Abstract 16009: Y RNA Fragments Enriched in Exosomes From Cardiosphere-derived Cells Mediate Cardioprotection and Macrophage Polarization

Background: Exosomes secreted by cardiosphere-derived cells (CDCs) are critical agents of regeneration and cardioprotection following ischemic injury, mediating the beneficial therapeutic effects of CDCs. Transfer of exosomal RNA to target cells is important for bioactivity. Objective: We sought to determine the RNA content of CDCs-secreted exosomes (CDC-exo), and to assess the contributions of selected small non-coding RNAs to the therapeutic efficacy of CDC-exo. Methods: Using next-generation sequencing (Illumina), we characterized the RNA content of CDC-exo. By direct transfection of fluorescently-labelled oligoribonucleotides, we delivered and tracked selected RNA fragments that are highly enriched in CDC-exo. In order to examine potential cytoprotective effects, neonatal rat ventricular myocytes (NRVMs) were pretreated with each of these fragments or a scrambled control fragment prior to H2O2-induced oxidative stress. Effects on gene expression were assessed by transfection of the fragments into bone marrow-derived macrophages. Results: Several noncoding RNA species were present in CDC-exo. Among these, Y RNAs (either whole or in fragments of the 5’ end) constituted 18% of all hits. From this data set, we selected two highly-enriched Y RNA fragments. Both fragments localized to the cytoplasm of CDC, NRVM and macrophages, and conferred augmented resistance to oxidative stress of NRVM (64.25±31.13% viability vs. 44±26.85%; p=0.06). Additionally, macrophages transfected with Y fragments exhibit rapid, robust polarization to a distinctive gene expression profile notable for upregulation of IL-10 (83.07 vs. 0.59 fold; p<0.0001), an anti-inflammatory cytokine. Conclusions: Here, we demonstrated that abundant noncoding RNA components of CDC-exo, Y RNA fragments, are bioactive components of CDC-exo. Two distinct fragments confer cardioprotection and also induce a strong anti-inflammatory response in macrophages. Although several components of the CDC-exo payload (including miRNA) contribute to functional efficacy, the present findings demonstrate the capacity of Y RNA fragments, an RNA species of previously-unknown function, to elicit therapeutic effects in vitro.

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IPSE, a urogenital parasite-derived immunomodulatory protein, ameliorates ifosfamide-induced hemorrhagic cystitis through downregulation of pro-inflammatory pathways

10.1101/381764 ◽

2018 ◽

Author(s):

Evaristus C. Mbanefo ◽

Loc Le ◽

Rebecca Zee ◽

Nirad Banskota ◽

Kenji Ishida ◽

...

Keyword(s):

Oxidative Stress ◽

Stress Responses ◽

Cellular Proliferation ◽

Transcriptional Profiling ◽

Hemorrhagic Cystitis ◽

Underlying Mechanism ◽

Protective Mechanism ◽

Therapeutic Effects ◽

Anti Inflammatory ◽

Oxidative Stress Responses

AbstractIfosfamide and other oxazaphosphorines can result in hemorrhagic cystitis, a constellation of complications caused by acrolein metabolites. We previously showed that a single dose of IPSE, a schistosome-derived host modulatory protein, can ameliorate ifosfamide-related cystitis; however, the exact mechanisms underlying this urotoxic effect and its prevention are not fully understood. To provide insights into IPSE’s protective mechanism, we undertook transcriptional profiling of bladders from ifosfamide-treated mice, with or without IPSE pretreatment. Following ifosfamide challenge, there was upregulation of a range of pro-inflammatory genes. The pro-inflammatory pathway involving the IL-1β, TNFαand IL-6 triad via NFκB and STAT3 signaling pathways was identified as the key driver of inflammation. The NRF2-mediated oxidative stress response pathway, which regulates bothHmox1-mediated heme homoeostasis and expression of antioxidant enzymes, was highly activated. Anti-inflammatory and cellular proliferation cascades implicated in tissue repair, namely Wnt, Hedgehog and PPAR pathways, were downregulated. IPSE administration before ifosfamide injection resulted in significant downregulation of major proinflammatory pathways including the triad of IL-1β, TNFαand IL-6 pathways, the interferon signaling pathway, and less apparent reduction in oxidative stress responses. Taken together, we have identified signatures of acute phase inflammation and oxidative stress responses in the ifosfamide-injured bladder, which are reversed by pretreatment with IPSE, a parasite derived anti-inflammatory molecule. In addition to providing new insights into the underlying mechanism of IPSE’s therapeutic effects, this work has revealed several pathways that could be therapeutically targeted to prevent and treat ifosfamide-induced hemorrhagic cystitis.

