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1
Schilke, Robert M., Cassidy M. R. Blackburn, Temitayo T. Bamgbose, and Matthew D. Woolard. "Interface of Phospholipase Activity, Immune Cell Function, and Atherosclerosis." Biomolecules 10, no. 10 (October 15, 2020): 1449. http://dx.doi.org/10.3390/biom10101449.
Анотація:
Phospholipases are a family of lipid-altering enzymes that can either reduce or increase bioactive lipid levels. Bioactive lipids elicit signaling responses, activate transcription factors, promote G-coupled-protein activity, and modulate membrane fluidity, which mediates cellular function. Phospholipases and the bioactive lipids they produce are important regulators of immune cell activity, dictating both pro-inflammatory and pro-resolving activity. During atherosclerosis, pro-inflammatory and pro-resolving activities govern atherosclerosis progression and regression, respectively. This review will look at the interface of phospholipase activity, immune cell function, and atherosclerosis.
2
Brennan, Eoin P., Muthukumar Mohan, Darrell Andrews, Madhura Bose, and Phillip Kantharidis. "Specialized pro-resolving mediators in diabetes: novel therapeutic strategies." Clinical Science 133, no. 21 (November 2019): 2121–41. http://dx.doi.org/10.1042/cs20190067.
Анотація:
Abstract Diabetes mellitus (DM) is an important metabolic disorder characterized by persistent hyperglycemia resulting from inadequate production and secretion of insulin, impaired insulin action, or a combination of both. Genetic disorders and insulin receptor disorders, environmental factors, lifestyle choices and toxins are key factors that contribute to DM. While it is often referred to as a metabolic disorder, modern lifestyle choices and nutrient excess induce a state of systemic chronic inflammation that results in the increased production and secretion of inflammatory cytokines that contribute to DM. It is chronic hyperglycemia and the low-grade chronic-inflammation that underlies the development of microvascular and macrovascular complications leading to damage in a number of tissues and organs, including eyes, vasculature, heart, nerves, and kidneys. Improvements in the management of risk factors have been beneficial, including focus on intensified glycemic control, but most current approaches only slow disease progression. Even with recent studies employing SGLT2 inhibitors demonstrating protection against cardiovascular and kidney diseases, kidney function continues to decline in people with established diabetic kidney disease (DKD). Despite the many advances and a greatly improved understanding of the pathobiology of diabetes and its complications, there remains a major unmet need for more effective therapeutics to prevent and reverse the chronic complications of diabetes. More recently, there has been growing interest in the use of specialised pro-resolving mediators (SPMs) as an exciting therapeutic strategy to target diabetes and the chronic complications of diabetes.
3
de Fáveri, Cássia, Paula M. Poeta Fermino, Anna P. Piovezan, and Lia K. Volpato. "The Inflammatory Role of Pro-Resolving Mediators in Endometriosis: An Integrative Review." International Journal of Molecular Sciences 22, no. 9 (April 22, 2021): 4370. http://dx.doi.org/10.3390/ijms22094370.
Анотація:
The pathogenesis of endometriosis is still controversial, although it is known that the inflammatory immune response plays a critical role in this process. The resolution of inflammation is an active process where the activation of endogenous factors allows the host tissue to maintain homeostasis. The mechanisms by which pro-resolving mediators (PRM) act in endometriosis are still little explored. Thus, this integrative review aims to synthesize the available content regarding the role of PRM in endometriosis. Experimental and in vitro studies with Lipoxin A4 demonstrate a potential inhibitory effect on endometrial lesions’ progression, attenuating pro-inflammatory and angiogenic signals, inhibiting proliferative and invasive action suppressing intracellular signaling induced by cytokines and estradiol, mainly through the FPR2/ALX. Investigations with Resolvin D1 demonstrated the inhibition of endometrial lesions and decreased pro-inflammatory factors. Annexin A1 is expressed in the endometrium and is specifically present in women with endometriosis, although the available studies are still inconsistent. Thus, we believe there is a gap in knowledge regarding the PRM pathways in patients with endometriosis. It is important to note that these substances’ therapeutic potential is evident since the immune and abnormal inflammatory responses play an essential role in endometriosis development and progression.
4
Onali, Favale, and Fantini. "The Resolution of Intestinal Inflammation: The Peace-Keeper’s Perspective." Cells 8, no. 4 (April 11, 2019): 344. http://dx.doi.org/10.3390/cells8040344.
Анотація:
The uncontrolled activation of the immune system toward antigens contained in the gut lumen in genetically predisposed subjects is believed to be the leading cause of inflammatory bowel disease (IBD). Two not mutually exclusive hypotheses can explain the pathogenic process leading to IBD. The first and mostly explored hypothesis states that the loss of tolerance toward gut microbiota antigens generates an aberrant inflammatory response that is perpetuated by continuous and unavoidable exposure to the triggering antigens. However, the discovery that the resolution of inflammation is not the mere consequence of clearing inflammatory triggers and diluting pro-inflammatory factors, but rather an active process in which molecular and cellular elements are involved, implies that a defect in the pro-resolving mechanisms might cause chronic inflammation in different immune-mediated diseases, including IBD. Here we review data on pro-resolving and counter-regulatory mechanisms involved in the resolution of inflammation, aiming to identify their possible involvement in the pathogenesis of IBD.
5
Klatte-Schulz, Franka, Nicole Bormann, Aysha Bonell, Jasmin Al-Michref, Hoang Le Nguyen, Pascal Klöckner, Kathi Thiele, et al. "Pro-Resolving Mediators in Rotator Cuff Disease: How Is the Bursa Involved?" Cells 13, no. 1 (December 20, 2023): 17. http://dx.doi.org/10.3390/cells13010017.
Анотація:
So far, tendon regeneration has mainly been analyzed independent from its adjacent tissues. However, the subacromial bursa in particular appears to influence the local inflammatory milieu in the shoulder. The resolution of local inflammation in the shoulder tissues is essential for tendon regeneration, and specialized pro-resolving mediators (SPMs) play a key role in regulating the resolution of inflammation. Here, we aimed to understand the influence of the bursa on disease-associated processes in neighboring tendon healing. Bursa tissue and bursa-derived cells from patients with intact, moderate and severe rotator cuff disease were investigated for the presence of pro-resolving and inflammatory mediators, as well their effect on tenocytes and sensitivity to mechanical loading by altering SPM signaling mediators in bursa cells. SPM signal mediators were present in the bursae and altered depending on the severity of rotator cuff disease. SPMs were particularly released from the bursal tissue of patients with rotator cuff disease, and the addition of bursa-released factors to IL-1β-challenged tenocytes improved tenocyte characteristics. In addition, mechanical loading modulated pro-resolving processes in bursa cells. In particular, pathological high loading (8% strain) increased the expression and secretion of SPM signaling mediators. Overall, this study confirms the importance of bursae in regulating inflammatory processes in adjacent rotator cuff tendons.
6
Tangeten, Cecilia, Karim Zouaoui Boudjeltia, Cedric Delporte, Pierre Van Antwerpen, and Keziah Korpak. "Unexpected Role of MPO-Oxidized LDLs in Atherosclerosis: In between Inflammation and Its Resolution." Antioxidants 11, no. 5 (April 28, 2022): 874. http://dx.doi.org/10.3390/antiox11050874.
Анотація:
Inflammation and its resolution are the result of the balance between pro-inflammatory and pro-resolving factors, such as specialized pro-resolving mediators (SPMs). This balance is crucial for plaque evolution in atherosclerosis, a chronic inflammatory disease. Myeloperoxidase (MPO) has been related to oxidative stress and atherosclerosis, and MPO-oxidized low-density lipoproteins (Mox-LDLs) have specific characteristics and effects. They participate in foam cell formation and cause specific reactions when interacting with macrophages and endothelial cells. They also increase the production of intracellular reactive oxygen species (ROS) in macrophages and the resulting antioxidant response. Mox-LDLs also drive macrophage polarization. Mox-LDLs are known to be pro-inflammatory particles. However, in the presence of Mox-LDLs, endothelial cells produce resolvin D1 (RvD1), a SPM. SPMs are involved in the resolution of inflammation by stimulating efferocytosis and by reducing the adhesion and recruitment of neutrophils and monocytes. RvD1 also induces the synthesis of other SPMs. In vitro, Mox-LDLs have a dual effect by promoting RvD1 release and inducing a more anti-inflammatory phenotype macrophage, thereby having a mixed effect on inflammation. In this review, we discuss the interrelationship between MPO, Mox-LDLs, and resolvins, highlighting a new perception of the role of Mox-LDLs in atherosclerosis.
7
Costa, Ambra, Davide Ceresa, Antonella De Palma, Rossana Rossi, Sara Turturo, Sara Santamaria, Carolina Balbi, et al. "Comprehensive Profiling of Secretome Formulations from Fetal- and Perinatal Human Amniotic Fluid Stem Cells." International Journal of Molecular Sciences 22, no. 7 (April 2, 2021): 3713. http://dx.doi.org/10.3390/ijms22073713.
Анотація:
We previously reported that c-KIT+ human amniotic-fluid derived stem cells obtained from leftover samples of routine II trimester prenatal diagnosis (fetal hAFS) are endowed with regenerative paracrine potential driving pro-survival, anti-fibrotic and proliferative effects. hAFS may also be isolated from III trimester clinical waste samples during scheduled C-sections (perinatal hAFS), thus offering a more easily accessible alternative when compared to fetal hAFS. Nonetheless, little is known about the paracrine profile of perinatal hAFS. Here we provide a detailed characterization of the hAFS total secretome (i.e., the entirety of soluble paracrine factors released by cells in the conditioned medium, hAFS-CM) and the extracellular vesicles (hAFS-EVs) within it, from II trimester fetal- versus III trimester perinatal cells. Fetal- and perinatal hAFS were characterized and subject to hypoxic preconditioning to enhance their paracrine potential. hAFS-CM and hAFS-EV formulations were analyzed for protein and chemokine/cytokine content, and the EV cargo was further investigated by RNA sequencing. The phenotype of fetal- and perinatal hAFS, along with their corresponding secretome formulations, overlapped; yet, fetal hAFS showed immature oxidative phosphorylation activity when compared to perinatal ones. The profiling of their paracrine cargo revealed some differences according to gestational stage and hypoxic preconditioning. Both cell sources provided formulations enriched with neurotrophic, immunomodulatory, anti-fibrotic and endothelial stimulating factors, and the immature fetal hAFS secretome was defined by a more pronounced pro-vasculogenic, regenerative, pro-resolving and anti-aging profile. Small RNA profiling showed microRNA enrichment in both fetal- and perinatal hAFS-EV cargo, with a stably- expressed pro-resolving core as a reference molecular signature. Here we confirm that hAFS represents an appealing source of regenerative paracrine factors; the selection of either fetal or perinatal hAFS secretome formulations for future paracrine therapy should be evaluated considering the specific clinical scenario.
8
Jain, Paridhi, and Suyesha Singh. "Nature Relatedness, Eco-centric Concerns, Future Time Perspective, and Pro-ecological Behavior in Young Adults." IOP Conference Series: Earth and Environmental Science 1279, no. 1 (December 1, 2023): 012031. http://dx.doi.org/10.1088/1755-1315/1279/1/012031.
