Oxidative Stress and Inflammation: From Mechanisms to Therapeutic Approaches 2.0

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 72960

Special Issue Editor

Special Issue Information

Dear Colleagues,

Oxidative stress and inflammation are two phenomena that are directly involved in practically all pathologies and especially in aging. However, they are not only involved in processes associated with damage. For instance, oxidative stress, which is associated with the redox state, constitutes an important mechanism in cell signaling and many physiological processes. Regarding inflammatory mediators, it is also known that they are essential in mechanisms such as the generation of gastric mucus for the protection of the stomach and the repair of tissues via the mobilization of stem cells. However, when these two phenomena are deregulated, their action is harmful. In this Special Issue, we ask ourselves several questions: How and when should we allow or block oxidative stress and inflammation? What is the advisable anti-inflammatory therapy associated with aging?

Prof. Dr. Juan Gambini
Guest Editor

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Keywords

  • oxidative stress
  • inflammation
  • molecular mechanisms
  • pharmacotherapy
  • longevity
  • aging

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Published Papers (17 papers)

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Research

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20 pages, 12989 KiB  
Article
S-Carboxymethyl Cysteine Protects against Oxidative Stress and Mitochondrial Impairment in a Parkinson’s Disease In Vitro Model
by Mariano Catanesi, Laura Brandolini, Michele d’Angelo, Maria Grazia Tupone, Elisabetta Benedetti, Margherita Alfonsetti, Massimiliano Quintiliani, Maddalena Fratelli, Daniela Iaconis, Annamaria Cimini, Vanessa Castelli and Marcello Allegretti
Biomedicines 2021, 9(10), 1467; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101467 - 14 Oct 2021
Cited by 9 | Viewed by 2001
Abstract
The mucolytic agent S-carboxymethylcysteine is widely used as an expectorant for the treatment of numerous respiratory disorders. The metabolic fate of S-carboxymethyl-L-cysteine is complex. Several clinical studies have demonstrated that the metabolism of this agent differs within the same individual, with sulfur oxygenated [...] Read more.
The mucolytic agent S-carboxymethylcysteine is widely used as an expectorant for the treatment of numerous respiratory disorders. The metabolic fate of S-carboxymethyl-L-cysteine is complex. Several clinical studies have demonstrated that the metabolism of this agent differs within the same individual, with sulfur oxygenated metabolites generated upon night-time administration. It has been indicated that this drug behaves like a free radical scavenger and that, in this regard, the sulfide is the active species with sulphoxide metabolites (already oxidized) being inactive. Consequently, a night-time consumption of the drug should be more effective upon daytime administration. Still, this diurnal variation in biotransformation (deactivation) is dependent on the genetic polymorphism on which relies the patient population capacities of S-carboxymethyl-L-cysteine sulphoxidation. It has been reported that those cohorts who are efficient sulfur oxidizers will generate inactive oxygenated metabolites. In contrast, those who have a relative deficiency in this mechanism will be subjected to the active sulfide for a more extended period. In this regard, it is noteworthy that 38–39% of Parkinson’s disease patients belong to the poor sulphoxide cohort, being exposed to higher levels of active sulfide, the active antioxidant metabolite of S-carboxymethyl-L-cysteine. Parkinson’s disease is a neurodegenerative disorder that affects predominately dopaminergic neurons. It has been demonstrated that oxidative stress and mitochondrial dysfunction play a crucial role in the degeneration of dopaminergic neurons. Based on this evidence, in this study, we evaluated the effects of S-carboxymethyl cysteine in an in vitro model of Parkinson’s disease in protecting against oxidative stress injury. The data obtained suggested that an S-carboxymethylcysteine-enriched diet could be beneficial during aging to protect neurons from oxidative imbalance and mitochondrial dysfunction, thus preventing the progression of neurodegenerative processes. Full article
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13 pages, 3194 KiB  
Article
Thioredoxin-1 and Correlations of the Plasma Cytokines Regarding Aortic Valve Stenosis Severity
by Peteris Tretjakovs, Juris Lurins, Simons Svirskis, Gita Gersone, Dace Lurina, Ulla Rozenberga, Leons Blumfelds, Guntis Bahs, Aivars Lejnieks and Vitolds Mackevics
Biomedicines 2021, 9(8), 1041; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9081041 - 18 Aug 2021
Cited by 5 | Viewed by 1921
Abstract
Aortic valve stenosis (AS) develops not only with a pronounced local inflammatory response, but also oxidative stress is involved. The aim of this study was to evaluate the plasma levels of thioredoxin-1 (TRX1), myeloperoxidase (MPO), chemerin, growth differentiation factor 15 (GDF-15), angiopoietin-2 (Ang-2), [...] Read more.
