Paradoxical modulation of influenza by intranasal administration of non-replicating adenovirus particles

Respiratory mucosal infection by airborne microbes is a common event that occurs every day. We report here that intranasal administration of non-replicating adenovirus (Ad) particles to mice could either confer rapid protection against influenza virus (IFV) challenge independent of adaptive immunity, or exacerbate influenza by triggering rapid death. The life-or-death outcome hinges on the time interval between Ad administration and IFV challenge in conjunction with specific mouse/IFV strains. Intranasal instillation of Ad particles 1–47 days prior to IFV challenge conferred rapid protection against influenza in Balb/c mice whereas exposure to Ad 39 days prior to challenge with a specific IFV strain or 1 day post-challenge with that IFV strain induced rapid death in C57BL/6 mice. Notably, consecutive administrations of Ad prior to IFV challenge conferred a synergy in triggering a potent anti-influenza state; even a detrimental Ad exposure 39 days before challenge with the deadly IFV strain was reversed to a beneficial one by subsequent Ad boosts. Results revealed an intricate relationship between infection and innate immunity that is a linchpin around which effects revolve from protective immunity to collateral damage. It is urgent to repeat the experiments with an expanded scope for characterizing the status that defines susceptibility or resistance to IFV infection and subsequently reveal the underlying mechanisms. Whether broad heterologous protective effects induced by AdE and adaptive immunity elicited by vaccination could confer synergy during mitigation of a pandemic remains to be seen.

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Anthocyanins As Modulators of Cell Redox-Dependent Pathways in Non-Communicable Diseases

Current Medicinal Chemistry ◽

10.2174/0929867325666181112093336 ◽

2020 ◽

Vol 27 (12) ◽

pp. 1955-1996 ◽

Cited By ~ 4

Author(s):

Antonio Speciale ◽

Antonella Saija ◽

Romina Bashllari ◽

Maria Sofia Molonia ◽

Claudia Muscarà ◽

...

Keyword(s):

Human Health ◽

Biological Activities ◽

Wide Spectrum ◽

Antioxidant Defenses ◽

Noncommunicable Diseases ◽

Protective Effects ◽

Pathological Conditions ◽

Chronic Pulmonary Diseases ◽

Underlying Mechanisms

: Chronic Noncommunicable Diseases (NCDs), mostly represented by cardiovascular diseases, diabetes, chronic pulmonary diseases, cancers, and several chronic pathologies, are one of the main causes of morbidity and mortality, and are mainly related to the occurrence of metabolic risk factors. Anthocyanins (ACNs) possess a wide spectrum of biological activities, such as anti-inflammatory, antioxidant, cardioprotective and chemopreventive properties, which are able to promote human health. Although ACNs present an apparent low bioavailability, their metabolites may play an important role in the in vivo protective effects observed. : This article directly addresses the scientific evidences supporting that ACNs could be useful to protect human population against several NCDs not only acting as antioxidant but through their capability to modulate cell redox-dependent signaling. In particular, ACNs interact with the NF-κB and AP-1 signal transduction pathways, which respond to oxidative signals and mediate a proinflammatory effect, and the Nrf2/ARE pathway and its regulated cytoprotective proteins (GST, NQO, HO-1, etc.), involved in both cellular antioxidant defenses and elimination/inactivation of toxic compounds, so countering the alterations caused by conditions of chemical/oxidative stress. In addition, supposed crosstalks could contribute to explain the protective effects of ACNs in different pathological conditions characterized by an altered balance among these pathways. Thus, this review underlines the importance of specific nutritional molecules for human health and focuses on the molecular targets and the underlying mechanisms of ACNs against various diseases.

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Intranasal Administration of a Recombinant RBD Vaccine Induced Protective Immunity Against SARS-CoV-2 in Mouse

Vaccine ◽

10.1016/j.vaccine.2021.03.006 ◽

2021 ◽

Author(s):

Yingying Du ◽

Yuhua Xu ◽

Jin Feng ◽

Longbo Hu ◽

Yanan Zhang ◽

...

