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Biomedicines, Volume 10, Issue 10 (October 2022) – 338 articles

Cover Story (view full-size image): The non-invasive application of weak and painless electrical current to the scalp (transcranial electrical stimulation—tES) causes neurophysiological and behavioural modifications as responses to the electric field (E-fields) induced in the brain. Computational simulations are currently the standard tool for spatial and temporal predictions of tES-induced E-fields, but the closest estimations come from in vivo recordings. However, due to methodological limitations, the results are still unclear. In this figure, we represent in a coronal section the portions of basal ganglia targeted for electric field recording during tES. The considered studies were performed on humans undergoing stereotactic neurosurgery. View this paper
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12 pages, 1143 KiB  
Article
Retinal Microvascular Abnormalities and Systemic Arterial Stiffness Are the First Manifestation of Cardiovascular Abnormalities in Patients with Untreated Moderate to Severe Obstructive Sleep Apnoea and with Low to Intermediate Cardiovascular Risk—A Pilot Study
by Swathi Seshadri, Hala Shokr and Doina Gherghel
Biomedicines 2022, 10(10), 2669; https://doi.org/10.3390/biomedicines10102669 - 21 Oct 2022
Cited by 4 | Viewed by 1408
Abstract
This study aimed to investigate macro- and microvascular function parameters and their relationship with known markers of cardiovascular risk in patients with untreated moderate to severe obstructive sleep apnoea (OSA). Fourteen patients with moderate to severe OSA and fourteen controls were included in [...] Read more.
This study aimed to investigate macro- and microvascular function parameters and their relationship with known markers of cardiovascular risk in patients with untreated moderate to severe obstructive sleep apnoea (OSA). Fourteen patients with moderate to severe OSA and fourteen controls were included in the present study. General assessments included BMI, systemic blood pressure (BP) and circulating markers for oxidative stress and endothelial function. Additional assessments included 24 h BP and heart rate monitoring, as well as the assessment of heart rate variability. Macro- and microvascular assessments included augmentation index, carotid intima-media thickness, brachial artery flow-mediated dilation, as well as various retinal microvascular function assessments, using the Dynamic Retinal Vessel Analyzer. All participants completed the Short Form Health Survey, Functional Outcomes of Sleep Questionnaire, and Epworth Sleepiness Scale. The results show that, in comparison to controls, BMI (p = 0.003) and AIx (p = 0.025) were significantly higher in the OSA group. There was, however, no significant difference between groups with regard to other measured systemic general, vascular and circulatory parameters (all p > 0.05). Nevertheless, the retinal microvascular function showed various alterations in the OSA patients, including a delayed reaction time in response to flicker (p = 0.047), as well as a decreased dilation amplitude (p = 0.004), dilation slope (p = 0.004), and post-flicker constriction (p = 0.015). In addition, the observed SlopeAD alterations correlated negatively with BMI values only in the OSA group (r = −0.46, p = 0.045). In conclusion, individuals with untreated moderate to severe OSA but without overt CVD, exhibit signs of increased arterial stiffness and retinal microvascular dysfunction, which can be early indicators for future vascular complications. Full article
(This article belongs to the Special Issue Advances in Cardiovascular Diseases (CVD))
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22 pages, 1391 KiB  
Review
Nrf2 Modulation in Breast Cancer
by Somayyeh Ghareghomi, Mehran Habibi-Rezaei, Marzia Arese, Luciano Saso and Ali Akbar Moosavi-Movahedi
Biomedicines 2022, 10(10), 2668; https://doi.org/10.3390/biomedicines10102668 - 21 Oct 2022
Cited by 39 | Viewed by 3437
Abstract
Reactive oxygen species (ROS) are identified to control the expression and activity of various essential signaling intermediates involved in cellular proliferation, apoptosis, and differentiation. Indeed, ROS represents a double-edged sword in supporting cell survival and death. Many common pathological processes, including various cancer [...] Read more.
Reactive oxygen species (ROS) are identified to control the expression and activity of various essential signaling intermediates involved in cellular proliferation, apoptosis, and differentiation. Indeed, ROS represents a double-edged sword in supporting cell survival and death. Many common pathological processes, including various cancer types and neurodegenerative diseases, are inflammation and oxidative stress triggers, or even initiate them. Keap1-Nrf2 is a master antioxidant pathway in cytoprotective mechanisms through Nrf2 target gene expression. Activation of the Nfr2 pathway benefits cells in the early stages and reduces the level of ROS. In contrast, hyperactivation of Keap1-Nrf2 creates a context that supports the survival of both healthy and cancerous cells, defending them against oxidative stress, chemotherapeutic drugs, and radiotherapy. Considering the dual role of Nrf2 in suppressing or expanding cancer cells, determining its inhibitory/stimulatory position and targeting can represent an impressive role in cancer treatment. This review focused on Nrf2 modulators and their roles in sensitizing breast cancer cells to chemo/radiotherapy agents. Full article
(This article belongs to the Special Issue Regulation of Keap1-Nrf2 Signaling in Health and Diseases)
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11 pages, 1183 KiB  
Article
A Novel Automated Chemiluminescence Method for Detecting Cerebrospinal Fluid Amyloid-Beta 1-42 and 1-40, Total Tau and Phosphorylated-Tau: Implications for Improving Diagnostic Performance in Alzheimer’s Disease
by Marina Arcaro, Chiara Fenoglio, Maria Serpente, Andrea Arighi, Giorgio G. Fumagalli, Luca Sacchi, Stefano Floro, Marianna D’Anca, Federica Sorrentino, Caterina Visconte, Alberto Perego, Elio Scarpini and Daniela Galimberti
Biomedicines 2022, 10(10), 2667; https://doi.org/10.3390/biomedicines10102667 - 21 Oct 2022
Cited by 9 | Viewed by 2005
Abstract
Recently, a fully automated instrument for the detection of the Cerebrospinal Fluid (CSF) biomarker for Alzheimer’s disease (AD) (low concentration of Amyloid-beta 42 (Aβ42), high concentration of total tau (T-tau) and Phosphorylated-tau (P-tau181)), has been implemented, namely CLEIA. We conducted a comparative analysis [...] Read more.
Recently, a fully automated instrument for the detection of the Cerebrospinal Fluid (CSF) biomarker for Alzheimer’s disease (AD) (low concentration of Amyloid-beta 42 (Aβ42), high concentration of total tau (T-tau) and Phosphorylated-tau (P-tau181)), has been implemented, namely CLEIA. We conducted a comparative analysis between ELISA and CLEIA methods in order to evaluate the analytical precision and the diagnostic performance of the novel CLEIA system on 111 CSF samples. Results confirmed a robust correlation between ELISA and CLEIA methods, with an improvement of the accuracy with the new CLEIA methodology in the detection of the single biomarkers and in their ratio values. For Aβ42 regression analysis with Passing–Bablok showed a Pearson correlation coefficient r = 0.867 (0.8120; 0.907% 95% CI p < 0.0001), T-tau analysis: r = 0.968 (0.954; 0.978% 95% CI p < 0.0001) and P-tau181: r = 0.946 (0.922; 0.962 5% 95% CI p < 0.0001). The overall ROC AUC comparison between ROC in ELISA and ROC in CLEIA confirmed a more accurate ROC AUC with the new automatic method: T-tau AUC ELISA = 0.94 (95% CI 0.89; 0.99 p < 0.0001) vs. AUC CLEIA = 0.95 (95% CI 0.89; 1.00 p < 0.0001), and P-tau181 AUC ELISA = 0.91 (95% CI 0.85; 0.98 p < 0.0001) vs. AUC CLEIA = 0.98 (95% CI 0.95; 1.00 p < 0.0001). The performance of the new CLEIA method in automation is comparable and, for tau and P-tau181, even better, as compared with standard ELISA. Hopefully, in the future, automation could be useful in clinical diagnosis and also in the context of clinical studies. Full article
(This article belongs to the Special Issue Molecular Research of Alzheimer's Disease 2.0)
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24 pages, 1131 KiB  
Article
Sleep Bruxism Contributes to Motor Activity Increase during Sleep in Apneic and Nonapneic Patients—A Polysomnographic Study
by Tomasz Wieczorek, Monika Michałek-Zrąbkowska, Mieszko Więckiewicz, Grzegorz Mazur, Joanna Rymaszewska, Joanna Smardz, Anna Wojakowska and Helena Martynowicz
Biomedicines 2022, 10(10), 2666; https://doi.org/10.3390/biomedicines10102666 - 21 Oct 2022
Cited by 3 | Viewed by 1808
Abstract
Background: Jaw motor activity (MA) in sleep bruxism (SB) has been demonstrated to accompany lower limb movements. However, it remains unknown whether SB activity coexists with other types of movements and what the possible underlying mechanisms of such temporal coexistence are. In obstructive [...] Read more.
