. However, light interactions with animal cell photoacceptors that are able to increase energetic metabolism (photo-biomodulation (PBM)) have been previously described. In the present study, we cut three specimens of Chondrosia [...] Read more.
Chemotrophic choice as a metabolic source of energy has characterised animal cell evolution. However, light interactions with animal cell photoacceptors that are able to increase energetic metabolism (photo-biomodulation (PBM)) have been previously described. In the present study, we cut three specimens of Chondrosia reniformis into four equal parts (12 fragments), and we irradiated the regenerating edge of six fragments with the previously characterised 810 nm near-infrared light, delivered at 1 W, 60 J/cm2, 1 W/cm2, and 60 J in a continuous-wave mode for 60 s through a flat-top hand-piece with a rounded spot-size area of 1 cm2. Six fragments were irradiated with 0 W for 60 s as the controls. We performed irradiation at the time 0 h and every 24 h for a total of five administrations. We monitored the regeneration process for five days (120 h) in aquaria by examining the macroscopic and histological changes. We analysed the gene expression profile of the inflammatory processes, apoptosis, heat stress, growth factors, and collagen production and determined oxidative stress enzyme activity and the total prokaryotic symbiont content. PBM sped up C. reniformis regeneration when compared to the controls. Particularly, transforming growth factor TGF3 and TGF6 upregulation during the early phase of regeneration and TGF5 upregulation 120 h postinjury in the irradiated samples supports the positive effect of PBM in sponge tissue recovery. Conversely, the expression of TGF4, a sponge fibroblast growth factor homologue, was not affected by irradiation, indicating that multiple, independent pathways regulate the TGF genes. The results are consistent with our previous data on a wide range of organisms and humans, suggesting that PBM interaction with primary and secondary cell targets has been conserved through the evolution of life forms. Full article
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15 pages, 1538 KiB  
Article
TRPC3-Nox2 Protein Complex Formation Increases the Risk of SARS-CoV-2 Spike Protein-Induced Cardiomyocyte Dysfunction through ACE2 Upregulation
by Yuri Kato, Kazuhiro Nishiyama, Jae Man Lee, Yuko Ibuki, Yumiko Imai, Takamasa Noda, Noriho Kamiya, Takahiro Kusakabe, Yasunari Kanda and Motohiro Nishida
Int. J. Mol. Sci. 2023, 24(1), 102; https://doi.org/10.3390/ijms24010102 - 21 Dec 2022
Cited by 3 | Viewed by 2491
Abstract
Myocardial damage caused by the newly emerged coronavirus (SARS-CoV-2) infection is one of the key determinants of COVID-19 severity and mortality. SARS-CoV-2 entry to host cells is initiated by binding with its receptor, angiotensin-converting enzyme (ACE) 2, and the ACE2 abundance is thought [...] Read more.
Myocardial damage caused by the newly emerged coronavirus (SARS-CoV-2) infection is one of the key determinants of COVID-19 severity and mortality. SARS-CoV-2 entry to host cells is initiated by binding with its receptor, angiotensin-converting enzyme (ACE) 2, and the ACE2 abundance is thought to reflect the susceptibility to infection. Here, we report that ibudilast, which we previously identified as a potent inhibitor of protein complex between transient receptor potential canonical (TRPC) 3 and NADPH oxidase (Nox) 2, attenuates the SARS-CoV-2 spike glycoprotein pseudovirus-evoked contractile and metabolic dysfunctions of neonatal rat cardiomyocytes (NRCMs). Epidemiologically reported risk factors of severe COVID-19, including cigarette sidestream smoke (CSS) and anti-cancer drug treatment, commonly upregulate ACE2 expression level, and these were suppressed by inhibiting TRPC3-Nox2 complex formation. Exposure of NRCMs to SARS-CoV-2 pseudovirus, as well as CSS and doxorubicin (Dox), induces ATP release through pannexin-1 hemi-channels, and this ATP release potentiates pseudovirus entry to NRCMs and human iPS cell-derived cardiomyocytes (hiPS-CMs). As the pseudovirus entry followed by production of reactive oxygen species was attenuated by inhibiting TRPC3-Nox2 complex in hiPS-CMs, we suggest that TRPC3-Nox2 complex formation triggered by panexin1-mediated ATP release participates in exacerbation of myocardial damage by amplifying ACE2-dependent SARS-CoV-2 entry. Full article
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18 pages, 5756 KiB  
Article
Detection of TRPM6 and TRPM7 Proteins in Normal and Diseased Cardiac Atrial Tissue and Isolated Cardiomyocytes
by Inga Andriulė, Dalia Pangonytė, Asfree Gwanyanya, Dainius Karčiauskas, Kanigula Mubagwa and Regina Mačianskienė
Int. J. Mol. Sci. 2022, 23(23), 14860; https://doi.org/10.3390/ijms232314860 - 28 Nov 2022
Cited by 6 | Viewed by 1717
Abstract
Magnesium-sensitive transient receptor potential melastatin (TRPM) ion channels, TRPM6 and TRPM7, are present in several organs, but their roles in the heart remain unclear. Therefore, here, we studied the expression patterns of TRPM6 and TRPM7 in normal and diseased myocardium. Cardiac atrial tissue [...] Read more.