Aortic valve stenosis (AS) develops not only with a pronounced local inflammatory response, but also oxidative stress is involved. The aim of this study was to evaluate the plasma levels of thioredoxin-1 (TRX1), myeloperoxidase (MPO), chemerin, growth differentiation factor 15 (GDF-15), angiopoietin-2 (Ang-2), vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2), fibroblast growth factor 21 (FGF-21), and metalloproteinase (MMP)-1, -3, and -9 in acquired AS patients as well as to clarify the correlations of TXR1 and the plasma inflammatory biomarkers regarding AS severity. AS patients were classified into three groups: 16 patients with mild AS stenosis, 19 with moderate and 11 with severe AS, and 30 subjects without AS were selected as a control group. AS patients had significantly higher plasma levels of TRX1 compared to controls, but the highest difference was found in mild AS patients compared to the controls. We conclude that AS is associated with significantly increased plasma TRX1 levels, and TRX1 might serve as a specific and sensitive biomarker of AS. TRX1 and also chemerin, GDF-15, VEGF-A, FGF-2 and FGF-21 significantly correlate with AS severity degrees. TRX1 also showed positive association with FGF-2, VEGF-A, and MMP-3 in all AS patients. Full article
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15 pages, 13344 KiB  
Article
Surface Phenotype Changes and Increased Response to Oxidative Stress in CD4+CD25high T Cells
by Yoshiki Yamamoto, Takaharu Negoro, Rui Tada, Michiaki Narushima, Akane Hoshi, Yoichi Negishi and Yasuko Nakano
Biomedicines 2021, 9(6), 616; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060616 - 29 May 2021
Cited by 1 | Viewed by 1951
Abstract
Conversion of CD4+CD25+FOXP3+ T regulatory cells (Tregs) from the immature (CD45RA+) to mature (CD45RO+) phenotype has been shown during development and allergic reactions. The relative frequencies of these Treg phenotypes and [...] Read more.
Conversion of CD4+CD25+FOXP3+ T regulatory cells (Tregs) from the immature (CD45RA+) to mature (CD45RO+) phenotype has been shown during development and allergic reactions. The relative frequencies of these Treg phenotypes and their responses to oxidative stress during development and allergic inflammation were analysed in samples from paediatric and adult subjects. The FOXP3lowCD45RA+ population was dominant in early childhood, while the percentage of FOXP3highCD45RO+ cells began increasing in the first year of life. These phenotypic changes were observed in subjects with and without asthma. Further, there was a significant increase in phosphorylated ERK1/2 (pERK1/2) protein in hydrogen peroxide (H2O2)-treated CD4+CD25high cells in adults with asthma compared with those without asthma. Increased pERK1/2 levels corresponded with increased Ca2+ response to T cell receptor stimulation. mRNA expression of peroxiredoxins declined in Tregs from adults with asthma. Finally, CD4+CD25high cells from paediatric subjects were more sensitive to oxidative stress than those from adults in vitro. The differential Treg sensitivity to oxidative stress observed in children and adults was likely dependent on phenotypic CD45 isoform switching. Increased sensitivity of Treg cells from adults with asthma to H2O2 resulted from a reduction of peroxiredoxin-2, -3, -4 and increased pERK1/2 via impaired Ca2+ response in these cells. Full article
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17 pages, 3781 KiB  
Article
In Vitro Evaluation of the Anti-Inflammatory Effect of KMUP-1 and In Vivo Analysis of Its Therapeutic Potential in Osteoarthritis
by Shang-En Huang, Erna Sulistyowati, Yu-Ying Chao, Bin-Nan Wu, Zen-Kong Dai, Jong-Hau Hsu and Jwu-Lai Yeh
Biomedicines 2021, 9(6), 615; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060615 - 28 May 2021
Cited by 9 | Viewed by 2968
Abstract
Osteoarthritis is a degenerative arthropathy that is mainly characterized by dysregulation of inflammatory responses. KMUP-1, a derived chemical synthetic of xanthine, has been shown to have anti-inflammatory and antioxidant properties. Here, we aimed to investigate the in vitro anti-inflammatory and in vivo anti-osteoarthritis [...] Read more.
