Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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16 pages, 2565 KiB  
Article
Distinct Subtyping of Successful Weaning from Acute Kidney Injury Requiring Renal Replacement Therapy by Consensus Clustering in Critically Ill Patients
by Heng-Chih Pan, Chiao-Yin Sun, Thomas Tao-Min Huang, Chun-Te Huang, Chun-Hao Tsao, Chien-Heng Lai, Yung-Ming Chen and Vin-Cent Wu
Biomedicines 2022, 10(7), 1628; https://doi.org/10.3390/biomedicines10071628 - 07 Jul 2022
Cited by 3 | Viewed by 1425
Abstract
Background: Clinical decisions regarding the appropriate timing of weaning off renal replacement therapy (RRT) in critically ill patients are complex and multifactorial. The aim of the current study was to identify which critical patients with acute kidney injury (AKI) may be more likely [...] Read more.
Background: Clinical decisions regarding the appropriate timing of weaning off renal replacement therapy (RRT) in critically ill patients are complex and multifactorial. The aim of the current study was to identify which critical patients with acute kidney injury (AKI) may be more likely to be successfully weaned off RRT using consensus cluster analysis. Methods: In this study, critically ill patients who received RRT at three multicenter referral hospitals at several timepoints from August 2016 to July 2018 were enrolled. An unsupervised consensus clustering algorithm was used to identify distinct phenotypes. The outcomes of interest were the ability to wean off RTT and 90-day mortality. Results: A total of 124 patients with AKI requiring RRT (AKI-RRT) were enrolled. The 90-day mortality rate was 30.7% (38/124), and 49.2% (61/124) of the patients were successfully weaned off RRT for over 90 days. The consensus clustering algorithm identified three clusters from a total of 45 features. The three clusters had distinct features and could be separated according to the combination of urinary neutrophil gelatinase-associated lipocalin to creatinine ratio (uNGAL/Cr), Sequential Organ Failure Assessment (SOFA) score, and estimated glomerular filtration rate at the time of weaning off RRT. uNGAL/Cr (hazard ratio [HR] 2.43, 95% confidence interval [CI]: 1.36–4.33) and clustering phenotype (cluster 1 vs. 3, HR 2.7, 95% CI: 1.11–6.57; cluster 2 vs. 3, HR 44.5, 95% CI: 11.92–166.39) could predict 90-day mortality or re-dialysis. Conclusions: Almost half of the critical patients with AKI-RRT could wean off dialysis for over 90 days. Urinary NGAL/Cr and distinct clustering phenotypes could predict 90-day mortality or re-dialysis. Full article
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15 pages, 3498 KiB  
Article
Solubility-Aware Protein Binding Peptide Design Using AlphaFold
by Takatsugu Kosugi and Masahito Ohue
Biomedicines 2022, 10(7), 1626; https://doi.org/10.3390/biomedicines10071626 - 07 Jul 2022
Cited by 7 | Viewed by 4579
Abstract
New protein–protein interactions (PPIs) are identified, but PPIs have different physicochemical properties compared with conventional targets, making it difficult to use small molecules. Peptides offer a new modality to target PPIs, but designing appropriate peptide sequences by computation is challenging. Recently, AlphaFold and [...] Read more.
New protein–protein interactions (PPIs) are identified, but PPIs have different physicochemical properties compared with conventional targets, making it difficult to use small molecules. Peptides offer a new modality to target PPIs, but designing appropriate peptide sequences by computation is challenging. Recently, AlphaFold and RoseTTAFold have made it possible to predict protein structures from amino acid sequences with ultra-high accuracy, enabling de novo protein design. We designed peptides likely to have PPI as the target protein using the “binder hallucination” protocol of AfDesign, a de novo protein design method using AlphaFold. However, the solubility of the peptides tended to be low. Therefore, we designed a solubility loss function using solubility indices for amino acids and developed a solubility-aware AfDesign binder hallucination protocol. The peptide solubility in sequences designed using the new protocol increased with the weight of the solubility loss function; moreover, they captured the characteristics of the solubility indices. Moreover, the new protocol sequences tended to have higher affinity than random or single residue substitution sequences when evaluated by docking binding affinity. Our approach shows that it is possible to design peptide sequences that can bind to the interface of PPI while controlling solubility. Full article
(This article belongs to the Special Issue Peptide-Based Drug Development)
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14 pages, 3477 KiB  
Article
Tuning the Degradation Rate of Alginate-Based Bioinks for Bioprinting Functional Cartilage Tissue
by Xavier Barceló, Kian F. Eichholz, Orquidea Garcia and Daniel J. Kelly
Biomedicines 2022, 10(7), 1621; https://doi.org/10.3390/biomedicines10071621 - 07 Jul 2022
Cited by 18 | Viewed by 2801
Abstract
Negative foreign body responses following the in vivo implantation of bioprinted implants motivate the development of novel bioinks which can rapidly degrade with the formation of functional tissue, whilst still maintaining desired shapes post-printing. Here, we investigated the oxidation of alginate as a [...] Read more.
Negative foreign body responses following the in vivo implantation of bioprinted implants motivate the development of novel bioinks which can rapidly degrade with the formation of functional tissue, whilst still maintaining desired shapes post-printing. Here, we investigated the oxidation of alginate as a means to modify the degradation rate of alginate-based bioinks for cartilage tissue engineering applications. Raw and partially oxidized alginate (OA) were combined at different ratios (Alginate:OA at 100:0; 75:25; 50:50; 25:75; 0:100) to provide finer control over the rate of bioink degradation. These alginate blends were then combined with a temporary viscosity modifier (gelatin) to produce a range of degradable bioinks with rheological properties suitable for extrusion bioprinting. The rate of degradation was found to be highly dependent on the OA content of the bioink. Despite this high mass loss, the initially printed geometry was maintained throughout a 4 week in vitro culture period for all bioink blends except the 0:100 group. All bioink blends also supported robust chondrogenic differentiation of mesenchymal stem/stromal cells (MSCs), resulting in the development of a hyaline-like tissue that was rich in type II collagen and negative for calcific deposits. Such tuneable inks offer numerous benefits to the field of 3D bioprinting, from providing space in a controllable manner for new extracellular matrix deposition, to alleviating concerns associated with a foreign body response to printed material inks in vivo. Full article
(This article belongs to the Special Issue Biomedical Properties of Hydrogels)
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19 pages, 1133 KiB  
Review
Activation of the Mitochondrial Unfolded Protein Response: A New Therapeutic Target?
by Juan M. Suárez-Rivero, Carmen J. Pastor-Maldonado, Suleva Povea-Cabello, Mónica Álvarez-Córdoba, Irene Villalón-García, Marta Talaverón-Rey, Alejandra Suárez-Carrillo, Manuel Munuera-Cabeza, Diana Reche-López, Paula Cilleros-Holgado, Rocío Piñero-Pérez and José A. Sánchez-Alcázar
Biomedicines 2022, 10(7), 1611; https://doi.org/10.3390/biomedicines10071611 - 06 Jul 2022
Cited by 16 | Viewed by 3664
Abstract
Mitochondrial dysfunction is a key hub that is common to many diseases. Mitochondria’s role in energy production, calcium homeostasis, and ROS balance makes them essential for cell survival and fitness. However, there are no effective treatments for most mitochondrial and related diseases to [...] Read more.
Mitochondrial dysfunction is a key hub that is common to many diseases. Mitochondria’s role in energy production, calcium homeostasis, and ROS balance makes them essential for cell survival and fitness. However, there are no effective treatments for most mitochondrial and related diseases to this day. Therefore, new therapeutic approaches, such as activation of the mitochondrial unfolded protein response (UPRmt), are being examined. UPRmt englobes several compensation processes related to proteostasis and antioxidant mechanisms. UPRmt activation, through an hormetic response, promotes cell homeostasis and improves lifespan and disease conditions in biological models of neurodegenerative diseases, cardiopathies, and mitochondrial diseases. Although UPRmt activation is a promising therapeutic option for many conditions, its overactivation could lead to non-desired side effects, such as increased heteroplasmy of mitochondrial DNA mutations or cancer progression in oncologic patients. In this review, we present the most recent UPRmt activation therapeutic strategies, UPRmt’s role in diseases, and its possible negative consequences in particular pathological conditions. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease 2.0)
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19 pages, 2206 KiB  
Review
Brain Cancer Chemotherapy through a Delivery System across the Blood-Brain Barrier into the Brain Based on Receptor-Mediated Transcytosis Using Monoclonal Antibody Conjugates
by Toshihiko Tashima
Biomedicines 2022, 10(7), 1597; https://doi.org/10.3390/biomedicines10071597 - 05 Jul 2022
Cited by 13 | Viewed by 4033
Abstract
Advances in pharmacotherapy have brought extraordinary benefits to humanity. However, unmet medical needs in patients remain, particularly in the treatment of central nervous system (CNS) diseases and cancers. CNS drug delivery into the brain across the endothelium is difficult due to the blood-brain [...] Read more.
Advances in pharmacotherapy have brought extraordinary benefits to humanity. However, unmet medical needs in patients remain, particularly in the treatment of central nervous system (CNS) diseases and cancers. CNS drug delivery into the brain across the endothelium is difficult due to the blood-brain barrier (BBB), which is composed mainly of tight junctions and efflux transporters, such as multiple drug resistance 1 (MDR1) (P-glycoprotein). On the other hand, the development of anti-cancer drugs is a challenging task due to their frequent off-target side effects and the complicated mechanisms of cancer pathogenesis and progression. Brain cancer treatment options are surgery, radiation therapy, and chemotherapy. It is difficult to remove all tumor cells, even by surgical removal after a craniotomy. Accordingly, innovative brain cancer drugs are needed. Currently, antibody (Ab) drugs that show high therapeutic effects are often used clinically. Furthermore, antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan, an anti-HER2 (human epidermal receptor 2) ADC with low-molecular cancer drugs through the suitable linker, have been developed. In the case of trastuzumab deruxtecan, it is internalized into cancer cells across the membrane via receptor-mediated endocytosis. Moreover, it is reported that drug delivery into the brain across the BBB was carried out via receptor-mediated transcytosis (RMT), using anti-receptor Abs as a vector against the transferrin receptor (TfR) or insulin receptor (InsR). Thus, anti-TfR ADCs with cancer drugs are promising brain cancer agents due to their precise distribution and low side effects. In this review, I introduce the implementations and potential of brain cancer drug delivery into the brain across the BBB, based on RMT using ADCs. Full article
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19 pages, 4954 KiB  
Article
N-3 PUFA Ameliorates the Gut Microbiota, Bile Acid Profiles, and Neuropsychiatric Behaviours in a Rat Model of Geriatric Depression
by Te-Hsuan Tung, Yang-Ching Chen, Ya-Tin Lin and Shih-Yi Huang
Biomedicines 2022, 10(7), 1594; https://doi.org/10.3390/biomedicines10071594 - 04 Jul 2022
Cited by 8 | Viewed by 2368
Abstract
The brain−gut−microbiome (BGM) axis affects host bioinformation. N-3 polyunsaturated fatty acids (PUFAs) alleviate cognitive impairment and depression in older adults. This study investigated altered microbiota−bile acid signalling as a potential mechanism linking fish oil-induced gut changes in microbiota to alleviate psychological symptoms. Sprague [...] Read more.
The brain−gut−microbiome (BGM) axis affects host bioinformation. N-3 polyunsaturated fatty acids (PUFAs) alleviate cognitive impairment and depression in older adults. This study investigated altered microbiota−bile acid signalling as a potential mechanism linking fish oil-induced gut changes in microbiota to alleviate psychological symptoms. Sprague Dawley rats were fed a fish oil diet and administered D-galactose combined with chronic unpredictable mild stress (CUMS) to simulate geriatric depression. The cognitive function, psychological symptoms, microbiota compositions, and faecal bile acid profiles of the rats were assessed thereafter. A correlation analysis was conducted to determine whether the fish oil-induced alteration of the rats’ microbiota and bile acid profiles affected the rats’ behaviour. D-galactose and CUMS resulted in lower concentrations of Firmicutes, significantly altered bile acid profiles, and abnormal neurobehaviours. Fish oil intake alleviated the rats’ emotional symptoms and increased the abundance of Bacteroidetes, Prevotellaceae, Marinifilaceae, and Bacteroidesuniformis. It also elevated the concentrations of primary bile acids and taurine-conjugated bile acids in the rats’ faeces. The rats’ taurine-conjugated bile acid levels were significantly correlated with their behavioural outcomes. In short, fish oil intake may alleviate psychological symptoms by altering the microbial metabolites involved in the BGM axis, especially in the conjugation of bile acids. Full article
(This article belongs to the Special Issue The Lipid Metabolism in Health and Diseases)
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20 pages, 1358 KiB  
Article
Novel Phenotyping for Acute Heart Failure—Unsupervised Machine Learning-Based Approach
by Szymon Urban, Mikołaj Błaziak, Maksym Jura, Gracjan Iwanek, Agata Zdanowicz, Mateusz Guzik, Artur Borkowski, Piotr Gajewski, Jan Biegus, Agnieszka Siennicka, Maciej Pondel, Petr Berka, Piotr Ponikowski and Robert Zymliński
Biomedicines 2022, 10(7), 1514; https://doi.org/10.3390/biomedicines10071514 - 27 Jun 2022
Cited by 8 | Viewed by 3209
Abstract
Acute heart failure (AHF) is a life-threatening, heterogeneous disease requiring urgent diagnosis and treatment. The clinical severity and medical procedures differ according to a complex interplay between the deterioration cause, underlying cardiac substrate, and comorbidities. This study aimed to analyze the natural phenotypic [...] Read more.