Magnesium-sensitive transient receptor potential melastatin (TRPM) ion channels, TRPM6 and TRPM7, are present in several organs, but their roles in the heart remain unclear. Therefore, here, we studied the expression patterns of TRPM6 and TRPM7 in normal and diseased myocardium. Cardiac atrial tissue and cardiomyocytes were obtained from healthy pigs and undiseased human hearts as well as from hearts of patients with ischemic heart disease (IHD) or atrial fibrillation (AF). Immunofluorescence and ELISA were used to detect TRP proteins. TRPM6 and TRPM7 immunofluorescence signals, localized at/near the cell surface or intracellularly, were detected in pig and human atrial tissues. The TRP channel modulators carvacrol (CAR, 100 µM) or 2-aminoethoxydiphenyl borate (2-APB, 500 µM) decreased the TRPM7 signal, but enhanced that of TRPM6. At a higher concentration (2 mM), 2-APB enhanced the signals of both proteins. TRPM6 and TRPM7 immunofluorescence signals and protein concentrations were increased in atrial cells and tissues from IHD or AF patients. TRPM6 and TRPM7 proteins were both detected in cardiac atrial tissue, with relatively similar subcellular localization, but distinctive drug sensitivity profiles. Their upregulated expression in IHD and AF suggests a possible role of the channels in cardiac atrial disease. Full article
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15 pages, 1746 KiB  
Article
Different Types of Chronic Inflammation Engender Distinctive Immunosenescent Profiles in Affected Patients
by Eleni Moysidou, Georgios Lioulios, Aliki Xochelli, Vasiliki Nikolaidou, Michalis Christodoulou, Zoi Mitsoglou, Stamatia Stai, Asimina Fylaktou, Aikaterini Papagianni and Maria Stangou
Int. J. Mol. Sci. 2022, 23(23), 14688; https://doi.org/10.3390/ijms232314688 - 24 Nov 2022
Cited by 4 | Viewed by 1487
Abstract
Immunosenescence encompasses a spectrum of lymphocyte phenotypic alterations. The aim of the study was to evaluate immunosenescent effect of two different forms of chronic inflammation, Systemic Lupus Erythematosous (SLE), a systemic autoimmune disease, and End-Stage Kidney Disease (ESKD), a chronic inflammatory disorder. Certain [...] Read more.
Immunosenescence encompasses a spectrum of lymphocyte phenotypic alterations. The aim of the study was to evaluate immunosenescent effect of two different forms of chronic inflammation, Systemic Lupus Erythematosous (SLE), a systemic autoimmune disease, and End-Stage Kidney Disease (ESKD), a chronic inflammatory disorder. Certain lymphocyte surface molecules, including CD31, CD45RA, CCR7, CD28, CD57, for T, and IgD, CD27 for B lymphocytes, were analyzed by flow cytometry in 30 SLE and 53 ESKD patients on hemodialysis (HD), and results were compared to 31 healthy controls (HC) of similar age, gender, and nationality. Significant Lymphopenia was evident in both SLE and ESKD-HD patients, compared to HC, affecting B cells 75.4 (14.4–520.8), 97 (32–341), and 214 (84–576) cells/μL, respectively, p < 0.0001, and CD4 cells 651.2 (71.1–1478.2), 713 (234–1509), and 986 (344–1591) cells/μL, respectively, p < 0.0001. The allocation of B cell subpopulations was remarkably different between SLE and ESKD-HD patients. SLE showed a clear shift to senescence (CD19IgD-CD27−) cells, compared to ESKD-HD and HC, 11.75 (10)% vs. 8 (6) vs. 8.1 (10), respectively. Regarding T lymphocytes, Central Memory CD8 cells predominated in both SLE and ESKD-HD patients compared to HC, 53 (50)%, 52 (63), and 24 (64)%, respectively, while ESKD-HD but not SLE patients also had increased expression of CD4CD28− and CD8CD28− cells. In conclusion, both diseases are followed by significant lymphopenia; however, the senescent phenomenon affects the B lymphocyte compartment in SLE patients and T lymphocytes in ESKD-HD patients. Full article
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14 pages, 1313 KiB  
Article
Exhausted but Not Senescent T Lymphocytes Predominate in Lupus Nephritis Patients
by Georgios Lioulios, Zoi Mitsoglou, Asimina Fylaktou, Aliki Xochelli, Michalis Christodoulou, Stamatia Stai, Eleni Moysidou, Afroditi Konstantouli, Vasiliki Nikolaidou, Aikaterini Papagianni and Maria Stangou
Int. J. Mol. Sci. 2022, 23(22), 13928; https://doi.org/10.3390/ijms232213928 - 11 Nov 2022
Cited by 5 | Viewed by 1480
Abstract
Lupus nephritis (LN), a chronic inflammatory disease, is characterized by the substantial disruption of immune homeostasis. This study examines its effects on the T lymphocyte phenotype and, particularly, its senescence- and exhaustion-related immune alterations. T cell subpopulations were determined with flow cytometry in [...] Read more.