Background: Jaw motor activity (MA) in sleep bruxism (SB) has been demonstrated to accompany lower limb movements. However, it remains unknown whether SB activity coexists with other types of movements and what the possible underlying mechanisms of such temporal coexistence are. In obstructive sleep apnea (OSA), increased movement activity is also reported, including SB activity; however, no studies have compared MA in apneic and nonapneic SB patients. Aim: This cross-sectional study focused on the phenomenon of “big body movements” in patients with either SB or OSA (or both) and intended to identify the primary factors contributing to their appearance, using polysomnography (PSG) recording. Methods: A whole-night videoPSG was carried out in 287 participants, and 124 apneic and 146 nonapneic participants were selected for the study. In both groups, participants were further divided into no SB, moderate SB, and severe SB (SSB) subgroups based on their bruxism episode index (BEI). MA was recorded using a built-in sensor of the central PSG unit located on the participant’s chest during the examination. Results: The presence of SB was related to the higher intensity of MA in both apneic and nonapneic participants, though in general the MA level was higher in apneic participants, with the highest level observed in SSB apneic participants. Conclusions: SB might contribute to MA. The prevalence of SB might be higher in nonapneic patients due to phasic and mixed SB activity, whereas the SB phenotype seems to be less relevant in apneic patients. SB activity is likely to increase MA in non-REM 1 sleep. Full article
(This article belongs to the Special Issue Sleep Disorders: An Interdisciplinary Approach)
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16 pages, 323 KiB  
Communication
Genetic Markers for Thrombophilia and Cardiovascular Disease Associated with Multiple Sclerosis
by Maria S. Hadjiagapiou, George Krashias, Elie Deeba, George Kallis, Andri Papaloizou, Paul Costeas, Christina Christodoulou, Marios Pantzaris and Anastasia Lambrianides
Biomedicines 2022, 10(10), 2665; https://doi.org/10.3390/biomedicines10102665 - 21 Oct 2022
Cited by 1 | Viewed by 2320
Abstract
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) with an unknown etiology, although genetic, epigenetic, and environmental factors are thought to play a role. Recently, coagulation components have been shown to provide immunomodulatory and pro-inflammatory effects in [...] Read more.
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) with an unknown etiology, although genetic, epigenetic, and environmental factors are thought to play a role. Recently, coagulation components have been shown to provide immunomodulatory and pro-inflammatory effects in the CNS, leading to neuroinflammation and neurodegeneration. The current study aimed to determine whether patients with MS exhibited an overrepresentation of polymorphisms implicated in the coagulation and whether such polymorphisms are associated with advanced disability and disease progression. The cardiovascular disease (CVD) strip assay was applied to 48 MS patients and 25 controls to analyze 11 genetic polymorphisms associated with thrombosis and CVD. According to our results, FXIIIVal34Leu heterozygosity was less frequent (OR: 0.35 (95% CI: 0.12–0.99); p = 0.04), whereas PAI-1 5G/5G homozygosity was more frequent in MS (OR: 6.33 (95% CI: 1.32–30.24); p = 0.016). In addition, carriers of the HPA-1a/1b were likely to have advanced disability (OR: 1.47 (95% CI: 1.03–2.18); p = 0.03) and disease worsening (OR: 1.42 (95% CI: 1.05–2.01); p = 0.02). The results of a sex-based analysis revealed that male HPA-1a/1b carriers were associated with advanced disability (OR: 3.04 (95% CI: 1.22–19.54); p = 0.01), whereas female carriers had an increased likelihood of disease worsening (OR: 1.56 (95% CI: 1.04–2.61); p = 0.03). Our findings suggest that MS may be linked to thrombophilia-related polymorphisms, which warrants further investigation. Full article
(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Advances in Multiple Sclerosis)
16 pages, 323 KiB  
Review
Critical Review on Toxicological Mechanisms Triggered by Inhalation of Alumina Nanoparticles on to the Lungs
by Samir Dekali, Alexandra Bourgois and Sabine François
Biomedicines 2022, 10(10), 2664; https://doi.org/10.3390/biomedicines10102664 - 21 Oct 2022
Cited by 4 | Viewed by 1598
Abstract
Alumina nanoparticles (Al2O3 NPs) can be released in occupational environments in different contexts such as industry, defense, and aerospace. Workers can be exposed by inhalation to these NPs, for instance, through welding fumes or aerosolized propellant combustion residues. Several clinical [...] Read more.
Alumina nanoparticles (Al2O3 NPs) can be released in occupational environments in different contexts such as industry, defense, and aerospace. Workers can be exposed by inhalation to these NPs, for instance, through welding fumes or aerosolized propellant combustion residues. Several clinical and epidemiological studies have reported that inhalation of Al2O3 NPs could trigger aluminosis, inflammation in the lung parenchyma, respiratory symptoms such as cough or shortness of breath, and probably long-term pulmonary fibrosis. The present review is a critical update of the current knowledge on underlying toxicological, molecular, and cellular mechanisms induced by exposure to Al2O3 NPs in the lungs. A major part of animal studies also points out inflammatory cells and secreted biomarkers in broncho-alveolar lavage fluid (BALF) and blood serum, while in vitro studies on lung cells indicate contradictory results regarding the toxicity of these NPs. Full article
16 pages, 1860 KiB  
Article
Multiple Sclerosis: Enzymatic Cross Site-Specific Recognition and Hydrolysis of H3 Histone by IgGs against H3, H1, H2A, H2B, H4 Histones, Myelin Basic Protein, and DNA
by Georgy A. Nevinsky, Valentina N. Buneva and Pavel S. Dmitrenok
Biomedicines 2022, 10(10), 2663; https://doi.org/10.3390/biomedicines10102663 - 21 Oct 2022
Cited by 2 | Viewed by 1009
Abstract
Histones have a specific key role in the remodeling of chromatin and gene transcription. In the blood, free histones are damage-connected proteins. Myelin basic protein (MBP) is the major component of the myelin-proteolipid sheath of axons. Antibodies possessing enzymatic activities (abzymes, ABZs) are [...] Read more.