Acute heart failure (AHF) is a life-threatening, heterogeneous disease requiring urgent diagnosis and treatment. The clinical severity and medical procedures differ according to a complex interplay between the deterioration cause, underlying cardiac substrate, and comorbidities. This study aimed to analyze the natural phenotypic heterogeneity of the AHF population and evaluate the possibilities offered by clustering (unsupervised machine-learning technique) in a medical data assessment. We evaluated data from 381 AHF patients. Sixty-three clinical and biochemical features were assessed at the admission of the patients and were included in the analysis after the preprocessing. The K-medoids algorithm was implemented to create the clusters, and optimization, based on the Davies-Bouldin index, was used. The clustering was performed while blinded to the outcome. The outcome associations were evaluated using the Kaplan-Meier curves and Cox proportional-hazards regressions. The algorithm distinguished six clusters that differed significantly in 58 variables concerning i.e., etiology, clinical status, comorbidities, laboratory parameters and lifestyle factors. The clusters differed in terms of the one-year mortality (p = 0.002). Using the clustering techniques, we extracted six phenotypes from AHF patients with distinct clinical characteristics and outcomes. Our results can be valuable for future trial constructions and customized treatment. Full article
(This article belongs to the Special Issue Advances in Therapy for Heart Failure)
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15 pages, 4918 KiB  
Article
Discovering the Effects of Fisetin on NF-κB/NLRP-3/NRF-2 Molecular Pathways in a Mouse Model of Vascular Dementia Induced by Repeated Bilateral Carotid Occlusion
by Marika Cordaro, Ramona D’Amico, Roberta Fusco, Alessio Filippo Peritore, Tiziana Genovese, Livia Interdonato, Gianluca Franco, Alessia Arangia, Enrico Gugliandolo, Rosalia Crupi, Rosalba Siracusa, Rosanna Di Paola, Salvatore Cuzzocrea and Daniela Impellizzeri
Biomedicines 2022, 10(6), 1448; https://doi.org/10.3390/biomedicines10061448 - 19 Jun 2022
Cited by 15 | Viewed by 3085
Abstract
Vascular dementia (VaD) is the second leading cause of dementia. The majority of VaD patients have cognitive abnormalities, which are caused by cerebral hypoperfusion-induced ischemia, endothelial dysfunction, oxidative stress, and neuroinflammation. Natural products are receiving increasing attention for the treatment of neuroinflammatory diseases. [...] Read more.
Vascular dementia (VaD) is the second leading cause of dementia. The majority of VaD patients have cognitive abnormalities, which are caused by cerebral hypoperfusion-induced ischemia, endothelial dysfunction, oxidative stress, and neuroinflammation. Natural products are receiving increasing attention for the treatment of neuroinflammatory diseases. The aim of this study was to investigate the molecular pathways underlying the protective effects of fisetin, a flavonoid present in many fruits and vegetables, in a mouse model of VaD induced by repeated ischemia-reperfusion (IR) of the total bilateral carotid artery. Here, we found that VaD caused brain injury, lipid peroxidation, and neuronal death in the hippocampus, as well as astrocyte and microglial activation, and reduced BDNF neurotrophic factor expression together with behavioral alterations. In addition, VaD induced the activation of inflammasome components (NLRP-3, ASC, and caspase 1), and their downstream products (IL-1β and IL-18) release and promote activation of apoptotic cell death. Fisetin attenuated histological injury, malondialdehyde levels, inflammasome pathway activation, apoptosis, as well as increased BDNF expression, reduced astrocyte, microglial activation, and cognitive deficits. In conclusion, the protective effects of fisetin could be due to the inhibition of the ROS-induced activation of NF-κB/NLRP3 inflammasome together with the activation of antioxidant Nrf2/HO-1, suggesting a possible crosstalk between these molecular pathways. Full article
(This article belongs to the Special Issue Molecular Pathology and Biomarkers of Neurodegenerative Diseases)
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18 pages, 3616 KiB  
Article
Isoliquiritigenin Inhibits Gastric Cancer Stemness, Modulates Tumor Microenvironment, and Suppresses Tumor Growth through Glucose-Regulated Protein 78 Downregulation
by Chien-Hsing Lee, Hsin-Yi Tsai, Chun-Lin Chen, Jen-Lung Chen, Chao-Chun Lu, Yi-Ping Fang, Deng-Chyang Wu, Yaw-Bin Huang and Ming-Wei Lin
Biomedicines 2022, 10(6), 1350; https://doi.org/10.3390/biomedicines10061350 - 08 Jun 2022
Cited by 16 | Viewed by 2859
Abstract
Chemotherapy is the treatment of choice for gastric cancer; however, the currently available therapeutic drugs for treatment have limited efficacy. Cancer stemness and the tumor microenvironment may play crucial roles in tumor growth and chemoresistance. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum [...] Read more.
Chemotherapy is the treatment of choice for gastric cancer; however, the currently available therapeutic drugs for treatment have limited efficacy. Cancer stemness and the tumor microenvironment may play crucial roles in tumor growth and chemoresistance. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum chaperone facilitating protein folding and cell homeostasis during stress and may participate in chemoresistance. Isoliquiritigenin (ISL) is a bioactive flavonoid found in licorice. In this study, we demonstrated the role of GRP78 in gastric cancer stemness and evaluated GRP78-mediated stemness inhibition, tumor microenvironment regulation, and chemosensitivity promotion by ISL. ISL not only suppressed GRP78-mediated gastric cancer stem cell–like characteristics, stemness-related protein expression, and cancer-associated fibroblast activation but also gastric tumor growth in xenograft animal studies. The findings indicated that ISL is a promising candidate for clinical use in combination chemotherapy. Full article
(This article belongs to the Special Issue Tumor Microenvironment Regulation and Anti-cancer Natural Products)
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20 pages, 1986 KiB  
Article
Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis
by Débora Lanznaster, Clément Bruno, Jérôme Bourgeais, Patrick Emond, Ilyess Zemmoura, Antoine Lefèvre, Pascal Reynier, Sébastien Eymieux, Emmanuelle Blanchard, Patrick Vourc'h, Christian R. Andres, Salah Eddine Bakkouche, Olivier Herault, Luc Favard, Philippe Corcia and Hélène Blasco
Biomedicines 2022, 10(6), 1307; https://doi.org/10.3390/biomedicines10061307 - 02 Jun 2022
Cited by 7 | Viewed by 4477
Abstract
Diverse biomarkers and pathological alterations have been found in muscle of patients with Amyotrophic lateral sclerosis (ALS), but the relation between such alterations and dysfunction in energetic metabolism remains to be investigated. We established the metabolome of muscle and serum of ALS patients [...] Read more.
Diverse biomarkers and pathological alterations have been found in muscle of patients with Amyotrophic lateral sclerosis (ALS), but the relation between such alterations and dysfunction in energetic metabolism remains to be investigated. We established the metabolome of muscle and serum of ALS patients and correlated these findings with the clinical status and pathological alterations observed in the muscle. We obtained data from 20 controls and 17 ALS patients (disease duration: 9.4 ± 6.8 months). Multivariate metabolomics analysis identified a distinct serum metabolome for ALS compared to controls (p-CV-ANOVA < 0.035) and revealed an excellent discriminant profile for muscle metabolome (p-CV-ANOVA < 0.0012). Citramalate was discriminant for both muscle and serum. High lauroylcarnitine levels in muscle were associated with low Forced Vital Capacity. Transcriptomics analysis of key antioxidant enzymes showed an upregulation of SOD3 (p = 0.0017) and GLRX2(1) (p = 0.0022) in ALS muscle. Analysis of mitochondrial enzymatic activity in muscle revealed higher complex II/CS (p = 0.04) and lower LDH (p = 0.03) activity in ALS than in controls. Our study showed, for the first time, a global dysfunction in the muscle of early-stage ALS patients. Furthermore, we identified novel metabolites to be employed as biomarkers for diagnosis and prognosis of ALS patients. Full article
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13 pages, 953 KiB  
Article
The Predictive Value of NLR, MLR, and PLR in the Outcome of End-Stage Kidney Disease Patients
by Adrian Vasile Mureșan, Eliza Russu, Emil Marian Arbănași, Réka Kaller, Ioan Hosu, Eliza Mihaela Arbănași and Septimiu Toader Voidăzan
Biomedicines 2022, 10(6), 1272; https://doi.org/10.3390/biomedicines10061272 - 29 May 2022
Cited by 35 | Viewed by 3433
Abstract
Background: Chronic kidney disease (CKD) is a global public health problem with a high mortality rate and a rapid progression to end-stage kidney disease (ESKD). Recently, the role of inflammation and the correlation between inflammatory markers and CKD progression have been studied. This [...] Read more.
Background: Chronic kidney disease (CKD) is a global public health problem with a high mortality rate and a rapid progression to end-stage kidney disease (ESKD). Recently, the role of inflammation and the correlation between inflammatory markers and CKD progression have been studied. This study aimed to analyze the predictive value of the neutrophil–lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) in assessing the outcome of ESKD patients. Methods: A retrospective study which included all patients admitted in the Department of Nephrology of the County Emergency Clinical Hospital, Târgu-Mureș, Romania, between January 2016 and December 2019, diagnosed with ESKD. Results: Mortality at 30 days was clearly higher in the case of the patients in the high-NLR groups (40.12% vs. 1.97%; p < 0.0001), high-MLR (32.35% vs. 4.81%; p < 0.0001), and respectively high-PLR (25.54% vs. 7.94%; p < 0.0001). There was also a significant increase in the number of hospital days and the average number of dialysis sessions in patients with high-NLR (p < 0.0001), high-MLR (p < 0.0001), and high-PLR (p < 0.0001). The multivariate analysis showed that a high baseline value for NLR (p < 0.0001), MLR (p < 0.0001), and PLR (p < 0.0001) was an independent predictor of 30-day mortality for all recruited patients. Conclusions: Our findings established that NLR, MLR, and PLR determined at hospital admission had a strong predictive capacity of all-cause 30-day mortality in ESKD patients who required RRT for at least 6 months. Elevated values of the ratios were also associated with longer hospital stays and more dialysis sessions per patient. Full article
(This article belongs to the Special Issue Kidney Disease: From Pathophysiology to Novel Therapeutic Approaches)
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16 pages, 1067 KiB  
Review
Health Benefits of Dietary Fiber for the Management of Inflammatory Bowel Disease
by Kafayat Yusuf, Subhrajit Saha and Shahid Umar
Biomedicines 2022, 10(6), 1242; https://doi.org/10.3390/biomedicines10061242 - 26 May 2022
Cited by 23 | Viewed by 11971
Abstract
Crohn’s disease (CD) and ulcerative colitis (UC), two components of inflammatory bowel disease (IBD), are painful conditions that affect children and adults. Despite substantial research, there is no permanent cure for IBD, and patients face an increased risk of colon cancer. Dietary fiber’s [...] Read more.
Crohn’s disease (CD) and ulcerative colitis (UC), two components of inflammatory bowel disease (IBD), are painful conditions that affect children and adults. Despite substantial research, there is no permanent cure for IBD, and patients face an increased risk of colon cancer. Dietary fiber’s health advantages have been thoroughly investigated, and it is recommended for its enormous health benefits. This review article discusses the importance of appropriate fiber intake in managing IBD, emphasizing how optimal fiber consumption can significantly help IBD patients. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Inflammatory Bowel Diseases 2.0)
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16 pages, 3784 KiB  
Article
Gasdermin D Deficiency Limits the Transition of Atherosclerotic Plaques to an Inflammatory Phenotype in ApoE Knock-Out Mice
by Pauline Puylaert, Melissa Van Praet, Frederik Vaes, Cédric H. G. Neutel, Lynn Roth, Pieter-Jan Guns, Guido R. Y. De Meyer and Wim Martinet
Biomedicines 2022, 10(5), 1171; https://doi.org/10.3390/biomedicines10051171 - 19 May 2022
Cited by 17 | Viewed by 2625
Abstract
Gasdermin D (GSDMD) is the key executor of pyroptotic cell death. Recent studies suggest that GSDMD-mediated pyroptosis is involved in atherosclerotic plaque destabilization. We report that cleaved GSDMD is expressed in macrophage- and smooth muscle cell-rich areas of human plaques. To determine the [...] Read more.