Lupus nephritis (LN), a chronic inflammatory disease, is characterized by the substantial disruption of immune homeostasis. This study examines its effects on the T lymphocyte phenotype and, particularly, its senescence- and exhaustion-related immune alterations. T cell subpopulations were determined with flow cytometry in 30 LN patients and 20 healthy controls (HCs), according to the expression of senescence- (CD45RA, CCR7, CD31, CD28, CD57), and exhaustion- (PD1) related markers. The immune phenotype was associated with disease activity and renal histology. LN patients were characterized by pronounced lymphopenia, mainly affecting the CD4 compartment, with a concurrent reduction in the naïve, central and effector memory subsets compared to the HCs. In the CD8 compartment, the naïve subsets were significantly lower than that of the HCs, but a shift in the T cells occurred towards the central memory population. CD4+PD1+ and CD8+PD1+ cells were increased in the LN patients compared to the HCs. However, in CD4 T cells, the increase was limited to CD45RA+, whereas in CD8 T cells, both CD45RA+ and CD45RA− subsets were affected. Disease activity was correlated with CD4+PD1+ and highly differentiated CD4+CD28-CD57+ cells. Histology was only associated with CD4 T cell disturbances, with stage IV presenting reduced naïve and increased senescent subsets. Exhausted T lymphocyte subpopulations predominate within LN patients, while the T cell phenotype varies depending on disease activity. Full article
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12 pages, 2135 KiB  
Article
Prolyl Carboxypeptidase Activity Is Present in Human Adipose Tissue and Is Elevated in Serum of Obese Men with Type 2 Diabetes
by Emilie De Hert, Kenneth Verboven, Kristiaan Wouters, Johan W. E. Jocken and Ingrid De Meester
Int. J. Mol. Sci. 2022, 23(21), 13529; https://doi.org/10.3390/ijms232113529 - 4 Nov 2022
Cited by 1 | Viewed by 1200
Abstract
Prolyl carboxypeptidase (PRCP) is involved in metabolic disorders by hydrolyzing anorexigenic peptides. A link between serum PRCP activity and obesity has been reported, but its origin/source is still unclear. Previously proven correlations between human serum PRCP activity and the amount of adipose tissue [...] Read more.
Prolyl carboxypeptidase (PRCP) is involved in metabolic disorders by hydrolyzing anorexigenic peptides. A link between serum PRCP activity and obesity has been reported, but its origin/source is still unclear. Previously proven correlations between human serum PRCP activity and the amount of adipose tissue may suggest that adipose tissue is an important source of circulating PRCP. We investigated PRCP activity in visceral, subcutaneous adipose tissue (VAT and SCAT), skeletal muscle tissue and serum of lean and obese men with or without type 2 diabetes (T2D). Correlations between PRCP activity, metabolic and biochemical parameters and immune cell populations were assessed. PRCP activity was the highest in VAT, compared to SCAT, and was very low in skeletal muscle tissue in the overall group. Serum PRCP activity was significantly higher in T2-diabetic obese men, compared to lean and obese non-diabetic men, and was positively correlated with glycemic control. A positive correlation was observed between serum PRCP activity and VAT immune cell populations, which might indicate that circulating PRCP activity is deriving rather from the immune fraction than from adipocytes. In conclusion, PRCP activity was observed in human adipose tissue for the first time and serum PRCP activity is correlated with T2D in obese men. Full article
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14 pages, 6215 KiB  
Article
Aspirin Inhibits the Inflammatory Response of Protease-Activated Receptor 1 in Pregnancy Neutrophils: Implications for Treating Women with Preeclampsia
by Scott W. Walsh, Marwah Al Dulaimi and Jerome F. Strauss III
Int. J. Mol. Sci. 2022, 23(21), 13218; https://doi.org/10.3390/ijms232113218 - 30 Oct 2022
Cited by 2 | Viewed by 1544
Abstract
Neutrophils expressing cyclooxygenase-2 (COX-2) extensively infiltrate maternal blood vessels in preeclampsia, associated with vascular inflammation. Because pregnancy neutrophils also express protease-activated receptor 1 (PAR-1, F2R thrombin receptor), which they do not in non-pregnant subjects, they can be activated by proteases. We tested the [...] Read more.
Neutrophils expressing cyclooxygenase-2 (COX-2) extensively infiltrate maternal blood vessels in preeclampsia, associated with vascular inflammation. Because pregnancy neutrophils also express protease-activated receptor 1 (PAR-1, F2R thrombin receptor), which they do not in non-pregnant subjects, they can be activated by proteases. We tested the hypothesis that aspirin at a dose sufficient to inhibit COX-2 would reduce inflammatory responses in preeclampsia neutrophils. Neutrophils were isolated from normal pregnant and preeclamptic women at approximately 30 weeks’ gestation. Normal pregnancy neutrophils were treated with elastase, a protease elevated in preeclampsia, or elastase plus aspirin to inhibit COX-2, or elastase plus pinane thromboxane, a biologically active structural analog of thromboxane and a thromboxane synthase inhibitor. Preeclamptic pregnancy neutrophils were treated with the same doses of aspirin or pinane thromboxane. Confocal microscopy with immunofluorescence staining was used to determine the cellular localization of the p65 subunit of nuclear factor-kappa B (NF-κB) and media concentrations of thromboxane were measured to evaluate the inflammatory response. In untreated neutrophils of normal pregnant women, p65 was localized to the cytosol. Upon stimulation with elastase, p65 translocated from the cytosol to the nucleus coincident with increased thromboxane production. When neutrophils were co-treated with aspirin or pinane thromboxane, elastase was not able to cause nuclear translocation of p65 or increase thromboxane. In untreated neutrophils of preeclamptic women, the p65 subunit was present in the nucleus and thromboxane production was elevated, but when preeclamptic neutrophils were treated with aspirin or pinane thromboxane, p65 was cleared from the nucleus and returned to the cytosol along with decreased thromboxane production. These findings suggest that COX-2 is a downstream mediator of PAR-1 and demonstrate that PAR-1- mediated inflammation can be inhibited by aspirin. Given the extensive and ubiquitous expression of PAR-1 and COX-2 in preeclamptic women, consideration should be given to treating women with preeclampsia using a dose of aspirin sufficient to inhibit COX-2. Full article
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19 pages, 4006 KiB  
Article
The Role of IGL-2 Preservation Solution on Rat Livers during SCS and HOPE
by Njikem Asong-Fontem, Arnau Panisello-Rosello, Mylène Sebagh, Mathilde Gonin, Joan Rosello-Catafau and René Adam
Int. J. Mol. Sci. 2022, 23(20), 12615; https://doi.org/10.3390/ijms232012615 - 20 Oct 2022
Cited by 8 | Viewed by 1791
Abstract
The scarcity of livers for transplantation is rising, and new strategies to extend the donor pool are being explored. One solution is to use marginal grafts from extended criteria donors, presenting, for example, liver steatosis. As current preservation solutions (UW, HTK, and IGL-1) [...] Read more.