Histones have a specific key role in the remodeling of chromatin and gene transcription. In the blood, free histones are damage-connected proteins. Myelin basic protein (MBP) is the major component of the myelin-proteolipid sheath of axons. Antibodies possessing enzymatic activities (abzymes, ABZs) are the specific features of several autoimmune pathologies. IgGs against five histones, MBP, and DNA were obtained from the sera of multiple sclerosis (MS) patients using several affinity chromatographies. The sites of H3 histone splitting by Abs against five individual histones, MBP, and DNA were revealed by MALDI mass spectrometry. It was shown that the number of H3 splitting sites by IgGs against five various histones is different (number of sites): H3 (11), H1 (14), H2A (11), H4 (17), MBP (22), and DNA (29). IgGs against five different histones hydrolyze H3 at different sites, and only a few them coincide. The main reason for the enzymatic cross-reactivity of Abs against H3 and four other histones, as well as MBP, might be the high level of these proteins’ homology. The effective hydrolysis of the H3 histone at 29 sites with IgGs against DNA can be explained by the formation of chimeric abzymes against hybrid antigenic determinants formed by different histones and MBP at the junction of these protein sequences with DNA. The active centers of such abzymes contain structural elements of canonical DNases and proteases. Since free histones are pernicious proteins, antibodies–ABZs against five histones, MBP, and DNA could have a negative role in the pathogenesis of MS and probably other various autoimmune diseases. Full article
(This article belongs to the Section Gene and Cell Therapy)
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15 pages, 3441 KiB  
Article
Temporal Evolution of Multiday, Epileptic Functional Networks Prior to Seizure Occurrence
by Petroula Laiou, Andrea Biondi, Elisa Bruno, Pedro F. Viana, Joel S. Winston, Zulqarnain Rashid, Yatharth Ranjan, Pauline Conde, Callum Stewart, Shaoxiong Sun, Yuezhou Zhang, Amos Folarin, Richard J. B. Dobson, Andreas Schulze-Bonhage, Matthias Dümpelmann, Mark P. Richardson and RADAR-CNS Consortium
Biomedicines 2022, 10(10), 2662; https://doi.org/10.3390/biomedicines10102662 - 21 Oct 2022
Viewed by 1434
Abstract
Epilepsy is one of the most common neurological disorders, characterized by the occurrence of repeated seizures. Given that epilepsy is considered a network disorder, tools derived from network neuroscience may confer the valuable ability to quantify the properties of epileptic brain networks. In [...] Read more.
Epilepsy is one of the most common neurological disorders, characterized by the occurrence of repeated seizures. Given that epilepsy is considered a network disorder, tools derived from network neuroscience may confer the valuable ability to quantify the properties of epileptic brain networks. In this study, we use well-established brain network metrics (i.e., mean strength, variance of strength, eigenvector centrality, betweenness centrality) to characterize the temporal evolution of epileptic functional networks over several days prior to seizure occurrence. We infer the networks using long-term electroencephalographic recordings from 12 people with epilepsy. We found that brain network metrics are variable across days and show a circadian periodicity. In addition, we found that in 9 out of 12 patients the distribution of the variance of strength in the day (or even two last days) prior to seizure occurrence is significantly different compared to the corresponding distributions on all previous days. Our results suggest that brain network metrics computed fromelectroencephalographic recordings could potentially be used to characterize brain network changes that occur prior to seizures, and ultimately contribute to seizure warning systems. Full article
(This article belongs to the Special Issue Electroencephalography (EEG) Signal Processing for Epilepsy)
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8 pages, 220 KiB  
Article
Predictive Risk Factors Associated with Severe Radiation-Induced Mucositis in Nasopharyngeal or Oropharyngeal Cancer Patients: A Retrospective Study
by Yumiko Kawashita, Sakiko Soutome, Masahiro Umeda and Toshiyuki Saito
Biomedicines 2022, 10(10), 2661; https://doi.org/10.3390/biomedicines10102661 - 21 Oct 2022
Cited by 5 | Viewed by 1772
Abstract
Radiation-induced mucositis in head and neck cancer patients generates difficulties in eating and swallowing, and may influence treatment tolerance, compliance, and quality of life. However, predictive factors have not been studied in detail. Thus, the aim of this study was to describe the [...] Read more.
Radiation-induced mucositis in head and neck cancer patients generates difficulties in eating and swallowing, and may influence treatment tolerance, compliance, and quality of life. However, predictive factors have not been studied in detail. Thus, the aim of this study was to describe the association between pre-radiotherapy clinical factors and the incidence of severe radiation-induced mucositis in nasopharyngeal or oropharyngeal cancer patients. This retrospective study included all patients with definitive radiotherapy or chemoradiotherapy for nasopharyngeal or oropharyngeal cancer between July 2011 and June 2021 in a single center. The eligibility criteria included patients who received oral management during radiotherapy. Exclusion criteria was patients who received postoperative radiotherapy. The data were acquired from the medical records of patients. One hundred patients were included in this retrospective study. Grade 3 radiation-induced mucositis occurred in 47 patients (47%). Lymphocyte count was significantly associated with grade 3 mucositis (OR = 0.40; 95% CI = 0.19–0.86; p = 0.018). It is suggested that pre-radiation lower lymphocyte counts are a predictive risk factor for severe mucositis in patients who undergo definitive radiotherapy or chemoradiotherapy for nasopharyngeal or oropharyngeal cancer Full article
19 pages, 7693 KiB  
Review
Inflammation Related to Obesity in the Etiopathogenesis of Gastroenteropancreatic Neuroendocrine Neoplasms
by Marlena Budek, Jarosław Nuszkiewicz, Anna Piórkowska, Jolanta Czuczejko and Karolina Szewczyk-Golec
Biomedicines 2022, 10(10), 2660; https://doi.org/10.3390/biomedicines10102660 - 21 Oct 2022
Cited by 4 | Viewed by 1782
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare neoplasms, which, due to their heterogeneous nature, non-specific symptoms, and lack of specific tumor markers pose many diagnostic and clinical challenges. In recent years, the effectiveness of GEP-NEN diagnosis has increased, which is probably associated with the [...] Read more.
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare neoplasms, which, due to their heterogeneous nature, non-specific symptoms, and lack of specific tumor markers pose many diagnostic and clinical challenges. In recent years, the effectiveness of GEP-NEN diagnosis has increased, which is probably associated with the greater availability of diagnostic tests and the cooperation of many experienced specialists in various scientific disciplines. In addition to the possible genetic etiology, the cause of GEP-NET development is not fully understood. Inflammation and obesity are known risks that contribute to the development of many diseases. Chronic inflammation accompanying obesity affects the hormonal balance and cell proliferation and causes the impairment of the immune system function, leading to neoplastic transformation. This review explores the role of inflammation and obesity in GEP-NETs. The exact mechanisms inducing tumor growth are unknown; however, the profile of inflammatory factors released in the GEP-NET tumor microenvironment is responsible for the progression or inhibition of tumor growth. Both the excess of adipose tissue and the impaired function of the immune system affect not only the initiation of cancer but also reduce the comfort and lifetime of patients. Full article
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18 pages, 1612 KiB  
Review
Periodontitis and Its Inflammatory Changes Linked to Various Systemic Diseases: A Review of Its Underlying Mechanisms
by Ruchi Bhuyan, Sanat Kumar Bhuyan, Jatindra Nath Mohanty, Srijit Das, Norsham Juliana and Izuddin Fahmy Juliana
Biomedicines 2022, 10(10), 2659; https://doi.org/10.3390/biomedicines10102659 - 21 Oct 2022
Cited by 26 | Viewed by 10616
Abstract
Periodontitis is a chronic inflammatory disease of the gums. The incidence of periodontitis is increasing all over the world. In patients with periodontitis, there is gradual destruction of the periodontal ligament and the alveolar bone, and later, in advanced stages, there is tooth [...] Read more.
Periodontitis is a chronic inflammatory disease of the gums. The incidence of periodontitis is increasing all over the world. In patients with periodontitis, there is gradual destruction of the periodontal ligament and the alveolar bone, and later, in advanced stages, there is tooth loss. Different microorganisms, the host’s immune response, and various environmental factors interact in the progression of this chronic inflammatory disease. In the present review, we discuss the epidemiology, clinical features, diagnosis, and complications of periodontitis. We also discuss the association of chronic inflammation found in periodontitis with various other systemic diseases, which include cardiovascular, respiratory, diabetes, Alzheimer’s, cancer, adverse pregnancy, and multiple myeloma, and also highlight microbial carcinogenesis and the microRNAs involved. The latest updates on the molecular mechanism, possible biomarkers, and treatment procedures may be beneficial for diagnostic and therapeutic purposes. Full article
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4 pages, 215 KiB  
Editorial
Amniotic Suspension Allograft for Treatment of Knee Osteoarthritis
by Ashim Gupta
Biomedicines 2022, 10(10), 2658; https://doi.org/10.3390/biomedicines10102658 - 21 Oct 2022
Cited by 2 | Viewed by 1231
Abstract
Osteoarthritis (OA) is an immensely pervasive joint disorder—typically concerning large weight-bearing joints—affecting over 30 million people in the United States, with this number predicted to reach 67 million by 2030 [...] Full article
(This article belongs to the Section Biomedical Engineering and Materials)
12 pages, 1080 KiB  
Commentary
Surgical Management of Synucleinopathies
by Sai Sriram, Kevin Root, Kevin Chacko, Aashay Patel and Brandon Lucke-Wold
Biomedicines 2022, 10(10), 2657; https://doi.org/10.3390/biomedicines10102657 - 21 Oct 2022
Cited by 3 | Viewed by 1483
Abstract
Synucleinopathies represent a diverse set of pathologies with significant morbidity and mortality. In this review, we highlight the surgical management of three synucleinopathies: Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). After examining underlying molecular mechanisms and the [...] Read more.