Keyword(s):

Protective Immunity ◽

Intranasal Administration

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Melatonin Successfully Rescues the Hippocampal Molecular Machinery and Enhances Anti-oxidative Activity Following Early-Life Sleep Deprivation Injury

Antioxidants ◽

10.3390/antiox10050774 ◽

2021 ◽

Vol 10 (5) ◽

pp. 774

Author(s):

Hung-Ming Chang ◽

Hsing-Chun Lin ◽

Hsin-Lin Cheng ◽

Chih-Kai Liao ◽

To-Jung Tseng ◽

...

Keyword(s):

Sleep Deprivation ◽

Early Life ◽

Cognitive Activity ◽

Oxidative Activity ◽

Protective Effects ◽

Long Term Effects ◽

Ionic Distribution ◽

Melatonin Administration ◽

Molecular Machinery ◽

Underlying Mechanisms

Early-life sleep deprivation (ESD) is a serious condition with severe cognitive sequelae. Considering hippocampus plays an essential role in cognitive regulation, the present study aims to determine whether melatonin, a neuroendocrine beard with significant anti-oxidative activity, would greatly depress the hippocampal oxidative stress, improves the molecular machinery, and consequently exerts the neuro-protective effects following ESD. Male weanling Wistar rats (postnatal day 21) were subjected to ESD for three weeks. During this period, the animals were administered normal saline or melatonin (10 mg/kg) via intraperitoneal injection between 09:00 and 09:30 daily. After three cycles of ESD, the animals were kept under normal sleep/wake cycle until they reached adulthood and were sacrificed. The results indicated that ESD causes long-term effects, such as impairment of ionic distribution, interruption of the expressions of neurotransmitters and receptors, decreases in the levels of several antioxidant enzymes, and impairment of several signaling pathways, which contribute to neuronal death in hippocampal regions. Melatonin administration during ESD prevented these effects. Quantitative evaluation of cells also revealed a higher number of neurons in the melatonin-treated animals when compared with the saline-treated animals. As the hippocampus is critical to cognitive activity, preserving or even improving the hippocampal molecular machinery by melatonin during ESD not only helps us to better understand the underlying mechanisms of ESD-induced neuronal dysfunction, but also the therapeutic use of melatonin to counteract ESD-induced neuronal deficiency.

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Vitamin E beyond Its Antioxidant Label

Antioxidants ◽

10.3390/antiox10050634 ◽

2021 ◽

Vol 10 (5) ◽

pp. 634

Author(s):

Anca Ungurianu ◽

Anca Zanfirescu ◽

Georgiana Nițulescu ◽

Denisa Margină

Keyword(s):

Vitamin E ◽

Signaling Pathways ◽

Molecular Mechanisms ◽

Protective Effects ◽

Cellular Effects ◽

Inflammatory Status ◽

Anti Cancer ◽

Key Factor ◽

Exciting Potential ◽

Underlying Mechanisms

Vitamin E, comprising tocopherols and tocotrienols, is mainly known as an antioxidant. The aim of this review is to summarize the molecular mechanisms and signaling pathways linked to inflammation and malignancy modulated by its vitamers. Preclinical reports highlighted a myriad of cellular effects like modulating the synthesis of pro-inflammatory molecules and oxidative stress response, inhibiting the NF-κB pathway, regulating cell cycle, and apoptosis. Furthermore, animal-based models have shown that these molecules affect the activity of various enzymes and signaling pathways, such as MAPK, PI3K/Akt/mTOR, JAK/STAT, and NF-κB, acting as the underlying mechanisms of their reported anti-inflammatory, neuroprotective, and anti-cancer effects. In clinical settings, not all of these were proven, with reports varying considerably. Nonetheless, vitamin E was shown to improve redox and inflammatory status in healthy, diabetic, and metabolic syndrome subjects. The anti-cancer effects were inconsistent, with both pro- and anti-malignant being reported. Regarding its neuroprotective properties, several studies have shown protective effects suggesting vitamin E as a potential prevention and therapeutic (as adjuvant) tool. However, source and dosage greatly influence the observed effects, with bioavailability seemingly a key factor in obtaining the preferred outcome. We conclude that this group of molecules presents exciting potential for the prevention and treatment of diseases with an inflammatory, redox, or malignant component.