Анотація:
Abstract Human civilization poses a grave threat to global biodiversity, evident in climate change, species extinction, infectious diseases, food production challenges, droughts, and floods. To reverse this peril, societal structures and individual behavior must transform. Embracing pro-ecological behavior is pivotal in combating environmental issues, reducing waste, curbing pollutants, and minimizing harm. Furthermore, fostering a connection to nature, embracing sustainability, and adopting a long-term perspective can aid in resolving these challenges. This research explores the link between nature-relatedness, eco-centric concerns, future time perspective, and pro-ecological behavior among 210 young adults. Utilizing multiple regression and Pearson’s correlation, the study reveals significant positive correlations between pro-ecological behavior and nature-relatedness, eco-centric concerns, and future time perspective. Moreover, these factors significantly predict pro-ecological behavior in young adults. These findings offer insights for developing strategies and interventions to nurture pro-ecological and sustainable behavior in future generations, bolstering environmental preservation efforts. The study discusses the limitation and their repercussions.
9
Dalli, Jesmond, Esteban Alberto Gomez, and Charlotte Camille Jouvene. "Utility of the Specialized Pro-Resolving Mediators as Diagnostic and Prognostic Biomarkers in Disease." Biomolecules 12, no. 3 (February 23, 2022): 353. http://dx.doi.org/10.3390/biom12030353.
Анотація:
A precision medicine approach is widely acknowledged to yield more effective therapeutic strategies in the treatment of patients with chronic inflammatory conditions than the prescriptive paradigm currently utilized in the management and treatment of these patients. This is because such an approach will take into consideration relevant factors including the likelihood that a patient will respond to given therapeutics based on their disease phenotype. Unfortunately, the application of this precision medicine paradigm in the daily treatment of patients has been greatly hampered by the lack of robust biomarkers, in particular biomarkers for determining early treatment responsiveness. Lipid mediators are central in the regulation of host immune responses during both the initiation and resolution of inflammation. Amongst lipid mediators, the specialized pro-resolving mediators (SPM) govern immune cells to promote the resolution of inflammation. These autacoids are produced via the stereoselective conversion of essential fatty acids to yield molecules that are dynamically regulated during inflammation and exert potent immunoregulatory activities. Furthermore, there is an increasing appreciation for the role that these mediators play in conveying the biological actions of several anti-inflammatory therapeutics, including statins and aspirin. Identification and quantitation of these mediators has traditionally been achieved using hyphenated mass spectrometric techniques, primarily liquid-chromatography tandem mass spectrometry. Recent advances in the field of chromatography and mass spectrometry have increased both the robustness and the sensitivity of this approach and its potential deployment for routine clinical diagnostics. In the present review, we explore the evidence supporting a role for specific SPM as potential biomarkers for patient stratification in distinct disease settings together with methodologies employed in the identification and quantitation of these autacoids.
10
Sufaru, Irina-Georgeta, Silvia Teslaru, Liliana Pasarin, Gianina Iovan, Simona Stoleriu, and Sorina Mihaela Solomon. "Host Response Modulation Therapy in the Diabetes Mellitus—Periodontitis Conjuncture: A Narrative Review." Pharmaceutics 14, no. 8 (August 18, 2022): 1728. http://dx.doi.org/10.3390/pharmaceutics14081728.
Анотація:
The inflammatory response of the host in periodontitis is the phenomenon that underlies the onset and evolution of periodontal destructive phenomena. A number of systemic factors, such as diabetes mellitus (DM), can negatively affect the patient with periodontitis, just as the periodontal disease can aggravate the status of the DM patient. Host response modulation therapy involves the use of anti-inflammatory and anti-oxidant products aimed at resolving inflammation, stopping destructive processes, and promoting periodontal healing, all important aspects in patients with high tissue loss rates, such as diabetic patients. This paper reviews the data available in the literature on the relationship between DM and periodontitis, the main substances modulating the inflammatory response (nonsteroidal anti-inflammatory drugs, sub-antimicrobial doses of doxycycline, or omega-3 fatty acids and their products, specialized pro-resolving mediators), as well as their application in diabetic patients.
11
Bolotov, Denis Dmitrievich, Alexey Alexeevich Novikov, Sergey Bolevich, Nina Aleksandrovna Novikova, and Andrey Vladimirovich Yakovchenko. "Influence of Systemic Inflammatory Response to Appearance of New Foci of Chronic Inflammation." Serbian Journal of Experimental and Clinical Research 21, no. 1 (March 1, 2020): 3–10. http://dx.doi.org/10.2478/sjecr-2020-0013.
Анотація:
AbstractChanges in the body in the presence of a chronic inflammatory process, even of a low intensity, lead to the change in the body’s reactivity, having a negative impact on the development, course and clinical prognosis of newly emerging inflammatory processes. Structural changes in the vascular network in the focus of chronic inflammation and following cellular reactions that occur under the action of chemokines and cytokines are the basis for the maintenance and development of the phlogogenic process, including subsequent structural changes in tissues. The failure to resolve the inflammation leads not only to the persistence of the process in the primary focus, but also to the formation of a multitude of the so-calledpathological circles, included at the system level, causing the imbalance among proinflammatory, anti-inflammatory and pro-resolving factors. As a result, conditions are formed for the emergence of new foci of the inflammation in other organs and tissues and in the case of their realization, new vicious circles are formed that contribute to the maintenance and progression of the inflammation. The complex application of etio-tropic, pathogenetic and sanogenetic principles of the treatment allows intensifying of the formation of specialized pro-resolving factors with the elimination of their relative insufficiency, contributing to the reduction of newly formed vessels and to the restoration of the normal cellular composition of the tissue as well as to the resolution of inflammation.
12
Hamidzadeh, Kajal, Ashton T. Belew, Najib M. El-Sayed, and David M. Mosser. "The transition of M-CSF–derived human macrophages to a growth-promoting phenotype." Blood Advances 4, no. 21 (November 9, 2020): 5460–72. http://dx.doi.org/10.1182/bloodadvances.2020002683.
Анотація:
Abstract Stimulated macrophages are potent producers of inflammatory mediators. This activity is highly regulated, in part, by resolving molecules to prevent tissue damage. In this study, we demonstrate that inflammation induced by Toll-like receptor stimulation is followed by the upregulation of receptors for adenosine (Ado) and prostaglandin E2 (PGE2), which help terminate macrophage activation and initiate tissue remodeling and angiogenesis. Macrophages can be hematopoietically derived from monocytes in response to 2 growth factors: macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). We examine how exposure to either of these differentiation factors shapes the macrophage response to resolving molecules. We analyzed the transcriptomes of human monocyte-derived macrophages stimulated in the presence of Ado or PGE2 and demonstrated that, in macrophages differentiated in M-CSF, Ado and PGE2 induce a shared transcriptional program involving the downregulation of inflammatory mediators and the upregulation of growth factors. In contrast, macrophages generated in GM-CSF fail to convert to a growth-promoting phenotype, which we attribute to the suppression of receptors for Ado and PGE2 and lower production of these endogenous regulators. These observations indicate that M-CSF macrophages are better prepared to transition to a program of tissue repair, whereas GM-CSF macrophages undergo more profound activation. We implicate the differential sensitivity to pro-resolving mediators as a contributor to these divergent phenotypes. This research highlights a number of molecular targets that can be exploited to regulate the strength and duration of macrophage activation.
13
Sansbury, Brian E., Xiaofeng Li, Blenda Wong, Andreas Patsalos, Nikolas Giannakis, Michael J. Zhang, Laszlo Nagy, and Matthew Spite. "Myeloid ALX/FPR2 regulates vascularization following tissue injury." Proceedings of the National Academy of Sciences 117, no. 25 (June 8, 2020): 14354–64. http://dx.doi.org/10.1073/pnas.1918163117.
Анотація:
Ischemic injury initiates a sterile inflammatory response that ultimately participates in the repair and recovery of tissue perfusion. Macrophages are required for perfusion recovery during ischemia, in part because they produce growth factors that aid in vascular remodeling. The input signals governing this pro-revascularization phenotype remain of interest. Here we found that hindlimb ischemia increases levels of resolvin D1 (RvD1), an inflammation-resolving lipid mediator that targets macrophages via its receptor, ALX/FPR2. Exogenous RvD1 enhances perfusion recovery during ischemia, and mice deficient inAlx/Fpr2have an endogenous defect in this process. Mechanistically, RNA sequencing revealed that RvD1 induces a transcriptional program in macrophages characteristic of a pro-revascularization phenotype. Vascularization of ischemic skeletal muscle, as well as cutaneous wounds, is impaired in mice with myeloid-specific deficiency ofAlx/Fpr2, and this is associated with altered expression of pro-revascularization genes in skeletal muscle and macrophages isolated from skeletal muscle. Collectively, these results uncover a role of ALX/FPR2 in revascularization that may be amenable to therapeutic targeting in diseases associated with altered tissue perfusion and repair.
14
Videla, Luis Alberto, Rodrigo Valenzuela, Andrea Del Campo, and Jessica Zúñiga-Hernández. "Omega-3 Lipid Mediators: Modulation of the M1/M2 Macrophage Phenotype and Its Protective Role in Chronic Liver Diseases." International Journal of Molecular Sciences 24, no. 21 (October 24, 2023): 15528. http://dx.doi.org/10.3390/ijms242115528.
Анотація:
The complex interplay between dietary factors, inflammation, and macrophage polarization is pivotal in the pathogenesis and progression of chronic liver diseases (CLDs). Omega-3 fatty acids (FAs) have brought in attention due to their potential to modulate inflammation and exert protective effects in various pathological conditions. Omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown promise in mitigating inflammation and enhancing the resolution of inflammatory responses. They influence the M1/M2 macrophage phenotype balance, promoting a shift towards the M2 anti-inflammatory phenotype. Specialized pro-resolving mediators (SPMs), such as resolvins (Rvs), protectins (PDs), and maresins (MaRs), have emerged as potent regulators of inflammation and macrophage polarization. They show anti-inflammatory and pro-resolving properties, by modulating the expression of cytokines, facilitate the phagocytosis of apoptotic cells, and promote tissue repair. MaR1, in particular, has demonstrated significant hepatoprotective effects by promoting M2 macrophage polarization, reducing oxidative stress, and inhibiting key inflammatory pathways such as NF-κB. In the context of CLDs, such as nonalcoholic fatty liver disease (NAFLD) and cirrhosis, omega-3s and their SPMs have shown promise in attenuating liver injury, promoting tissue regeneration, and modulating macrophage phenotypes. The aim of this article was to analyze the emerging role of omega-3 FAs and their SPMs in the context of macrophage polarization, with special interest in the mechanisms underlying their effects and their interactions with other cell types within the liver microenvironment, focused on CLDs and the development of novel therapeutic strategies.
15
Gindri dos Santos, Bernardo, and Leigh Goedeke. "Macrophage immunometabolism in diabetes-associated atherosclerosis." Immunometabolism 5, no. 4 (October 2023): e00032. http://dx.doi.org/10.1097/in9.0000000000000032.
Анотація:
Macrophages play fundamental roles in atherosclerotic plaque formation, growth, and regression. These cells are extremely plastic and perform different immune functions depending on the stimuli they receive. Initial in vitro studies have identified specific metabolic pathways that are crucial for the proper function of pro-inflammatory and pro-resolving macrophages. However, the plaque microenvironment, especially in the context of insulin resistance and type 2 diabetes, constantly challenges macrophages with several simultaneous inflammatory and metabolic stimuli, which may explain why atherosclerosis is accelerated in diabetic patients. In this mini review, we discuss how macrophage mitochondrial function and metabolism of carbohydrates, lipids, and amino acids may be affected by this complex plaque microenvironment and how risk factors associated with type 2 diabetes alter the metabolic rewiring of macrophages and disease progression. We also briefly discuss current challenges in assessing macrophage metabolism and identify future tools and possible strategies to alter macrophage metabolism to improve treatment options for diabetes-associated atherosclerosis.