Synucleinopathies represent a diverse set of pathologies with significant morbidity and mortality. In this review, we highlight the surgical management of three synucleinopathies: Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). After examining underlying molecular mechanisms and the medical management of these diseases, we explore the role of deep brain stimulation (DBS) in the treatment of synuclein pathophysiology. Further, we examine the utility of focused ultrasound (FUS) in the treatment of synucleinopathies such as PD, including its role in blood–brain barrier (BBB) opening for the delivery of novel drug therapeutics and gene therapy vectors. We also discuss other recent advances in the surgical management of MSA and DLB. Together, we give a diverse overview of current techniques in the neurosurgical management of these pathologies. Full article
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15 pages, 2294 KiB  
Article
Prognostic Impact of LAG-3 mRNA Expression in Early Breast Cancer
by Anne-Sophie Heimes, Katrin Almstedt, Slavomir Krajnak, Anne Runkel, Annika Droste, Roxana Schwab, Kathrin Stewen, Antje Lebrecht, Marco J. Battista, Walburgis Brenner, Annette Hasenburg, Mathias Gehrmann, Jan G. Hengstler and Marcus Schmidt
Biomedicines 2022, 10(10), 2656; https://doi.org/10.3390/biomedicines10102656 - 21 Oct 2022
Cited by 3 | Viewed by 1640
Abstract
Background: Monoclonal antibodies against PD-1 or PD-L1 have been established in clinical practice for the treatment of both early and advanced/metastatic triple-negative breast cancer. Beyond the established immune checkpoints (ICPs) (PD-1 and CTLA-4), additional ICPs, such as lymphocyte activation gene-3 (LAG-3), are subject [...] Read more.
Background: Monoclonal antibodies against PD-1 or PD-L1 have been established in clinical practice for the treatment of both early and advanced/metastatic triple-negative breast cancer. Beyond the established immune checkpoints (ICPs) (PD-1 and CTLA-4), additional ICPs, such as lymphocyte activation gene-3 (LAG-3), are subject of current research. In the present retrospective gene-expression analysis, we evaluated the prognostic significance of LAG-3 in 461 patients with early breast cancer. In addition, we examined whether there was a correlation between the different ICP and CD8 expressions. Methods: Using microarray-based gene-expression analysis, we examined the prognostic significance of LAG-3 mRNA expression for metastasis-free survival (MFS) in the whole cohort of 461 breast cancer patients and among different molecular subtypes. Correlations were analyzed using Spearman’s rho correlation coefficient. Results: In the whole cohort, LAG-3 expression had no significant impact on MFS (p = 0.712, log-rank). In the subgroup analyses, there was a trend that a higher LAG-3 expression was associated with a favorable outcome in the luminal B (p = 0.217), basal-like (p = 0.370) and HER2 (p = 0.089) subtypes, although significance was not reached. In contrast, in a multivariate Cox regression analysis, adjusted for age, tumor size, axillary nodal status, histological grade of differentiation and proliferation marker Ki-67, LAG-3 showed a significant influence on MFS (HR 0.574; 95% CI 0.369–0.894; p = 0.014). High LAG-3 significantly correlated with CD8 (ρ = 0.571; p < 0.001). Conclusions: LAG-3 expression had an independent impact on MFS. In addition to PD-1 and PD-L1, further immune checkpoints, such as LAG-3, could serve as therapeutic targets in breast cancer. Full article
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31 pages, 10384 KiB  
Article
Expression of Amyloid Precursor Protein, Caveolin-1, Alpha-, Beta-, and Gamma-Secretases in Penumbra Cells after Photothrombotic Stroke and Evaluation of Neuroprotective Effect of Secretase and Caveolin-1 Inhibitors
by Svetlana Sharifulina, Andrey Khaitin, Valeria Guzenko, Yuliya Kalyuzhnaya, Valentina Dzreyan, Alexandr Logvinov, Natalia Dobaeva, Yan Li, Lei Chen, Bin He and Svetlana Demyanenko
Biomedicines 2022, 10(10), 2655; https://doi.org/10.3390/biomedicines10102655 - 20 Oct 2022
Cited by 1 | Viewed by 2060
Abstract
Our studies reveal changes in the expression of the main participants in the processing of amyloid precursor protein (APP) in neurons and astrocytes after photothrombotic stroke (PTS). Here we show the increase in the level of N- and C-terminal fragments of APP in [...] Read more.
Our studies reveal changes in the expression of the main participants in the processing of amyloid precursor protein (APP) in neurons and astrocytes after photothrombotic stroke (PTS). Here we show the increase in the level of N- and C-terminal fragments of APP in the cytoplasm of ischemic penumbra cells at 24 h after PTS and their co-immunoprecipitation with caveolin-1. The ADAM10 α-secretase level decreased in the rat brain cortex on the first day after PTS. Levels of γ-secretase complex proteins presenilin-1 and nicastrin were increased in astrocytes, but not in neurons, in the penumbra after PTS. Inhibitory analysis showed that these changes lead to neuronal death and activation of astrocytes in the early recovery period after PTS. The caveolin-1 inhibitor daidzein shifted APP processing towards Aβ synthesis, which caused astroglial activation. γ-secretase inhibitor DAPT down-regulated glial fibrillary acidic protein (GFAP) in astrocytes, prevented mouse cerebral cortex cells from PTS-induced apoptosis, and reduced the infarction volume. Thus, new generation γ-secretase inhibitors may be considered as potential agents for the treatment of stroke. Full article
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17 pages, 2573 KiB  
Article
Prevention and Therapy of Metastatic HER-2+ Mammary Carcinoma with a Human Candidate HER-2 Virus-like Particle Vaccine
by Francesca Ruzzi, Arianna Palladini, Stine Clemmensen, Anette Strøbæk, Nicolaas Buijs, Tanja Domeyer, Jerzy Dorosz, Vladislav Soroka, Dagmara Grzadziela, Christina Jo Rasmussen, Ida Busch Nielsen, Max Soegaard, Maria Sofia Semprini, Laura Scalambra, Stefania Angelicola, Lorena Landuzzi, Pier-Luigi Lollini and Mette Thorn
Biomedicines 2022, 10(10), 2654; https://doi.org/10.3390/biomedicines10102654 - 20 Oct 2022
Cited by 1 | Viewed by 3928
Abstract
Vaccines are a promising therapeutic alternative to monoclonal antibodies against HER-2+ breast cancer. We present the preclinical activity of an ES2B-C001, a VLP-based vaccine being developed for human breast cancer therapy. FVB mice challenged with HER-2+ mammary carcinoma cells QD developed [...] Read more.