Osteoarthritis is a degenerative arthropathy that is mainly characterized by dysregulation of inflammatory responses. KMUP-1, a derived chemical synthetic of xanthine, has been shown to have anti-inflammatory and antioxidant properties. Here, we aimed to investigate the in vitro anti-inflammatory and in vivo anti-osteoarthritis effects of KMUP-1. Protein and gene expressions of inflammation markers were determined by ELISA, Western blotting and microarray, respectively. RAW264.7 mouse macrophages were cultured and pretreated with KMUP-1 (1, 5, 10 μM). The productions of TNF-α, IL-6, MMP-2 and MMP- 9 were reduced by KMUP-1 pretreatment in LPS-induced inflammation of RAW264.7 cells. The expressions of iNOS, TNF-α, COX-2, MMP-2 and MMP-9 were also inhibited by KMUP-1 pretreatment. The gene expression levels of TNF and COX families were also downregulated. In addition, KMUP-1 suppressed the activations of ERK, JNK and p38 as well as phosphorylation of IκBα/NF-κB signaling pathways. Furthermore, SIRT1 inhibitor attenuated the inhibitory effect of KMUP-1 in LPS-induced NF-κB activation. In vivo study showed that KMUP-1 reduced mechanical hyperalgesia in monoiodoacetic acid (MIA)-induced rats OA. Additionally, KMUP-1 pretreatment reduced the serum levels of TNF-α and IL-6 in MIA-injected rats. Moreover, macroscopic and histological observation showed that KMUP-1 reduced articular cartilage erosion in rats. Our results demonstrated that KMUP-1 inhibited the inflammatory responses and restored SIRT1 in vitro, alleviated joint-related pain and cartilage destruction in vivo. Taken together, KMUP-1 has the potential to improve MIA-induced articular cartilage degradation by inhibiting the levels and expression of inflammatory mediators suggesting that KMUP-1 might be a potential therapeutic agent for OA. Full article
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16 pages, 1646 KiB  
Article
MicroRNA Signatures Associated with Bronchopulmonary Dysplasia Severity in Tracheal Aspirates of Preterm Infants
by Roopa Siddaiah, Christiana N. Oji-Mmuo, Deborah T. Montes, Nathalie Fuentes, Debra Spear, Ann Donnelly and Patricia Silveyra
Biomedicines 2021, 9(3), 257; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9030257 - 05 Mar 2021
Cited by 10 | Viewed by 2215
Abstract
Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that develops in neonates as a consequence of preterm birth, arrested fetal lung development, and inflammation. The incidence of BPD remains on the rise as a result of increasing survival of extremely preterm [...] Read more.
Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that develops in neonates as a consequence of preterm birth, arrested fetal lung development, and inflammation. The incidence of BPD remains on the rise as a result of increasing survival of extremely preterm infants. Severe BPD contributes to significant health care costs and is associated with prolonged hospitalizations, respiratory infections, and neurodevelopmental deficits. In this study, we aimed to detect novel biomarkers of BPD severity. We collected tracheal aspirates (TAs) from preterm babies with mild/moderate (n = 8) and severe (n = 17) BPD, and we profiled the expression of 1048 miRNAs using a PCR array. Associations with biological pathways were determined with the Ingenuity Pathway Analysis (IPA) software. We found 31 miRNAs differentially expressed between the two disease groups (2-fold change, false discovery rate (FDR) < 0.05). Of these, 4 miRNAs displayed significantly higher expression levels, and 27 miRNAs had significantly lower expression levels in the severe BPD group when compared to the mild/moderate BPD group. IPA identified cell signaling and inflammation pathways associated with miRNA signatures. We conclude that TAs of extremely premature infants contain miRNA signatures associated with severe BPD. These may serve as potential biomarkers of disease severity in infants with BPD. Full article
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17 pages, 5487 KiB  
Article
Dual Acting Carbon Monoxide Releasing Molecules and Carbonic Anhydrase Inhibitors Differentially Modulate Inflammation in Human Tenocytes
by Marialucia Gallorini, Anna C. Berardi, Alessia Ricci, Cristina Antonetti Lamorgese Passeri, Susi Zara, Francesco Oliva, Amelia Cataldi, Fabrizio Carta and Simone Carradori
Biomedicines 2021, 9(2), 141; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020141 - 01 Feb 2021
Cited by 12 | Viewed by 2281
Abstract
Sustained oxidative stress and inflammation have been reported as the major factors responsible for the failure of tendon healing during rotator cuff tears (RCTs) and rotator cuff disease (RCD). Although, their therapeutic management remains still challenging. Carbonic anhydrases (CAs) are involved in many [...] Read more.