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Green Tea and Epigallocatechin Gallate (EGCG) for the Management of Nonalcoholic Fatty Liver Diseases (NAFLD): Insights into the Role of Oxidative Stress and Antioxidant Mechanism

Antioxidants ◽

10.3390/antiox10071076 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1076

Author(s):

Guoyi Tang ◽

Yu Xu ◽

Cheng Zhang ◽

Ning Wang ◽

Huabin Li ◽

...

Keyword(s):

Oxidative Stress ◽

Fatty Liver ◽

Green Tea ◽

Liver Diseases ◽

Randomized Clinical Trials ◽

Epigallocatechin Gallate ◽

Protective Effects ◽

Nonalcoholic Fatty Liver ◽

Nonalcoholic Fatty Liver Diseases ◽

Underlying Mechanisms

Nonalcoholic fatty liver diseases (NAFLD) represent a set of liver disorders progressing from steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma, which induce huge burden to human health. Many pathophysiological factors are considered to influence NAFLD in a parallel pattern, involving insulin resistance, oxidative stress, lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, inflammatory cascades, fibrogenic reaction, etc. However, the underlying mechanisms, including those that induce NAFLD development, have not been fully understood. Specifically, oxidative stress, mainly mediated by excessive accumulation of reactive oxygen species, has participated in the multiple NAFLD-related signaling by serving as an accelerator. Ameliorating oxidative stress and maintaining redox homeostasis may be a promising approach for the management of NAFLD. Green tea is one of the most important dietary resources of natural antioxidants, above which epigallocatechin gallate (EGCG) notably contributes to its antioxidative action. Accumulative evidence from randomized clinical trials, systematic reviews, and meta-analysis has revealed the beneficial functions of green tea and EGCG in preventing and managing NAFLD, with acceptable safety in the patients. Abundant animal and cellular studies have demonstrated that green tea and EGCG may protect against NAFLD initiation and development by alleviating oxidative stress and the related metabolism dysfunction, inflammation, fibrosis, and tumorigenesis. The targeted signaling pathways may include, but are not limited to, NRF2, AMPK, SIRT1, NF-κB, TLR4/MYD88, TGF-β/SMAD, and PI3K/Akt/FoxO1, etc. In this review, we thoroughly discuss the oxidative stress-related mechanisms involved in NAFLD development, as well as summarize the protective effects and underlying mechanisms of green tea and EGCG against NAFLD.

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Total flavonoids from Astragalus alleviate endothelial dysfunction by activating the Akt/eNOS pathway

Journal of International Medical Research ◽

10.1177/0300060517717358 ◽

2017 ◽

Vol 46 (6) ◽

pp. 2096-2103 ◽

Cited By ~ 4

Author(s):

Qian Liu ◽

Ling Zhang ◽

Qiyuan Shan ◽

Yuxia Ding ◽

Zhaocai Zhang ◽

...

Keyword(s):

Cell Proliferation ◽

Vascular Endothelial Cells ◽

Ex Vivo ◽

Umbilical Vein ◽

Cell Counting ◽

Total Flavonoids ◽

Vascular Endothelial ◽

Protective Effects ◽

Hypoxic Conditions ◽

Underlying Mechanisms

Objective To investigate the vasodilative and endothelial-protective effects and the underlying mechanisms of total flavonoids from Astragalus (TFA). Methods The vasodilative activities of TFA were measured with a myograph ex vivo using rat superior mesenteric arterial rings. The primary human umbilical vein endothelial cell (HUVEC) viabilities were assayed using the cell counting kit-8 after hypoxia or normoxia treatment with or without TFA. Akt, P-Akt, eNOS, P-eNOS, Erk, P-Erk, Bcl-2 and Bax expression were analyzed using western blotting. Results TFA showed concentration-dependent vasodilative effects on rat superior mesenteric arterial rings, but had no effects on normal or potassium chloride precontracted arterial rings. TFA did not affect HUVEC viabilities in normoxia, but dramatically promoted cell proliferation in the concentration range of 1 to 30 µg/mL under hypoxia. Moreover, TFA significantly increased the ratios of P-Akt/Akt and P-eNOS/eNOS in vascular endothelial cells under hypoxic conditions, but did not change the P-Erk/Erk or Bcl-2/Bax ratios. Conclusions TFA might exhibit vasorelaxant and endothelial-protective effects via the Akt/eNOS signaling pathway.