Gasdermin D (GSDMD) is the key executor of pyroptotic cell death. Recent studies suggest that GSDMD-mediated pyroptosis is involved in atherosclerotic plaque destabilization. We report that cleaved GSDMD is expressed in macrophage- and smooth muscle cell-rich areas of human plaques. To determine the effects of GSDMD deficiency on atherogenesis, ApoE−/− Gsdmd−/− (n = 16) and ApoE−/−Gsdmd+/+ (n = 18) mice were fed a western-type diet for 16 weeks. Plaque initiation and formation of stable proximal aortic plaques were not altered. However, plaques in the brachiocephalic artery (representing more advanced lesions compared to aortic plaques) of ApoE−/− Gsdmd−/− mice were significantly smaller (115 ± 18 vs. 186 ± 16 × 103 µm2, p = 0.006) and showed features of increased stability, such as decreased necrotic core area (19 ± 4 vs. 37 ± 7 × 103 µm2, p = 0.03) and increased αSMA/MAC3 ratio (1.6 ± 0.3 vs. 0.7 ± 0.1, p = 0.01), which was also observed in proximal aortic plaques. Interestingly, a significant increase in TUNEL positive cells was observed in brachiocephalic artery plaques from ApoE−/− Gsdmd−/− mice (141 ± 25 vs. 62 ± 8 cells/mm2, p = 0.005), indicating a switch to apoptosis. This switch from pyroptosis to apoptosis was also observed in vitro in Gsdmd−/− macrophages. In conclusion, targeting GSDMD appears to be a promising approach for limiting the transition to an inflammatory, vulnerable plaque phenotype. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)
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11 pages, 1705 KiB  
Article
Natural Polyphenols, 1,2,3,4,6-O-Pentagalloyglucose and Proanthocyanidins, as Broad-Spectrum Anticoronaviral Inhibitors Targeting Mpro and RdRp of SARS-CoV-2
by Young-Hee Jin, Jihye Lee, Sangeun Jeon, Seungtaek Kim, Jung Sun Min and Sunoh Kwon
Biomedicines 2022, 10(5), 1170; https://doi.org/10.3390/biomedicines10051170 - 18 May 2022
Cited by 10 | Viewed by 2000
Abstract
The natural plant dietary polyphenols 1,2,3,4,6-O-Pentagalloylglucose (PGG) and proanthocyanidin (PAC) have potent antioxidant activity and a variety of pharmacological activities, including antiviral activity. In this study, we examined the inhibitory effect of PGG and PAC on SARS-CoV-2 virus infection, and elucidated its mode [...] Read more.
The natural plant dietary polyphenols 1,2,3,4,6-O-Pentagalloylglucose (PGG) and proanthocyanidin (PAC) have potent antioxidant activity and a variety of pharmacological activities, including antiviral activity. In this study, we examined the inhibitory effect of PGG and PAC on SARS-CoV-2 virus infection, and elucidated its mode of action. PGG and PAC have dose-dependent inhibitory activity against SARS-CoV-2 infection in Vero cells. PGG has a lower IC50 (15.02 ± 0.75 μM) than PAC (25.90 ± 0.81 μM), suggesting that PGG has better inhibitory activity against SARS-CoV-2 than PAC. The PGG and PAC inhibit similar Mpro activities in a protease activity assay, with IC50 values of 25–26 μM. The effects of PGG and PAC on the activity of the other essential SARS-CoV-2 viral protein, RdRp, were analyzed using a cell-based activity assay system. The activity of RdRp is inhibited by PGG and PAC, and PGG has a lower IC50 (5.098 ± 1.089 μM) than PAC (21.022 ± 1.202 μM), which is consistent with their inhibitory capacity of SARS-CoV-2 infection. PGG and PAC also inhibit infection by SARS-CoV and MERS-CoV. These data indicate that PGG and PAC may be candidate broad-spectrum anticoronaviral therapeutic agents, simultaneously targeting the Mpro and RdRp proteins of SARS-CoV-2. Full article
(This article belongs to the Special Issue Non-antiviral Agents for Treatment of COVID-19)
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14 pages, 3636 KiB  
Article
Use of Urinary Cytokine and Chemokine Levels for Identifying Bladder Conditions and Predicting Treatment Outcomes in Patients with Interstitial Cystitis/Bladder Pain Syndrome
by Wan-Ru Yu, Yuan-Hong Jiang, Jia-Fong Jhang and Hann-Chorng Kuo
Biomedicines 2022, 10(5), 1149; https://doi.org/10.3390/biomedicines10051149 - 17 May 2022
Cited by 13 | Viewed by 3517
Abstract
Background: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a condition causing bladder inflammation. Urinary biomarkers have been assessed as suitable for the diagnosis and treatment. This study aimed at investigating the role of urinary biomarkers in identifying bladder conditions and predicting the treatment outcome [...] Read more.
Background: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a condition causing bladder inflammation. Urinary biomarkers have been assessed as suitable for the diagnosis and treatment. This study aimed at investigating the role of urinary biomarkers in identifying bladder conditions and predicting the treatment outcome of IC/BPS. Methods: A total of 309 patients with IC/BPS and 30 controls were enrolled in this study. All patients underwent a comprehensive urological workup of symptoms, pain severity, and cystoscopic hydrodistention findings including maximal bladder capacity (MBC) and glomerulation grade. Urine samples were collected to investigate the levels of urinary cytokines and chemokines. According to MBC and glomerulation grade, patients with IC/BPS were further classified into the Hunner’s IC (HIC) and non-HIC groups. The urinary biomarkers between IC/BPS and control groups and HIC and non-HIC groups were compared. Moreover, the treatment response was graded according to global response assessment (GRA) scores, and urinary biomarker levels were analyzed based on different GRAs. Results: Patients with IC/BPS had significantly high urinary monocyte chemoattractant protein-1, eotaxin, tumor necrosis factor -alpha (TNF-α), and prostaglandin E2 levels. Significantly higher levels of urinary interleukin-8, C-X-C motif chemokine ligand 10 (CXCL 10), brain-derived neurotrophic factor, eotaxin, and regulated-on-activation, normal T-cell expressed and secreted (RANTES) were noted in HIC than those with non-HIC and controls. Among all biomarkers, TNF-α had the best sensitivity, specificity, positive predictive value, and negative predictive value. There was a significant correlation between biomarker levels and GRA. Conclusions: Significantly higher urine cytokines and chemokine levels were found in patients with IC/BPS. Most urinary biomarkers were significantly associated with MBC, glomerulation grade, and treatment outcome. Full article
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22 pages, 5020 KiB  
Article
Butyrate Inhibits Colorectal Cancer Cell Proliferation through Autophagy Degradation of β-Catenin Regardless of APC and β-Catenin Mutational Status
by Beatrice Garavaglia, Letizia Vallino, Alessandra Ferraresi, Andrea Esposito, Amreen Salwa, Chiara Vidoni, Sergio Gentilli and Ciro Isidoro
Biomedicines 2022, 10(5), 1131; https://doi.org/10.3390/biomedicines10051131 - 13 May 2022
Cited by 17 | Viewed by 4360
Abstract
Colorectal cancer (CRC) pathogenesis is mainly driven by alterations in WNT signaling, which results in altered transcriptional activity of β-Catenin. Mutations in APC (Adenomatous Polyposis Coli) are reflected in β-Catenin hyperactivation and loss of proliferation control. Certain intestinal bacteria metabolites have shown the [...] Read more.
Colorectal cancer (CRC) pathogenesis is mainly driven by alterations in WNT signaling, which results in altered transcriptional activity of β-Catenin. Mutations in APC (Adenomatous Polyposis Coli) are reflected in β-Catenin hyperactivation and loss of proliferation control. Certain intestinal bacteria metabolites have shown the ability to limit CRC cell proliferation and CRC pathogenesis. Here, we investigated the molecular mechanism underlying the anti-proliferative activity of butyrate, a microbiota-derived short chain fatty acid, in two CRC cell lines, namely HCT116 and SW620, which bear a mutation in β-Catenin and APC, respectively. In particular, we focused on autophagy, a lysosome-dependent degradation pathway, which was shown to control intestinal tissue homeostasis. Butyrate reduced CRC cell proliferation, as witnessed by the downregulation of proliferation markers. TCGA bioinformatic transcriptomic analysis of CTNNB1 (β-Catenin) gene correlation in CRC patients showed that β-Catenin negatively correlates with the autophagy gene ATG4D. In CRC cells, regardless of the mutational state of APC or β-Catenin genes, butyrate caused the autophagy-mediated degradation of β-Catenin; thus, preventing its transcriptional activity. Autophagy gene silencing restored β-Catenin levels, allowing it to translocate into the nucleus to promote the expression of downstream genes associated with cancer cell proliferation. CRC-affected patients show driver mutations in the WNT pathway; thus, targeting its crucial effector may be a promising therapeutic strategy in CRC treatment; for instance, by using ad hoc probiotics that stimulate autophagy. Full article
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18 pages, 2800 KiB  
Review
Targeted Strategy in Lipid-Lowering Therapy
by Ezgi Dayar and Olga Pechanova
Biomedicines 2022, 10(5), 1090; https://doi.org/10.3390/biomedicines10051090 - 08 May 2022
Cited by 19 | Viewed by 7306
Abstract
Dyslipidemia is characterized by a diminished lipid profile, including increased level of total cholesterol and low-density lipoprotein cholesterol (LDL-c) and reduced level of high-density lipoprotein cholesterol (HDL-c). Lipid-lowering agents represent an efficient tool for the prevention or reduction of progression of atherosclerosis, coronary [...] Read more.
Dyslipidemia is characterized by a diminished lipid profile, including increased level of total cholesterol and low-density lipoprotein cholesterol (LDL-c) and reduced level of high-density lipoprotein cholesterol (HDL-c). Lipid-lowering agents represent an efficient tool for the prevention or reduction of progression of atherosclerosis, coronary heart diseases and metabolic syndrome. Statins, ezetimibe, and recently proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are the most effective and used drugs in clinical lipid-lowering therapy. These drugs are mainly aimed to lower cholesterol levels by different mechanisms of actions. Statins, the agents of the first-line therapy—known as 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors—suppress the liver cholesterol synthesis. Ezetimibe as the second-line therapy can decrease cholesterol by inhibiting cholesterol absorption. Finally, the PCSK9 inhibitors act as an inducer of LDL excretion. In spite of their beneficial lipid-lowering properties, many patients suffer from their serious side effects, route of administration, or unsatisfactory physicochemical characteristics. Clinical demand for dose reduction and the improvement of bioavailability as well as pharmacodynamic and pharmacokinetic profile has resulted in the development of a new targeted therapy that includes nanoparticle carriers, emulsions or vaccination often associated with another more subtle form of administration. Targeted therapy aims to exert a more potent drug profile with lipid-lowering properties either alone or in mutual combination to potentiate their beneficial effects. This review describes the most effective lipid-lowering drugs, their favorable and adverse effects, as well as targeted therapy and alternative treatments to help reduce or prevent atherosclerotic processes and cardiovascular events. Full article
(This article belongs to the Special Issue The Lipid Metabolism in Health and Diseases)
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16 pages, 9344 KiB  
Article
Non-Invasive Physical Plasma Generated by a Medical Argon Plasma Device Induces the Expression of Regenerative Factors in Human Gingival Keratinocytes, Fibroblasts, and Tissue Biopsies
by Benedikt Eggers, Matthias Bernhard Stope, Jana Marciniak, Werner Götz, Alexander Mustea, James Deschner, Marjan Nokhbehsaim and Franz-Josef Kramer
Biomedicines 2022, 10(4), 889; https://doi.org/10.3390/biomedicines10040889 - 13 Apr 2022
Cited by 8 | Viewed by 2142
Abstract
After oral surgery, intraoral wound healing and tissue regeneration is an important factor for the success of the entire therapy. In recent years, non-invasive medical plasma (NIPP) has been shown to accelerate wound healing, which would be particularly beneficial for patients with wound [...] Read more.
After oral surgery, intraoral wound healing and tissue regeneration is an important factor for the success of the entire therapy. In recent years, non-invasive medical plasma (NIPP) has been shown to accelerate wound healing, which would be particularly beneficial for patients with wound healing disorders. Since the application of NIPP in dentistry has not been sufficiently understood, the aim of the present study was to investigate the effect of a medical argon plasma device on gingival cells. Human gingival fibroblasts, keratinocytes, and tissue biopsies were treated with NIPP for different durations. Crucial markers associated with wound healing were examined at the mRNA and protein levels by real-time PCR, ELISA and immunohistochemistry. NIPP treatment led to an increase in Ki67 and MMP1 at mRNA and protein levels. NIPP application lasting longer than 60 s resulted in an increase in apoptotic genes at mRNA level and superficial damage to the epithelium in the tissue biopsies. Overall, our experimental setup demonstrated that NIPP application times of 30 s were most suitable for the treatment of gingival cells and tissue biopsies. Our study provides evidence for potential use of NIPP in dentistry, which would be a promising treatment option for oral surgery. Full article
(This article belongs to the Special Issue The Advances of Cold Plasma in the Biomedicines)
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20 pages, 2871 KiB  
Review
The Selenoprotein Glutathione Peroxidase 4: From Molecular Mechanisms to Novel Therapeutic Opportunities
by Kamari Weaver and Rachid Skouta
Biomedicines 2022, 10(4), 891; https://doi.org/10.3390/biomedicines10040891 - 13 Apr 2022
Cited by 41 | Viewed by 7073
Abstract
The selenoprotein glutathione peroxidase 4 (GPX4) is one of the main antioxidant mediators in the human body. Its central function involves the reduction of complex hydroperoxides into their respective alcohols often using reduced Glutathione (GSH) as a reducing agent. GPX4 has become a [...] Read more.