Sustained oxidative stress and inflammation have been reported as the major factors responsible for the failure of tendon healing during rotator cuff tears (RCTs) and rotator cuff disease (RCD). Although, their therapeutic management remains still challenging. Carbonic anhydrases (CAs) are involved in many pathological conditions, and the overexpression of both CA9 and 12 in inflamed joints has been recently reported. Consequently, a selective CA9/12 inhibition could be a feasible strategy for improving tendon recovery after injury. In addition, since carbon monoxide (CO) has been proven to have an important role in modulating inflammation, CO releasing molecules (CORMs) can be also potentially suitable compounds. The present study aims at evaluating five newly synthesized dual-mode acting CA inhibitors (CAIs)-CORMs compounds, belonging to two chemical scaffolds, on tendon-derived human primary cells under H2O2 stimulation in comparison with Meloxicam. Our results show that compounds 2 and 7 are the most promising of the series in counteracting oxidative stress-induced cytotoxicity and display a better profile in terms of enhanced viability, decreased LDH release, and augmented tenocyte proliferation compared to Meloxicam. Moreover, compound 7, as a potent superoxide scavenger, exerts its action inhibiting NF-ĸB translocation and downregulating iNOS, whereas compound 2 is more effective in increasing collagen I deposition. Taken together, our data highlight a potential role of CA in RCTs and RCD and the prospective effectiveness of compounds acting as CAI-CORM during inflammation. Full article
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Review

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13 pages, 620 KiB  
Review
Does Chemotherapy-Induced Gastrointestinal Mucositis Affect the Bioavailability and Efficacy of Anti-Infective Drugs?
by Ana Rita da Silva Ferreira, Anne-Grete Märtson, Alyse de Boer, Hannah R. Wardill, Jan-Willem Alffenaar, Hermie J. M. Harmsen and Wim J. E. Tissing
Biomedicines 2021, 9(10), 1389; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101389 - 04 Oct 2021
Cited by 2 | Viewed by 3001
Abstract
Antimicrobial prophylaxis is increasingly being used in patients with hematological malignancies receiving high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT). However, few studies have focused on the potential impact of gastrointestinal mucositis (GI-M), a frequently observed side effect of chemotherapy in patients with [...] Read more.
Antimicrobial prophylaxis is increasingly being used in patients with hematological malignancies receiving high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT). However, few studies have focused on the potential impact of gastrointestinal mucositis (GI-M), a frequently observed side effect of chemotherapy in patients with cancer that affects the gastrointestinal microenvironment, on drug absorption. In this review, we discuss how chemotherapy leads to an overall loss of mucosal surface area and consequently to uncontrolled transport across the barrier. The barrier function is depending on intestinal luminal pH, intestinal motility, and diet. Another factor contributing to drug absorption is the gut microbiota, as it modulates the bioavailability of orally administrated drugs by altering the gastrointestinal properties. To better understand the complex interplay of factors in GI-M and drug absorption we suggest: (i) the longitudinal characterization of the impact of GI-M severity on drug exposure in patients, (ii) the development of tools to predict drug absorption, and (iii) strategies that allow the support of the gut microbiota. These studies will provide relevant data to better design strategies to reduce the severity and impact of GI-M in patients with cancer. Full article
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27 pages, 34030 KiB  
Review
Pharmacological Properties of Polyphenols: Bioavailability, Mechanisms of Action, and Biological Effects in In Vitro Studies, Animal Models, and Humans
by Kristine Stromsnes, Rudite Lagzdina, Gloria Olaso-Gonzalez, Lucia Gimeno-Mallench and Juan Gambini
Biomedicines 2021, 9(8), 1074; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9081074 - 23 Aug 2021
Cited by 30 | Viewed by 3653
Abstract
Drugs are bioactive compounds originally discovered from chemical structures present in both the plant and animal kingdoms. These have the ability to interact with molecules found in our body, blocking them, activating them, or increasing or decreasing their levels. Their actions have allowed [...] Read more.