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Guarana (Paullinia cupana) Extract Protects Caenorhabditis elegans Models for Alzheimer Disease and Huntington Disease through Activation of Antioxidant and Protein Degradation Pathways

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/9241308 ◽

2018 ◽

Vol 2018 ◽

pp. 1-16 ◽

Cited By ~ 15

Author(s):

Patrícia Ferreira Boasquívis ◽

Giovanna Melo Martins Silva ◽

Franciny Aparecida Paiva ◽

Rodrigo Marinho Cavalcanti ◽

Cecília Verônica Nunez ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Protein Misfolding ◽

Therapeutic Potential ◽

High Energy ◽

Protective Effects ◽

Independent Manner ◽

Paullinia Cupana ◽

Age Related ◽

Polyq Protein ◽

Underlying Mechanisms

Guarana (Paullinia cupana) is largely consumed in Brazil in high energy drinks and dietary supplements because of its stimulant activity on the central nervous system. Although previous studies have indicated that guarana has some protective effects in Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s (HD) disease models, the underlying mechanisms are unknown. Here, we investigated the protective effects of guarana hydroalcoholic extract (GHE) in Caenorhabditis elegans models of HD and AD. GHE reduced polyglutamine (polyQ) protein aggregation in the muscle and also reduced polyQ-mediated neuronal death in ASH sensory neurons and delayed β-amyloid-induced paralysis in a caffeine-independent manner. Moreover, GHE’s protective effects were not mediated by caloric restriction, antimicrobial effects, or development and reproduction impairment. Inactivation of the transcription factors SKN-1 and DAF-16 by RNAi partially blocked the protective effects of GHE treatment in the AD model. We show that the protective effect of GHE is associated with antioxidant activity and modulation of proteostasis, since it increased the lifespan and proteasome activity, reduced intracellular ROS and the accumulation of autophagosomes, and increased the expression of SOD-3 and HSP-16.2. Our findings suggest that GHE has therapeutic potential in combating age-related diseases associated with protein misfolding and accumulation.

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Interleukin-17/Interleukin-17 Receptor-Mediated Signaling Is Important for Generation of an Optimal Polymorphonuclear Response against Toxoplasma gondii Infection

Infection and Immunity ◽

10.1128/iai.73.1.617-621.2005 ◽

2005 ◽

Vol 73 (1) ◽

pp. 617-621 ◽

Cited By ~ 244

Author(s):

Michelle N. Kelly ◽

Jay K. Kolls ◽

Kyle Happel ◽

Joseph D. Schwartzman ◽

Paul Schwarzenberger ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Adaptive Immunity ◽

Protective Immunity ◽

Polymorphonuclear Leukocytes ◽

Early Infection ◽

Interleukin 17 ◽

Toxoplasma Gondii Infection ◽

Knockout Animals

ABSTRACT We investigated the role of interleukin-17 (IL-17)/IL-17 receptor (IL-17R)-mediated signaling in the protective immunity against Toxoplasma gondii. IL-17R−/− mice developed a normal adaptive immunity against the parasite. However, increased mortality in the knockout animals can be attributed to a defect in the migration of polymorphonuclear leukocytes to infected sites during early infection.

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Abstract WP139: Intranasal Administration of Mesenchymal Stem Cell (MSC)-Derived Exosomes Confers Acute Neuroprotection After Neonatal Stroke

Stroke ◽

10.1161/str.51.suppl_1.wp139 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Praneeti Pathipati ◽

Joel Faustino ◽

Matthieu Lecuyer ◽

Jacqueline Strivelli ◽

Donald Phinney ◽

...