The selenoprotein glutathione peroxidase 4 (GPX4) is one of the main antioxidant mediators in the human body. Its central function involves the reduction of complex hydroperoxides into their respective alcohols often using reduced Glutathione (GSH) as a reducing agent. GPX4 has become a hotspot therapeutic target in biomedical research following its characterization as a chief regulator of ferroptosis, and its subsequent recognition as a specific pharmacological target for the treatment of an extensive variety of human diseases including cancers and neurodegenerative disorders. Several recent studies have provided insights into how GPX4 is distinguished from the rest of the glutathione peroxidase family, the unique biochemical properties of GPX4, how GPX4 is related to lipid peroxidation and ferroptosis, and how the enzyme may be modulated as a potential therapeutic target. This current report aims to review the literature underlying all these insights and present an up-to-date perspective on the current understanding of GPX4 as a potential therapeutic target. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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23 pages, 19124 KiB  
Review
Ion Channels and Transporters as Therapeutic Agents: From Biomolecules to Supramolecular Medicinal Chemistry
by Giacomo Picci, Silvia Marchesan and Claudia Caltagirone
Biomedicines 2022, 10(4), 885; https://doi.org/10.3390/biomedicines10040885 - 12 Apr 2022
Cited by 15 | Viewed by 5463
Abstract
Ion channels and transporters typically consist of biomolecules that play key roles in a large variety of physiological and pathological processes. Traditional therapies include many ion-channel blockers, and some activators, although the exact biochemical pathways and mechanisms that regulate ion homeostasis are yet [...] Read more.
Ion channels and transporters typically consist of biomolecules that play key roles in a large variety of physiological and pathological processes. Traditional therapies include many ion-channel blockers, and some activators, although the exact biochemical pathways and mechanisms that regulate ion homeostasis are yet to be fully elucidated. An emerging area of research with great innovative potential in biomedicine pertains the design and development of synthetic ion channels and transporters, which may provide unexplored therapeutic opportunities. However, most studies in this challenging and multidisciplinary area are still at a fundamental level. In this review, we discuss the progress that has been made over the last five years on ion channels and transporters, touching upon biomolecules and synthetic supramolecules that are relevant to biological use. We conclude with the identification of therapeutic opportunities for future exploration. Full article
(This article belongs to the Collection Feature Papers in Cell Biology and Pathology)
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14 pages, 2595 KiB  
Article
Effects of CB2 Receptor Modulation on Macrophage Polarization in Pediatric Celiac Disease
by Chiara Tortora, Alessandra Di Paola, Maura Argenziano, Mara Creoli, Maria Maddalena Marrapodi, Sabrina Cenni, Carlo Tolone, Francesca Rossi and Caterina Strisciuglio
Biomedicines 2022, 10(4), 874; https://doi.org/10.3390/biomedicines10040874 - 09 Apr 2022
Cited by 23 | Viewed by 2199
Abstract
Celiac Disease (CD) represents an autoimmune disorder triggered by the exposure to gluten in genetically susceptible individuals. Recent studies suggest the involvement of macrophages in CD pathogenesis. Macrophages are immune cells, present as pro-inflammatory classically activated macrophages (M1) or as anti-inflammatory alternatively activated [...] Read more.
Celiac Disease (CD) represents an autoimmune disorder triggered by the exposure to gluten in genetically susceptible individuals. Recent studies suggest the involvement of macrophages in CD pathogenesis. Macrophages are immune cells, present as pro-inflammatory classically activated macrophages (M1) or as anti-inflammatory alternatively activated macrophages (M2). The Cannabinoid Receptor 2 (CB2) has important anti-inflammatory and immunoregulatory properties. We previously demonstrated that a common CB2 functional variant, Q63R, causing CB2 reduced function, is associated with several inflammatory and autoimmune diseases The first aim of this study was to investigate the phenotype of macrophages isolated from peripheral blood of CD patients and CB2 expression. The second aim was to evaluate the effects of CB2 pharmacological modulation on CD macrophage polarization. Moreover, by an in vitro model of “immunocompetent gut” we investigated the role of CD macrophages in inducing intestinal barrier damage and the possibility to restore its functionality modulating their polarization. We found an increased expression of M1 macrophages and a CB2 reduced expression. We also demonstrated CD M1 macrophages in inducing the typical mucosal barrier damage of CD. CB2 stimulation switches macrophage polarization towards the anti-inflammatory M2 phenotype thus reducing inflammation but also limiting the epithelial dysfunction. Therefore, we suggest CB2 receptor as a possible novel therapeutic target for CD by regulating macrophages polarization and by preventing mucosal barrier damage. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 3.0)
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14 pages, 3327 KiB  
Article
The Impact of Prolonged Inflammation on Wound Healing
by Judith C. J. Holzer-Geissler, Simon Schwingenschuh, Martin Zacharias, Johanna Einsiedler, Sonja Kainz, Peter Reisenegger, Christian Holecek, Elisabeth Hofmann, Barbara Wolff-Winiski, Hermann Fahrngruber, Thomas Birngruber, Lars-Peter Kamolz and Petra Kotzbeck
Biomedicines 2022, 10(4), 856; https://doi.org/10.3390/biomedicines10040856 - 06 Apr 2022
Cited by 34 | Viewed by 5222
Abstract
The treatment of chronic wounds still challenges modern medicine because of these wounds’ heterogenic pathophysiology. Processes such as inflammation, ischemia and bacterial infection play major roles in the progression of a chronic wound. In recent years, preclinical wound models have been used to [...] Read more.
The treatment of chronic wounds still challenges modern medicine because of these wounds’ heterogenic pathophysiology. Processes such as inflammation, ischemia and bacterial infection play major roles in the progression of a chronic wound. In recent years, preclinical wound models have been used to understand the underlying processes of chronic wound formation. However, the wound models used to investigate chronic wounds often lack translatability from preclinical models to patients, and often do not take exaggerated inflammation into consideration. Therefore, we aimed to investigate prolonged inflammation in a porcine wound model by using resiquimod, a TLR7 and TLR8 agonist. Pigs received full thickness excisional wounds, where resiquimod was applied daily for 6 days, and untreated wounds served as controls. Dressing change, visual documentation and wound scoring were performed daily. Biopsies were collected for histological as well as gene expression analysis. Resiquimod application on full thickness wounds induced a visible inflammation of wounds, resulting in delayed wound healing compared to non-treated control wounds. Gene expression analysis revealed high levels of IL6, MMP1 and CD68 expression after resiquimod application, and histological analysis showed increased immune cell infiltration. By using resiquimod, we were able to show that prolonged inflammation delayed wound healing, which is often observed in chronic wounds in patients. The model we used shows the importance of inflammation in wound healing and gives an insight into the progression of chronic wounds. Full article
(This article belongs to the Special Issue Wound Healing at the Cellular Level)
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18 pages, 2750 KiB  
Article
Memory Enhancement with Kynurenic Acid and Its Mechanisms in Neurotransmission
by Diána Martos, Bernadett Tuka, Masaru Tanaka, László Vécsei and Gyula Telegdy
Biomedicines 2022, 10(4), 849; https://doi.org/10.3390/biomedicines10040849 - 05 Apr 2022
Cited by 55 | Viewed by 5630
Abstract
Kynurenic acid (KYNA) is an endogenous tryptophan (Trp) metabolite known to possess neuroprotective property. KYNA plays critical roles in nociception, neurodegeneration, and neuroinflammation. A lower level of KYNA is observed in patients with neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases or psychiatric [...] Read more.
Kynurenic acid (KYNA) is an endogenous tryptophan (Trp) metabolite known to possess neuroprotective property. KYNA plays critical roles in nociception, neurodegeneration, and neuroinflammation. A lower level of KYNA is observed in patients with neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases or psychiatric disorders such as depression and autism spectrum disorders, whereas a higher level of KYNA is associated with the pathogenesis of schizophrenia. Little is known about the optimal concentration for neuroprotection and the threshold for neurotoxicity. In this study the effects of KYNA on memory functions were investigated by passive avoidance test in mice. Six different doses of KYNA were administered intracerebroventricularly to previously trained CFLP mice and they were observed for 24 h. High doses of KYNA (i.e., 20–40 μg/2 μL) significantly decreased the avoidance latency, whereas a low dose of KYNA (0.5 μg/2 μL) significantly elevated it compared with controls, suggesting that the low dose of KYNA enhanced memory function. Furthermore, six different receptor blockers were applied to reveal the mechanisms underlying the memory enhancement induced by KYNA. The series of tests revealed the possible involvement of the serotonergic, dopaminergic, α and β adrenergic, and opiate systems in the nootropic effect. This study confirmed that a low dose of KYNA improved a memory component of cognitive domain, which was mediated by, at least in part, four systems of neurotransmission in an animal model of learning and memory. Full article
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19 pages, 1255 KiB  
Review
Development of Alzheimer’s Disease Biomarkers: From CSF- to Blood-Based Biomarkers
by Sakulrat Mankhong, Sujin Kim, Seongju Lee, Hyo-Bum Kwak, Dong-Ho Park, Kyung-Lim Joa and Ju-Hee Kang
Biomedicines 2022, 10(4), 850; https://doi.org/10.3390/biomedicines10040850 - 05 Apr 2022
Cited by 18 | Viewed by 11111
Abstract
In the 115 years since the discovery of Alzheimer’s disease (AD), our knowledge, diagnosis, and therapeutics have significantly improved. Biomarkers are the primary tools for clinical research, diagnostics, and therapeutic monitoring in clinical trials. They provide much insightful information, and while they are [...] Read more.
In the 115 years since the discovery of Alzheimer’s disease (AD), our knowledge, diagnosis, and therapeutics have significantly improved. Biomarkers are the primary tools for clinical research, diagnostics, and therapeutic monitoring in clinical trials. They provide much insightful information, and while they are not clinically used routinely, they help us to understand the mechanisms of this disease. This review charts the journey of AD biomarker discovery and development from cerebrospinal fluid (CSF) amyloid-beta 1-42 (Aβ42), total tau (T-tau), and phosphorylated tau (p-tau) biomarkers and imaging technologies to the next generation of biomarkers. We also discuss advanced high-sensitivity assay platforms for CSF Aβ42, T-tau, p-tau, and blood analysis. The recently proposed Aβ deposition/tau biomarker/neurodegeneration or neuronal injury (ATN) scheme might facilitate the definition of the biological status underpinning AD and offer a common language among researchers across biochemical biomarkers and imaging. Moreover, we highlight blood-based biomarkers for AD that offer a scalable alternative to CSF biomarkers through cost-saving and reduced invasiveness, and may provide an understanding of disease initiation and development. We discuss different groups of blood-based biomarker candidates, their advantages and limitations, and paths forward, from identification and analysis to clinical validation. The development of valid blood-based biomarkers may facilitate the implementation of future AD therapeutics and diagnostics. Full article
(This article belongs to the Special Issue Alzheimer's Disease—115 Years after Its Discovery)
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31 pages, 4172 KiB  
Review
The Role of Osteopontin in Microglia Biology: Current Concepts and Future Perspectives
by Dennis-Dominik Rosmus, Clemens Lange, Franziska Ludwig, Bahareh Ajami and Peter Wieghofer
Biomedicines 2022, 10(4), 840; https://doi.org/10.3390/biomedicines10040840 - 03 Apr 2022
Cited by 26 | Viewed by 10490
Abstract
The innate immune landscape of the central nervous system (CNS), including the brain and the retina, consists of different myeloid cell populations with distinct tasks to fulfill. Whereas the CNS borders harbor extraparenchymal CNS-associated macrophages whose main duty is to build up a [...] Read more.
The innate immune landscape of the central nervous system (CNS), including the brain and the retina, consists of different myeloid cell populations with distinct tasks to fulfill. Whereas the CNS borders harbor extraparenchymal CNS-associated macrophages whose main duty is to build up a defense against invading pathogens and other damaging factors from the periphery, the resident immune cells of the CNS parenchyma and the retina, microglia, are highly dynamic cells with a plethora of functions during homeostasis and disease. Therefore, microglia are constantly sensing their environment and closely interacting with surrounding cells, which is in part mediated by soluble factors. One of these factors is Osteopontin (OPN), a multifunctional protein that is produced by different cell types in the CNS, including microglia, and is upregulated in neurodegenerative and neuroinflammatory conditions. In this review, we discuss the current literature about the interaction between microglia and OPN in homeostasis and several disease entities, including multiple sclerosis (MS), Alzheimer’s and cerebrovascular diseases (AD, CVD), amyotrophic lateral sclerosis (ALS), age-related macular degeneration (AMD) and diabetic retinopathy (DR), in the context of the molecular pathways involved in OPN signaling shaping the function of microglia. As nearly all CNS diseases are characterized by pathological alterations in microglial cells, accompanied by the disturbance of the homeostatic microglia phenotype, the emergence of disease-associated microglia (DAM) states and their interplay with factors shaping the DAM-signature, such as OPN, is of great interest for therapeutical interventions in the future. Full article
(This article belongs to the Special Issue 30 Years of OPN Milestones and Future Avenues)
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22 pages, 3797 KiB  
Review
The Hallmarks of Glioblastoma: Heterogeneity, Intercellular Crosstalk and Molecular Signature of Invasiveness and Progression
by Filippo Torrisi, Cristiana Alberghina, Simona D’Aprile, Anna M. Pavone, Lucia Longhitano, Sebastiano Giallongo, Daniele Tibullo, Michelino Di Rosa, Agata Zappalà, Francesco P. Cammarata, Giorgio Russo, Massimo Ippolito, Giacomo Cuttone, Giovanni Li Volti, Nunzio Vicario and Rosalba Parenti
Biomedicines 2022, 10(4), 806; https://doi.org/10.3390/biomedicines10040806 - 30 Mar 2022
Cited by 35 | Viewed by 5956
Abstract
In 2021 the World Health Organization published the fifth and latest version of the Central Nervous System tumors classification, which incorporates and summarizes a long list of updates from the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy work. Among [...] Read more.