16
Frana, Ilaria. "The Role of Discourse Prominence in the Resolution of Referential Ambiguities Evidence from Co-reference in Italian." International Journal of Linguistics 9, no. 3 (July 16, 2017): 205. http://dx.doi.org/10.5296/ijl.v9i3.11326.
Анотація:
In this paper, I investigate the role of discourse prominence in the resolution of referential ambiguities displayed by anaphoric null subject pronouns (pro) and relational nouns (RNs) in Italian. I advance the hypothesis that, in case of referential ambiguity (when more than one discourse referent qualifies as possible antecedent), the preferred antecedent for pro (or RN) is the most prominent discourse referent available. I will refer to this hypothesis as the Discourse-Prominence Hypothesis of Antecedent Assignment (DPH). To support the DPH, I present evidence from two questionnaire studies on intra-sentential anaphora and RNs in Italian. Experiment 1 investigates the DPH with respect to the resolution of anaphoric pro in Italian, thus contributing to the debate on whether the referring preferences of pronouns in pro-drop languages are governed by purely syntactic factors or information (Samek-Lodovici 1996; Carminati 2002; Frana 2007; Mayol & Clark 2010). This experiment shows that the preferred antecedent for Italian pro is the DP that realizes the most prominent discourse referent (Topic), independently of its syntactic position (subject/object). Experiment 2 , tested the DPH on the interpretation of ambiguous RNs. The results of this experiment showed an interesting trend in the direction predicted by the DPH, however, the data was not statistically significant. Both experiments provide evidence against a purely syntactic account of referential ambiguity resolutions and support the idea that information about the prominence status of discourse referents influences the processor in resolving referential ambiguities.
17
Yasukawa, Ken, Toshiaki Okuno, and Takehiko Yokomizo. "Eicosanoids in Skin Wound Healing." International Journal of Molecular Sciences 21, no. 22 (November 10, 2020): 8435. http://dx.doi.org/10.3390/ijms21228435.
Анотація:
Wound healing is an important process in the human body to protect against external threats. A dysregulation at any stage of the wound healing process may result in the development of various intractable ulcers or excessive scar formation. Numerous factors such as growth factors, cytokines, and chemokines are involved in this process and play vital roles in tissue repair. Moreover, recent studies have demonstrated that lipid mediators derived from membrane fatty acids are also involved in the process of wound healing. Among these lipid mediators, we focus on eicosanoids such as prostaglandins, thromboxane, leukotrienes, and specialized pro-resolving mediators, which are produced during wound healing processes and play versatile roles in the process. This review article highlights the roles of eicosanoids on skin wound healing, especially focusing on the biosynthetic pathways and biological functions, i.e., inflammation, proliferation, migration, angiogenesis, remodeling, and scarring.
18
Kipper, Franciele Cristina, Jianjun Deng, Eva Rothenberger, Abigail Kelly, Madeline Duncan, Sui Huang, Charles N. Serhan, and Dipak Panigrahy. "Abstract 1329: Maresins prevent breast cancer dormancy escape via resolution of inflammation." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1329. http://dx.doi.org/10.1158/1538-7445.am2022-1329.
Анотація:
Abstract Cytotoxic cancer therapies reduce tumor burden by killing tumor cells. However, the resulting apoptotic and necrotic cell bodies (tumor cell “debris”) may stimulate tumor initiation and progression by disrupting the resolution of inflammation. Thus, chemotherapy and anti-estrogen breast cancer therapy, including tamoxifen, may be a double-edged sword. A paradigm shift is emerging in understanding the resolution of inflammation as an active biochemical process with the discovery of novel specialized pro-resolving lipid autocoid mediators (SPMs), such as maresins and endogenous resolution programs. Despite approaches to block systemic inflammation, there are no current “pro-resolving” therapies in cancer. To determine whether debris stimulates breast cancer growth, we utilized tumor dormancy models with a subthreshold (nontumorigenic) inoculum of tumor cells. We demonstrated that breast tumor “debris” generated by cytotoxic anti-estrogen therapy (tamoxifen or fulvestrant) or chemotherapy (eribulin) stimulates dormancy escape by triggering a macrophage-derived pro-inflammatory and pro-angiogenic “cytokine storm”. Thus, tumor cell debris is a critical pro-tumorigenic factor in breast cancer initiation and progression. To assess whether stimulating the clearance of debris would suppress breast cancer progression, we utilized the SPMs maresin 1 (MaR1) and maresin conjugates in tissue regeneration (MCTR1, MCTR2). Each maresin (MaR1, MCTR1 and MCTR2) sharply reduced tumor growth in both debris-stimulated and spontaneous (e.g. MMTV-PyMT) breast cancer models at nanogram concentrations (15 ng/day) without toxicity. Notably, maresins enhanced immunotherapy (anti-CTLA4) to induce tumor regression in estrogen receptor (ER) positive (EO771) and inhibit ER negative tumor growth (4T1). Maresins stimulated macrophage phagocytosis of therapy (fulvestrant and tamoxifen)-generated breast cancer debris at only nanomolar concentrations (0.1 - 10 nM). Remarkably, maresins alone or in combination with chemotherapy (paclitaxel) reduced levels of pro-angiogenic factors (e.g. CXCL12/SDF-1) in the tumor microenvironment and decreased microvessel density/size, thereby inhibiting tumor angiogenesis. Maresins dampened the therapy-induced cytokine storm, by reducing levels of TNF-α, MIP-2/CXCL2, CCL2/MCP-1, IL-1ra/IL-1F3, CCL5, CXCL13, Serpin E1/PAI-1, IL-1β and G-CSF both in vitro in debris-stimulated macrophages and in vivo in plasma and tumor tissue. Stimulating the resolution of inflammation via pro-resolution lipid mediators to enhance immunotherapy is a novel host-centric therapeutic approach to prevent breast cancer initiation, dormancy escape and tumor progression via debris clearance and counter-regulation of the cytokine storm. Altogether, the maresin pathway mediators may represent a new therapeutic approach to stimulate the resolution of inflammation in breast cancer. Citation Format: Franciele Cristina Kipper, Jianjun Deng, Eva Rothenberger, Abigail Kelly, Madeline Duncan, Sui Huang, Charles N. Serhan, Dipak Panigrahy. Maresins prevent breast cancer dormancy escape via resolution of inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1329.
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Singh, Kameshwar P., Gina Lawyer, Thivanka Muthumalage, Krishna P. Maremanda, Naushad Ahmad Khan, Samantha R. McDonough, Dongxia Ye, Scott McIntosh, and Irfan Rahman. "Systemic biomarkers in electronic cigarette users: implications for noninvasive assessment of vaping-associated pulmonary injuries." ERJ Open Research 5, no. 4 (October 2019): 00182–2019. http://dx.doi.org/10.1183/23120541.00182-2019.
Анотація:
BackgroundElectronic cigarettes (e-cigs) were introduced as electronic nicotine delivery systems, and have become very popular in the USA and globally. There is a paucity of data on systemic injury biomarkers of vaping in e-cig users that can be used as a noninvasive assessment of vaping-associated lung injuries. We hypothesised that characterisation of systemic biomarkers of inflammation, anti-inflammatory, oxidative stress, vascular and lipid mediators, growth factors, and extracellular matrix breakdown may provide information regarding the toxicity of vaping in e-cig users.MethodsWe collected various biological fluids, i.e. plasma, urine, saliva and exhaled breath condensate (EBC), measured pulmonary function and vaping characteristics, and assessed various biomarkers in e-cig users and nonusers.ResultsThe plasma samples of e-cig users showed a significant increase in biomarkers of inflammation (interleukin (IL)-1β, IL-6, IL-8, IL-13, interferon (IFN)-γ, matrix metalloproteinase-9, intercellular cell adhesion molecule-1) and extracellular matrix breakdown (desmosine), and decreased pro-resolving lipid mediators (resolvin D1 and resolvin D2). There was a significant increase in growth factor (endothelial growth factor, vascular endothelial growth factor, β-nerve growth factor, platelet-derived growth factor-AA, stem cell factor, hepatocyte growth factor and placental growth factor) levels in plasma of e-cig users versus nonusers. E-cig users showed a significant increase in levels of inflammatory biomarker IFN-γ, oxidative stress biomarker 8-isoprostane and oxidative DNA damage biomarker 8-oxo-dG in urine samples, and of inflammatory biomarker IL-1β in saliva samples. EBC showed a slight increase in levels of triglycerides and 8-isoprostane in e-cig users compared with normal nonusers.ConclusionE-cig users have increased levels of biomarkers of inflammation and oxidative stress, reduced pro-resolving anti-inflammatory mediators, and endothelial dysfunction, which may act as risk factors for increasing susceptibility to systemic diseases. The identified noninvasive biomarkers can be used for determining e-cig vaping-associated lung injuries, and for regulatory and diagnostic aspects of vaping in humans.
20
Miranda-Guzman, Jael, Aaron Morris, Miguel Quiros, Jennifer Brazil, Charles Parkos, and Asma Nusrat. "NANOPARTICLE ENCAPSULATION OF THE SPECIALIZED PRO-RESOLVING MEDIATOR MARESIN-2: A NOVEL APPROACH FOR PROMOTING MUCOSAL REPAIR IN THE INTESTINE." Inflammatory Bowel Diseases 30, Supplement_1 (January 25, 2024): S61. http://dx.doi.org/10.1093/ibd/izae020.125.
Анотація:
Abstract Epithelial cells form protective barriers at mucosal surfaces and play a critical role in maintaining tissue homeostasis. Active inflammation in inflammatory bowel disease (IBD) is associated with epithelial barrier disruption and mucosal erosions/wounds that contribute to the inflammatory response and disease symptoms. Therefore, efficient repair of epithelial erosions/wounds is crucial for restoring intestinal barrier function and resolving mucosal inflammation. In response to injury, epithelial cells proliferate and migrate to cover denuded surfaces and restore critical barrier properties. Resident and recruited immune cells at sites of injury release factors that play an important role in orchestrating mucosal repair. Bioactive lipid mediators released by leukocytes, including leukotrienes and specialized pro-resolving mediators (SPMs), regulate epithelial signaling pathways to influence mucosal repair processes. Liquid chromatography-mass spectrometry (LCMS) analyses of healing colonic mucosal wounds performed to detect SPMs identified high levels of MaR2 in healing colonic wounds. In vitro studies using primary colonic epithelial cells revealed MaR2-driven increases in epithelial wound repair that were potentiated by the pro-inflammatory cytokines TNFα and IFNγ. While MaR2 increased epithelial migration by activating cell matrix adhesion proteins, including Src-paxillin and focal adhesion kinase, we did not observe any influence of MaR2 on the activation of cyclin D1/D2 or on epithelial proliferation. Importantly, in vivo studies demonstrated enhanced colonic mucosal wound repair and recovery from dextran sulfate-induced colitis in mice administered MaR2. Given the thermolabile nature of MaR2 (and associated ultracold storage requirements), thermostable polylactic acid (PLA) nanoparticles (NP) containing MaR2 (PLA MaR2) were generated. PLA MaR2 nanoparticles retained bioactivity following extended storage at room temperature and exhibited potent effects on in vivo colonic biopsy induced wound repair. Taken together these data reveal that thermostable MaR2 containing nanoparticles represent a promising new therapeutic approach for regenerating epithelial barrier function and restoring mucosal homeostasis in individuals with IBD.