The scarcity of livers for transplantation is rising, and new strategies to extend the donor pool are being explored. One solution is to use marginal grafts from extended criteria donors, presenting, for example, liver steatosis. As current preservation solutions (UW, HTK, and IGL-1) were mainly designed for static cold storage (SCS) only, IGL-2, a modified version of IGL-1, was developed to be suitable for SCS and dynamic preservation, such as hypothermic oxygenated perfusion (HOPE). In this study, we investigated the combined effect of IGL-2, SCS, and HOPE and compared it to the most used preservation solution (UW and Belzer MPS). Four experimental groups with six rats each were designed using Zucker rats. All groups underwent 24 h of SCS (in IGL-2 or UW) + 2 h of normothermic machine perfusion (NMP) at 37 °C to mimic transplantation. HOPE (IGL-2 or Belzer MPS) was performed before NMP on half of the rats. The IGL-2 group demonstrated lower transaminases and a significantly low level of glycocalyx proteins, CASP3, and HMGB1 in the perfusates. These data suggest the protective role of IGL-2 for fatty livers in preserving the endothelial glycocalyx, apoptosis, and inflammation. Full article
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30 pages, 1419 KiB  
Article
Assessing and Evaluating the Scope and Constraints of Idylla Molecular Assays by Using Different Source Materials in Routine Diagnostic Settings
by Sanga Mitra Boppudi, Stefanie Scheil-Bertram, Elisabeth Faust, Anil Annamneedi and Annette Fisseler-Eckhoff
Int. J. Mol. Sci. 2022, 23(20), 12515; https://doi.org/10.3390/ijms232012515 - 19 Oct 2022
Cited by 4 | Viewed by 1882
Abstract
For cancer treatment, diagnostics concerning tumor type and determination of molecular markers in short TAT is critical. The fully automated, real-time PCR-based molecular diagnostic Idylla assays are well established in many laboratories for qualitative detection, short TAT and routine screening of clinically relevant [...] Read more.
For cancer treatment, diagnostics concerning tumor type and determination of molecular markers in short TAT is critical. The fully automated, real-time PCR-based molecular diagnostic Idylla assays are well established in many laboratories for qualitative detection, short TAT and routine screening of clinically relevant oncogenic mutations. According to the manufacturer, all IVD assays are recommended for use only with FFPE tissue samples of 5–10 µM dissections with at least 10% tumor content. In this study, we tested the performance and accuracy of the IVD assays along with the gene fusion assay (RUO) with different tissue/source materials like isolated DNA/RNA, cryomaterial, etc. The study also included testing archival FFPE tissue sections dating back from 20 years and a performance check for different pan-cancer samples individually. All the assays tested with FFPE sections and gDNA/RNA input showed above 96% accuracy and sensitivity, individually with 100% specificity. The Idylla assays also performed exceptionally well on the archival FFPE tissues, and the use of assays for other solid tumors was also remarkable. The performance test and accuracy of Idylla assays showed high efficiency with certain limitations. For the use of Idylla assays, both qualitative and quantitative applicability of different tumor source materials could produce efficient results in different diagnostic settings within a short TAT. Full article
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16 pages, 1923 KiB  
Article
Chronic Alcohol Exposure Promotes Cancer Stemness and Glycolysis in Oral/Oropharyngeal Squamous Cell Carcinoma Cell Lines by Activating NFAT Signaling
by Anthony Nguyen, Anna H. Kim, Mo K. Kang, No-Hee Park, Reuben H. Kim, Yong Kim and Ki-Hyuk Shin
Int. J. Mol. Sci. 2022, 23(17), 9779; https://doi.org/10.3390/ijms23179779 - 29 Aug 2022
Cited by 9 | Viewed by 2176
Abstract
Alcohol consumption is associated with an increased risk of several cancers, including oral/oropharyngeal squamous cell carcinoma (OSCC). Alcohol also enhances the progression and aggressiveness of existing cancers; however, its underlying molecular mechanism remains elusive. Especially, the local carcinogenic effects of alcohol on OSCC [...] Read more.