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Evaluation of Therapeutic Effects of Quercetin Against Achilles Tendinopathy in Rats via Oxidative Stress, Inflammation, Apoptosis, Autophagy, and Metalloproteinases

The American Journal of Sports Medicine ◽

10.1177/03635465211059821 ◽

2021 ◽

pp. 036354652110598

Author(s):

Halil Sezgin Semis ◽

Cihan Gur ◽

Mustafa Ileriturk ◽

Fatih Mehmet Kandemir ◽

Ozgur Kaynar

Keyword(s):

Oxidative Stress ◽

Achilles Tendinopathy ◽

Therapeutic Effects ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Alternative Treatment Option ◽

Markers Of Oxidative Stress ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

The One

Background: Achilles tendinopathy, seen in athletes and manual labor workers, is an inflammatory condition characterized by chronic tendon pain. Owing to the toxicity that develops in various organs attributed to the use of anti–inflammatory drugs, there is a need for new therapeutic agents. Purpose: In the present study, the effects of quercetin (Que), the one that attracted the most attention of researchers studying this group of flavonoids, were investigated against collagenase–induced tendinopathy. Study Design: Controlled laboratory study. Methods: A total of 35 Sprague-Dawley rats were used in the study. Tendinopathy was created by injecting a single dose of collagenase (10 μL; 10 mg/mL) into the tendons of rats. Thirty minutes after the injection, Que was administered at doses of 25 or 50 mg/kg. Que administration was carried out for 7 days. Animals underwent a motility test at the end of the study. In addition, markers of oxidative stress, inflammation, apoptosis, and autophagy, as well as the expression levels of matrix metalloproteinases (MMPs 2, 3, 9, and 13), ICAM-1, and STAT3, were measured in tendon tissues with biochemical, molecular, and Western blot techniques. Results: The results showed that oxidative stress, inflammation, apoptosis, and autophagy were triggered by the injection of collagenase. In addition, MMPs, ICAM-1, and STAT3 were activated to participate in the development of tendinopathy. Que was found to reduce ICAM-1 levels in tendon tissue. Moreover, Que showed antioxidant, anti–inflammatory, antiapoptotic, and antiautophagic effects on tendons against tendinopathy. More important, Que suppressed the expression of MMPs in the tendon tissues. Conclusion: Que has protective properties against collagenase–induced tendon damage in rats. Clinical Relevance: We believe that with further study, Que may be shown to be an alternative treatment option for athletes or others who experience tendon injuries.

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Anti-aging effects of M2000 (β-D-mannuronic acid) as a novel immunosuppressive drug on the enzymatic and non-enzymatic oxidative stress parameters in an experimental model

Journal of Basic and Clinical Physiology and Pharmacology ◽

10.1515/jbcpp-2016-0092 ◽

2017 ◽

Vol 28 (3) ◽

Cited By ~ 9

Author(s):

Soma Hosseini ◽

Mohammad Abdollahi ◽

Gholamreza Azizi ◽

Mohammad Javad Fattahi ◽

Noshin Rastkari ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Protein Oxidation ◽