21
Federti, Enrica, Domenico Mattoscio, Antonio Recchiuti, Alessandro Mattè, Maria Monti, Flora Cozzolino, Martina Ceci, et al. "17R-Resolvin D1 Improves Inflammatory Cardiomyopathy in a Mouse Model of Sickle Cell Disease." Blood 142, Supplement 1 (November 28, 2023): 2496. http://dx.doi.org/10.1182/blood-2023-185603.
Анотація:
Sickle cell disease (SCD) is a severely invalidating genetic red cell disorder. Inflammatory vasculopathy and cardiopulmonary complications markedly impact quality of life and survival. Limited studies are available on the pathogenesis of sickle cell related cardiomyopathy. However, the combination of inflammatory vasculopathy, heart ischemia, and myocardial fibrosis have been suggested to play a role in sickle cell related cardiomyopathy. This is supported by the amelioration of cardiomyopathy in SCD patients, early and intensively treated with either hydroxyurea or chronic transfusion regimen (Niss O et al. Blood 140: 1322, 2022). Recently, we have highlighted an impairment of pro-resolving events in SCD with a deleterious effect on acute sickle cell related organ damage (Matte A et al. Blood 133: 252, 2019). Growing evidence links impairment of pro-resolving mechanisms with atherosclerosis and ischemic cardiomyopathy (Kain V et al. J Mol Cell Cardiol 84: 24, 2015; Conte MS et al. JCI 128: 3727, 2018). Among specialized pro-resolving mediators, 17R-resolvin D1 (17R-RvD1) has been shown to play important protective actions in cardiovascular diseases (Kain V et al. J Mol Cell Cardiol 84: 24, 2015). Here, we first determined the appropriate window of time to study cardiac response to hypoxia/reoxygenation (H/R) stress, mimicking sickle cell related acute vaso-occlusive crisis. We show that humanized SCD mice (TT model) exposed to H/R (10 hours hypoxia 8% oxygen, followed by 3 hours reoxygenation) display increased markers of myocardial dysfunction with neutrophil heart infiltration compared to either SCD mice under normoxia or to healthy (AA) animals exposed to H/R stress. With integrated proteomic and miRNA analyses we have identified upregulation of proteins and miRNAs involved in fibrosis, hypertrophy of the heart, and cardiomyocyte apoptosis. Differentially expressed miRNAs in SCD-hearts compared to AA included miR-16-5p, miR-122-5p, and miR-206-3p, which are involved in angiogenesis and heart fibrosis and hypertrophy. Upregulated proteins in SCD hearts in response to H/R encompassed: NF-kB, Nrf2, hemeoxygenase-1, glutathione peroxidase, and peroxiredoxins (associated to response to oxidative stress), the profibrotic factors FGF and PDGF as well as the TGF-ß1 receptor, and the pro-angiogenic VEGF pathway. Treatment with 17R-RvD1 (100 ng administrated by gavage 1 hour before H/R, see also Matte A et al. Blood 133: 252, 2019) protected heart of SCD mice from H/R-induced stress as supported by significant reduction of ANP, a marker of cardiovascular dysfunction, decrease in neutrophil infiltration, and NF-kB activation (Figure 1). 17R-RvD1 also diminished the H/R-driven upregulation of miR-16-5p, while it enhanced miR-206-3p that was downregulated by H/R, suggesting that 17R-RvD1 can reduce cardiac fibrosis and other pathological processes associated with these miRNAs in SCD. We also found that 17R-RvD1 administration to SCD mice blunted the activation of TGF-ß1 pathway and of markers of extracellular remodeling, supporting the beneficial effect of 17R-RvD1 against H/R stress. Taken together, our data show that 17R-RvD1 reduced heart remodeling and fibrosis in SCD mice undergoing H/R, a model of acute VOCs. This improved understanding in basic pathophysiology of SCD-related inflammatory cardiomyopathy, providing new evidence for protective therapeutic effects of 17R-RvD1 on SCD cardiovascular diseases.
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Soto, Gonzalo, María José Rodríguez, Roberto Fuentealba, Adriana V. Treuer, Iván Castillo, Daniel R. González, and Jessica Zúñiga-Hernández. "Maresin 1, a Proresolving Lipid Mediator, Ameliorates Liver Ischemia-Reperfusion Injury and Stimulates Hepatocyte Proliferation in Sprague-Dawley Rats." International Journal of Molecular Sciences 21, no. 2 (January 15, 2020): 540. http://dx.doi.org/10.3390/ijms21020540.
Анотація:
Maresin-1 (MaR1) is a specialized pro-resolving mediator, derived from omega-3 fatty acids, whose functions are to decrease the pro-inflammatory and oxidative mediators, and also to stimulate cell division. We investigated the hepatoprotective actions of MaR1 in a rat model of liver ischemia-reperfusion (IR) injury. MaR1 (4 ng/gr body weight) was administered prior to ischemia (1 h) and reperfusion (3 h), and controls received isovolumetric vehicle solution. To analyze liver function, transaminases levels and tissue architecture were assayed, and serum cytokines TNF-α, IL-6, and IL-10, mitotic activity index, and differential levels of NF-κB and Nrf-2 transcription factors, were analyzed. Transaminase, TNF-α levels, and cytoarchitecture were normalized with the administration of MaR1 and associated with changes in NF-κB. IL-6, mitotic activity index, and nuclear translocation of Nrf-2 increased in the MaR1-IR group, which would be associated with hepatoprotection and cell proliferation. Taken together, these results suggest that MaR1 alleviated IR liver injury, facilitated by the activation of hepatocyte cell division, increased IL-6 cytokine levels, and the nuclear localization of Nrf-2, with a decrease of NF-κB activity. All of them were related to an improvement of liver injury parameters. These results open the possibility of MaR1 as a potential therapeutic tool in IR and other hepatic pathologies.
23
Buckner, Teresa, Randi K. Johnson, Lauren A. Vanderlinden, Patrick M. Carry, Alex Romero, Suna Onengut-Gumuscu, Wei-Min Chen, et al. "An Oxylipin-Related Nutrient Pattern and Risk of Type 1 Diabetes in the Diabetes Autoimmunity Study in the Young (DAISY)." Nutrients 15, no. 4 (February 14, 2023): 945. http://dx.doi.org/10.3390/nu15040945.
Анотація:
Oxylipins, pro-inflammatory and pro-resolving lipid mediators, are associated with the risk of type 1 diabetes (T1D) and may be influenced by diet. This study aimed to develop a nutrient pattern related to oxylipin profiles and test their associations with the risk of T1D among youth. The nutrient patterns were developed with a reduced rank regression in a nested case-control study (n = 335) within the Diabetes Autoimmunity Study in the Young (DAISY), a longitudinal cohort of children at risk of T1D. The oxylipin profiles (adjusted for genetic predictors) were the response variables. The nutrient patterns were tested in the case-control study (n = 69 T1D cases, 69 controls), then validated in the DAISY cohort using a joint Cox proportional hazards model (n = 1933, including 81 T1D cases). The first nutrient pattern (NP1) was characterized by low beta cryptoxanthin, flavanone, vitamin C, total sugars and iron, and high lycopene, anthocyanidins, linoleic acid and sodium. After adjusting for T1D family history, the HLA genotype, sex and race/ethnicity, NP1 was associated with a lower risk of T1D in the nested case-control study (OR: 0.44, p = 0.0126). NP1 was not associated with the risk of T1D (HR: 0.54, p-value = 0.1829) in the full DAISY cohort. Future studies are needed to confirm the nested case-control findings and investigate the modifiable factors for oxylipins.
24
Kwok, Kelvin Hiu Fai. "A New Approach to Resolving Refusal to License Intellectual Property Rights Disputes." World Competition 34, Issue 2 (June 1, 2011): 261–86. http://dx.doi.org/10.54648/woco2011021.
Анотація:
This article proposes a new approach to resolving the conundrum of a monopolist refusing to license Intellectual Property Rights (IPRs) to a competitor, one of the most complex issues at the interface between Intellectual Property (IP) and competition law. It reviews the approaches adopted by the competition authorities in both the European Union (EU) and United States when confronted with this perplexing issue and argues that the extreme positions they took - either that competition should trump IPRs or that IPRs should trump competition - were mistakenly simplistic. This article proceeds to argue that the preferred approach is to strike an appropriate balance between anti-competitive effects and pro-competitive effects of a refusal to license and, accordingly, allocative efficiency losses and dynamic efficiency gains. A substantial part of this article is devoted to a proposed framework illustrating how the balance can be struck, emphasizing how the refusal at issue interacts with various circumstantial factors such as market power, network effects, monopoly leveraging, predatory intent, degree of follow-on innovation, and the causal connection between IPR protection and innovation incentives. Reference will be made to precedents from the EU (Magill, IMS, and Microsoft) and United States (Kodak and Xerox) in explaining how the framework works in practice.
25
Allen, Joselyn Natasha, Mary Kennett, Andrew Patterson, and Pamela A. Hankey-Giblin. "Loss of MSP-dependent Ron receptor signaling exacerbates liver fibrosis in a high fat high cholesterol diet-induced ApoE KO mouse model." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 42.26. http://dx.doi.org/10.4049/jimmunol.200.supp.42.26.
Анотація:
Abstract Liver fibrosis marks the turning point of non-alcoholic steatohepatitis and with no specific and effective anti-fibrotic therapies available, this disease is a major global health burden. Here, we established the novel role of the Ron receptor in mitigating liver fibrosis. For 18 weeks, apolipoprotein E (ApoE KO) and ApoE x Ron double knockout (DKO) mice were fed a fat and cholesterol-rich diet. Livers from DKO animals exhibited increased accumulation of sirius red-stained collagen. Immunohistochemistry of αSMA revealed that DKO livers had increased activation of collagen-producing hepatic stellate cells. In agreement with this, DKO livers exhibited higher expression of pro-fibrogenic molecules, PDGF, CTGF, and TGFβ. Additionally, DKO mice exhibited increased hepatic expression of collagens (Types 1, 3, and 4) and ECM remodeling proteins (MMP-2 and TIMP-1). The expression of pro-fibrogenic inflammatory cytokines (TNFα and IL-12b), receptors (TLR-4), and chemokines (MIP-2, CCL2, and CCL5) were significantly higher in DKO livers. DKO livers also exhibited increased infiltration of F4/80+ Kupffer cells, which are well-known to mediate the majority of cytokine and chemokine expression in fibrotic livers. Ron also attenuated several risk factors of liver fibrosis including insulin resistance, steatosis, hepatocellular damage, and inflammation. Despite lifestyle changes and pharmacotherapies for treating etiologies of liver fibrosis, the disrupted liver homeostasis often remains and requires effective treatments. Investigating the protective functions of Ron offers a pharmacological target for resolving the steatohepatitis spectrum.
26
VIJAY, RAHUL, Michael Gelb, Makoto Murakami, and Stanley Perlman. "Age-related dysregulation in the lipidome compromises the immune response to the severe acute respiratory coronavirus (VIR5P.1140)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 148.8. http://dx.doi.org/10.4049/jimmunol.194.supp.148.8.