Drugs are bioactive compounds originally discovered from chemical structures present in both the plant and animal kingdoms. These have the ability to interact with molecules found in our body, blocking them, activating them, or increasing or decreasing their levels. Their actions have allowed us to cure diseases and improve our state of health, which has led us to increase the longevity of our species. Among the molecules with pharmacological activity produced by plants are the polyphenols. These, due to their molecular structure, as drugs, also have the ability to interact with molecules in our body, presenting various pharmacological properties. In addition, these compounds are found in multiple foods in our diet. In this review, we focused on discussing the bioavailability of these compounds when we ingested them through diet and the specific mechanisms of action of polyphenols, focusing on studies carried out in vitro, in animals and in humans over the last five years. Knowing which foods have these pharmacological activities could allow us to prevent and aid as concomitant treatment against various pathologies. Full article
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28 pages, 3115 KiB  
Review
Anti-Inflammatory Properties of Diet: Role in Healthy Aging
by Kristine Stromsnes, Angela G. Correas, Jenny Lehmann, Juan Gambini and Gloria Olaso-Gonzalez
Biomedicines 2021, 9(8), 922; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9080922 - 30 Jul 2021
Cited by 31 | Viewed by 11272
Abstract
Inflammation is a physiological process involved in the defenses of the body and the repair of tissues. It is acutely activated by infections, trauma, toxins, or allergic reactions. However, if it becomes chronic, inflammation can end up stimulating the development of diseases such [...] Read more.
Inflammation is a physiological process involved in the defenses of the body and the repair of tissues. It is acutely activated by infections, trauma, toxins, or allergic reactions. However, if it becomes chronic, inflammation can end up stimulating the development of diseases such as cardiovascular disease, autoimmune disease, neurological disease, or cancer. Additionally, during aging, inflammation becomes increasingly more chronic. Furthermore, we found that certain foods, such as saturated fats, have pro-inflammatory activity. Taking this into account, in this review we have discussed different diets with possible anti-inflammatory activity, the commonly ingested components of each diet and their active compounds. In addition, we have proposed some dietary guidelines, as well as a list of compounds present in foods with anti-inflammatory activity, outlining how to combine them to achieve optimal anti-inflammatory effects. Therefore, we can conclude that the compounds in our diet with anti-inflammatory activity could help alleviate the inflammatory processes derived from diseases and unhealthy diets, and thereby promote healthy aging. Full article
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17 pages, 1724 KiB  
Review
Interlink between Inflammation and Oxidative Stress in Age-Related Macular Degeneration: Role of Complement Factor H
by Sara Romero-Vazquez, Víctor Llorens, Alba Soler-Boronat, Marc Figueras-Roca, Alfredo Adan and Blanca Molins
Biomedicines 2021, 9(7), 763; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070763 - 30 Jun 2021
Cited by 20 | Viewed by 3366
Abstract
Age-related macular degeneration (AMD) heads the list of legal blindness among the elderly population in developed countries. Due to the complex nature of the retina and the variety of risk factors and mechanisms involved, the molecular pathways underlying AMD are not yet fully [...] Read more.