Alcohol consumption is associated with an increased risk of several cancers, including oral/oropharyngeal squamous cell carcinoma (OSCC). Alcohol also enhances the progression and aggressiveness of existing cancers; however, its underlying molecular mechanism remains elusive. Especially, the local carcinogenic effects of alcohol on OSCC in closest contact with ingestion of alcohol are poorly understood. We demonstrated that chronic ethanol exposure to OSCC increased cancer stem cell (CSC) populations and their stemness features, including self-renewal capacity, expression of stem cell markers, ALDH activity, and migration ability. The ethanol exposure also led to a significant increase in aerobic glycolysis. Moreover, increased aerobic glycolytic activity was required to support the stemness phenotype of ethanol-exposed OSCC, suggesting a molecular coupling between cancer stemness and metabolic reprogramming. We further demonstrated that chronic ethanol exposure activated NFAT (nuclear factor of activated T cells) signaling in OSCC. Functional studies revealed that pharmacological and genetic inhibition of NFAT suppressed CSC phenotype and aerobic glycolysis in ethanol-exposed OSCC. Collectively, chronic ethanol exposure promotes cancer stemness and aerobic glycolysis via activation of NFAT signaling. Our study provides a novel insight into the roles of cancer stemness and metabolic reprogramming in the molecular mechanism of alcohol-mediated carcinogenesis. Full article
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Review

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48 pages, 16770 KiB  
Review
Systematic Review and Meta-Analysis of the Impact of Bariatric Surgery on Future Cancer Risk
by Robert B. Wilson, Dhruvi Lathigara and Devesh Kaushal
Int. J. Mol. Sci. 2023, 24(7), 6192; https://doi.org/10.3390/ijms24076192 - 24 Mar 2023
Cited by 24 | Viewed by 7818
Abstract
The study aimed to perform a systematic review and meta-analysis of the evidence for the prevention of future cancers following bariatric surgery. A systematic literature search of the Cochrane Library, Embase, Scopus, Web of Science and PubMed databases (2007–2023), Google Scholar and grey [...] Read more.
The study aimed to perform a systematic review and meta-analysis of the evidence for the prevention of future cancers following bariatric surgery. A systematic literature search of the Cochrane Library, Embase, Scopus, Web of Science and PubMed databases (2007–2023), Google Scholar and grey literature was conducted. A meta-analysis was performed using the inverse variance method and random effects model. Thirty-two studies involving patients with obesity who received bariatric surgery and control patients who were managed with conventional treatment were included. The meta-analysis suggested bariatric surgery was associated with a reduced overall incidence of cancer (RR 0.62, 95% CI 0.46–0.84, p < 0.002), obesity-related cancer (RR 0.59, 95% CI 0.39–0.90, p = 0.01) and cancer-associated mortality (RR 0.51, 95% CI 0.42–0.62, p < 0.00001). In specific cancers, bariatric surgery was associated with reduction in the future incidence of hepatocellular carcinoma (RR 0.35, 95% CI 0.22–0.55, p < 0.00001), colorectal cancer (RR 0.63, CI 0.50–0.81, p = 0.0002), pancreatic cancer (RR 0.52, 95% CI 0.29–0.93, p = 0.03) and gallbladder cancer (RR 0.41, 95% CI 0.18–0.96, p = 0.04), as well as female specific cancers, including breast cancer (RR 0.56, 95% CI 0.44–0.71, p < 0.00001), endometrial cancer (RR 0.38, 95% CI 0.26–0.55, p < 0.00001) and ovarian cancer (RR 0.45, 95% CI 0.31–0.64, p < 0.0001). There was no significant reduction in the incidence of oesophageal, gastric, thyroid, kidney, prostate cancer or multiple myeloma after bariatric surgery as compared to patients with morbid obesity who did not have bariatric surgery. Obesity-associated carcinogenesis is closely related to metabolic syndrome; visceral adipose dysfunction; aromatase activity and detrimental cytokine, adipokine and exosomal miRNA release. Bariatric surgery results in long-term weight loss in morbidly obese patients and improves metabolic syndrome. Bariatric surgery may decrease future overall cancer incidence and mortality, including the incidence of seven obesity-related cancers. Full article
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17 pages, 914 KiB  
Review
Drug-Induced Gingival Overgrowth—Molecular Aspects of Drug Actions
by Agnieszka Droździk and Marek Droździk
Int. J. Mol. Sci. 2023, 24(6), 5448; https://doi.org/10.3390/ijms24065448 - 13 Mar 2023
Cited by 9 | Viewed by 4162
Abstract
Drug-induced gingival overgrowth (DIGO) is one of the side effects produced by therapeutic agents, most commonly phenytoin, nifedipine and cyclosporin A. However, the precise mechanism of DIGO is not entirely understood. A literature search of the MEDLINE/PubMed databases was conducted to identify the [...] Read more.
Drug-induced gingival overgrowth (DIGO) is one of the side effects produced by therapeutic agents, most commonly phenytoin, nifedipine and cyclosporin A. However, the precise mechanism of DIGO is not entirely understood. A literature search of the MEDLINE/PubMed databases was conducted to identify the mechanisms involved in DIGO. The available information suggests that the pathogenesis of DIGO is multifactorial, but common pathogenic sequelae of events emerge, i.e., sodium and calcium channel antagonism or disturbed intracellular handling of calcium, which finally lead to reductions in intracellular folic acid levels. Disturbed cellular functions, mainly in keratinocytes and fibroblasts, result in increased collagen and glycosaminoglycans accumulation in the extracellular matrix. Dysregulation of collagenase activity, as well as integrins and membrane receptors, are key mechanisms of reduced degradation or excessive synthesis of connective tissue components. This manuscript describes the cellular and molecular factors involved in the epithelial–mesenchymal transition and extracellular matrix remodeling triggered by agents producing DIGO. Full article
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31 pages, 1814 KiB  
Review
To Predict, Prevent, and Manage Post-Traumatic Stress Disorder (PTSD): A Review of Pathophysiology, Treatment, and Biomarkers
by Ghazi I. Al Jowf, Ziyad T. Ahmed, Rick A. Reijnders, Laurence de Nijs and Lars M. T. Eijssen
Int. J. Mol. Sci. 2023, 24(6), 5238; https://doi.org/10.3390/ijms24065238 - 9 Mar 2023
Cited by 15 | Viewed by 15999
Abstract
Post-traumatic stress disorder (PTSD) can become a chronic and severely disabling condition resulting in a reduced quality of life and increased economic burden. The disorder is directly related to exposure to a traumatic event, e.g., a real or threatened injury, death, or sexual [...] Read more.