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Intranasal Administration ◽

Therapeutic Option ◽

Cell Types ◽

Artery Occlusion ◽

Neonatal Stroke ◽

Beneficial Effects ◽

The Status

Background: Brain injury caused by stroke is a surprisingly common occurrence in neonates and is associated with significant long-term disabilities. We and others have shown delayed mesenchymal stem cell (MSC)-based therapy to be beneficial after neonatal stroke. Mounting evidence suggests MSC-derived soluble factors as key mediators of their neuroprotective/regenerative effects. We wanted to test whether Exosomes (Exo) derived from MSC carry beneficial effects after neonatal stroke. Objectives: Characterize effects of intranasal administration of MSC-derived Exo after neonatal stroke. Methods: MSCs enriched from the bone marrow of C57Bl6 mice (immuno-depletion) were cultured for 3 days in Exo-free FBS and confirmed by flow cytometry to be CD44 + /CD29 + and CD11b - /CD45 - . Exo were isolated (ExoQuick, SBI), their size distribution determined (NanoSight™), and Exo labeled with CellVue® before intranasal administration. Postnatal day 9 (P9) mice were subjected to a 3h middle cerebral artery occlusion (tMCAO), Exo (5ug, 1uL in PBS) administered into the nostril ipsilateral to injury, and injury volume and cell types that uptake Exo determined. Results: By 24h after administration, labelled Exo were visible ipsilateral along the lateral ventricle, in the SVZ, corpus callosum and in the penumbra, localized largely to Glut1 + -vessels and Iba1 + -microglia (MG). By 72h, labeled Exo were predominantly localized in Iba1 + -MG peri-infarct. Very few Exo were seen contralateral. Compared to vehicle/untreated mice, intranasal Exo significantly reduced injury volume at 72h (p<0.01, n=5). Preliminary in vitro experiments using MG isolated from acutely injured neonatal brain (CD11b-conjugated beads) confirmed significantly higher Exo uptake by MG from the ipsilateral Vs. contralateral cortex (p<0.05, n=2). Summary: We demonstrate that MSC-Exo exert short-term protection against neonatal stroke and that the magnitude of Exo uptake depends on the status of MG activation after injury. We are characterizing longer-term effects of MSC-Exo on stroke outcome to further explore potential for intranasal MSC-Exo as a clinically suitable therapeutic option for neonatal stroke. Funding: CPA PG0816 (ZV); AHA Innovation Award 17IRG33430004 (ZV); R01HL139685 (ZV)

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Emerging Roles of Exosomes in T1DM

Frontiers in Immunology ◽

10.3389/fimmu.2020.593348 ◽

2020 ◽

Vol 11 ◽

Author(s):

Haipeng Pang ◽

Shuoming Luo ◽

Yang Xiao ◽

Ying Xia ◽

Xia Li ◽

...

Keyword(s):

Autoimmune Disorder ◽

Elevated Blood Glucose Level ◽

The Status ◽

Life Threatening ◽

Novel Biomarkers ◽

Therapeutic Tools ◽

Underlying Mechanisms ◽

The Relationship

Type 1 diabetes mellitus (T1DM) is a complex autoimmune disorder that mainly affects children and adolescents. The elevated blood glucose level of patients with T1DM results from absolute insulin deficiency and leads to hyperglycemia and the development of life-threatening diabetic complications. Although great efforts have been made to elucidate the pathogenesis of this disease, the precise underlying mechanisms are still obscure. Emerging evidence indicates that small extracellular vesicles, namely, exosomes, take part in intercellular communication and regulate interorgan crosstalk. More importantly, many findings suggest that exosomes and their cargo are associated with the development of T1DM. Therefore, a deeper understanding of exosomes is beneficial for further elucidating the pathogenic process of T1DM. Exosomes are promising biomarkers for evaluating the risk of developingty T1DM, monitoring the disease state and predicting related complications because their number and composition can reflect the status of their parent cells. Additionally, since exosomes are natural carriers of functional proteins, RNA and DNA, they can be used as therapeutic tools to deliver these molecules and drugs. In this review, we briefly introduce the current understanding of exosomes. Next, we focus on the relationship between exosomes and T1DM from three perspectives, i.e., the pathogenic role of exosomes in T1DM, exosomes as novel biomarkers of T1DM and exosomes as therapeutic tools for T1DM.

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