Age-related macular degeneration (AMD) heads the list of legal blindness among the elderly population in developed countries. Due to the complex nature of the retina and the variety of risk factors and mechanisms involved, the molecular pathways underlying AMD are not yet fully defined. Persistent low-grade inflammation and oxidative stress eventually lead to retinal pigment epithelium dysfunction and outer blood–retinal barrier (oBRB) breakdown. The identification of AMD susceptibility genes encoding complement factors, and the presence of inflammatory mediators in drusen, the hallmark deposits of AMD, supports the notion that immune-mediated processes are major drivers of AMD pathobiology. Complement factor H (FH), the main regulator of the alternative pathway of the complement system, may have a key contribution in the pathogenesis of AMD as it is able to regulate both inflammatory and oxidative stress responses in the oBRB. Indeed, genetic variants in the CFH gene account for the strongest genetic risk factors for AMD. In this review, we focus on the roles of inflammation and oxidative stress and their connection with FH and related proteins as regulators of both phenomena in the context of AMD. Full article
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12 pages, 719 KiB  
Review
Oxidative Stress and Inflammation in SARS-CoV-2- and Chlamydia pneumoniae-Associated Cardiovascular Diseases
by Simone Filardo, Marisa Di Pietro, Fabiana Diaco, Silvio Romano and Rosa Sessa
Biomedicines 2021, 9(7), 723; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070723 - 24 Jun 2021
Cited by 5 | Viewed by 2502
Abstract
Throughout the years, a growing number of studies have provided evidence that oxidative stress and inflammation may be involved in the pathogenesis of infectious agent-related cardiovascular diseases. Amongst the numerous respiratory pathogens, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus responsible [...] Read more.
Throughout the years, a growing number of studies have provided evidence that oxidative stress and inflammation may be involved in the pathogenesis of infectious agent-related cardiovascular diseases. Amongst the numerous respiratory pathogens, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus responsible for the global ongoing pandemic, and Chlamydia pneumoniae, a widely known intracellular obligate bacteria, seem to have an essential role in promoting reactive oxygen species and cytokine production. The present review highlights the common oxidative and inflammatory molecular pathways underlying the cardiovascular diseases associated with SARS-CoV-2 or C. pneumoniae infections. The main therapeutic and preventive approaches using natural antioxidant compounds will be also discussed. Full article
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19 pages, 1712 KiB  
Review
The Pathways Underlying the Multiple Roles of p62 in Inflammation and Cancer
by Paulina Hennig, Gabriele Fenini, Michela Di Filippo, Tugay Karakaya and Hans-Dietmar Beer
Biomedicines 2021, 9(7), 707; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070707 - 22 Jun 2021
Cited by 27 | Viewed by 5462
Abstract
p62 is a highly conserved, multi-domain, and multi-functional adaptor protein critically involved in several important cellular processes. Via its pronounced domain architecture, p62 binds to numerous interaction partners, thereby influencing key pathways that regulate tissue homeostasis, inflammation, and several common diseases including cancer. [...] Read more.
p62 is a highly conserved, multi-domain, and multi-functional adaptor protein critically involved in several important cellular processes. Via its pronounced domain architecture, p62 binds to numerous interaction partners, thereby influencing key pathways that regulate tissue homeostasis, inflammation, and several common diseases including cancer. Via binding of ubiquitin chains, p62 acts in an anti-inflammatory manner as an adaptor for the auto-, xeno-, and mitophagy-dependent degradation of proteins, pathogens, and mitochondria. Furthermore, p62 is a negative regulator of inflammasome complexes. The transcription factor Nrf2 regulates expression of a bundle of ROS detoxifying genes. p62 activates Nrf2 by interaction with and autophagosomal degradation of the Nrf2 inhibitor Keap1. Moreover, p62 activates mTOR, the central kinase of the mTORC1 sensor complex that controls cell proliferation and differentiation. Through different mechanisms, p62 acts as a positive regulator of the transcription factor NF-κB, a central player in inflammation and cancer development. Therefore, p62 represents not only a cargo receptor for autophagy, but also a central signaling hub, linking several important pro- and anti-inflammatory pathways. This review aims to summarize knowledge about the molecular mechanisms underlying the roles of p62 in health and disease. In particular, different types of tumors are characterized by deregulated levels of p62. The elucidation of how p62 contributes to inflammation and cancer progression at the molecular level might promote the development of novel therapeutic strategies. Full article
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23 pages, 1132 KiB  
Review
Neuroinflammation in Ischemic Stroke: Inhibition of cAMP-Specific Phosphodiesterases (PDEs) to the Rescue
by Laura Ponsaerts, Lotte Alders, Melissa Schepers, Rúbia Maria Weffort de Oliveira, Jos Prickaerts, Tim Vanmierlo and Annelies Bronckaers
Biomedicines 2021, 9(7), 703; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070703 - 22 Jun 2021
Cited by 15 | Viewed by 3521
Abstract
Ischemic stroke is caused by a thromboembolic occlusion of a major cerebral artery, with the impaired blood flow triggering neuroinflammation and subsequent neuronal damage. Both the innate immune system (e.g., neutrophils, monocytes/macrophages) in the acute ischemic stroke phase and the adaptive immune system [...] Read more.