Анотація:
Abstract Age-associated changes have long been known to cause dysregulation in antiviral immune responses. The SARS epidemic of 2002-03 was characteristic in this respect that it exhibited an age-associated increase in mortality. We recently reported that an age-related increase in an eicosanoid, prostaglandin D2 (PGD2) contributed to the observed higher mortality in SARS-CoV infected aged compared to young mice. To examine the factors that resulted in elevated levels of PGD2 in aged mouse lungs, we analyzed the gene expression levels of several enzymes in the eicosanoid pathway. Remarkably, secretory phospholipase A2 group 2D (Pla2g2d), which is preferentially expressed in lung CD11c+ cells, was significantly higher in aged compared to young mice. Lipid profiling of aged and young SARS-CoV-infected mice revealed that unlike young mice, aged mice failed to upregulate many pro-inflammatory lipid mediators although both groups upregulated the pro-resolving ones. Further, aged mice lacking PLA2G2D expression (Pla2g2d-/-) mice exhibited enhanced virus clearance, increased lung DC migration to the draining lymph nodes and increased virus specific T cell responses. Infection of aged Pla2g2d-/- mice with SARS-CoV increased survival from 20% to 80-90%, compared to Pla2g2d+/+ mice. Altogether our data identify a novel role for Pla2g2d in the lungs of aged mice in skewing the lipidome to an anti-inflammatory state and thus predisposing the animal to a worse outcome following SARS-CoV infection.
27
Trojan, Ewa, Natalia Bryniarska, Monika Leśkiewicz, Magdalena Regulska, Katarzyna Chamera, Magdalena Szuster-Głuszczak, Marcello Leopoldo, Enza Lacivita, and Agnieszka Basta-Kaim. "The Contribution of Formyl Peptide Receptor Dysfunction to the Course of Neuroinflammation: A Potential Role in the Brain Pathology." Current Neuropharmacology 18, no. 3 (February 14, 2020): 229–49. http://dx.doi.org/10.2174/1570159x17666191019170244.
Анотація:
: Chronic inflammatory processes within the central nervous system (CNS) are in part responsible for the development of neurodegenerative and psychiatric diseases. These processes are associated with, among other things, the increased and disturbed activation of microglia and the elevated production of proinflammatory factors. Recent studies indicated that the disruption of the process of resolution of inflammation (RoI) may be the cause of CNS disorders. It is shown that the RoI is regulated by endogenous molecules called specialized pro-resolving mediators (SPMs), which interact with specific membrane receptors. Some SPMs activate formyl peptide receptors (FPRs), which belong to the family of seven-transmembrane G protein-coupled receptors. These receptors take part not only in the proinflammatory response but also in the resolution of the inflammation process. Therefore, the activation of FPRs might have complex consequences. : This review discusses the potential role of FPRs, and in particular the role of FPR2 subtype, in the brain under physiological and pathological conditions and their involvement in processes underlying neurodegenerative and psychiatric disorders as well as ischemia, the pathogenesis of which involves the dysfunction of inflammatory processes.
28
Gakis, Athanasios G., Tzortzis Nomikos, Anastassios Philippou, and Smaragdi Antonopoulou. "The Involvement of Lipid Mediators in the Mechanisms of Exercise-Induced Muscle Damage." Physiologia 3, no. 2 (May 10, 2023): 305–28. http://dx.doi.org/10.3390/physiologia3020022.
Анотація:
Lipid mediators are a class of signaling molecules that play important roles in various physiological processes, including inflammation, blood pressure regulation, and energy metabolism. Exercise has been shown to affect the production and metabolism of several types of lipid mediators, including prostaglandins, leukotrienes, sphingolipids, platelet-activating factors and endocannabinoids. Eicosanoids, which include prostaglandins and leukotrienes, are involved in the regulation of inflammation and immune function. Endocannabinoids, such as anandamide and 2-arachidonoylglycerol, are involved in the regulation of pain, mood, and appetite. Pro-resolving lipid mediators are involved in the resolution of inflammation. Sphingolipids have a role in the function of skeletal muscle during and after exercise. There are many studies that have examined the effects of exercise on the production and release of these and other lipid mediators. Some of these studies have focused on the effects of exercise on inflammation and immune function, while others have examined the effects on muscle function and metabolism. However, much less is known about their involvement in the phenomenon of exercise-induced muscle damage that follows after intense or unaccustomed exercise.
29
Carranza, Claudia, Laura Elena Carreto-Binaghi, Silvia Guzmán-Beltrán, Marcela Muñoz-Torrico, Martha Torres, Yolanda González, and Esmeralda Juárez. "Sex-Dependent Differential Expression of Lipidic Mediators Associated with Inflammation Resolution in Patients with Pulmonary Tuberculosis." Biomolecules 12, no. 4 (March 24, 2022): 490. http://dx.doi.org/10.3390/biom12040490.
Анотація:
There is a sex bias in tuberculosis’s severity, prevalence, and pathogenesis, and the rates are higher in men. Immunological and physiological factors are fundamental contributors to the development of the disease, and sex-related factors could play an essential role in making women more resistant to severe forms of the disease. In this study, we evaluated sex-dependent differences in inflammatory markers. Serum samples were collected from 34 patients diagnosed with pulmonary TB (19 male and 15 female) and 27 healthy controls (18 male and 9 female). Cytokines IL2, IL4, IL6, IL8, IL10, IFNγ, TNFα, and GM-CSF, and eicosanoids PGE2, LTB4, RvD1, and Mar1 were measured using commercially available immunoassays. The MDA, a product of lipidic peroxidation, was measured by detecting thiobarbituric-acid-reactive substances (TBARS). Differential inflammation patterns between men and women were observed. Men had higher levels of IL6, IL8, and TNFα than women. PGE2 and LTB4 levels were higher in patients than healthy controls, but there were no differences for RvD1 and Mar1. Women had higher RvD1/PGE2 and RvD1/LTB4 ratios among patients. RvD1 plays a vital role in resolving the inflammatory process of TB in women. Men are the major contributors to the typical pro-inflammatory profile observed in the serum of tuberculosis patients.
30
Costa, Ambra, Rodolfo Quarto, and Sveva Bollini. "Small Extracellular Vesicles from Human Amniotic Fluid Samples as Promising Theranostics." International Journal of Molecular Sciences 23, no. 2 (January 6, 2022): 590. http://dx.doi.org/10.3390/ijms23020590.
Анотація:
Since the first evidence that stem cells can provide pro-resolving effects via paracrine secretion of soluble factors, growing interest has been addressed to define the most ideal cell source for clinical translation. Leftover or clinical waste samples of human amniotic fluid obtained following prenatal screening, clinical intervention, or during scheduled caesarean section (C-section) delivery at term have been recently considered an appealing source of mesenchymal progenitors with peculiar regenerative capacity. Human amniotic fluid stem cells (hAFSC) have been demonstrated to support tissue recovery in several preclinical models of disease by exerting paracrine proliferative, anti-inflammatory and regenerative influence. Small extracellular vesicles (EVs) concentrated from the hAFSC secretome (the total soluble trophic factors secreted in the cell-conditioned medium, hAFSC-CM) recapitulate most of the beneficial cell effects. Independent studies in preclinical models of either adult disorders or severe diseases in newborns have suggested a regenerative role of hAFSC-EVs. EVs can be eventually concentrated from amniotic fluid (hAF) to offer useful prenatal information, as recently suggested. In this review, we focus on the most significant aspects of EVs obtained from either hAFSC and hAF and consider the current challenges for their clinical translation, including isolation, characterization and quantification methods.
31
El-Sayed, Eman M., Khadiga S Ibrahim, and Eman Refaat Youness. "Omega-3 Polyunsaturated Fatty Acids as Adjunctive Therapy for COVID-19 Management: Review." Biomedical and Pharmacology Journal 16, no. 3 (September 30, 2023): 1271–81. http://dx.doi.org/10.13005/bpj/2708.
Анотація:
Patients with severe Coronavirus disease 2019 (COVID-19) experience thrombotic complications, cytokine storm, immune disorder, hypoxia, numerous disturbances in iron homeostasis, and increased oxidative stress. In addition to the appearance of the classic onset symptoms of COVID-19 which are cough fever and chest pain. Dietary supplements or nutraceuticals can be used as an adjunct treatment to improve patients' recovery. Omega 3-polyunsaturated fatty acids (ω-3PUFAs) in particular, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) exhibit anti-inflammatory, anticoagulant, and immunomodulatory properties that, when combined with the appropriate therapeutic intervention, may improve patient outcomes. Upon oxidation, EPA and DHA produce specialized pro-resolving lipid mediators (SPMs) that induce resolution of inflammation through inhibiting neutrophil migration, enhancing macrophage phagocytosis, and decreasing proinflammatory mediators which are risk factors for COVID-19 and increasing its severity. Moreover, ω-3PUFAs have many pathways to ameliorate various metabolic changes induced by viral infection. In this review, we attempted to summarize the available literature to understand the actual role of ω-3PUFAs that might improve or protect against COVID-19 and to determine whether it is possible to administer ω-3PUFAs as a co-therapy with conventional COVID-19 treatments.
32
Терехина, О. Л., and Ю. И. Кирова. "Analysis of the causes and approaches to the regulation of the cytotoxic state of microglia in the aging brain." Zhurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» 67, no. 1 (March 17, 2023): 94–109. http://dx.doi.org/10.25557/0031-2991.2023.01.94-109.
Анотація:
С момента эпохального открытия микроглии Пио дель Рио Ортегой минуло столетие многоплановых исследований, которые подтвердили гениально предсказанные испанским гистологом свойства и функции микроглиальных клеток. Однако причины возрастзависимого снижения гомеостатического/репаративного потенциала микроглии, также как подходы к модуляции цитотоксического состояния микроглии стареющего мозга остаются нерешенными вопросами на текущем этапе развития нейробиологии, в то время как возраст-ассоциированные нейровоспаление, нейродегенерация и нейродисфункция представляют собой угрожающий вызов современному «стареющему» социуму. Цель обзора – анализ представлений о причинах развития дистрофического/старческого фенотипа микроглии и подходов к увеличению ее нейрорепаративного потенциала в стареющем мозге. В работе обсуждаются прогрессирующая с возрастом глюкокортикоидная гиперпродукция и недостаточность проразрешающих/про-анаболических факторов как ведущие механизмы в развитии возрастных дистрофических изменений микроглии. Since the epoch-making discovery of microglia by Pio del Rio Ortega, a century of multifaceted studies has passed, which confirmed the properties and functions of microglial cells ingeniously predicted by the Spanish histologist. However, the reasons for the steady age-dependent decrease in the homeostatic/reparative potential of microglia, as well as approaches to modulating the cytotoxic state of microglia in the aging brain, remain unresolved issues at the current state of neurobiology, while age-associated neuroinflammation, neurodegeneration and neurodysfunction represent a threatening challenge to the modern “aging” society. The aim of this review was to analyze the ideas about the causes for the development of the microglia dystrophic/senescent phenotype of microglia and approaches to enhancing its neuroreparative potential in the aging brain. The authors discussed the age-related progression of glucocorticoid hyperproduction and the shortage of pro-resolving/pro-anabolic factors as the leading mechanisms in the development of age-related dystrophic changes in microglia.
33
Zgorzynska, Emilia, Barbara Dziedzic, Monika Markiewicz та Anna Walczewska. "Omega-3 PUFAs Suppress IL-1β-Induced Hyperactivity of Immunoproteasomes in Astrocytes". International Journal of Molecular Sciences 22, № 11 (21 травня 2021): 5410. http://dx.doi.org/10.3390/ijms22115410.