Aging Effects ◽

Mannuronic Acid ◽

Carbonyl Protein ◽

Significant Difference ◽

Aging Property ◽

Lipid And Protein Oxidation ◽

Anti Inflammatory

AbstractBackground:The anti-aging property of β-D-mannuronic acid (M2000) as a novel non-steroidal anti-inflammatory and immunosuppressive agent was investigated on several determinants relative to the oxidative stress in an animal model.Methods:Sprague-Dawley rats were used for evaluating the safety and efficacy properties of M2000 on some oxidative stress enzymes, including the following: mitochondrial superoxide dismutase (SOD2), catalase (CAT), glutathione peroxidase (GPX1), glutathione S-transferase (GST), myeloperoxidase (MPO), and inducible nitric oxide synthase (iNOS) gene expression by real-time PCR. Malondialdehyde (MDA), carbonyl protein (PCO) (the lipid and protein oxidation marker, respectively), and total antioxidant capacity (TAC) were tested in serum by biochemical analysis. In addition, cortisol as a steroid hormone was surveyed by chemiluminescence immunoassay after 12 weeks of M2000 consumption. The rats were sacrificed 3 months after daily oral administration of M2000.Results:Our findings revealed the favorable effects of M2000 on several antioxidant enzyme and gene expression, including SOD2, CAT, GPX1, and GST; however, our results were not statistically significant. Moreover, there was no significant difference in MDA and PCO as lipid and protein oxidation markers, TAC, and cortisol compared with the control group following M2000 consumption. A slight weight increase in the M2000-treated group was also observed.Conclusions:Our data showed the anti-aging property of M2000 as a novel designed non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive property on various oxidative stress determinants.

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Screening anti-inflammatory compounds in injured spinal cord with microarrays: a comparison of bioinformatics analysis approaches

Physiological Genomics ◽

10.1152/physiolgenomics.00177.2003 ◽

2004 ◽

Vol 17 (2) ◽

pp. 201-214 ◽

Cited By ~ 13

Author(s):

Jonathan Z. Pan ◽

Rebecka Jörnsten ◽

Ronald P. Hart

Keyword(s):

Gene Expression ◽

Spinal Cord ◽

Inflammatory Responses ◽

Expression Profiles ◽

Slice Culture ◽

Data Set ◽

Cord Injury ◽

In Vivo Testing ◽

Anti Inflammatory

Inflammatory responses contribute to secondary tissue damage following spinal cord injury (SCI). A potent anti-inflammatory glucocorticoid, methylprednisolone (MP), is the only currently accepted therapy for acute SCI but its efficacy has been questioned. To search for additional anti-inflammatory compounds, we combined microarray analysis with an explanted spinal cord slice culture injury model. We compared gene expression profiles after treatment with MP, acetaminophen, indomethacin, NS398, and combined cytokine inhibitors (IL-1ra and soluble TNFR). Multiple gene filtering methods and statistical clustering analyses were applied to the multi-dimensional data set and results were compared. Our analysis showed a consistent and unique gene expression profile associated with NS398, the selective cyclooxygenase-2 (COX-2) inhibitor, in which the overall effect of these upregulated genes could be interpreted as neuroprotective. In vivo testing demonstrated that NS398 reduced lesion volumes, unlike MP or acetaminophen, consistent with a predicted physiological effect in spinal cord. Combining explanted spinal cultures, microarrays, and flexible clustering algorithms allows us to accelerate selection of compounds for in vivo testing.

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Olive Polyphenols: Antioxidant and Anti-Inflammatory Properties

Antioxidants ◽

10.3390/antiox10071044 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1044

Author(s):

Monica Bucciantini ◽

Manuela Leri ◽

Pamela Nardiello ◽

Fiorella Casamenti ◽

Massimo Stefani

Keyword(s):

Oxidative Stress ◽

Chronic Diseases ◽

Meta Analysis ◽

Virgin Olive Oil ◽

Bioactive Molecules ◽

Therapeutic Effects ◽

Molecular Signaling ◽

Anti Inflammatory

Oxidative stress and inflammation triggered by increased oxidative stress are the cause of many chronic diseases. The lack of anti-inflammatory drugs without side-effects has stimulated the search for new active substances. Plant-derived compounds provide new potential anti-inflammatory and antioxidant molecules. Natural products are structurally optimized by evolution to serve particular biological functions, including the regulation of endogenous defense mechanisms and interaction with other organisms. This property explains their relevance for infectious diseases and cancer. Recently, among the various natural substances, polyphenols from extra virgin olive oil (EVOO), an important element of the Mediterranean diet, have aroused growing interest. Extensive studies have shown the potent therapeutic effects of these bioactive molecules against a series of chronic diseases, such as cardiovascular diseases, diabetes, neurodegenerative disorders and cancer. This review begins from the chemical structure, abundance and bioavailability of the main EVOO polyphenols to highlight the effects and the possible molecular mechanism(s) of action of these compounds against inflammation and oxidation, in vitro and in vivo. In addition, the mechanisms of inhibition of molecular signaling pathways activated by oxidative stress by EVOO polyphenols are discussed, together with their possible roles in inflammation-mediated chronic disorders, also taking into account meta-analysis of population studies and clinical trials.