Ischemic stroke is caused by a thromboembolic occlusion of a major cerebral artery, with the impaired blood flow triggering neuroinflammation and subsequent neuronal damage. Both the innate immune system (e.g., neutrophils, monocytes/macrophages) in the acute ischemic stroke phase and the adaptive immune system (e.g., T cells, B cells) in the chronic phase contribute to this neuroinflammatory process. Considering that the available therapeutic strategies are insufficiently successful, there is an urgent need for novel treatment options. It has been shown that increasing cAMP levels lowers neuroinflammation. By inhibiting cAMP-specific phosphodiesterases (PDEs), i.e., PDE4, 7, and 8, neuroinflammation can be tempered through elevating cAMP levels and, thereby, this can induce an improved functional recovery. This review discusses recent preclinical findings, clinical implications, and future perspectives of cAMP-specific PDE inhibition as a novel research interest for the treatment of ischemic stroke. In particular, PDE4 inhibition has been extensively studied, and is promising for the treatment of acute neuroinflammation following a stroke, whereas PDE7 and 8 inhibition more target the T cell component. In addition, more targeted PDE4 gene inhibition, or combined PDE4 and PDE7 or 8 inhibition, requires more extensive research. Full article
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20 pages, 669 KiB  
Review
Novel Combined Antioxidant Strategy against Hypertension, Acute Myocardial Infarction and Postoperative Atrial Fibrillation
by Ramón Rodrigo, Jaime González-Montero and Camilo G. Sotomayor
Biomedicines 2021, 9(6), 620; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060620 - 30 May 2021
Cited by 11 | Viewed by 3287
Abstract
Reactive oxygen species (ROS) play a physiological role in the modulation of several functions of the vascular wall; however, increased ROS have detrimental effects. Hence, oxidative stress has pathophysiological impacts on the control of the vascular tone and cardiac functions. Recent experimental studies [...] Read more.
Reactive oxygen species (ROS) play a physiological role in the modulation of several functions of the vascular wall; however, increased ROS have detrimental effects. Hence, oxidative stress has pathophysiological impacts on the control of the vascular tone and cardiac functions. Recent experimental studies reported the involvement of increased ROS in the mechanism of hypertension, as this disorder associates with increased production of pro-oxidants and decreased bioavailability of antioxidants. In addition, increased ROS exposure is found in ischemia-reperfusion, occurring in acute myocardial infarction and cardiac surgery with extracorporeal circulation, among other settings. Although these effects cause major heart damage, at present, there is no available treatment. Therefore, it should be expected that antioxidants counteract the oxidative processes, thereby being suitable against cardiovascular disease. Nevertheless, although numerous experimental studies agree with this notion, interventional trials have provided mixed results. A better knowledge of ROS modulation and their specific interaction with the molecular targets should contribute to the development of novel multitarget antioxidant effective therapeutic strategies. The complex multifactorial nature of hypertension, acute myocardial infarction, and postoperative atrial fibrillation needs a multitarget antioxidant strategy, which may give rise to additive or synergic protective effects to achieve optimal cardioprotection. Full article
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25 pages, 1517 KiB  
Review
Mitochondrial Oxidative Stress and “Mito-Inflammation”: Actors in the Diseases
by Simone Patergnani, Esmaa Bouhamida, Sara Leo, Paolo Pinton and Alessandro Rimessi
Biomedicines 2021, 9(2), 216; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020216 - 20 Feb 2021
Cited by 61 | Viewed by 6131
Abstract
A decline in mitochondrial redox homeostasis has been associated with the development of a wide range of inflammatory-related diseases. Continue discoveries demonstrate that mitochondria are pivotal elements to trigger inflammation and stimulate innate immune signaling cascades to intensify the inflammatory response at front [...] Read more.