In 2021 the World Health Organization published the fifth and latest version of the Central Nervous System tumors classification, which incorporates and summarizes a long list of updates from the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy work. Among the adult-type diffuse gliomas, glioblastoma represents most primary brain tumors in the neuro-oncology practice of adults. Despite massive efforts in the field of neuro-oncology diagnostics to ensure a proper taxonomy, the identification of glioblastoma-tumor subtypes is not accompanied by personalized therapies, and no improvements in terms of overall survival have been achieved so far, confirming the existence of open and unresolved issues. The aim of this review is to illustrate and elucidate the state of art regarding the foremost biological and molecular mechanisms that guide the beginning and the progression of this cancer, showing the salient features of tumor hallmarks in glioblastoma. Pathophysiology processes are discussed on molecular and cellular levels, highlighting the critical overlaps that are involved into the creation of a complex tumor microenvironment. The description of glioblastoma hallmarks shows how tumoral processes can be linked together, finding their involvement within distinct areas that are engaged for cancer-malignancy establishment and maintenance. The evidence presented provides the promising view that glioblastoma represents interconnected hallmarks that may led to a better understanding of tumor pathophysiology, therefore driving the development of new therapeutic strategies and approaches. Full article
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20 pages, 6442 KiB  
Article
Heart Failure Severity Closely Correlates with Intestinal Dysbiosis and Subsequent Metabolomic Alterations
by Martina E. Spehlmann, Ashraf Y. Rangrez, Dhiraj P. Dhotre, Nesrin Schmiedel, Nikita Chavan, Corinna Bang, Oliver J. Müller, Yogesh S. Shouche, Andre Franke, Derk Frank and Norbert Frey
Biomedicines 2022, 10(4), 809; https://doi.org/10.3390/biomedicines10040809 - 30 Mar 2022
Cited by 12 | Viewed by 2486
Abstract
Growing evidence suggests an altered gut microbiome in patients with heart failure (HF). However, the exact interrelationship between microbiota, HF, and its consequences on the metabolome are still unknown. We thus aimed here to decipher the association between the severity and progression of [...] Read more.
Growing evidence suggests an altered gut microbiome in patients with heart failure (HF). However, the exact interrelationship between microbiota, HF, and its consequences on the metabolome are still unknown. We thus aimed here to decipher the association between the severity and progression of HF and the gut microbiome composition and circulating metabolites. Using a mouse model of transverse aortic constriction (TAC), gut bacterial diversity was found to be significantly lower in mice as early as day 7 post-TAC compared to Sham controls (p = 0.03), with a gradual progressive decrease in alpha-diversity on days 7, 14, and 42 (p = 0.014, p = 0.0016, p = 0.0021) compared to day 0, which coincided with compensated hypertrophy, maladaptive hypertrophy, and overtly failing hearts, respectively. Strikingly, segregated analysis based on the severity of the cardiac dysfunction (EF < 40% vs. EF 40–55%) manifested marked differences in the abundance and the grouping of several taxa. Multivariate analysis of plasma metabolites and bacterial diversity produced a strong correlation of metabolic alterations, such as reduced short-chain fatty acids and an increase in primary bile acids, with a differential abundance of distinct bacteria in HF. In conclusion, we showed that HF begets HF, likely via a vicious cycle of an altered microbiome and metabolic products. Full article
(This article belongs to the Special Issue Host-Microbiome Crosstalk in Cardiometabolic Diseases)
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16 pages, 2123 KiB  
Review
Lignin-Based Porous Biomaterials for Medical and Pharmaceutical Applications
by Nan Nan, Wanhe Hu and Jingxin Wang
Biomedicines 2022, 10(4), 747; https://doi.org/10.3390/biomedicines10040747 - 23 Mar 2022
Cited by 28 | Viewed by 6053
Abstract
Over the past decade, lignin-based porous biomaterials have been found to have strong potential applications in the areas of drug delivery, tissue engineering, wound dressing, pharmaceutical excipients, biosensors, and medical devices. Lignin-based porous biomaterials have the addition of lignin obtained from lignocellulosic biomass. [...] Read more.
Over the past decade, lignin-based porous biomaterials have been found to have strong potential applications in the areas of drug delivery, tissue engineering, wound dressing, pharmaceutical excipients, biosensors, and medical devices. Lignin-based porous biomaterials have the addition of lignin obtained from lignocellulosic biomass. Lignin as an aromatic compound is likely to modify the materials’ mechanical properties, thermal properties, antioxidant, antibacterial property, biodegradability, and biocompatibility. The size, shape, and distribution of pores can determine the materials’ porous structure, porosity, surface areas, permeability, porosity, water solubility, and adsorption ability. These features could be suitable for medical applications, especially controlled drug delivery systems, wound dressing, and tissue engineering. In this review, we provide an overview of the current status and future potential of lignin-based porous materials for medical and pharmaceutical uses, focusing on material types, key properties, approaches and techniques of modification and fabrication, and promising medical applications. Full article
(This article belongs to the Special Issue Bio-Inspired Porous Materials and Biomaterials)
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20 pages, 2153 KiB  
Review
The Neurobiological Correlates of Gaze Perception in Healthy Individuals and Neurologic Patients
by Simone Battaglia, Jasper H. Fabius, Katarina Moravkova, Alessio Fracasso and Sara Borgomaneri
Biomedicines 2022, 10(3), 627; https://doi.org/10.3390/biomedicines10030627 - 09 Mar 2022
Cited by 45 | Viewed by 5485
Abstract
The ability to adaptively follow conspecific eye movements is crucial for establishing shared attention and survival. Indeed, in humans, interacting with the gaze direction of others causes the reflexive orienting of attention and the faster object detection of the signaled spatial location. The [...] Read more.
The ability to adaptively follow conspecific eye movements is crucial for establishing shared attention and survival. Indeed, in humans, interacting with the gaze direction of others causes the reflexive orienting of attention and the faster object detection of the signaled spatial location. The behavioral evidence of this phenomenon is called gaze-cueing. Although this effect can be conceived as automatic and reflexive, gaze-cueing is often susceptible to context. In fact, gaze-cueing was shown to interact with other factors that characterize facial stimulus, such as the kind of cue that induces attention orienting (i.e., gaze or non-symbolic cues) or the emotional expression conveyed by the gaze cues. Here, we address neuroimaging evidence, investigating the neural bases of gaze-cueing and the perception of gaze direction and how contextual factors interact with the gaze shift of attention. Evidence from neuroimaging, as well as the fields of non-invasive brain stimulation and neurologic patients, highlights the involvement of the amygdala and the superior temporal lobe (especially the superior temporal sulcus (STS)) in gaze perception. However, in this review, we also emphasized the discrepancies of the attempts to characterize the distinct functional roles of the regions in the processing of gaze. Finally, we conclude by presenting the notion of invariant representation and underline its value as a conceptual framework for the future characterization of the perceptual processing of gaze within the STS. Full article
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14 pages, 5998 KiB  
Article
Nobiletin Alleviates Ferroptosis-Associated Renal Injury, Inflammation, and Fibrosis in a Unilateral Ureteral Obstruction Mouse Model
by Yi-Hsin Lo, Shun-Fa Yang, Ching-Chang Cheng, Kuo-Chiang Hsu, Yu-Syuan Chen, Yu-Ya Chen, Chun-Wei Wang, Siao-Syun Guan and Cheng-Tien Wu
Biomedicines 2022, 10(3), 595; https://doi.org/10.3390/biomedicines10030595 - 03 Mar 2022
Cited by 20 | Viewed by 3650
Abstract
Nobiletin (Nob), a critical active flavonoid of citrus fruits, has received attention for its superior physical functions, which have shown to improve the progression of diseases. Chronic kidney disease (CKD) is recognized as a global health problem, and its mortality and morbidity rates [...] Read more.
Nobiletin (Nob), a critical active flavonoid of citrus fruits, has received attention for its superior physical functions, which have shown to improve the progression of diseases. Chronic kidney disease (CKD) is recognized as a global health problem, and its mortality and morbidity rates are worsened with an increased risk of accompanying disorders. In this study, we aimed to elucidate whether Nob treatment ameliorates kidney fibrosis and also to identify the potential signaling networks in a unilateral ureteral obstructive (UUO) mouse model, which was used to mimic the progression of CKD. Six-week-old C57BL/6J mice were orally treated with 50 mg/kg of Nob for 14 constitutive days after UUO surgery. We found that the administration of Nob diminished kidney fibrosis and the expression of EMT markers, ameliorated oxidative stress and ferroptosis-associated injury, and mitigated the inflammatory response in the kidneys of UUO mice. Our results suggested that Nob treatment has antiferroptosis, anti-inflammatory, and antifibrotic effects, improving the progression of CKD in UUO mice. Nob may serve as a potential therapeutic candidate for the improvement of progressive CKD in further studies. Full article
(This article belongs to the Topic Novel Therapeutic Nutrient Molecules)
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15 pages, 3173 KiB  
Article
Cytoprotective Effect of Idebenone through Modulation of the Intrinsic Mitochondrial Pathway of Apoptosis in Human Retinal Pigment Epithelial Cells Exposed to Oxidative Stress Induced by Hydrogen Peroxide
by Maria Elisabetta Clementi, Michela Pizzoferrato, Giada Bianchetti, Anna Brancato, Beatrice Sampaolese, Giuseppe Maulucci and Giuseppe Tringali
Biomedicines 2022, 10(2), 503; https://doi.org/10.3390/biomedicines10020503 - 21 Feb 2022
Cited by 19 | Viewed by 3601
Abstract
Idebenone is a ubiquinone short-chain synthetic analog with antioxidant properties, which is believed to restore mitochondrial ATP synthesis. As such, idebenone is investigated in numerous clinical trials for diseases of mitochondrial aetiology and it is authorized as a drug for the treatment of [...] Read more.
Idebenone is a ubiquinone short-chain synthetic analog with antioxidant properties, which is believed to restore mitochondrial ATP synthesis. As such, idebenone is investigated in numerous clinical trials for diseases of mitochondrial aetiology and it is authorized as a drug for the treatment of Leber’s hereditary optic neuropathy. Mitochondria of retinal pigment epithelium (RPE) are particularly vulnerable to oxidative damage associated with cellular senescence. Therefore, the aim of this study was to explore idebenone’s cytoprotective effect and its underlying mechanism. We used a human-RPE cell line (ARPE-19) exposed to idebenone pre-treatment for 24 h followed by conditions inducing H2O2 oxidative damage for a further 24 h. We found that idebenone: (a) ameliorated H2O2-lowered cell viability in the RPE culture; (b) activated Nrf2 signaling pathway by promoting Nrf2 nuclear translocation; (c) increased Bcl-2 protein levels, leaving unmodified those of Bax, thereby reducing the Bax/Bcl-2 ratio; (d) maintained the mitochondrial membrane potential (ΔΨm) at physiological levels, preserving the functionality of mitochondrial respiratory complexes and counteracting the excessive production of ROS; and (e) reduced mitochondrial cytochrome C-mediated caspase-3 activity. Taken together, our findings show that idebenone protects RPE from oxidative damage by modulating the intrinsic mitochondrial pathway of apoptosis, suggesting its possible role in retinal epitheliopathies associated with mitochondrial dysfunction. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress in Aging and Disease)
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15 pages, 711 KiB  
Review
Gastrointestinal Microbiome and Neurologic Injury
by Eric J. Panther, William Dodd, Alec Clark and Brandon Lucke-Wold
Biomedicines 2022, 10(2), 500; https://doi.org/10.3390/biomedicines10020500 - 21 Feb 2022
Cited by 24 | Viewed by 4103
Abstract
Communication between the enteric nervous system (ENS) of the gastrointestinal (GI) tract and the central nervous system (CNS) is vital for maintaining systemic homeostasis. Intrinsic and extrinsic neurological inputs of the gut regulate blood flow, peristalsis, hormone release, and immunological function. The health [...] Read more.