Post-traumatic stress disorder (PTSD) can become a chronic and severely disabling condition resulting in a reduced quality of life and increased economic burden. The disorder is directly related to exposure to a traumatic event, e.g., a real or threatened injury, death, or sexual assault. Extensive research has been done on the neurobiological alterations underlying the disorder and its related phenotypes, revealing brain circuit disruption, neurotransmitter dysregulation, and hypothalamic–pituitary–adrenal (HPA) axis dysfunction. Psychotherapy remains the first-line treatment option for PTSD given its good efficacy, although pharmacotherapy can also be used as a stand-alone or in combination with psychotherapy. In order to reduce the prevalence and burden of the disorder, multilevel models of prevention have been developed to detect the disorder as early as possible and to reduce morbidity in those with established diseases. Despite the clinical grounds of diagnosis, attention is increasing to the discovery of reliable biomarkers that can predict susceptibility, aid diagnosis, or monitor treatment. Several potential biomarkers have been linked with pathophysiological changes related to PTSD, encouraging further research to identify actionable targets. This review highlights the current literature regarding the pathophysiology, disease development models, treatment modalities, and preventive models from a public health perspective, and discusses the current state of biomarker research. Full article
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36 pages, 2364 KiB  
Review
Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies
by María E. Casado, Roberto Collado-Pérez, Laura M. Frago and Vicente Barrios
Int. J. Mol. Sci. 2023, 24(2), 1422; https://doi.org/10.3390/ijms24021422 - 11 Jan 2023
Cited by 23 | Viewed by 5933
Abstract
Excess body weight is frequently associated with low-grade inflammation. Evidence indicates a relationship between obesity and cancer, as well as with other diseases, such as diabetes and non-alcoholic fatty liver disease, in which inflammation and the actions of various adipokines play a role [...] Read more.
Excess body weight is frequently associated with low-grade inflammation. Evidence indicates a relationship between obesity and cancer, as well as with other diseases, such as diabetes and non-alcoholic fatty liver disease, in which inflammation and the actions of various adipokines play a role in the pathological mechanisms involved in these disorders. Leptin is mainly produced by adipose tissue in proportion to fat stores, but it is also synthesized in other organs, where leptin receptors are expressed. This hormone performs numerous actions in the brain, mainly related to the control of energy homeostasis. It is also involved in neurogenesis and neuroprotection, and central leptin resistance is related to some neurological disorders, e.g., Parkinson’s and Alzheimer’s diseases. In peripheral tissues, leptin is implicated in the regulation of metabolism, as well as of bone density and muscle mass. All these actions can be affected by changes in leptin levels and the mechanisms associated with resistance to this hormone. This review will present recent advances in the molecular mechanisms of leptin action and their underlying roles in pathological situations, which may be of interest for revealing new approaches for the treatment of diseases where the actions of this adipokine might be compromised. Full article
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11 pages, 773 KiB  
Review
The Diagnostic Performance of Ultrasonography in the Evaluation of Extrathyroidal Extension in Papillary Thyroid Carcinoma: A Systematic Review and Meta-Analysis
by Peter P. Issa, Aaron L. Albuck, Eslam Hossam, Mohammad Hussein, Mohamed Aboueisha, Abdallah S. Attia, Mahmoud Omar, Seif Abdelrahman, Gehad Naser, Robert D. E. Clark, Eman Toraih and Emad Kandil
Int. J. Mol. Sci. 2023, 24(1), 371; https://doi.org/10.3390/ijms24010371 - 26 Dec 2022
Cited by 2 | Viewed by 2052
Abstract
Extrathyroidal extension (ETE) in patients with papillary thyroid carcinoma (PTC) is an indication of disease progression and can influence treatment aggressiveness. This meta-analysis assesses the diagnostic accuracy of ultrasonography (US) in detecting ETE. A systematic review and meta-analysis were performed by searching PubMed, [...] Read more.