Анотація:
The role of immunoproteasome (iP) in astroglia, the cellular component of innate immunity, has not been clarified. The results so far indicate that neuroinflammation, a prominent hallmark of Alzheimer’s disease, strongly activates the iP subunits expression. Since omega-3 PUFAs possess anti-inflammatory and pro-resolving activity in the brain, we investigated the effect of DHA and EPA on the gene expression of constitutive (β1 and β5) and inducible (iβ1/LMP2 and iβ5/LMP7) proteasome subunits and proteasomal activity in IL-1β-stimulated astrocytes. We found that both PUFAs downregulated the expression of IL-1β-induced the iP subunits, but not the constitutive proteasome subunits. The chymotrypsin-like activity was inhibited in a dose-dependent manner by DHA, and much strongly in the lower concentration by EPA. Furthermore, we established that C/EBPα and C/EBPβ transcription factors, being the cis-regulatory element of the transcription complex, frequently activated by inflammatory mediators, participate in a reduction in the iP subunits’ expression. Moreover, the expression of connexin 43 the major gap junction protein in astrocytes, negatively regulated by IL-1β was markedly increased in PUFA-treated cells. These findings indicate that omega-3 PUFAs attenuate inflammation-induced hyperactivity of iPs in astrocytes and have a beneficial effect on preservation of interastrocytic communication by gap junctions.
34
Romaldini, Ulivi, Nardini, Mastrogiacomo, Cancedda та Descalzi. "Platelet Lysate Inhibits NF-κB Activation and Induces Proliferation and an Alert State in Quiescent Human Umbilical Vein Endothelial Cells Retaining Their Differentiation Capability". Cells 8, № 4 (9 квітня 2019): 331. http://dx.doi.org/10.3390/cells8040331.
Анотація:
: Injured blood vessel repair and blood circulation re-establishment are crucial events for tissue repair. We investigated in primary cultures of human umbilical vein endothelial cells (HUVEC), the effects of platelet lysate (PL), a cocktail of factors released by activated platelets following blood vessel disruption and involved in the wound-healing process triggering. PL exerted a protective effect on HUVEC in an inflammatory milieu by inhibiting IL-1α-activated NF-κB pathway and by inducing the secretion of PGE2, a pro-resolving molecule in the wound microenvironment. Moreover, PL enhanced HUVEC proliferation, without affecting their capability of forming tube-like structures on matrigel, and activated resting quiescent cells to re-enter cell cycle. In agreement with these findings, proliferation-related pathways Akt and ERK1/2 were activated. The expression of the cell-cycle activator Cyclin D1 was also enhanced, as well as the expression of the High Mobility Group Box-1 (HMGB1), a protein of the alarmin group involved in tissue homeostasis, repair, and remodeling. These in vitro data suggest a possible in vivo contribution of PL to new vessel formation after a wound by activation of cells resident in vessel walls. Our biochemical study provides a rationale for the clinical use of PL in the treatment of wound healing-related pathologies.
35
Barker, Grant, Christiaan Leeuwenburgh, Todd Brusko, Lyle Moldawer, Srinivasa T. Reddy, and Faheem W. Guirgis. "Lipid and Lipoprotein Dysregulation in Sepsis: Clinical and Mechanistic Insights into Chronic Critical Illness." Journal of Clinical Medicine 10, no. 8 (April 14, 2021): 1693. http://dx.doi.org/10.3390/jcm10081693.
Анотація:
In addition to their well-characterized roles in metabolism, lipids and lipoproteins have pleiotropic effects on the innate immune system. These undergo clinically relevant alterations during sepsis and acute inflammatory responses. High-density lipoprotein (HDL) plays an important role in regulating the immune response by clearing bacterial toxins, supporting corticosteroid release, decreasing platelet aggregation, inhibiting endothelial cell apoptosis, reducing the monocyte inflammatory response, and inhibiting expression of endothelial cell adhesion molecules. It undergoes quantitative as well as qualitative changes which can be measured using the HDL inflammatory index (HII). Pro-inflammatory, or dysfunctional HDL (dysHDL) lacks the ability to perform these functions, and we have also found it to independently predict adverse outcomes and organ failure in sepsis. Another important class of lipids known as specialized pro-resolving mediators (SPMs) positively affect the escalation and resolution of inflammation in a temporal fashion. These undergo phenotypic changes in sepsis and differ significantly between survivors and non-survivors. Certain subsets of sepsis survivors go on to have perilous post-hospitalization courses where this inflammation continues in a low grade fashion. This is associated with immunosuppression in a syndrome of persistent inflammation, immunosuppression, and catabolism syndrome (PICS). The continuous release of tissue damage-related patterns and viral reactivation secondary to immunosuppression feed this chronic cycle of inflammation. Animal data indicate that dysregulation of endogenous lipids and SPMs play important roles in this process. Lipids and their associated pathways have been the target of many clinical trials in recent years which have not shown mortality benefit. These results are limited by patient heterogeneity and poor animal models. Considerations of sepsis phenotypes and novel biomarkers in future trials are important factors to be considered in future research. Further characterization of lipid dysregulation and chronic inflammation during sepsis will aid mortality risk stratification, detection of sepsis, and inform individualized pharmacologic therapies.
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Tylek, Kinga, Ewa Trojan, Monika Leśkiewicz, Imane Ghafir El Idrissi, Enza Lacivita, Marcello Leopoldo, and Agnieszka Basta-Kaim. "Microglia Depletion Attenuates the Pro-Resolving Activity of the Formyl Peptide Receptor 2 Agonist AMS21 Related to Inhibition of Inflammasome NLRP3 Signalling Pathway: A Study of Organotypic Hippocampal Cultures." Cells 12, no. 21 (November 3, 2023): 2570. http://dx.doi.org/10.3390/cells12212570.
Анотація:
Microglial cells have been demonstrated to be significant resident immune cells that maintain homeostasis under physiological conditions. However, prolonged or excessive microglial activation leads to disturbances in the resolution of inflammation (RoI). Formyl peptide receptor 2 (FPR2) is a crucial player in the RoI, interacting with various ligands to induce distinct conformational changes and, consequently, diverse biological effects. Due to the poor pharmacokinetic properties of endogenous FPR2 ligands, the aim of our study was to evaluate the pro-resolving effects of a new ureidopropanamide agonist, compound AMS21, in hippocampal organotypic cultures (OHCs) stimulated with lipopolysaccharide (LPS). Moreover, to assess whether AMS21 exerts its action via FPR2 specifically located on microglial cells, we conducted a set of experiments in OHCs depleted of microglial cells using clodronate. We demonstrated that the protective and anti-inflammatory activity of AMS21 manifested as decreased levels of lactate dehydrogenase (LDH), nitric oxide (NO), and proinflammatory cytokines IL-1β and IL-6 release evoked by LPS in OHCs. Moreover, in LPS-stimulated OHCs, AMS21 treatment downregulated NLRP3 inflammasome-related factors (CASP1, NLRP3, PYCARD) and this effect was mediated through FPR2 because it was blocked by the FPR2 antagonist WRW4 pre-treatment. Importantly this beneficial effect of AMS21 was only observed in the presence of microglial FPR2, and absent in OHCs depleted with microglial cells using clodronate. Our results strongly suggest that the compound AMS21 exerts, at nanomolar doses, protective and anti-inflammatory properties and an FPR2 receptor located specifically on microglial cells mediates the anti-inflammatory response of AMS21. Therefore, microglial FPR2 represents a promising target for the enhancement of RoI.
37
Wang, Fuquan, Ming Chen, Chenchen Wang, Haifa Xia, Dingyu Zhang, and Shanglong Yao. "Single-Cell Sequencing Reveals the Regulatory Role of Maresin1 on Neutrophils during Septic Lung Injury." Cells 11, no. 23 (November 23, 2022): 3733. http://dx.doi.org/10.3390/cells11233733.
Анотація:
Acute lung injury (ALI) is the most common type of organ injury in sepsis, with high morbidity and mortality. Sepsis is characterized by an inappropriate inflammatory response while neutrophils exert an important role in the excessive inflammatory response. The discovery of specialized pro-resolving mediators (SPMs) provides a new direction for the treatment of a series of inflammatory-related diseases including sepsis. Among them, the regulation of Maresin1 on immune cells was widely demonstrated. However, current research on the regulatory effects of Maresin1 on immune cells has remained at the level of certain cell types. Under inflammatory conditions, the immune environment is complex and immune cells exhibit obvious heterogeneity. Neutrophils play a key role in the occurrence and development of septic lung injury. Whether there is a subpopulation bias in the regulation of neutrophils by Maresin1 has not been elucidated. Therefore, with the well-established cecal ligation and puncture (CLP) model and single-cell sequencing technology, our study reveals for the first time the regulatory mechanism of Maresin1 on neutrophils at the single-cell level. Our study suggested that Maresin1 can significantly reduce neutrophil infiltration in septic lung injury and that this regulatory effect is more concentrated in the Neutrophil-Cxcl3 subpopulation. Maresin1 can significantly reduce the infiltration of the Neutrophil-Cxcl3 subpopulation and inhibit the expression of related inflammatory genes and key transcription factors in the Neutrophil-Cxcl3 subpopulation. Our study provided new possibilities for specific modulation of neutrophil function in septic lung injury.
38
Alton, Mitchell W., Harald J. Stark, Manjula R. Canagaratna, and Eleanor C. Browne. "Generalized Kendrick analysis for improved visualization of atmospheric mass spectral data." Atmospheric Measurement Techniques 16, no. 12 (June 29, 2023): 3273–82. http://dx.doi.org/10.5194/amt-16-3273-2023.
Анотація:
Abstract. Mass spectrometry is an important analytical technique within the field of atmospheric chemistry. Owing to advances in instrumentation, particularly with regards to mass-resolving power and instrument response factors (sensitivities), hundreds of different mass-to-charge (m/z) signals are routinely measured. This large number of detected ions creates challenges for data visualization. Furthermore, assignment of chemical formulas to these ions is time consuming and increases in difficulty at the higher m/z ranges. Here, we describe generalized Kendrick analysis (GKA) to facilitate the visualization and peak identification processes for typical atmospheric organic (and to some extent inorganic) compounds. GKA is closely related to resolution-enhanced Kendrick mass defect analysis (REKMD), which introduces a tunable integer into the Kendrick equation that effectively contracts or expands the mass scale. A characteristic of all Kendrick analysis methods is that these changes maintain the horizontal alignment of ion series related by integer multiples of the chosen base unit. Compared to traditional Kendrick analysis, GKA and REKMD use a tunable parameter (“scaling factor”) to alter the mass defect spacing between different homologue ion series. As a result, the entire mass defect range (−0.5 to 0.5) is more effectively used simplifying data visualization and facilitating chemical formula assignment. We describe the mechanism of this transformation and discuss base unit and scaling factor selections appropriate for compounds typically found in atmospheric measurements. We present an open-source graphical user interface (GUI) for calculating and visualizing GKA results within the Igor Pro environment.
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Suau, R., E. Pardina, L. Clua, B. Cordobilla, Y. Zabana, M. Calafat, J. Carmona-Maurici та ін. "P168 Specialized pro-resolving lipid mediator Resolvin D1 and omega 6 dihomo-γ-linolenic acid are unable to solve inflammation in the creeping fat of patients with severe postoperative recurrence in Crohn's disease". Journal of Crohn's and Colitis 18, Supplement_1 (1 січня 2024): i473—i474. http://dx.doi.org/10.1093/ecco-jcc/jjad212.0298.