Communication between the enteric nervous system (ENS) of the gastrointestinal (GI) tract and the central nervous system (CNS) is vital for maintaining systemic homeostasis. Intrinsic and extrinsic neurological inputs of the gut regulate blood flow, peristalsis, hormone release, and immunological function. The health of the gut microbiome plays a vital role in regulating the overall function and well-being of the individual. Microbes release short-chain fatty acids (SCFAs) that regulate G-protein-coupled receptors to mediate hormone release, neurotransmitter release (i.e., serotonin, dopamine, noradrenaline, γ-aminobutyric acid (GABA), acetylcholine, and histamine), and regulate inflammation and mood. Further gaseous factors (i.e., nitric oxide) are important in regulating inflammation and have a response in injury. Neurologic injuries such as ischemic stroke, spinal cord injury, traumatic brain injury, and hemorrhagic cerebrovascular lesions can all lead to gut dysbiosis. Additionally, unfavorable alterations in the composition of the microbiota may be associated with increased risk for these neurologic injuries due to increased proinflammatory molecules and clotting factors. Interventions such as probiotics, fecal microbiota transplantation, and oral SCFAs have been shown to stabilize and improve the composition of the microbiome. However, the effect this has on neurologic injury prevention and recovery has not been studied extensively. The purpose of this review is to elaborate on the complex relationship between the nervous system and the microbiome and to report how neurologic injury modulates the status of the microbiome. Finally, we will propose various interventions that may be beneficial in the recovery from neurologic injury. Full article
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24 pages, 1677 KiB  
Review
Role of Microbiota-Gut-Brain Axis in Regulating Dopaminergic Signaling
by Sevag Hamamah, Armin Aghazarian, Anthony Nazaryan, Andras Hajnal and Mihai Covasa
Biomedicines 2022, 10(2), 436; https://doi.org/10.3390/biomedicines10020436 - 13 Feb 2022
Cited by 67 | Viewed by 12548
Abstract
Dopamine is a neurotransmitter that plays a critical role both peripherally and centrally in vital functions such as cognition, reward, satiety, voluntary motor movements, pleasure, and motivation. Optimal dopamine bioavailability is essential for normal brain functioning and protection against the development of neurological [...] Read more.
Dopamine is a neurotransmitter that plays a critical role both peripherally and centrally in vital functions such as cognition, reward, satiety, voluntary motor movements, pleasure, and motivation. Optimal dopamine bioavailability is essential for normal brain functioning and protection against the development of neurological diseases. Emerging evidence shows that gut microbiota have significant roles in maintaining adequate concentrations of dopamine via intricate, bidirectional communication known as the microbiota-gut-brain axis. The vagus nerve, immune system, hypothalamus–pituitary–adrenal axis, and microbial metabolites serve as important mediators of the reciprocal microbiota-gut-brain signaling. Furthermore, gut microbiota contain intrinsic enzymatic activity that is highly involved in dopamine metabolism, facilitating dopamine synthesis as well as its metabolite breakdown. This review examines the relationship between key genera of gut microbiota such as Prevotella, Bacteroides, Lactobacillus, Bifidobacterium, Clostridium,Enterococcus, and Ruminococcus and their effects on dopamine. The effects of gut dysbiosis on dopamine bioavailability and the subsequent impact on dopamine-related pathological conditions such as Parkinson’s disease are also discussed. Understanding the role of gut microbiota in modulating dopamine activity and bioavailability both in the periphery and in the central nervous system can help identify new therapeutic targets as well as optimize available methods to prevent, delay, or restore dopaminergic deficits in neurologic and metabolic disorders. Full article
(This article belongs to the Special Issue Dopamine in Health and Disease 2.0)
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22 pages, 941 KiB  
Review
Neutrophil Extracellular Traps, Angiogenesis and Cancer
by Remo Poto, Leonardo Cristinziano, Luca Modestino, Amato de Paulis, Gianni Marone, Stefania Loffredo, Maria Rosaria Galdiero and Gilda Varricchi
Biomedicines 2022, 10(2), 431; https://doi.org/10.3390/biomedicines10020431 - 12 Feb 2022
Cited by 35 | Viewed by 8318
Abstract
Human neutrophils, the most abundant circulating leukocytes, are fundamental components of the host response against different pathogens. Until a few years ago, neutrophils received limited attention in cancer immunology. Recently, it was discovered that both circulating, and tumor-associated, neutrophils possess functional plasticity when [...] Read more.
Human neutrophils, the most abundant circulating leukocytes, are fundamental components of the host response against different pathogens. Until a few years ago, neutrophils received limited attention in cancer immunology. Recently, it was discovered that both circulating, and tumor-associated, neutrophils possess functional plasticity when exposed to various inflammatory stimuli and in the tumor microenvironment. Neutrophils and their mediators can exert several pro-tumor activities in cancer and promote metastasis through different mechanisms. Angiogenesis plays a pivotal role in inflammation and tumor growth. Activated human neutrophils release several angiogenic factors [vascular endothelial growth factor-A (VEGF-A), angiopoietin-1 (ANGPT1), CXCL8, hepatocyte growth factor (HGF), and metalloproteinase 9 (MMP-9)] and form neutrophil extracellular traps (NETs). NETs promote tumor growth and metastasis formation through several mechanisms: they can awake dormant cancer cells, capture circulating tumor cells, coat and shield cancer cells, thus preventing CD8+- and natural killer (NK) cell-mediated cytotoxicity. ANGPTs released by endothelial and periendothelial mural cells induce platelet-activating factor (PAF) synthesis and neutrophil adhesion to endothelial cells. NETs can directly exert several proangiogenic activities in human endothelial cells and NETs induced by ANGPTs and PAF increase several aspects of angiogenesis in vitro and in vivo. A better understanding of the pathophysiological functions of NETs in cancer and angiogenesis could be of importance in the early diagnosis, prevention and treatment of tumors. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-angiogenesis in Health and Diseases)
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40 pages, 1213 KiB  
Review
Emerging Therapeutic Strategies for Parkinson’s Disease and Future Prospects: A 2021 Update
by Noha A. Gouda, Ahmed Elkamhawy and Jungsook Cho
Biomedicines 2022, 10(2), 371; https://doi.org/10.3390/biomedicines10020371 - 03 Feb 2022
Cited by 28 | Viewed by 6376
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder pathologically distinguished by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Muscle rigidity, tremor, and bradykinesia are all clinical motor hallmarks of PD. Several pathways have been implicated in PD etiology, including mitochondrial dysfunction, [...] Read more.
Parkinson’s disease (PD) is a neurodegenerative disorder pathologically distinguished by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Muscle rigidity, tremor, and bradykinesia are all clinical motor hallmarks of PD. Several pathways have been implicated in PD etiology, including mitochondrial dysfunction, impaired protein clearance, and neuroinflammation, but how these factors interact remains incompletely understood. Although many breakthroughs in PD therapy have been accomplished, there is currently no cure for PD, only trials to alleviate the related motor symptoms. To reduce or stop the clinical progression and mobility impairment, a disease-modifying approach that can directly target the etiology rather than offering symptomatic alleviation remains a major unmet clinical need in the management of PD. In this review, we briefly introduce current treatments and pathophysiology of PD. In addition, we address the novel innovative therapeutic targets for PD therapy, including α-synuclein, autophagy, neurodegeneration, neuroinflammation, and others. Several immunomodulatory approaches and stem cell research currently in clinical trials with PD patients are also discussed. Moreover, preclinical studies and clinical trials evaluating the efficacy of novel and repurposed therapeutic agents and their pragmatic applications with encouraging outcomes are summarized. Finally, molecular biomarkers under active investigation are presented as potentially valuable tools for early PD diagnosis. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Treatments on Neurodegenerative Diseases)
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9 pages, 969 KiB  
Article
Influence of DNA Mismatch Repair (MMR) System in Survival and Response to Immune Checkpoint Inhibitors (ICIs) in Non-Small Cell Lung Cancer (NSCLC): Retrospective Analysis
by Alejandro Olivares-Hernández, Edel del Barco Morillo, Carmen Parra Pérez, José Pablo Miramontes-González, Luis Figuero-Pérez, Teresa Martín-Gómez, Roberto Escala-Cornejo, Lorena Bellido Hernández, Rogelio González Sarmiento, Juan Jesús Cruz-Hernández and María Dolores Ludeña de la Cruz
Biomedicines 2022, 10(2), 360; https://doi.org/10.3390/biomedicines10020360 - 02 Feb 2022
Cited by 18 | Viewed by 2546
Abstract
Mutations in the mismatch repair (MMR) system predict the response to immune checkpoint inhibitors (ICIs) like colon or gastric cancer. However, the MMR system’s involvement in non-small cell lung cancer (NSCLC) remains unknown. Addressing this issue will improve clinical guidelines in the case [...] Read more.
Mutations in the mismatch repair (MMR) system predict the response to immune checkpoint inhibitors (ICIs) like colon or gastric cancer. However, the MMR system’s involvement in non-small cell lung cancer (NSCLC) remains unknown. Addressing this issue will improve clinical guidelines in the case of mutations in the main genes of the MMR system (MLH1, MSH2, MSH6, and PMS2). This work retrospectively assessed the role that these gene mutations play in the response to and survival of ICIs in NSCLC. Patients with NSCLC treated with nivolumab as the second-line treatment in the University Hospital of Salamanca were enrolled in this study. Survival and response analyses were performed according to groups of MMR system gene expression (MMR expression present or deficiency) and other subgroups, such as toxicity. There was a statistically significant relationship between the best response obtained and the expression of the MMR system (p = 0.045). The presence of toxicity grade ≥ 3 was associated with the deficiency expression of MMR (dMMR/MSI-H) group (p = 0.022; odds ratio = 10.167, 95% confidence interval (CI) 1.669–61.919). A trend towards greater survival and response to ICIs was observed in NSCLC and dMMR. Assessing the genes in the MMR system involved in NSCLC is key to obtaining personalized immunotherapy treatments. Full article
(This article belongs to the Section Cancer Biology and Oncology)
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11 pages, 2909 KiB  
Article
Gel-Forming of Self-Assembling Peptides Functionalized with Food Bioactive Motifs Modulate DPP-IV and ACE Inhibitory Activity in Human Intestinal Caco-2 Cells
by Raffaele Pugliese, Martina Bartolomei, Carlotta Bollati, Giovanna Boschin, Anna Arnoldi and Carmen Lammi
Biomedicines 2022, 10(2), 330; https://doi.org/10.3390/biomedicines10020330 - 31 Jan 2022
Cited by 10 | Viewed by 2723
Abstract
Food bioactive peptides are increasingly used for formulating food products, nutraceuticals, and functional food, since they are generally considered safe for human consumption and metabolic syndrome prevention. They are also becoming popular as sustainable sources of novel functional biomaterials such as hydrogels, edible [...] Read more.
Food bioactive peptides are increasingly used for formulating food products, nutraceuticals, and functional food, since they are generally considered safe for human consumption and metabolic syndrome prevention. They are also becoming popular as sustainable sources of novel functional biomaterials such as hydrogels, edible nanonutraceuticals, delivery systems, and packing materials. However, such food peptides are mostly unstable, and degrade during food processing, or in a gastrointestinal environment, thus resulting in low bioavailability precluding their practical applications. Here, we decided to functionalize the well-known and characterized self-assembling peptide RADA16 with two synthetic analogues of food bioactive peptides deriving from the hydrolysis of soybean glycinin and lupin β-conglutin (namely IAVPTGVA and LTFPGSAED) for control of and improvement in their gel-forming nanostructures, biomechanics, and biological features. Extensive characterization was performed via Circular Dichroism (CD) spectroscopy, Fourier Transform Infrared spectroscopy (FT-IR), Thioflavin T (ThT) binding assay, rheological measurements, and Atomic Force Microscopy (AFM) analysis. Lastly, since self-assembling peptides (SAPs) can be co-assembled with diluent SAPs (without a bioactive epitope) as an approach to control the density of biological signals and therefore attain enhanced bioactivity, we investigated the effect of the co-assembly of RADA16 and functionalized food bioactive SAPs (dubbed cAP-Soy1 and cAP-Lup1) for the growth of Caco-2 human intestinal cells and contextually we characterized their biological activities as DPP-IV and ACE inhibitors, in order to demonstrate their potential use for the prevention of metabolic syndrome. Full article
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22 pages, 3081 KiB  
Article
An Early Th1 Response Is a Key Factor for a Favorable COVID-19 Evolution
by Francisco Javier Gil-Etayo, Sara Garcinuño, Alberto Utrero-Rico, Oscar Cabrera-Marante, Daniel Arroyo-Sanchez, Esther Mancebo, Daniel Enrique Pleguezuelo, Edgard Rodríguez-Frías, Luis M. Allende, Pablo Morales-Pérez, María José Castro-Panete, Antonio Lalueza, Carlos Lumbreras, Estela Paz-Artal and Antonio Serrano
Biomedicines 2022, 10(2), 296; https://doi.org/10.3390/biomedicines10020296 - 27 Jan 2022
Cited by 19 | Viewed by 3575
Abstract
The Th1/Th2 balance plays a crucial role in the progression of different pathologies and is a determining factor in the evolution of infectious diseases. This work has aimed to evaluate the early, or on diagnosis, T-cell compartment response, T-helper subsets and anti-SARS-CoV-2 antibody [...] Read more.