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Malvidin Protects against and Repairs Peptic Ulcers in Mice by Alleviating Oxidative Stress and Inflammation

Nutrients ◽

10.3390/nu13103312 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3312

Author(s):

Felipe Leonardo Fagundes ◽

Quélita Cristina Pereira ◽

Melina Luzzi Zarricueta ◽

Raquel de Cássia dos Santos

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Acetic Acid ◽

Peptic Ulcer ◽

Gastric Ulcer ◽

Defense Mechanisms ◽

Ischemia Reperfusion ◽

Peptic Ulcers ◽

Anti Inflammatory ◽

And Oxidative Stress

Peptic ulcer episodes cause damage to the stomach and intestine, with inflammatory cell infiltration and oxidative stress as the main players. In this study, we investigated the potential of anthocyanidin malvidin for preventive and curative peptic ulcer treatment. The anthocyanidin effects were examined in gastric ulcer mouse models induced by ethanol, non-steroidal anti-inflammatory drugs (NSAIDs), ischemia-reperfusion (IR), acetic acid and duodenal ulcer induced by polypharmacy. Expression levels of oxidative and inflammatory genes were measured to investigate the mechanism of anthocyanin activity. At a dose of 5 mg·kg−1, Malvidin prevented gastric ulcer induction by ethanol, NSAID and repaired the tissue after 6 days of IR. Moreover, the anthocyanidin accelerated the healing of acetic acid-induced ulcer, increased the gene expression of EGF and COX-1, and downregulated MMP-9. Anthocyanin treatment mitigated the effect of polypharmacy on inflammation and oxidative stress observed in the intestine. Additionally, the compound downregulated cytokine expression and TLR4 and upregulated HMOX-1 and IL-10, exhibiting protective activity in the mouse gut. Malvidin thus prevented gastric and duodenal ulcers due to prominent anti-inflammatory and antioxidative effects on the gastrointestinal tract that were related to gene expression modulation and an increase in endogenous defense mechanisms.

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Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model

10.1101/495283 ◽

2018 ◽

Cited By ~ 1

Author(s):

Faycal Guedj ◽

Jeroen LA Pennings ◽

Ashley E Siegel ◽

Fatimah Alsebaa ◽

Lauren J Massingham ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Down Syndrome ◽

Mouse Model ◽

Trisomy 21 ◽

Therapeutic Effects ◽

Prenatal Treatment ◽

Wild Type Littermate

ABSTRACTHuman fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. Prenatal diagnosis provides a potential opportunity to begin treatment in utero. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with DS and mouse models we can discover novel targets for therapy. Here, we tested the safety and efficacy of apigenin (4’, 5, 7-trihydroxyflavone), identified using this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model. The experiments compared treated to untreated results in T21 and euploid cells, as well as in Ts1Cje mice and their wild-type littermate controls. T21 cells cultured with apigenin (2µM) had significantly reduced oxidative stress and improved antioxidant defense response in vitro. Apigenin (333-400 mg/kg/day), mixed with chow, was initiated prenatally to the dams and fed to the pups over their lifetimes. There was no significant increase in birth defects or pup deaths resulting from prenatal apigenin treatment. Apigenin significantly improved several developmental milestones and spatial olfactory memory in Ts1Cje neonates. In addition, we noted sex-specific effects on exploratory behavior and long-term hippocampal memory in adult mice, with males showing significantly more improvement than females. Global gene expression analyses demonstrated that apigenin targets similar signaling pathways through common upstream regulators both in vitro and in vivo. These studies provide proof-of-principle that apigenin has therapeutic effects in preclinical models of Down syndrome.ONE SENTENCE SUMMARYAs a candidate prenatal treatment for Down syndrome, apigenin improved oxidative stress/antioxidant capacity imbalance and reduced pathways associated with inflammation in human cells while improving aspects of behavior in the Ts1Cje mouse model.