Анотація:
Abstract Background The ω3 derivate resolvin D1 (RvD1), and the ω6 dihomo-γ-linolenic acid (DGLA) prevent collateral damage by overcoming inflammation and enhancing microbial clearance. In Crohn's disease, the mesenteric adipose tissue becomes inflamed and hyperplasies due to transmural lesions and bacterial translocation, developing the so-called creeping fat. This tissue is unable to clear inflammation and has been linked to severer intestinal inflammation and post-operative recurrence (POR). Recently, we have described the presence of DGLA and the increase in the ω6/ω3 ratio together with pro-inflammatory mediators in the creeping fat at surgery. Our aims were study the mechanisms within the inflammatory resolution related to polyunsaturated fatty acids depending on POR severity. Methods Creeping fat samples were obtained in the intestinal resection of Crohn's disease patients and endoscopic POR was evaluated according to the Rutgeerts score: non recurrence (i0+i1; n=18), mild recurrence (i2; n=14) and severe recurrence (i3+i4; n=10). Mesenteric adipose tissue was also collected from patients with colorectal cancer (n=10) and severe obesity (n=11) as reference groups. RvD1 was evaluated by C18/ELISA, lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) activity by radioassay, and the free fatty acid receptor 1 (FFAR1) expression by qRT-PCR. Results RvD1 was increased in the creeping fat in comparison to the mesenteric adipose tissues of the reference groups (Graphical abstract A) and correlated antagonistically with pro-inflammatory mediators in non-recurrence versus severe recurrence (B). Specifically, factors such as TNF-α, CD14 or IL-18 showed significant positive correlations with RvD1 in severe recurrence while negative in non recurrence. The LPL/HSL ratio indicated greater storage of fatty acids in severe recurrence creeping fats (C), and only in these patients, DGLA negatively correlated with HSL (D) and FFAR1 (E), a receptor that was only detected in Crohn's disease (F). At the same time, this receptor antagonistically correlated with pro-inflammatory mediators such as IL-8 in the creeping fat, positively in non-recurrence and negatively in severe recurrence (G). Conclusion The RvD1 increase suggests a greater production of this factor from ω3, but that would be insufficient to resolve inflammation in severe recurrent creeping fat at surgery time. In this phenotype, HSL activity is linked to a lower presence of DGLA, the only anti-inflammatory ω6. In contrast, the presence of this ligand in severe recurrents seems to reduce the expression of the FFAR1, which acts on the neutrophil function. Thus, immune-inflammation derived from lipid metabolism is antagonistic among the most disparate cases of POR in the creeping fat at surgery.
40
Frederick, Rosanne E., Robert Bearden, Aleksa Jovanovic, Nasreen Jacobson, Rajiv Sood, and Sandeep Dhall. "Clostridium Collagenase Impact on Zone of Stasis Stabilization and Transition to Healthy Tissue in Burns." International Journal of Molecular Sciences 22, no. 16 (August 11, 2021): 8643. http://dx.doi.org/10.3390/ijms22168643.
Анотація:
Clostridium collagenase has provided superior clinical results in achieving digestion of immediate and accumulating devitalized collagen tissue. Recent studies suggest that debridement via Clostridium collagenase modulates a cellular response to foster an anti-inflammatory microenvironment milieu, allowing for a more coordinated healing response. In an effort to better understand its role in burn wounds, we evaluated Clostridium collagenase’s ability to effectively minimize burn progression using the classic burn comb model in pigs. Following burn injury, wounds were treated with Clostridium collagenase or control vehicle daily and biopsied at various time points. Biopsies were evaluated for factors associated with progressing necrosis as well as inflammatory response associated with treatment. Data presented herein showed that Clostridium collagenase treatment prevented destruction of dermal collagen. Additionally, treatment with collagenase reduced necrosis (HMGB1) and apoptosis (CC3a) early in burn injuries, allowing for increased infiltration of cells and protecting tissue from conversion. Furthermore, early epidermal separation and epidermal loss with a clearly defined basement membrane was observed in the treated wounds. We also show that collagenase treatment provided an early and improved inflammatory response followed by faster resolution in neutrophils. In assessing the inflammatory response, collagenase-treated wounds exhibited significantly greater neutrophil influx at day 1, with macrophage recruitment throughout days 2 and 4. In further evaluation, macrophage polarization to MHC II and vascular network maintenance were significantly increased in collagenase-treated wounds, indicative of a pro-resolving macrophage environment. Taken together, these data validate the impact of clostridial collagenases in the pathophysiology of burn wounds and that they complement patient outcomes in the clinical scenario.
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Menon, Riyesh, Paulina Krzyszczyk, and François Berthiaume. "Pro-Resolution Potency of Resolvins D1, D2 and E1 on Neutrophil Migration and in Dermal Wound Healing." Nano LIFE 07, no. 01 (March 2017): 1750002. http://dx.doi.org/10.1142/s1793984417500027.
Анотація:
An exuberant inflammatory response may exacerbate the primary tissue damage caused by injuries to the skin due to burns, surgery, excessive pressure, and other etiologies, thus increasing the time to heal. We hypothesized that application of factors that decrease inflammation would allow the skin to more quickly restore its barrier function, and promote the return to homeostasis. Resolvins are endogenous, pro-resolving lipid mediators derived from omega-3 fatty acids that serve to inhibit neutrophil migration and enhance macrophage phagocytosis, thus promoting the resolution of inflammation and the beginning of the proliferative phase of wound healing. Resolvins are derived either from docosahexaenoic (D-series) or eicosapentaenoic (E-series) acid. Herein, we compare the effects of resolvins D1 (RvD1), D2 (RvD2) and E1 (RvE1) on their abilities to inhibit neutrophil migration in vitro and to promote wound healing in vivo. In Transwell experiments, all resolvins inhibited neutrophil migration, with RvE1 being the most effective at a 2000[Formula: see text]nM concentration. In an in vivo murine excisional wound (1[Formula: see text]cm[Formula: see text][Formula: see text][Formula: see text]1[Formula: see text]cm) healing model, topically applied resolvins accelerated wound closure. RvE1-treated wounds healed by 19.4[Formula: see text][Formula: see text][Formula: see text]1.5 days post-wounding, which was significantly shorter than the RvD2-treated and RvD1-treated groups ([Formula: see text]0.05), which closed by an average of 22.8[Formula: see text][Formula: see text][Formula: see text]1.8 and 24.4[Formula: see text][Formula: see text][Formula: see text]2.2 days, respectively. Furthermore, all resolvin-treated groups healed faster than vehicle controls ([Formula: see text]0.05), which closed at 28.6[Formula: see text][Formula: see text][Formula: see text]1.5 days. There was a strong linear correlation ([Formula: see text]0.9384) between each resolvin’s potency in inhibiting neutrophil migration in vitro versus accelerating wound healing in vivo. Furthermore, upon histological analysis, the RvE1-treated group exhibited more mature collagen organization and re-epithelialization.
42
Djuricic, Ivana, and Philip C. Calder. "Omega-3 (n-3) Fatty Acid–Statin Interaction: Evidence for a Novel Therapeutic Strategy for Atherosclerotic Cardiovascular Disease." Nutrients 16, no. 7 (March 27, 2024): 962. http://dx.doi.org/10.3390/nu16070962.
Анотація:
Managing atherosclerotic cardiovascular disease (ASCVD) often involves a combination of lifestyle modifications and medications aiming to decrease the risk of cardiovascular outcomes, such as myocardial infarction and stroke. The aim of this article is to discuss possible omega-3 (n-3) fatty acid–statin interactions in the prevention and treatment of ASCVD and to provide evidence to consider for clinical practice, highlighting novel insights in this field. Statins and n-3 fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) are commonly used to control cardiovascular risk factors in order to treat ASCVD. Statins are an important lipid-lowering therapy, primarily targeting low-density lipoprotein cholesterol (LDL-C) levels, while n-3 fatty acids address triglyceride (TG) concentrations. Both statins and n-3 fatty acids have pleiotropic actions which overlap, including improving endothelial function, modulation of inflammation, and stabilizing atherosclerotic plaques. Thus, both statins and n-3 fatty acids potentially mitigate the residual cardiovascular risk that remains beyond lipid lowering, such as persistent inflammation. EPA and DHA are both substrates for the synthesis of so-called specialized pro-resolving mediators (SPMs), a relatively recently recognized feature of their ability to combat inflammation. Interestingly, statins seem to have the ability to promote the production of some SPMs, suggesting a largely unrecognized interaction between statins and n-3 fatty acids with relevance to the control of inflammation. Although n-3 fatty acids are the major substrates for the production of SPMs, these signaling molecules may have additional therapeutic benefits beyond those provided by the precursor n-3 fatty acids themselves. In this article, we discuss the accumulating evidence that supports SPMs as a novel therapeutic tool and the possible statin–n-3 fatty acid interactions relevant to the prevention and treatment of ASCVD.
43
Camba Gómez, M., L. Arosa, D. Ait Eldjoudi, M. Gonzalez-Rodríguez, O. Gualillo, and J. Conde-Aranda. "P084 Natural extracts and omega-3 derived molecule: role in resolution of intestinal inflammation." Journal of Crohn's and Colitis 18, Supplement_1 (January 1, 2024): i359. http://dx.doi.org/10.1093/ecco-jcc/jjad212.0214.
Анотація:
Abstract Background In the last years there is a great interest in the characterization of natural compounds extracted from plants or omega-3 derived molecules for their possible therapeutic effects. In this scenario, the seeds of Nigella sativa and Nigella orientalis (plants with great relevance in North African traditional medicine) have shown beneficial effects in reducing inflammation. Similarly, the addition of Maresin 2 (pro-resolving mediator) to experimental animals improved symptoms in various models of inflammation. However, there is no information on the role that these potential therapies may play in the cellular and molecular processes leading to the resolution of inflammation at the intestinal level. Methods Eight-week-old female C57Bl/6 mice (n=30) were subjected to a DSS-induced colitis model; mice received 1.8% (weight/volume) DSS in the drinking water for 6 days followed by 6 days of regular drinking water. Mice were treated from day 5 to day 12 with vehicle, Nigella Sativa, Nigella Orientalis, and Maresin-2. After that, histology studies, flow cytometry, expression analysis and migration experiments were performed. Results In all the treatment groups there was a significant reduction in weight loss and improved DAI scores compared to control group. Significant differences were also observed in the epithelial score and in the infiltration score. Analysis of the immune cell infiltrate revealed that only neutrophil numbers were downregulated after the administration of the indicated treatments. Further in vivo and in vitro studies demonstrated that Nigella Sativa and Nigella Orientalis were able to decrease neutrophil viability and migration. By contrast, Mar2 seemed to affect neutrophil infiltration through indirect mechanisms and by regulating the expression of chemotactic factors Conclusion Overall, our study reveals novel compounds able to regulate the resolution of intestinal inflammation in vivo, and this occurs, by the modulation of neutrophil presence into the colon lamina propria.
44
Karasova, T. A. "New Trends in Israel Regional Policy (2009-2019)." MGIMO Review of International Relations 12, no. 4 (September 9, 2019): 180–200. http://dx.doi.org/10.24833/2071-8160-2019-4-67-180-200.