Vaccines are a promising therapeutic alternative to monoclonal antibodies against HER-2+ breast cancer. We present the preclinical activity of an ES2B-C001, a VLP-based vaccine being developed for human breast cancer therapy. FVB mice challenged with HER-2+ mammary carcinoma cells QD developed progressive tumors, whereas all mice vaccinated with ES2B-C001+Montanide ISA 51, and 70% of mice vaccinated without adjuvant, remained tumor-free. ES2B-C001 completely inhibited lung metastases in mice challenged intravenously. HER-2 transgenic Delta16 mice developed mammary carcinomas by 4–8 months of age; two administrations of ES2B-C001+Montanide prevented tumor onset for >1 year. Young Delta16 mice challenged intravenously with QD cells developed a mean of 68 lung nodules in 13 weeks, whereas all mice vaccinated with ES2B-C001+Montanide, and 73% of mice vaccinated without adjuvant, remained metastasis-free. ES2B-C001 in adjuvant elicited strong anti-HER-2 antibody responses comprising all Ig isotypes; titers ranging from 1–10 mg/mL persisted for many months. Antibodies inhibited the 3D growth of human HER-2+ trastuzumab-sensitive and -resistant breast cancer cells. Vaccination did not induce cytokine storms; however, it increased the ELISpot frequency of IFN-γ secreting HER-2-specific splenocytes. ES2B-C001 is a promising candidate vaccine for the therapy of tumors expressing HER-2. Preclinical results warrant further development towards human clinical studies. Full article
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9 pages, 621 KiB  
Article
Decrease in Nitric Oxide Production as a Key Mediator in the Pathogenesis of Preeclampsia and a Potential Therapeutic Target: A Case-Control Study
by Maciej W. Socha, Martyna Stankiewicz, Krzysztof Żołnieżewicz, Oskar Puk and Mateusz Wartęga
Biomedicines 2022, 10(10), 2653; https://doi.org/10.3390/biomedicines10102653 - 20 Oct 2022
Cited by 2 | Viewed by 1386
Abstract
Pregnancy-induced hypertension (GH) complicates 6–10% of all pregnancies and, in 2019, was responsible for approximately 28,000 deaths. The most common cause of gestational hypertension is pre-eclampsia (PE), which afflicts 2–8% of all pregnancies and is one of the three leading causes of maternal [...] Read more.
Pregnancy-induced hypertension (GH) complicates 6–10% of all pregnancies and, in 2019, was responsible for approximately 28,000 deaths. The most common cause of gestational hypertension is pre-eclampsia (PE), which afflicts 2–8% of all pregnancies and is one of the three leading causes of maternal morbidity and mortality worldwide. The aim of this study was to clarify how NO metabolism changes during the course of PE. Due to the short half-life of NO, we measured the concentrations of its stable metabolites, nitrite and nitrate (NOx). Out of 100 enrolled patients: 58 pregnant women with a diagnosed early form of PE formed a study group, and 42 healthy pregnant women formed a control group. NOx concentrations were significantly lower in the PE group than in the control group, with mean values of 5.33 and 27.64 μmol/L, respectively (p < 0.0001). The decrease in NO is most likely the result and mediator of systemic endothelial dysfunction. The impairment of NO metabolism in PE appears to play an important role in its pathogenesis. Therefore, it is a potential therapeutic target. Full article
(This article belongs to the Special Issue The Pathophysiology of Pregnancy-Related Conditions)
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17 pages, 4844 KiB  
Article
Investigation of the Effect of Exendin-4 on Oleic Acid-Induced Steatosis in HepG2 Cells Using Fourier Transform Infrared Spectroscopy
by Olfa Khalifa, Kamal H. Mroue, Raghvendra Mall, Ehsan Ullah, Nayla S. Al-Akl and Abdelilah Arredouani
Biomedicines 2022, 10(10), 2652; https://doi.org/10.3390/biomedicines10102652 - 20 Oct 2022
Cited by 3 | Viewed by 1943
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common liver lesion that is untreatable with medications. Glucagon-like peptide-1 receptor (GLP-1R) agonists have recently emerged as a potential NAFLD pharmacotherapy. However, the molecular mechanisms underlying these drugs’ beneficial effects are not fully understood. Using Fourier [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is a common liver lesion that is untreatable with medications. Glucagon-like peptide-1 receptor (GLP-1R) agonists have recently emerged as a potential NAFLD pharmacotherapy. However, the molecular mechanisms underlying these drugs’ beneficial effects are not fully understood. Using Fourier transform infrared (FTIR) spectroscopy, we sought to investigate the biochemical changes in a steatosis cell model treated or not with the GLP-1R agonist Exendin-4 (Ex-4). HepG2 cells were made steatotic with 400 µM of oleic acid and then treated with 200 nM Ex-4 in order to reduce lipid accumulation. We quantified steatosis using the Oil Red O staining method. We investigated the biochemical alterations induced by steatosis and Ex-4 treatment using Fourier transform infrared (FTIR) spectroscopy and chemometric analyses. Analysis of the Oil Red O staining showed that Ex-4 significantly reduces steatosis. This reduction was confirmed by FTIR analysis, as the phospholipid band (C=O) at 1740 cm−1 in Ex-4 treated cells is significantly decreased compared to steatotic cells. The principal component analysis score plots for both the lipid and protein regions showed that the untreated and Ex-4-treated samples, while still separated, are clustered close to each other, far from the steatotic cells. The biochemical and structural changes induced by OA-induced lipotoxicity are at least partially reversed upon Ex-4 treatment. FTIR and chemometric analyses revealed that Ex-4 significantly reduces OA-induced lipid accumulation, and Ex-4 also restored the lipid and protein biochemical alterations caused by lipotoxicity-induced oxidative stress. In combination with chemometric analyses, FTIR spectroscopy may offer new approaches for investigating the mechanisms underpinning NAFLD. Full article
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22 pages, 3991 KiB  
Article
Injectable Crosslinked Genipin Hybrid Gelatin–PVA Hydrogels for Future Use as Bioinks in Expediting Cutaneous Healing Capacity: Physicochemical Characterisation and Cytotoxicity Evaluation
by Syafira Masri, Manira Maarof, Nor Fatimah Mohd, Yosuke Hiraoka, Yasuhiko Tabata and Mh Busra Fauzi
Biomedicines 2022, 10(10), 2651; https://doi.org/10.3390/biomedicines10102651 - 20 Oct 2022
Cited by 6 | Viewed by 2109
Abstract
The irregular shape and depth of wounds could be the major hurdles in wound healing for the common three-dimensional foam, sheet, or film treatment design. The injectable hydrogel is a splendid alternate technique to enhance healing efficiency post-implantation via injectable or 3D-bioprinting technologies. [...] Read more.
The irregular shape and depth of wounds could be the major hurdles in wound healing for the common three-dimensional foam, sheet, or film treatment design. The injectable hydrogel is a splendid alternate technique to enhance healing efficiency post-implantation via injectable or 3D-bioprinting technologies. The authentic combination of natural and synthetic polymers could potentially enhance the injectability and biocompatibility properties. Thus, the purpose of this study was to characterise a hybrid gelatin–PVA hydrogel crosslinked with genipin (GNP; natural crosslinker). In brief, gelatin (GE) and PVA were prepared in various concentrations (w/v): GE, GPVA3 (3% PVA), and GPVA5 (5% PVA), followed by a 0.1% (w/v) genipin (GNP) crosslink, to achieve polymerisation in three minutes. The physicochemical and biocompatibility properties were further evaluated. GPVA3_GNP and GPVA5_GNP with GNP demonstrated excellent physicochemical properties compared to GE_GNP and non-crosslinked hydrogels. GPVA5_GNP significantly displayed the optimum swelling ratio (621.1 ± 93.18%) and excellent hydrophilicity (38.51 ± 2.58°). In addition, GPVA5_GNP showed an optimum biodegradation rate (0.02 ± 0.005 mg/h) and the highest mechanical strength with the highest compression modulus (2.14 ± 0.06 MPa). In addition, the surface and cross-sectional view for scanning electron microscopy (SEM) displayed that all of the GPVA hydrogels have optimum average pore sizes (100–199 μm) with interconnected pores. There were no substantial changes in chemical analysis, including FTIR, XRD, and EDX, after PVA and GNP intervention. Furthermore, GPVA hydrogels influenced the cell biocompatibility, which successfully indicated >85% of cell viability. In conclusion, gelatin–PVA hydrogels crosslinked with GNP were proven to have excellent physicochemical, mechanical, and biocompatibility properties, as required for potential bioinks for chronic wound healing. Full article
(This article belongs to the Special Issue Biomaterial Modifications and Improvement of Their Biocompatibility)
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10 pages, 1584 KiB  
Article
Portrait of Molecular Signaling and Putative Therapeutic Targets in Prostate Cancer with ETV4 Fusion
by Ye Ji Shin, Jae Won Yun and Hong Sook Kim
Biomedicines 2022, 10(10), 2650; https://doi.org/10.3390/biomedicines10102650 - 20 Oct 2022
Viewed by 1377
Abstract
Gene fusion between androgen receptor (AR) response genes and E26 transformation-specific (ETS) family members increases the gene expression of ETS family members, and promotes tumorigenesis in prostate cancer. However, the molecular features of ETV4 fusion in prostate cancer are not fully understood, and [...] Read more.