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The Antioxidant and Anti-Inflammatory Effects of Quercus brantii Extract on TNBS-Induced Ulcerative Colitis in Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/3075973 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Mahvash Alizade Naini ◽

Shayan Mehrvarzi ◽

Asal Zargari-Samadnejadi ◽

Nader Tanideh ◽

Mohammad Ghorbani ◽

...

Keyword(s):

Oxidative Stress ◽

Ulcerative Colitis ◽

Body Weight Loss ◽

Trinitrobenzene Sulfonic Acid ◽

High Morbidity ◽

Therapeutic Effects ◽

Dependent Manner ◽

Sod Activity ◽

Anti Inflammatory ◽

Quercus Brantii

Objectives. Ulcerative colitis is a common subtype of persistent inflammatory bowel disease with high morbidity consequences. Despite unknown definite pathogenesis, multiple anti-inflammatory medications are used for its treatment. Traditionally, Quercus brantii (QB), mostly available in the Middle East, has been used for gastrointestinal disorders. Other beneficial effects associated with QB include reduction of oxidative stress, inflammations, homeostatic instability, and improvement in clinical conditions. Materials and Methods. This experimental study was designed to assess the possible therapeutic effects of QB on UC and compare its effects with those of sulfasalazine. Of the 70 Wistar rats clustered in seven groups, ten received only alcohols and sixty were confirmed to be suffering from trinitrobenzene sulfonic acid- (TNBS-) induced colitis. Four groups received different dosages of QB extract via oral and rectal routes, one received sulfasalazine, and the other remaining two groups received nothing. The effects of QB were evaluated by assessing macroscopic and histologic scoring, measuring inflammatory mediators, and determining oxidative stress markers. Results. Comparing to the untreated TNBS-induced control groups, QB-treated groups showed a dose- and route-dependent improvement comparable with sulfasalazine. Treating rats with QB reduced the microscopic and macroscopic damage, decreased TNF-α, IL-6, NO, MPO activity, and MDA content, increased superoxide dismutase (SOD) activity, and reduced body weight loss. Conclusions. Our data recommended the anti-inflammatory and antioxidant effects of QB extract in a dose-dependent manner.

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Biological Responses to Hydrogen Molecule and its Preventive Effects on Inflammatory Diseases

Current Pharmaceutical Design ◽

10.2174/1381612826666200925123510 ◽

2020 ◽

Vol 26 ◽

Author(s):

Ikuroh Ohsawa

Keyword(s):

Oxidative Stress ◽

Hydroxyl Radical ◽

Inflammatory Diseases ◽

Ischemia Reperfusion ◽

The Body ◽

Therapeutic Effects ◽

Ophthalmic Surgery ◽

Protective Function ◽

Oxidation Of H2 ◽

Anti Inflammatory

: Because multicellular organisms do not have hydrogenase, H2 has been considered to be biologically inactive in these species, and enterobacteria to be largely responsible for the oxidation of H2 taken into the body. However, we showed previously that inhalation of H2 markedly suppresses brain injury induced by focal ischemia–reperfusion by buffering oxidative stress. Although the reaction constant of H2 with hydroxyl radical in aqueous solution is two to three orders of magnitude lower than that of conventional antioxidants, we showed that hydroxyl radical generated by the Fenton reaction reacts with H2 at room temperature without a catalyst. Suppression of hydroxyl radical by H2 has been applied in ophthalmic surgery. However, many of the anti-inflammatory and other therapeutic effects of H2 cannot be completely explained by its ability to scavenge reactive oxygen species. H2 administration is protective in several disease models, and preculture in the presence of H2 suppresses oxidative stress-induced cell death. Specifically, H2 administration induces mitochondrial oxidative stress and activates Nrf2; this phenomenon, in which mild mitochondrial stress leaves the cell less susceptible to subsequent perturbations, is called mitohormesis. Based on these findings, we conclude that crosstalk between antioxidative stress pathways and the anti-inflammatory response is the most important molecular mechanism involved in the protective function of H2 , and that regulation of the immune system underlies H2 efficacy. For further medical applications of H2 , it will be necessary to identify the biomolecule on which H2 first acts.

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