The Th1/Th2 balance plays a crucial role in the progression of different pathologies and is a determining factor in the evolution of infectious diseases. This work has aimed to evaluate the early, or on diagnosis, T-cell compartment response, T-helper subsets and anti-SARS-CoV-2 antibody specificity in COVID-19 patients and to classify them according to evolution based on infection severity. A unicenter, randomized group of 146 COVID-19 patients was divided into four groups in accordance with the most critical events during the course of disease. The immunophenotype and T-helper subsets were analyzed by flow cytometry. Asymptomatic SARS-CoV-2 infected individuals showed a potent and robust Th1 immunity, with a lower Th17 and less activated T-cells at the time of sample acquisition compared not only with symptomatic patients, but also with healthy controls. Conversely, severe COVID-19 patients presented with Th17-skewed immunity, fewer Th1 responses and more activated T-cells. The multivariate analysis of the immunological and inflammatory parameters, together with the comorbidities, showed that the Th1 response was an independent protective factor for the prevention of hospitalization (OR 0.17, 95% CI 0.03–0.81), with an AUC of 0.844. Likewise, the Th1 response was found to be an independent protective factor for severe forms of the disease (OR 0.09, 95% CI: 0.01–0.63, p = 0.015, AUC: 0.873). In conclusion, a predominant Th1 immune response in the acute phase of the SARS-CoV-2 infection could be used as a tool to identify patients who might have a good disease evolution. Full article
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27 pages, 2084 KiB  
Review
Implication of Intestinal Barrier Dysfunction in Gut Dysbiosis and Diseases
by Carmine Stolfi, Claudia Maresca, Giovanni Monteleone and Federica Laudisi
Biomedicines 2022, 10(2), 289; https://doi.org/10.3390/biomedicines10020289 - 27 Jan 2022
Cited by 74 | Viewed by 10364
Abstract
The intestinal mucosal barrier, also referred to as intestinal barrier, is widely recognized as a critical player in gut homeostasis maintenance as it ensures the complex crosstalk between gut microbes (both commensals and pathogens) and the host immune system. Highly specialized epithelial cells [...] Read more.
The intestinal mucosal barrier, also referred to as intestinal barrier, is widely recognized as a critical player in gut homeostasis maintenance as it ensures the complex crosstalk between gut microbes (both commensals and pathogens) and the host immune system. Highly specialized epithelial cells constantly cope with several protective and harmful agents to maintain the multiple physiological functions of the barrier as well as its integrity. However, both genetic defects and environmental factors can break such equilibrium, thus promoting gut dysbiosis, dysregulated immune-inflammatory responses, and even the development of chronic pathological conditions. Here, we review and discuss the molecular and cellular pathways underlying intestinal barrier structural and functional homeostasis, focusing on potential alterations that may undermine this fine balance. Full article
(This article belongs to the Special Issue Gut Dysbiosis: Molecular Mechanisms and Therapies)
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14 pages, 3485 KiB  
Article
Different Transcutaneous Auricular Vagus Nerve Stimulation Parameters Modulate the Anti-Inflammatory Effects on Lipopolysaccharide-Induced Acute Inflammation in Mice
by Yoon-Young Go, Won-Min Ju, Chan-Mi Lee, Sung-Won Chae and Jae-Jun Song
Biomedicines 2022, 10(2), 247; https://doi.org/10.3390/biomedicines10020247 - 24 Jan 2022
Cited by 17 | Viewed by 4678
Abstract
Vagus nerve stimulation (VNS) is considered a potential method for anti-inflammation due to the involvement of the VN in the cholinergic anti-inflammatory pathway (CAP) formation of a connection between the central nervous system and peripheral immune cells that help relieve inflammation. However, whether [...] Read more.
Vagus nerve stimulation (VNS) is considered a potential method for anti-inflammation due to the involvement of the VN in the cholinergic anti-inflammatory pathway (CAP) formation of a connection between the central nervous system and peripheral immune cells that help relieve inflammation. However, whether a non-invasive transcutaneous auricular VNS (taVNS) modulates the inflammation levels via altering the parameter of taVNS is poorly understood. This study aimed to determine the differential inhibitory effects of taVNS on lipopolysaccharide (LPS)-induced systemic inflammation using electrical stimulation parameters such as pulse frequency and time. The taVNS-promoted CAP activity significantly recovered LPS-induced tissue injuries (lung, spleen, and intestine) and decreased inflammatory cytokine levels and tissue-infiltrated immune cells. Interestingly, the anti-inflammatory capacity of taVNS with 15 Hz was much higher than that of taVNS with 25 Hz. When a cytokine array was used to investigate the changes of inflammation and immune response-related cytokines/chemokines expression in taVNS with 15 Hz or 25 Hz treatment in LPS-induced endotoxemia in mice, most of the expression of cytokines/chemokines associated with pro-inflammation was severely decreased in taVNS with 15 Hz compared to 25 Hz. This study demonstrated that the taVNS parameter could differentially modulate the inflammation levels of animals, suggesting the importance of taVNS parameter selection for use in feasible interventions for acute inflammation treatment. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
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13 pages, 2191 KiB  
Article
Penetration of the SARS-CoV-2 Spike Protein across the Blood–Brain Barrier, as Revealed by a Combination of a Human Cell Culture Model System and Optical Biosensing
by Dániel Petrovszki, Fruzsina R. Walter, Judit P. Vigh, Anna Kocsis, Sándor Valkai, Mária A. Deli and András Dér
Biomedicines 2022, 10(1), 188; https://doi.org/10.3390/biomedicines10010188 - 17 Jan 2022
Cited by 20 | Viewed by 8375
Abstract
Since the outbreak of the global pandemic caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), several clinical aspects of the disease have come into attention. Besides its primary route of infection through the respiratory system, SARS-CoV-2 is known to have neuroinvasive capacity, causing [...] Read more.
Since the outbreak of the global pandemic caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), several clinical aspects of the disease have come into attention. Besides its primary route of infection through the respiratory system, SARS-CoV-2 is known to have neuroinvasive capacity, causing multiple neurological symptoms with increased neuroinflammation and blood–brain barrier (BBB) damage. The viral spike protein disseminates via circulation during infection, and when reaching the brain could possibly cross the BBB, which was demonstrated in mice. Therefore, its medical relevance is of high importance. The aim of this study was to evaluate the barrier penetration of the S1 subunit of spike protein in model systems of human organs highly exposed to the infection. For this purpose, in vitro human BBB and intestinal barrier cell–culture systems were investigated by an optical biosensing method. We found that spike protein crossed the human brain endothelial cell barrier effectively. Additionally, spike protein passage was found in a lower amount for the intestinal barrier cell layer. These observations were corroborated with parallel specific ELISAs. The findings on the BBB model could provide a further basis for studies focusing on the mechanism and consequences of spike protein penetration across the BBB to the brain. Full article
(This article belongs to the Special Issue Biosensors at the Aid of Medicine)
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16 pages, 1987 KiB  
Article
Selective Isolation of Liver-Derived Extracellular Vesicles Redefines Performance of miRNA Biomarkers for Non-Alcoholic Fatty Liver Disease
by Lauren A. Newman, Zivile Useckaite, Jillian Johnson, Michael J. Sorich, Ashley M. Hopkins and Andrew Rowland
Biomedicines 2022, 10(1), 195; https://doi.org/10.3390/biomedicines10010195 - 17 Jan 2022
Cited by 26 | Viewed by 4028
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Definitive diagnosis of the progressive form, non-alcoholic steatohepatitis (NASH), requires liver biopsy, which is highly invasive and unsuited to early disease or tracking changes. Inadequate performance of current minimally invasive tools [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Definitive diagnosis of the progressive form, non-alcoholic steatohepatitis (NASH), requires liver biopsy, which is highly invasive and unsuited to early disease or tracking changes. Inadequate performance of current minimally invasive tools is a critical barrier to managing NAFLD burden. Altered circulating miRNA profiles show potential for minimally invasive tracking of NAFLD. The selective isolation of the circulating extracellular vesicle subset that originates from hepatocytes presents an important opportunity for improving the performance of miRNA biomarkers of liver disease. The expressions of miR-122, -192, and -128-3p were quantified in total cell-free RNA, global EVs, and liver-specific EVs from control, NAFL, and NASH subjects. In ASGR1+ EVs, each miR biomarker trended positively with disease severity and expression was significantly higher in NASH subjects compared with controls. The c-statistic defining the performance of ASGR1+ EV derived miRNAs was invariably >0.78. This trend was not observed in the alternative sources. This study demonstrates the capacity for liver-specific isolation to transform the performance of EV-derived miRNA biomarkers for NAFLD, robustly distinguishing patients with NAFL and NASH. Full article
(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)
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12 pages, 1667 KiB  
Article
A Unique Immune-Related Gene Signature Represents Advanced Liver Fibrosis and Reveals Potential Therapeutic Targets
by Pil-Soo Sung, Chang-Min Kim, Jung-Hoon Cha, Jin-Young Park, Yun-Suk Yu, Hee-Jung Wang, Jin-Kyeoung Kim and Si-Hyun Bae
Biomedicines 2022, 10(1), 180; https://doi.org/10.3390/biomedicines10010180 - 16 Jan 2022
Cited by 5 | Viewed by 2708
Abstract
Innate and adaptive immune responses are critically associated with the progression of fibrosis in chronic liver diseases. In this study, we aim to identify a unique immune-related gene signature representing advanced liver fibrosis and to reveal potential therapeutic targets. Seventy-seven snap-frozen liver tissues [...] Read more.
Innate and adaptive immune responses are critically associated with the progression of fibrosis in chronic liver diseases. In this study, we aim to identify a unique immune-related gene signature representing advanced liver fibrosis and to reveal potential therapeutic targets. Seventy-seven snap-frozen liver tissues with various chronic liver diseases at different fibrosis stages (1: n = 12, 2: n = 12, 3: n = 25, 4: n = 28) were subjected to expression analyses. Gene expression analysis was performed using the nCounter PanCancer Immune Profiling Panel (NanoString Technologies, Seattle, WA, USA). Biological meta-analysis was performed using the CBS Probe PINGSTM (CbsBioscience, Daejeon, Korea). Using non-tumor tissues from surgically resected specimens, we identified the immune-related, five-gene signature (CHIT1_FCER1G_OSM_VEGFA_ZAP70) that reliably differentiated patients with low- (F1 and F2) and high-grade fibrosis (F3 and F4; accuracy = 94.8%, specificity = 91.7%, sensitivity = 96.23%). The signature was independent of all pathological and clinical features and was independently associated with high-grade fibrosis using multivariate analysis. Among these genes, the expression of inflammation-associated FCER1G, OSM, VEGFA, and ZAP70 was lower in high-grade fibrosis than in low-grade fibrosis, whereas CHIT1 expression, which is associated with fibrogenic activity of macrophages, was higher in high-grade fibrosis. Meta-analysis revealed that STAT3, a potential druggable target, highly interacts with the five-gene signature. Overall, we identified an immune gene signature that reliably predicts advanced fibrosis in chronic liver disease. This signature revealed potential immune therapeutic targets to ameliorate liver fibrosis. Full article
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15 pages, 4563 KiB  
Article
Puerarin Attenuates Obesity-Induced Inflammation and Dyslipidemia by Regulating Macrophages and TNF-Alpha in Obese Mice
by Ji-Won Noh, Hee-Kwon Yang, Min-Soo Jun and Byung-Cheol Lee
Biomedicines 2022, 10(1), 175; https://doi.org/10.3390/biomedicines10010175 - 14 Jan 2022
Cited by 14 | Viewed by 2447
Abstract
Obesity causes low-grade inflammation that results in dyslipidemia and insulin resistance. We evaluated the effect of puerarin on obesity and metabolic complications both in silico and in vivo and investigated the underlying immunological mechanisms. Twenty C57BL/6 mice were divided into four groups: normal [...] Read more.
Obesity causes low-grade inflammation that results in dyslipidemia and insulin resistance. We evaluated the effect of puerarin on obesity and metabolic complications both in silico and in vivo and investigated the underlying immunological mechanisms. Twenty C57BL/6 mice were divided into four groups: normal chow, control (HFD), HFD + puerarin (PUE) 200 mg/kg, and HFD + atorvastatin (ATO) 10 mg/kg groups. We examined bodyweight, oral glucose tolerance test, serum insulin, oral fat tolerance test, serum lipids, and adipocyte size. We also analyzed the percentage of total, M1, and M2 adipose tissue macrophages (ATMs) and the expression of F4/80, tumor necrosis factor-α (TNF-α), C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5, and C-X-C motif chemokine receptor 4. In silico, we identified the treatment-targeted genes of puerarin and simulated molecular docking with puerarin and TNF, M1, and M2 macrophages based on functionally enriched pathways. Puerarin did not significantly change bodyweight but significantly improved fat pad weight, adipocyte size, fat area in the liver, free fatty acids, triglycerides, total cholesterol, and HDL-cholesterol in vivo. In addition, puerarin significantly decreased the ATM population and TNF-α expression. Therefore, puerarin is a potential anti-obesity treatment based on its anti-inflammatory effects in adipose tissue. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 3.0)
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14 pages, 5440 KiB  
Article
Humoral Immune Response in IBD Patients Three and Six Months after Vaccination with the SARS-CoV-2 mRNA Vaccines mRNA-1273 and BNT162b2
by Richard Vollenberg, Phil-Robin Tepasse, Joachim Ewald Kühn, Marc Hennies, Markus Strauss, Florian Rennebaum, Tina Schomacher, Göran Boeckel, Eva Lorentzen, Arne Bokemeyer and Tobias Max Nowacki
Biomedicines 2022, 10(1), 171; https://doi.org/10.3390/biomedicines10010171 - 13 Jan 2022
Cited by 20 | Viewed by 3309
Abstract
Severe acute respiratory syndrome coronovirus-2 (SARS-CoV-2) is the cause of the coronavirus disease 2019 (COVID-19) pandemic. Vaccination is considered the core approach to containing the pandemic. There is currently insufficient evidence on the efficacy of these vaccines in immunosuppressed inflammatory bowel disease (IBD) [...] Read more.