Gene fusion between androgen receptor (AR) response genes and E26 transformation-specific (ETS) family members increases the gene expression of ETS family members, and promotes tumorigenesis in prostate cancer. However, the molecular features of ETV4 fusion in prostate cancer are not fully understood, and drugs targeting ETV4 fusion have not been developed. To examine key cellular signaling pathways and explore therapeutic targets and drugs for ETV4-fusion-positive prostate cancer, we analyzed RNA sequencing data and clinical information for prostate cancer. The ETV4-fusion-positive group was selected through prior study and analysis comparing ETV4-fusion-positive and -negative groups was conducted using a Pearson correlation test. We obtained 393 genes correlated with ETV4 expression. Pathway analysis was performed using over-representation analysis (ORA), and six cancer-specific molecular signaling pathways (the irinotecan pathway, metabolism, androgen receptor signaling, interferon signaling, MAPK/NF-kB signaling, and the tamoxifen pathway) were altered in the ETV4-fusion-positive group. Furthermore, a gene–drug database was used to find an actionable drug and therapeutic target for the ETV4-fusion-positive group. Here, we have identified significantly altered genes and oncogenic signaling pathways in ETV4-fusion-positive prostate cancer, and we suggest therapeutic targets and potential drugs for ETV4-fusion-positive prostate patients. Full article
(This article belongs to the Special Issue Signaling Pathways and Targeted Molecular Therapy in Prostate Cancer)
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27 pages, 745 KiB  
Review
Cellular Models of Alpha-Synuclein Aggregation: What Have We Learned and Implications for Future Study
by Katrina Albert, Sara Kälvälä, Vili Hakosalo, Valtteri Syvänen, Patryk Krupa, Jonna Niskanen, Sanni Peltonen, Tuuli-Maria Sonninen and Šárka Lehtonen
Biomedicines 2022, 10(10), 2649; https://doi.org/10.3390/biomedicines10102649 - 20 Oct 2022
Cited by 4 | Viewed by 4178
Abstract
Alpha-synuclein’s role in diseases termed “synucleinopathies”, including Parkinson’s disease, has been well-documented. However, after over 25 years of research, we still do not fully understand the alpha-synuclein protein and its role in disease. In vitro cellular models are some of the most powerful [...] Read more.
Alpha-synuclein’s role in diseases termed “synucleinopathies”, including Parkinson’s disease, has been well-documented. However, after over 25 years of research, we still do not fully understand the alpha-synuclein protein and its role in disease. In vitro cellular models are some of the most powerful tools that researchers have at their disposal to understand protein function. Advantages include good control over experimental conditions, the possibility for high throughput, and fewer ethical issues when compared to animal models or the attainment of human samples. On the flip side, their major disadvantages are their questionable relevance and lack of a “whole-brain” environment when it comes to modeling human diseases, such as is the case of neurodegenerative disorders. Although now, with the advent of pluripotent stem cells and the ability to create minibrains in a dish, this is changing. With this review, we aim to wade through the recent alpha-synuclein literature to discuss how different cell culture setups (immortalized cell lines, primary neurons, human induced pluripotent stem cells (hiPSCs), blood–brain barrier models, and brain organoids) can help us understand aggregation pathology in Parkinson’s and other synucleinopathies. Full article
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14 pages, 4069 KiB  
Article
Skin, Liver, and Kidney Interactions Contribute to Skin Dryness in Aging KK-Ay/Tajcl Mice
by Keiichi Hiramoto, Kenji Goto, Shota Tanaka, Tsuneki Horikawa and Kazuya Ooi
Biomedicines 2022, 10(10), 2648; https://doi.org/10.3390/biomedicines10102648 - 20 Oct 2022
Cited by 6 | Viewed by 1537
Abstract
Type 2 diabetes is a lifestyle-related disease that affects people worldwide and is especially prevalent in the elderly. Many elderly people with diabetes also complain of dry skin; however, the relationship between aging and dry skin in type 2 diabetes is unknown. The [...] Read more.
Type 2 diabetes is a lifestyle-related disease that affects people worldwide and is especially prevalent in the elderly. Many elderly people with diabetes also complain of dry skin; however, the relationship between aging and dry skin in type 2 diabetes is unknown. The purpose of this study was to examine the interaction between aging and dry skin using the specific pathogen-free KK-Ay/TaJcl type 2 diabetes mouse model. Skin dryness in this model increases with age and was evaluated at 10, 27, 40, and 50 weeks. We observed increased mast cell expression, increased histamine and matrix metalloproteinase-1 levels, and decreased collagen expression in the skin of aging KK-Ay/TaJcl mice. In addition, the increased expression of angiopoietin 2, interleukin-6, tumor necrosis factor-α, and endostatin in the blood indicated kidney damage in this model. Aging KK-Ay/TaJcl mice also showed fatty liver pathology, which led to increased reactive oxygen species in the blood and liver, as well as the increased expression of M1 macrophages in the liver. These results showed that dry skin is associated with skin, kidney, and liver interactions in an aging type 2 diabetes mouse model. Full article
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22 pages, 3856 KiB  
Article
The Transcriptional Regulator Prdm1 Is Essential for the Early Development of the Sensory Whisker Follicle and Is Linked to the Beta-Catenin First Dermal Signal
by Pierluigi G. Manti, Fabrice Darbellay, Marion Leleu, Aisling Y. Coughlan, Bernard Moret, Julien Cuennet, Frederic Droux, Magali Stoudmann, Gian-Filippo Mancini, Agnès Hautier, Jessica Sordet-Dessimoz, Stephane D. Vincent, Giuseppe Testa, Giulio Cossu and Yann Barrandon
Biomedicines 2022, 10(10), 2647; https://doi.org/10.3390/biomedicines10102647 - 20 Oct 2022
Cited by 1 | Viewed by 4090
Abstract
Prdm1 mutant mice are one of the rare mutant strains that do not develop whisker hair follicles while still displaying a pelage. Here, we show that Prdm1 is expressed at the earliest stage of whisker development in clusters of mesenchymal cells before placode [...] Read more.