Анотація:
Changes in Israeli regional politics were triggered by the current political situation in the Middle East, characterized by a high degree of intensity and unpredictability. The region experiences a complex process of serious political changes making Israel adjust its regional policy to the new challenges. The article focuses upon the new elements of Israelis strategy on key regional issues: the settlement of Palestinian-Israeli conflict; new approaches to countering Iranian nuclear program; the Syrian civil war and escalation of terrorism activities. The aim of the article is to describe and analyze new trends in Israeli regional strategy over the past 10 years identifying its external and internal factors. The main external factor is a close partnership of Israel with US, which plays a key role in supporting Israel’s regional and international status. The changes taking place inside the region could be considered as internal factors. They include Arab Spring; prospects for settlement of the Palestinian-Israeli conflict; the growth of the Islamic radicalism and terrorism, new terrorist groups such as ISIS, and the civil war in Syria.The main changes of Israeli regional policy include toughening approaches to resolving the Palestinian-Israeli conflict, in particular, de facto abandonment of the «two states for two peoples» formula. Equally important are events that, although not directly related to Israel, are changing its regional agenda. Assessment of Iran’s nuclear program as an existential threat explains Israel’s negative attitude to the international agreement with Iran in 2015 during the presidency of B. Obama (JCPOA). The subsequent withdrawal of the Trump administration from this agreement strengthened Israel’s anti-Iranian position. This also allowed Israel to develop cooperative ties with the so-called pro-Western states of the region, such as Saudi Arabia and some Persian Gulf countries in pursuit of containing the Iranian nuclear threat and its growing regional influence. Saudi Arabia and the Gulf countries became real partners of Israel in confronting Iran. This gives the Israeli state the opportunity to at last enter the regional system and free itself from the traditional image of rogue state among the Muslim countries in the Middle East.
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Decker, Christa, Sudeshna Sadhu, and Gabrielle Fredman. "Pro-Resolving Ligands Orchestrate Phagocytosis." Frontiers in Immunology 12 (June 10, 2021). http://dx.doi.org/10.3389/fimmu.2021.660865.
Анотація:
The resolution of inflammation is a tissue protective program that is governed by several factors including specialized pro-resolving mediators (SPMs), proteins, gasses and nucleotides. Pro-resolving mediators activate counterregulatory programs to quell inflammation and promote tissue repair in a manner that does not compromise host defense. Phagocytes like neutrophils and macrophages play key roles in the resolution of inflammation because of their ability to remove debris, microbes and dead cells through processes including phagocytosis and efferocytosis. Emerging evidence suggests that failed resolution of inflammation and defective phagocytosis or efferocytosis underpins several prevalent human diseases. Therefore, understanding factors and mechanisms associated with enhancing these processes is a critical need. SPMs enhance phagocytosis and efferocytosis and this review will highlight mechanisms associated with their actions.
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Martin-Rodriguez, Omayra, Thierry Gauthier, Francis Bonnefoy, Mélanie Couturier, Anna Daoui, Cécile Chagué, Séverine Valmary-Degano, Claire Gay, Philippe Saas, and Sylvain Perruche. "Pro-Resolving Factors Released by Macrophages After Efferocytosis Promote Mucosal Wound Healing in Inflammatory Bowel Disease." Frontiers in Immunology 12 (December 22, 2021). http://dx.doi.org/10.3389/fimmu.2021.754475.
Анотація:
Nonresolving inflammation is a critical driver of several chronic inflammatory diseases, including inflammatory bowel diseases (IBD). This unresolved inflammation may result from the persistence of an initiating stimulus or from the alteration of the resolution phase of inflammation. Elimination of apoptotic cells by macrophages (a process called efferocytosis) is a critical step in the resolution phase of inflammation. Efferocytosis participates in macrophage reprogramming and favors the release of numerous pro-resolving factors. These pro-resolving factors exert therapeutic effects in experimental autoimmune arthritis. Here, we propose to evaluate the efficacy of pro-resolving factors produced by macrophages after efferocytosis, a secretome called SuperMApo, in two IBD models, namely dextran sodium sulfate (DSS)-induced and T cell transfer-induced colitis. Reintroducing these pro-resolving factors was sufficient to decrease clinical, endoscopic and histological colitis scores in ongoing naive T cell-transfer-induced colitis and in DSS-induced colitis. Mouse primary fibroblasts isolated from the colon demonstrated enhanced healing properties in the presence of SuperMApo, as attested by their increased migratory, proliferative and contractive properties. This was confirmed by the use of human fibroblasts isolated from patients with IBD. Exposure of an intestinal epithelial cell (IEC) line to these pro-resolving factors increased their proliferative properties and IEC acquired the capacity to capture apoptotic cells. The improvement of wound healing properties induced by SuperMApo was confirmed in vivo in a biopsy forceps-wound colonic mucosa model. Further in vivo analysis in naive T cell transfer-induced colitis model demonstrated an improvement of intestinal barrier permeability after administration of SuperMApo, an intestinal cell proliferation and an increase of α-SMA expression by fibroblasts, as well as a reduction of the transcript coding for fibronectin (Fn1). Finally, we identified TGF-β, IGF-I and VEGF among SuperMApo as necessary to favor mucosal healing and confirmed their role both in vitro (using neutralizing antibodies) and in vivo by depleting these factors from efferocytic macrophage secretome using antibody-coated microbeads. These growth factors only explained some of the beneficial effects induced by factors released by efferocytic macrophages. Overall, the administration of pro-resolving factors released by efferocytic macrophages limits intestinal inflammation and enhance tissue repair, which represents an innovative treatment of IBD.
47
Saas, Philippe, Mathieu Vetter, Melissa Maraux, Francis Bonnefoy, and Sylvain Perruche. "Resolution therapy: Harnessing efferocytic macrophages to trigger the resolution of inflammation." Frontiers in Immunology 13 (October 28, 2022). http://dx.doi.org/10.3389/fimmu.2022.1021413.
Анотація:
Several chronic inflammatory diseases are associated with non-resolving inflammation. Conventional anti-inflammatory drugs fail to completely cure these diseases. Resolution pharmacology is a new therapeutic approach based on the use of pro-resolving mediators that accelerate the resolution phase of inflammation by targeting the productive phase of inflammation. Indeed, pro-resolving mediators prevent leukocyte recruitment and induce apoptosis of accumulated leukocytes. This approach is now called resolution therapy with the introduction of complex biological drugs and cell-based therapies. The main objective of resolution therapy is to specifically reduce the duration of the resolution phase to accelerate the return to homeostasis. Under physiological conditions, macrophages play a critical role in the resolution of inflammation. Indeed, after the removal of apoptotic cells (a process called efferocytosis), macrophages display anti-inflammatory reprogramming and subsequently secrete multiple pro-resolving factors. These factors can be used as resolution therapy. Here, we review the different mechanisms leading to anti-inflammatory reprogramming of macrophages after efferocytosis and the pro-resolving factors released by these efferocytic macrophages. We classify these mechanisms in three different categories: macrophage reprogramming induced by apoptotic cell-derived factors, by molecules expressed by apoptotic cells (i.e., “eat-me” signals), and induced by the digestion of apoptotic cell-derived materials. We also evoke that macrophage reprogramming may result from cooperative mechanisms, for instance, implicating the apoptotic cell-induced microenvironment (including cellular metabolites, specific cytokines or immune cells). Then, we describe a new drug candidate belonging to this resolution therapy. This candidate, called SuperMApo, corresponds to the secretome of efferocytic macrophages. We discuss its production, the pro-resolving factors present in this drug, as well as the results obtained in experimental models of chronic (e.g., arthritis, colitis) and acute (e.g., peritonitis or xenogeneic graft-versus-host disease) inflammatory diseases.
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Emre, Ceren, Luis E. Arroyo-García, Khanh V. Do, Bokkyoo Jun, Makiko Ohshima, Silvia Gómez Alcalde, Megan L. Cothern, et al. "Intranasal delivery of pro-resolving lipid mediators rescues memory and gamma oscillation impairment in AppNL-G-F/NL-G-F mice." Communications Biology 5, no. 1 (March 21, 2022). http://dx.doi.org/10.1038/s42003-022-03169-3.
Анотація:
AbstractSustained microglial activation and increased pro-inflammatory signalling cause chronic inflammation and neuronal damage in Alzheimer’s disease (AD). Resolution of inflammation follows neutralization of pathogens and is a response to limit damage and promote healing, mediated by pro-resolving lipid mediators (LMs). Since resolution is impaired in AD brains, we decided to test if intranasal administration of pro-resolving LMs in the AppNL-G-F/NL-G-F mouse model for AD could resolve inflammation and ameliorate pathology in the brain. A mixture of the pro-resolving LMs resolvin (Rv) E1, RvD1, RvD2, maresin 1 (MaR1) and neuroprotectin D1 (NPD1) was administered to stimulate their respective receptors. We examined amyloid load, cognition, neuronal network oscillations, glial activation and inflammatory factors. The treatment ameliorated memory deficits accompanied by a restoration of gamma oscillation deficits, together with a dramatic decrease in microglial activation. These findings open potential avenues for therapeutic exploration of pro-resolving LMs in AD, using a non-invasive route.
49
Fredman, Gabrielle, and Katherine C. MacNamara. "Atherosclerosis is a major human killer and non-resolving inflammation is a prime suspect." Cardiovascular Research, October 5, 2021. http://dx.doi.org/10.1093/cvr/cvab309.
Анотація:
Abstract The resolution of inflammation (or inflammation-resolution) is an active and highly coordinated process. Inflammation-resolution is governed by several endogenous factors, and specialized pro-resolving mediators (SPMs) are one such class of molecules that have robust biological function. Non-resolving inflammation is associated with a variety of human diseases, including atherosclerosis. Moreover, non-resolving inflammation is a hallmark of ageing, an inevitable process associated with increased risk for cardiovascular disease. Uncovering mechanisms as to why inflammation-resolution is impaired in ageing and in disease and identifying useful biomarkers for non-resolving inflammation are unmet needs. Recent work has pointed to a critical role for balanced ratios of SPMs and pro-inflammatory lipids (i.e. leucotrienes and/or specific prostaglandins) as a key determinant of timely inflammation resolution. This review will focus on the accumulating findings that support the role of non-resolving inflammation and imbalanced pro-resolving and pro-inflammatory mediators in atherosclerosis. We aim to provide insight as to why these imbalances occur, the importance of ageing in disease progression, and how haematopoietic function impacts inflammation-resolution and atherosclerosis. We highlight open questions regarding therapeutic strategies and mechanisms of disease to provide a framework for future studies that aim to tackle this important human disease.
50
Berrueta, Lisbeth, Dennis Muñoz‐Vergara, Daniel Martin, Rebecca Thompson, Brian E. Sansbury, Matthew Spite, Gary J. Badger, and Helene M. Langevin. "Effect of stretching on inflammation in a subcutaneous carrageenan mouse model analyzed at single‐cell resolution." Journal of Cellular Physiology, November 2023. http://dx.doi.org/10.1002/jcp.31133.
Анотація:
AbstractUnderstanding the factors that influence the biological response to inflammation is crucial, due to its involvement in physiological and pathological processes, including tissue repair/healing, cancer, infections, and autoimmune diseases. We have previously demonstrated that in vivo stretching can reduce inflammation and increase local pro‐resolving lipid mediators in rats, suggesting a direct mechanical effect on inflammation resolution. Here we aimed to explore further the effects of stretching at the cellular/molecular level in a mouse subcutaneous carrageenan‐inflammation model. Stretching for 10 min twice a day reduced inflammation, increased the production of pro‐resolving mediator pathway intermediate 17‐HDHA at 48 h postcarrageenan injection, and decreased both pro‐resolving and pro‐inflammatory mediators (e.g., PGE2 and PGD2) at 96 h. Single‐cell RNA sequencing analysis of inflammatory lesions at 96 h showed that stretching increased the expression of both pro‐inflammatory (Nos2) and pro‐resolution (Arg1) genes in M1 and M2 macrophages at 96 h. An intercellular communication analysis predicted specific ligand–receptor interactions orchestrated by neutrophils and M2a macrophages, suggesting a continuous neutrophil presence recruiting immune cells such as activated macrophages to contain the antigen while promoting resolution and preserving tissue homeostasis.