Severe acute respiratory syndrome coronovirus-2 (SARS-CoV-2) is the cause of the coronavirus disease 2019 (COVID-19) pandemic. Vaccination is considered the core approach to containing the pandemic. There is currently insufficient evidence on the efficacy of these vaccines in immunosuppressed inflammatory bowel disease (IBD) patients. The aim of this study was to investigate the humoral response in immunosuppressed IBD patients after COVID-19 mRNA vaccination. In this prospective study, IgG antibody levels (AB) against the SARS-CoV-2 receptor-binding domain (spike-protein) were quantitatively determined. For assessing the potential neutralizing capacity, a SARS-CoV-2 surrogate neutralization test (sVNT) was employed in IBD patients (n = 95) and healthy controls (n = 38). Sera were examined prior to the first/second vaccination and 3/6 months after second vaccination. Patients showed lower sVNT (%) and IgG-S (AU/mL) AB both before the second vaccination (sVNT p < 0.001; AB p < 0.001) and 3 (sVNT p = 0.002; AB p = 0.001) and 6 months (sVNT p = 0.062; AB p = 0.061) after the second vaccination. Although seroconversion rates (sVNT, IgG-S) did not differ between the two groups 3 months after second vaccination, a significant difference was seen 6 months after second vaccination (sVNT p = 0.045). Before and three months after the second vaccination, patients treated with anti-tumor necrosis factor (TNF) agents showed significantly lower AB than healthy subjects. In conclusion, an early booster shot vaccination should be discussed for IBD patients on anti-TNF therapy. Full article
(This article belongs to the Special Issue Next-Generation Vaccines and Antivirals against SARS-CoV-2)
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17 pages, 1651 KiB  
Review
Interplay of Oxidative Stress and Necrosis-like Cell Death in Cardiac Ischemia/Reperfusion Injury: A Focus on Necroptosis
by Adriana Adameova, Csaba Horvath, Safa Abdul-Ghani, Zoltan V. Varga, M. Saadeh Suleiman and Naranjan S. Dhalla
Biomedicines 2022, 10(1), 127; https://doi.org/10.3390/biomedicines10010127 - 07 Jan 2022
Cited by 20 | Viewed by 5538
Abstract
Extensive research work has been carried out to define the exact significance and contribution of regulated necrosis-like cell death program, such as necroptosis to cardiac ischemic injury. This cell damaging process plays a critical role in the pathomechanisms of myocardial infarction (MI) and [...] Read more.
Extensive research work has been carried out to define the exact significance and contribution of regulated necrosis-like cell death program, such as necroptosis to cardiac ischemic injury. This cell damaging process plays a critical role in the pathomechanisms of myocardial infarction (MI) and post-infarction heart failure (HF). Accordingly, it has been documented that the modulation of key molecules of the canonical signaling pathway of necroptosis, involving receptor-interacting protein kinases (RIP1 and RIP3) as well as mixed lineage kinase domain-like pseudokinase (MLKL), elicit cardioprotective effects. This is evidenced by the reduction of the MI-induced infarct size, alleviation of myocardial dysfunction, and adverse cardiac remodeling. In addition to this molecular signaling of necroptosis, the non-canonical pathway, involving Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated regulation of mitochondrial permeability transition pore (mPTP) opening, and phosphoglycerate mutase 5 (PGAM5)–dynamin-related protein 1 (Drp-1)-induced mitochondrial fission, has recently been linked to ischemic heart injury. Since MI and HF are characterized by an imbalance between reactive oxygen species production and degradation as well as the occurrence of necroptosis in the heart, it is likely that oxidative stress (OS) may be involved in the mechanisms of this cell death program for inducing cardiac damage. In this review, therefore, several observations from different studies are presented to support this paradigm linking cardiac OS, the canonical and non-canonical pathways of necroptosis, and ischemia-induced injury. It is concluded that a multiple therapeutic approach targeting some specific changes in OS and necroptosis may be beneficial in improving the treatment of ischemic heart disease. Full article
(This article belongs to the Special Issue Oxidative Stress and Antioxidants in Cardiovascular Diseases)
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11 pages, 3156 KiB  
Article
Identification of Druggable Genes for Asthma by Integrated Genomic Network Analysis
by Wirawan Adikusuma, Wan-Hsuan Chou, Min-Rou Lin, Jafit Ting, Lalu Muhammad Irham, Dyah Aryani Perwitasari, Wei-Pin Chang and Wei-Chiao Chang
Biomedicines 2022, 10(1), 113; https://doi.org/10.3390/biomedicines10010113 - 06 Jan 2022
Cited by 16 | Viewed by 4394
Abstract
Asthma is a common and heterogeneous disease characterized by chronic airway inflammation. Currently, the two main types of asthma medicines are inhaled corticosteroids and long-acting β2-adrenoceptor agonists (LABAs). In addition, biological drugs provide another therapeutic option, especially for patients with severe asthma. However, [...] Read more.
Asthma is a common and heterogeneous disease characterized by chronic airway inflammation. Currently, the two main types of asthma medicines are inhaled corticosteroids and long-acting β2-adrenoceptor agonists (LABAs). In addition, biological drugs provide another therapeutic option, especially for patients with severe asthma. However, these drugs were less effective in preventing severe asthma exacerbation, and other drug options are still limited. Herein, we extracted asthma-associated single nucleotide polymorphisms (SNPs) from the genome-wide association studies (GWAS) and phenome-wide association studies (PheWAS) catalog and prioritized candidate genes through five functional annotations. Genes enriched in more than two categories were defined as “biological asthma risk genes.” Then, DrugBank was used to match target genes with FDA-approved medications and identify candidate drugs for asthma. We discovered 139 biological asthma risk genes and identified 64 drugs targeting 22 of these genes. Seven of them were approved for asthma, including reslizumab, mepolizumab, theophylline, dyphylline, aminophylline, oxtriphylline, and enprofylline. We also found 17 drugs with clinical or preclinical evidence in treating asthma. In addition, eleven of the 40 candidate drugs were further identified as promising asthma therapy. Noteworthy, IL6R is considered a target for asthma drug repurposing based on its high target scores. Through in silico drug repurposing approach, we identified sarilumab and satralizumab as the most promising drug for asthma treatment. Full article
(This article belongs to the Special Issue Feature Papers in Drug Discovery and Development)
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25 pages, 2815 KiB  
Review
Neurogenic Inflammation: The Participant in Migraine and Recent Advancements in Translational Research
by Eleonóra Spekker, Masaru Tanaka, Ágnes Szabó and László Vécsei
Biomedicines 2022, 10(1), 76; https://doi.org/10.3390/biomedicines10010076 - 30 Dec 2021
Cited by 61 | Viewed by 11647
Abstract
Migraine is a primary headache disorder characterized by a unilateral, throbbing, pulsing headache, which lasts for hours to days, and the pain can interfere with daily activities. It exhibits various symptoms, such as nausea, vomiting, sensitivity to light, sound, and odors, and physical [...] Read more.
Migraine is a primary headache disorder characterized by a unilateral, throbbing, pulsing headache, which lasts for hours to days, and the pain can interfere with daily activities. It exhibits various symptoms, such as nausea, vomiting, sensitivity to light, sound, and odors, and physical activity consistently contributes to worsening pain. Despite the intensive research, little is still known about the pathomechanism of migraine. It is widely accepted that migraine involves activation and sensitization of the trigeminovascular system. It leads to the release of several pro-inflammatory neuropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses, including vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Convincing evidence obtained in rodent models suggests that neurogenic inflammation is assumed to contribute to the development of a migraine attack. Chemical stimulation of the dura mater triggers activation and sensitization of the trigeminal system and causes numerous molecular and behavioral changes; therefore, this is a relevant animal model of acute migraine. This narrative review discusses the emerging evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology of migraine, presenting the most recent advances in preclinical research and the novel therapeutic approaches to the disease. Full article
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16 pages, 1449 KiB  
Article
Post-COVID-19 Patients Who Develop Lung Fibrotic-like Changes Have Lower Circulating Levels of IFN-β but Higher Levels of IL-1α and TGF-β
by Chiara Colarusso, Angelantonio Maglio, Michela Terlizzi, Carolina Vitale, Antonio Molino, Aldo Pinto, Alessandro Vatrella and Rosalinda Sorrentino
Biomedicines 2021, 9(12), 1931; https://doi.org/10.3390/biomedicines9121931 - 17 Dec 2021
Cited by 44 | Viewed by 3386
Abstract
Purpose: SARS-CoV-2 infection induces in some patients a condition called long-COVID-19, herein post-COVID-19 (PC), which persists for longer than the negative oral-pharyngeal swab. One of the complications of PC is pulmonary fibrosis. The purpose of this study was to identify blood biomarkers to [...] Read more.
Purpose: SARS-CoV-2 infection induces in some patients a condition called long-COVID-19, herein post-COVID-19 (PC), which persists for longer than the negative oral-pharyngeal swab. One of the complications of PC is pulmonary fibrosis. The purpose of this study was to identify blood biomarkers to predict PC patients undergoing pulmonary fibrosis. Patients and Methods: We analyzed blood samples of healthy, anti-SARS-CoV-2 vaccinated (VAX) subjects and PC patients who were stratified according to the severity of the disease and chest computed tomography (CT) scan data. Results: The inflammatory C reactive protein (CRP), complement complex C5b-9, LDH, but not IL-6, were higher in PC patients, independent of the severity of the disease and lung fibrotic areas. Interestingly, PC patients with ground-glass opacities (as revealed by chest CT scan) were characterized by higher plasma levels of IL-1α, CXCL-10, TGF-β, but not of IFN-β, compared to healthy and VAX subjects. In particular, 19 out of 23 (82.6%) severe PC and 8 out of 29 (27.6%) moderate PC patients presented signs of lung fibrosis, associated to lower levels of IFN-β, but higher IL-1α and TGF-β. Conclusions: We found that higher IL-1α and TGF-β and lower plasma levels of IFN-β could predict an increased relative risk (RR = 2.8) of lung fibrosis-like changes in PC patients. Full article
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14 pages, 991 KiB  
Systematic Review
Systematic Review with Meta-Analysis: Diagnostic Accuracy of Pro-C3 for Hepatic Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease
by Anne Linde Mak, Jenny Lee, Anne-Marieke van Dijk, Yasaman Vali, Guruprasad P. Aithal, Jörn M. Schattenberg, Quentin M. Anstee, M. Julia Brosnan, Mohammad Hadi Zafarmand, Dewkoemar Ramsoekh, Stephen A. Harrison, Max Nieuwdorp, Patrick M. Bossuyt and Adriaan G. Holleboom
Biomedicines 2021, 9(12), 1920; https://doi.org/10.3390/biomedicines9121920 - 15 Dec 2021
Cited by 24 | Viewed by 3620
Abstract
The prevalence and severity of non-alcoholic fatty liver disease (NAFLD) is increasing, yet adequately validated tests for care paths are limited and non-invasive markers of disease progression are urgently needed. The aim of this work was to summarize the performance of Pro-C3, a [...] Read more.
The prevalence and severity of non-alcoholic fatty liver disease (NAFLD) is increasing, yet adequately validated tests for care paths are limited and non-invasive markers of disease progression are urgently needed. The aim of this work was to summarize the performance of Pro-C3, a biomarker of active fibrogenesis, in detecting significant fibrosis (F ≥ 2), advanced fibrosis (F ≥ 3), cirrhosis (F4) and non-alcoholic steatohepatitis (NASH) in patients with NAFLD. A sensitive search of five databases was performed in July 2021. Studies reporting Pro-C3 measurements and liver histology in adults with NAFLD without co-existing liver diseases were eligible. Meta-analysis was conducted by applying a bivariate random effects model to produce summary estimates of Pro-C3 accuracy. From 35 evaluated reports, eight studies met our inclusion criteria; 1568 patients were included in our meta-analysis of significant fibrosis and 2058 in that of advanced fibrosis. The area under the summary curve was 0.81 (95% CI 0.77–0.84) in detecting significant fibrosis and 0.79 (95% CI 0.73–0.82) for advanced fibrosis. Our results support Pro-C3 as an important candidate biomarker for non-invasive assessment of liver fibrosis in NAFLD. Further direct comparisons with currently recommended non-invasive tests will demonstrate whether Pro-C3 panels can outperform these tests, and improve care paths for patients with NAFLD. Full article
(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)
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