Prdm1 mutant mice are one of the rare mutant strains that do not develop whisker hair follicles while still displaying a pelage. Here, we show that Prdm1 is expressed at the earliest stage of whisker development in clusters of mesenchymal cells before placode formation. Its conditional knockout in the murine soma leads to the loss of expression of Bmp2, Shh, Bmp4, Krt17, Edar, and Gli1, though leaving the β-catenin-driven first dermal signal intact. Furthermore, we show that Prdm1 expressing cells not only act as a signaling center but also as a multipotent progenitor population contributing to the several lineages of the adult whisker. We confirm by genetic ablation experiments that the absence of macro vibrissae reverberates on the organization of nerve wiring in the mystacial pads and leads to the reorganization of the barrel cortex. We demonstrate that Lef1 acts upstream of Prdm1 and identify a primate-specific deletion of a Lef1 enhancer named Leaf. This loss may have been significant in the evolutionary process, leading to the progressive defunctionalization and disappearance of vibrissae in primates. Full article
(This article belongs to the Section Molecular Genetics and Genetic Diseases)
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14 pages, 982 KiB  
Article
Bacterial Pulmonary Co-Infections on ICU Admission: Comparison in Patients with SARS-CoV-2 and Influenza Acute Respiratory Failure: A Multicentre Cohort Study
by Grégoire Delhommeau, Niccolò Buetti, Mathilde Neuville, Shidasp Siami, Yves Cohen, Virginie Laurent, Bruno Mourvillier, Jean Reignier, Dany Goldgran-Toledano, Carole Schwebel, Stéphane Ruckly, Etienne de Montmollin, Bertrand Souweine, Jean-François Timsit and Claire Dupuis
Biomedicines 2022, 10(10), 2646; https://doi.org/10.3390/biomedicines10102646 - 20 Oct 2022
Cited by 3 | Viewed by 1414
Abstract
Background: Few data are available on the impact of bacterial pulmonary co-infection (RespCoBact) during COVID-19 (CovRespCoBact). The aim of this study was to compare the prognosis of patients admitted to an ICU for influenza pneumonia and for SARS-CoV-2 pneumonia with and without RespCoBact. [...] Read more.
Background: Few data are available on the impact of bacterial pulmonary co-infection (RespCoBact) during COVID-19 (CovRespCoBact). The aim of this study was to compare the prognosis of patients admitted to an ICU for influenza pneumonia and for SARS-CoV-2 pneumonia with and without RespCoBact. Methods: This was a multicentre (n = 11) observational study using the Outcomerea© database. Since 2008, all patients admitted with influenza pneumonia or SARS-CoV-2 pneumonia and discharged before 30 June 2021 were included. Risk factors for day-60 death and for ventilator-associated-pneumonia (VAP) in patients with influenza pneumonia or SARS-CoV-2 pneumonia with or without RespCoBact were determined. Results: Of the 1349 patients included, 157 were admitted for influenza and 1192 for SARS-CoV-2. Compared with the influenza patients, those with SARS-CoV-2 had lower severity scores, were more often under high-flow nasal cannula, were less often under invasive mechanical ventilation, and had less RespCoBact (8.2% for SARS-CoV-2 versus 24.8% for influenza). Day-60 death was significantly higher in patients with SARS-CoV-2 pneumonia with no increased risk of mortality with RespCoBact. Patients with influenza pneumonia and those with SARS-CoV-2 pneumonia had no increased risk of VAP with RespCoBact. Conclusions: SARS-CoV-2 pneumonia was associated with an increased risk of mortality compared with Influenza pneumonia. Bacterial pulmonary co-infections on admission were not associated with patient survival rates nor with an increased risk of VAP. Full article
(This article belongs to the Special Issue Issues and Challenges in Ventilator-Associated Pneumonia in COVID-19)
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16 pages, 5969 KiB  
Article
Atomic Force Microscopy Study of the Temperature and Storage Duration Dependencies of Horseradish Peroxidase Oligomeric State
by Irina A. Ivanova, Maria O. Ershova, Ivan D. Shumov, Anastasia A. Valueva, Yuri D. Ivanov and Tatyana O. Pleshakova
Biomedicines 2022, 10(10), 2645; https://doi.org/10.3390/biomedicines10102645 - 20 Oct 2022
Cited by 2 | Viewed by 1219
Abstract
This paper presents an investigation of the temperature dependence of the oligomeric state of the horseradish peroxidase (HRP) enzyme on the temperature of its solution, and on the solution storage time, at the single-molecule level. Atomic force microscopy has been employed to determine [...] Read more.
This paper presents an investigation of the temperature dependence of the oligomeric state of the horseradish peroxidase (HRP) enzyme on the temperature of its solution, and on the solution storage time, at the single-molecule level. Atomic force microscopy has been employed to determine how the temperature and the storage time of the HRP solution influence its aggregation upon direct adsorption of the enzyme from the solution onto bare mica substrates. In parallel, spectrophotometric measurements have been performed in order to estimate whether the HRP enzymatic activity changes over time upon the storage of the enzyme solution. The temperature dependence of the HRP oligomeric state has been studied within a broad (15–40 °C) temperature range. It has been demonstrated that the storage of the HRP solution for 14 days does not have any considerable effect on the oligomeric state of the enzyme, neither does it affect its activity. At longer storage times, AFM has allowed us to reveal a tendency of HRP to oligomerization during the storage of its buffered solution, while the enzymatic activity remains virtually unchanged even after a 1-month-long storage. By AFM, it has been revealed that after the incubation of a mica substrate in the HRP solution at various temperatures, the content of the mica-adsorbed oligomers increases insignificantly owing to a high-temperature stability of the enzyme. Full article
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21 pages, 3986 KiB  
Article
Neuroprotective Effects of gH625-lipoPACAP in an In Vitro Fluid Dynamic Model of Parkinson’s Disease
by Teresa Barra, Annarita Falanga, Rosa Bellavita, Jessica Pisano, Vincenza Laforgia, Marina Prisco, Stefania Galdiero and Salvatore Valiante
Biomedicines 2022, 10(10), 2644; https://doi.org/10.3390/biomedicines10102644 - 20 Oct 2022
Cited by 2 | Viewed by 1537
Abstract
Parkinson’s disease (PD) is an aggressive and devastating age-related disorder. Although the causes are still unclear, several factors, including genetic and environmental, are involved. Except for symptomatic drugs, there are not, to date, any real cures for PD. For this purpose, it is [...] Read more.
Parkinson’s disease (PD) is an aggressive and devastating age-related disorder. Although the causes are still unclear, several factors, including genetic and environmental, are involved. Except for symptomatic drugs, there are not, to date, any real cures for PD. For this purpose, it is necessary develop a model to better study this disease. Neuroblastoma cell line, SH-SY5Y, differentiated with retinoic acid represents a good in vitro model to explore PD, since it maintains growth cells to differentiated neurons. In the present study, SH-SY5Y cells were treated with 1-methyl-4-phenylpyridinium (MPP+), a neurotoxin that induces Parkinsonism, and the neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP), delivered by functionalized liposomes in a blood–brain barrier fluid dynamic model, were evaluated. We demonstrated PACAP neuroprotective effects when delivered by gH625-liposome on MPP+-damaged SH-SY5Y spheroids. Full article
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13 pages, 2579 KiB  
Article
Porphyromonas gingivalis Outer Membrane Vesicles Stimulate Gingival Epithelial Cells to Induce Pro-Inflammatory Cytokines via the MAPK and STING Pathways
by Yuta Uemura, Yuka Hiroshima, Ayano Tada, Keiji Murakami, Kaya Yoshida, Yuji Inagaki, Tomomi Kuwahara, Akikazu Murakami, Hideki Fujii and Hiromichi Yumoto
Biomedicines 2022, 10(10), 2643; https://doi.org/10.3390/biomedicines10102643 - 20 Oct 2022
Cited by 10 | Viewed by 2445
Abstract
Porphyromonas gingivalis (Pg) is a keystone pathogen associated with chronic periodontitis and produces outer membrane vesicles (OMVs) that contain lipopolysaccharide (LPS), gingipains, and pathogen-derived DNA and RNA. Pg-OMVs are involved in the pathogenesis of periodontitis. Pg-OMV-activated pathways that induce [...] Read more.