A decline in mitochondrial redox homeostasis has been associated with the development of a wide range of inflammatory-related diseases. Continue discoveries demonstrate that mitochondria are pivotal elements to trigger inflammation and stimulate innate immune signaling cascades to intensify the inflammatory response at front of different stimuli. Here, we review the evidence that an exacerbation in the levels of mitochondrial-derived reactive oxygen species (ROS) contribute to mito-inflammation, a new concept that identifies the compartmentalization of the inflammatory process, in which the mitochondrion acts as central regulator, checkpoint, and arbitrator. In particular, we discuss how ROS contribute to specific aspects of mito-inflammation in different inflammatory-related diseases, such as neurodegenerative disorders, cancer, pulmonary diseases, diabetes, and cardiovascular diseases. Taken together, these observations indicate that mitochondrial ROS influence and regulate a number of key aspects of mito-inflammation and that strategies directed to reduce or neutralize mitochondrial ROS levels might have broad beneficial effects on inflammatory-related diseases. Full article
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16 pages, 630 KiB  
Review
Review on Inflammation Markers in Chronic Kidney Disease
by Tadej Petreski, Nejc Piko, Robert Ekart, Radovan Hojs and Sebastjan Bevc
Biomedicines 2021, 9(2), 182; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020182 - 11 Feb 2021
Cited by 27 | Viewed by 6824
Abstract
Chronic kidney disease (CKD) is one of the major health problems of the modern age. It represents an important public health challenge with an ever-lasting rising prevalence, which reached almost 700 million by the year 2017. Therefore, it is very important to identify [...] Read more.
Chronic kidney disease (CKD) is one of the major health problems of the modern age. It represents an important public health challenge with an ever-lasting rising prevalence, which reached almost 700 million by the year 2017. Therefore, it is very important to identify patients at risk for CKD development and discover risk factors that cause the progression of the disease. Several studies have tackled this conundrum in recent years, novel markers have been identified, and new insights into the pathogenesis of CKD have been gained. This review summarizes the evidence on markers of inflammation and their role in the development and progression of CKD. It will focus primarily on cytokines, chemokines, and cell adhesion molecules. Nevertheless, further large, multicenter studies are needed to establish the role of these markers and confirm possible treatment options in everyday clinical practice. Full article
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15 pages, 1039 KiB  
Review
Effect of Methionine Restriction on Aging: Its Relationship to Oxidative Stress
by Munehiro Kitada, Yoshio Ogura, Itaru Monno, Jing Xu and Daisuke Koya
Biomedicines 2021, 9(2), 130; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020130 - 29 Jan 2021
Cited by 40 | Viewed by 8212
Abstract
Enhanced oxidative stress is closely related to aging and impaired metabolic health and is influenced by diet-derived nutrients and energy. Recent studies have shown that methionine restriction (MetR) is related to longevity and metabolic health in organisms from yeast to rodents. The effect [...] Read more.
Enhanced oxidative stress is closely related to aging and impaired metabolic health and is influenced by diet-derived nutrients and energy. Recent studies have shown that methionine restriction (MetR) is related to longevity and metabolic health in organisms from yeast to rodents. The effect of MetR on lifespan extension and metabolic health is mediated partially through a reduction in oxidative stress. Methionine metabolism is involved in the supply of methyl donors such as S-adenosyl-methionine (SAM), glutathione synthesis and polyamine metabolism. SAM, a methionine metabolite, activates mechanistic target of rapamycin complex 1 and suppresses autophagy; therefore, MetR can induce autophagy. In the process of glutathione synthesis in methionine metabolism, hydrogen sulfide (H2S) is produced through cystathionine-β-synthase and cystathionine-γ-lyase; however, MetR can induce increased H2S production through this pathway. Similarly, MetR can increase the production of polyamines such as spermidine, which are involved in autophagy. In addition, MetR decreases oxidative stress by inhibiting reactive oxygen species production in mitochondria. Thus, MetR can attenuate oxidative stress through multiple mechanisms, consequently associating with lifespan extension and metabolic health. In this review, we summarize the current understanding of the effects of MetR on lifespan extension and metabolic health, focusing on the reduction in oxidative stress. Full article
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