Extrathyroidal extension (ETE) in patients with papillary thyroid carcinoma (PTC) is an indication of disease progression and can influence treatment aggressiveness. This meta-analysis assesses the diagnostic accuracy of ultrasonography (US) in detecting ETE. A systematic review and meta-analysis were performed by searching PubMed, Embase, and Cochrane for studies published up to April 2022. The pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated. The areas under the curve (AUC) for summary receiver operating curves were compared. A total of 11 studies analyzed ETE in 3795 patients with PTC. The sensitivity of ETE detection was 76% (95%CI = 74–78%). The specificity of ETE detection was 51% (95%CI = 49–54%). The DOR of detecting ETE by US was 5.32 (95%CI = 2.54–11.14). The AUC of ETE detection was determined to be 0.6874 ± 0.0841. We report an up-to-date analysis elucidating the diagnostic accuracy of ETE detection by US. Our work suggests the diagnostic accuracy of US in detecting ETE is adequate. Considering the importance of ETE detection on preoperative assessment, ancillary studies such as adjunct imaging studies and genetic testing should be considered. Full article
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22 pages, 1243 KiB  
Review
Innate Immune System Activation, Inflammation and Corneal Wound Healing
by Nyemkuna Fortingo, Samuel Melnyk, Sarah H. Sutton, Mitchell A. Watsky and Wendy B. Bollag
Int. J. Mol. Sci. 2022, 23(23), 14933; https://doi.org/10.3390/ijms232314933 - 29 Nov 2022
Cited by 24 | Viewed by 2989
Abstract
Corneal wounds resulting from injury, surgeries, or other intrusions not only cause pain, but also can predispose an individual to infection. While some inflammation may be beneficial to protect against microbial infection of wounds, the inflammatory process, if excessive, may delay corneal wound [...] Read more.
Corneal wounds resulting from injury, surgeries, or other intrusions not only cause pain, but also can predispose an individual to infection. While some inflammation may be beneficial to protect against microbial infection of wounds, the inflammatory process, if excessive, may delay corneal wound healing. An examination of the literature on the effect of inflammation on corneal wound healing suggests that manipulations that result in reductions in severe or chronic inflammation lead to better outcomes in terms of corneal clarity, thickness, and healing. However, some acute inflammation is necessary to allow efficient bacterial and fungal clearance and prevent corneal infection. This inflammation can be triggered by microbial components that activate the innate immune system through toll-like receptor (TLR) pathways. In particular, TLR2 and TLR4 activation leads to pro-inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) activation. Similarly, endogenous molecules released from disrupted cells, known as damage-associated molecular patterns (DAMPs), can also activate TLR2, TLR4 and NFκB, with the resultant inflammation worsening the outcome of corneal wound healing. In sterile keratitis without infection, inflammation can occur though TLRs to impact corneal wound healing and reduce corneal transparency. This review demonstrates the need for acute inflammation to prevent pathogenic infiltration, while supporting the idea that a reduction in chronic and/or excessive inflammation will allow for improved wound healing. Full article
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18 pages, 1691 KiB  
Review
Relevance of Plasma Homocysteine and Methylenetetrahydrofolate Reductase 677TT Genotype in Sickle Cell Disease: A Systematic Review and Meta-Analysis
by Paul R. J. Ames, Alessia Arcaro, Matilde Caruso, Maria Graf, Vincenzo Marottoli and Fabrizio Gentile
Int. J. Mol. Sci. 2022, 23(23), 14641; https://doi.org/10.3390/ijms232314641 - 24 Nov 2022
Cited by 2 | Viewed by 1603
Abstract
We evaluated the relevance of plasma homocysteine (HC) and the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) in sickle cell disease (SCD) and associated vaso-occlusive crisis (VOC) and ischemic stroke (IS). We identified in Embase and Medline 22 studies on [...] Read more.
We evaluated the relevance of plasma homocysteine (HC) and the TT genotype of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) in sickle cell disease (SCD) and associated vaso-occlusive crisis (VOC) and ischemic stroke (IS). We identified in Embase and Medline 22 studies on plasma HC and 22 on MTHFR genotypes. Due to age-related HC differences, adult and paediatric SCD were separated: 879 adult SCD and 834 controls (CTR) yielded a neutral effect size; 427 paediatric SCD and 625 CTR favoured SCD (p = 0.001) with wide heterogeneity (I2 = 95.5%) and were sub-grouped by country: six studies (Dutch Antilles n = 1, USA n = 5) yielded a neutral effect size, four (India n = 1, Arab countries n = 3) favoured SCD (p < 0.0001). Moreover, 249 SCD in VOC and 419 out of VOC yielded a neutral effect size. The pooled prevalence of the MTHFR TT genotype in 267 SCD equalled that of 1199 CTR (4.26% vs. 2.86%, p = 0.45), and in 84 SCD with IS equalled that of 86 without IS (5.9% vs. 3.7%, p = 0.47); removal of one paediatric study yielded a significant effect size (p = 0.006). Plasma HC in paediatric SCD from Middle East and India was higher, possibly due to vitamin deficiencies. Despite its low prevalence in SCD, the MTHFR TT genotype relates to adult IS. Full article
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15 pages, 1183 KiB  
Review
Pathology of Initial Axon Segments in Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Related Disorders
by Edyta Dziadkowiak, Marta Nowakowska-Kotas, Sławomir Budrewicz and Magdalena Koszewicz
Int. J. Mol. Sci. 2022, 23(21), 13621; https://doi.org/10.3390/ijms232113621 - 7 Nov 2022
Cited by 2 | Viewed by 2094
Abstract
The diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is based on a combination of clinical, electrodiagnostic and laboratory features. The different entities of the disease include chronic immune sensory polyradiculopathy (CISP) and autoimmune nodopathies. It is debatable whether CIDP occurring in the course [...] Read more.
The diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is based on a combination of clinical, electrodiagnostic and laboratory features. The different entities of the disease include chronic immune sensory polyradiculopathy (CISP) and autoimmune nodopathies. It is debatable whether CIDP occurring in the course of other conditions, i.e., monoclonal IgG or IgA gammopathy, should be treated as a separate disease entity from idiopathic CIDP. This study aims to evaluate the molecular differences of the nodes of Ranvier and the initial axon segment (AIS) and juxtaparanode region (JXP) as the potential cause of phenotypic variation of CIDP while also seeking new pathomechanisms since JXP is sequestered behind the paranode and autoantibodies may not access the site easily. The authors initially present the structure of the different parts of the neuron and its functional significance, then discuss the problem of whether damage to the juxtaparanodal region, Schwann cells and axons could cause CIDP or if these damages should be separated as separate disease entities. In particular, AIS’s importance for modulating neural excitability and carrying out transport along the axon is highlighted. The disclosure of specific pathomechanisms, including novel target antigens, in the heterogeneous CIDP syndrome is important for diagnosing and treating these patients. Full article
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23 pages, 3608 KiB  
Review
The Role of Inflammation in Cardiovascular Disease
by Michael Y. Henein, Sergio Vancheri, Giovanni Longo and Federico Vancheri
Int. J. Mol. Sci. 2022, 23(21), 12906; https://doi.org/10.3390/ijms232112906 - 26 Oct 2022
Cited by 111 | Viewed by 10375
Abstract
Atherosclerosis is a chronic inflammatory disease, in which the immune system has a prominent role in its development and progression. Inflammation-induced endothelial dysfunction results in an increased permeability to lipoproteins and their subendothelial accumulation, leukocyte recruitment, and platelets activation. Recruited monocytes differentiate into [...] Read more.
Atherosclerosis is a chronic inflammatory disease, in which the immune system has a prominent role in its development and progression. Inflammation-induced endothelial dysfunction results in an increased permeability to lipoproteins and their subendothelial accumulation, leukocyte recruitment, and platelets activation. Recruited monocytes differentiate into macrophages which develop pro- or anti-inflammatory properties according to their microenvironment. Atheroma progression or healing is determined by the balance between these functional phenotypes. Macrophages and smooth muscle cells secrete inflammatory cytokines including interleukins IL-1β, IL-12, and IL-6. Within the arterial wall, low-density lipoprotein cholesterol undergoes an oxidation. Additionally, triglyceride-rich lipoproteins and remnant lipoproteins exert pro-inflammatory effects. Macrophages catabolize the oxidized lipoproteins and coalesce into a lipid-rich necrotic core, encapsulated by a collagen fibrous cap, leading to the formation of fibro-atheroma. In the conditions of chronic inflammation, macrophages exert a catabolic effect on the fibrous cap, resulting in a thin-cap fibro-atheroma which makes the plaque vulnerable. However, their morphology may change over time, shifting from high-risk lesions to more stable calcified plaques. In addition to conventional cardiovascular risk factors, an exposure to acute and chronic psychological stress may increase the risk of cardiovascular disease through inflammation mediated by an increased sympathetic output which results in the release of inflammatory cytokines. Inflammation is also the link between ageing and cardiovascular disease through increased clones of leukocytes in peripheral blood. Anti-inflammatory interventions specifically blocking the cytokine pathways reduce the risk of myocardial infarction and stroke, although they increase the risk of infections. Full article
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12 pages, 13006 KiB  
Hypothesis
Cell-Free Filtrates (CFF) as Vectors of a Transmissible Pathologic Tissue Memory Code: A Hypothetical and Narrative Review
by Jorge Berlanga-Acosta, Maday Fernandez-Mayola, Yssel Mendoza-Mari, Ariana Garcia-Ojalvo, Indira Martinez-Jimenez, Nadia Rodriguez-Rodriguez, Diana Garcia del Barco Herrera and Gerardo Guillén-Nieto
Int. J. Mol. Sci. 2022, 23(19), 11575; https://doi.org/10.3390/ijms231911575 - 30 Sep 2022
Cited by 2 | Viewed by 1711
Abstract
Cellular memory is a controversial concept representing the ability of cells to “write and memorize” stressful experiences via epigenetic operators. The progressive course of chronic, non-communicable diseases such as type 2 diabetes mellitus, cancer, and arteriosclerosis, is likely driven through an abnormal epigenetic [...] Read more.
Cellular memory is a controversial concept representing the ability of cells to “write and memorize” stressful experiences via epigenetic operators. The progressive course of chronic, non-communicable diseases such as type 2 diabetes mellitus, cancer, and arteriosclerosis, is likely driven through an abnormal epigenetic reprogramming, fostering the hypothesis of a cellular pathologic memory. Accordingly, cultured diabetic and cancer patient-derived cells recall behavioral traits as when in the donor’s organism irrespective to culture time and conditions. Here, we analyze the data of studies conducted by our group and led by a cascade of hypothesis, in which we aimed to validate the hypothetical existence and transmissibility of a cellular pathologic memory in diabetes, arteriosclerotic peripheral arterial disease, and cancer. These experiments were based on the administration to otherwise healthy animals of cell-free filtrates prepared from human pathologic tissue samples representative of each disease condition. The administration of each pathologic tissue homogenate consistently induced the faithful recapitulation of: (1) Diabetic archetypical changes in cutaneous arterioles and nerves. (2) Non-thrombotic arteriosclerotic thickening, collagenous arterial encroachment, aberrant angiogenesis, and vascular remodeling. (3) Pre-malignant and malignant epithelial and mesenchymal tumors in different organs; all evocative of the donor’s tissue histopathology and with no barriers for interspecies transmission. We hypothesize that homogenates contain pathologic tissue memory codes represented in soluble drivers that “infiltrate” host’s animal cells, and ultimately impose their phenotypic signatures. The identification and validation of the actors in behind may pave the way for future therapies. Full article
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