Porphyromonas gingivalis (Pg) is a keystone pathogen associated with chronic periodontitis and produces outer membrane vesicles (OMVs) that contain lipopolysaccharide (LPS), gingipains, and pathogen-derived DNA and RNA. Pg-OMVs are involved in the pathogenesis of periodontitis. Pg-OMV-activated pathways that induce the production of the pro-inflammatory cytokines, interleukin (IL)-6, and IL-8 in the human gingival epithelial cell line, OBA-9, were investigated. The role of mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB in levels of Pg-OMV-induced pro-inflammatory cytokines was investigated using Western blot analysis and specific pathway inhibitors. Pg-OMVs induced IL-6 and IL-8 production via the extracellular signal-regulated kinase (Erk) 1/2, c-Jun N-terminal kinase (JNK), p38 MAPK, and NF-κB signaling pathways in OBA-9 cells. In addition, the stimulator of interferon genes (STING), an essential innate immune signaling molecule, was triggered by a cytosolic pathogen DNA. Pg-OMV-induced IL-6 and IL-8 mRNA expression and production were significantly suppressed by STING-specific small interfering RNA. Taken together, these results demonstrated that Pg-OMV-activated Erk1/2, JNK, p38 MAPK, STING, and NF-κB signaling pathways resulting in increased IL-6 and IL-8 expression in human gingival epithelial cells. These results suggest that Pg-OMVs may play important roles in periodontitis exacerbation by stimulating various pathways. Full article
(This article belongs to the Special Issue Immune Response to Viruses and Bacteria)
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19 pages, 1922 KiB  
Review
New Insights into Adiponectin and Leptin Roles in Chronic Kidney Disease
by Susana Coimbra, Susana Rocha, Maria João Valente, Cristina Catarino, Elsa Bronze-da-Rocha, Luís Belo and Alice Santos-Silva
Biomedicines 2022, 10(10), 2642; https://doi.org/10.3390/biomedicines10102642 - 20 Oct 2022
Cited by 6 | Viewed by 1872
Abstract
Chronic kidney disease (CKD) is commonly associated with a high burden of comorbidities and poor clinical outcomes. Malnutrition–inflammation–atherosclerosis syndrome is common in the more severe stages of CKD, suggesting a close interplay for these three comorbid conditions. Both malnutrition and obesity are associated [...] Read more.
Chronic kidney disease (CKD) is commonly associated with a high burden of comorbidities and poor clinical outcomes. Malnutrition–inflammation–atherosclerosis syndrome is common in the more severe stages of CKD, suggesting a close interplay for these three comorbid conditions. Both malnutrition and obesity are associated with a disturbed adipokine profile and inflammation, contributing to a higher risk of cardiovascular disease (CVD) events. Adiponectin and leptin have important roles in carbohydrate and lipid metabolism, and in the inflammatory process. The effects of adiponectin and leptin alterations in CKD, which are usually increased, and their association with the different comorbidities found in CKD, will be focused on to understand their crosstalk with the risk of CVD events. Nonetheless, although adiponectin and leptin contribute to a higher risk of CVD events, further studies are warranted to fully clarify their roles, especially when different comorbidities exist. Full article
(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Recent Advances on Adipokines)
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13 pages, 574 KiB  
Article
Differences in the Pro/Antioxidative Status and Cellular Stress Response in Elderly Women after 6 Weeks of Exercise Training Supported by 1000 mg of Vitamin C Supplementation
by Małgorzata Żychowska, Ewa Sadowska-Krępa, Elisabetta Damiani, Luca Tiano, Ewa Ziemann, Alicja Nowak-Zaleska, Patrycja Lipińska, Anna Piotrowska, Olga Czerwińska-Ledwig, Wanda Pilch and Jędrzej Antosiewicz
Biomedicines 2022, 10(10), 2641; https://doi.org/10.3390/biomedicines10102641 - 20 Oct 2022
Viewed by 1930
Abstract
Vitamin C supplementation and exercise influence pro/antioxidative status and the cellular stress response. We tested the effects of exercise training for 6 weeks, supported by 1000 mg of vitamin C supplementation in elderly women. Thirty-six women were divided into two groups: a control [...] Read more.
Vitamin C supplementation and exercise influence pro/antioxidative status and the cellular stress response. We tested the effects of exercise training for 6 weeks, supported by 1000 mg of vitamin C supplementation in elderly women. Thirty-six women were divided into two groups: a control group (CON) (n = 18, age 69.4 ± 6.4 years, 70.4 ±10.4 kg body mass) and a supplemented group (SUPP) (n = 18, aged 67.7 ± 5.6 years, body mass 71.46 ± 5.39 kg). Blood samples were taken twice (at baseline and 24 h after the whole period of training), in order to determine vitamin C concentration, the total oxidative status/capacity (TOS/TOC), total antioxidant status/capacity (TAS/TAC), and gene expression associated with cellular stress response: encoding heat shock factor (HSF1), heat shock protein 70 (HSPA1A), heat shock protein 27 (HSPB1), and tumor necrosis factor alpha (TNF-α). We observed a significant increase in TOS/TOC, TAS/TAC, and prooxidant/antioxidant balance in the SUPP group. There was a significant decrease in HSPA1A in the CON group and a different tendency in the expression of HSF1 and TNF-α between groups. In conclusion, vitamin C supplementation enhanced the pro-oxidation in elderly women with a normal plasma vitamin C concentration and influenced minor changes in training adaptation gene expression. Full article
(This article belongs to the Special Issue The Role of Vitamins in Human Health and Disease)
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12 pages, 1741 KiB  
Article
Suppressive Role of ACVR1/ALK2 in Basal and TGFβ1-Induced Cell Migration in Pancreatic Ductal Adenocarcinoma Cells and Identification of a Self-Perpetuating Autoregulatory Loop Involving the Small GTPase RAC1b
by Hendrik Ungefroren, Rüdiger Braun, Olha Lapshyna, Björn Konukiewitz, Ulrich F. Wellner, Hendrik Lehnert and Jens-Uwe Marquardt
Biomedicines 2022, 10(10), 2640; https://doi.org/10.3390/biomedicines10102640 - 20 Oct 2022
Cited by 3 | Viewed by 1329
Abstract
Pancreatic ductal adenocarcinoma (PDAC) cells are known for their high invasive/metastatic potential, which is regulated in part by the transforming growth factor β1 (TGFβ1). The involvement of at least two type I receptors, ALK5 and ALK2, that transmit downstream signals of the TGFβ [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) cells are known for their high invasive/metastatic potential, which is regulated in part by the transforming growth factor β1 (TGFβ1). The involvement of at least two type I receptors, ALK5 and ALK2, that transmit downstream signals of the TGFβ via different Smad proteins, SMAD2/3 and SMAD1/5, respectively, poses the issue of their relative contribution in regulating cell motility. Real-time cell migration assays revealed that the selective inhibition of ALK2 by RNAi or dominant-negative interference with a kinase-dead mutant (ALK2-K233R) strongly enhanced the cells’ migratory activity in the absence or presence of TGFβ1 stimulation. Ectopic ALK2-K233R expression was associated with an increase in the protein levels of RAC1 and its alternatively spliced isoform, RAC1b, both of which are implicated in driving cell migration and invasion. Conversely, the RNAi-mediated knockdown or CRISPR/Cas9-mediated knockout of RAC1b resulted in the upregulation of the expression of ALK2, but not that of the related BMP type I receptors, ALK3 or ALK6, and elevated the phosphorylation of SMAD1/5. PDAC is a heterogeneous disease encompassing tumors with different histomorphological subtypes, ranging from epithelial/classical to extremely mesenchymal. Upon treatment of various established and primary PDAC cell lines representing these subtypes with the ALK2 inhibitor, LDN-193189, well-differentiated, epithelial cell lines responded with a much stronger increase in the basal and TGFβ1-dependent migratory activity than poorly differentiated, mesenchymal ones. These data show that (i) ALK2 inhibits migration by suppressing RAC1/RAC1b proteins, (ii) ALK2 and RAC1b act together in a self-perpetuating the autoregulatory negative feedback loop to mutually control their expression, and (iii) the ALK2 antimigratory function appears to be particularly crucial in protecting epithelial subtype cells from becoming invasive, both spontaneously and in a TGFβ-rich tumor microenvironment. Full article
(This article belongs to the Special Issue Advanced Research in Cell Motility 2.0)
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