Flavonoids Ameliorate Stress-Induced Depression by Preventing NLRP3 Inflammasome Priming

Abstract Objectives Chronic stress activates danger-associated molecular patterns (DAMPs), stimulating the NLRP3 inflammasome. NLRP3 activation triggers the release of pro-inflammatory cytokine IL-1β. The activity of the NLRP3 inflammasome propagates pro-inflammatory signaling cascades implicated in the onset of depression. Our previous studies show that polyphenolic compounds were found to ameliorate stress induced depression in mouse models. However, the relevant mechanism has not been identified. This study examined the effect of administering polyphenols on DAMP signaling in enriched mice microglia. Methods This study examined the effect of administering polyphenols on DAMP signaling in mice microglia. To recapitulate stress-induced depression, mice underwent chronic unpredictable stress (CUS). Microglia were isolated at various time points throughout the CUS protocol. We also assessed long-term persistent changes after CUS and susceptibility to subthreshold unpredictable stress (US) re-exposure. Results Interestingly, the development of US – induced depression and anxiety depended upon a previous exposure to CUS. We found that CUS caused robust upregulation of IL-1β mRNA in enriched microglia, an effect that persists for up to 4 weeks following CUS exposure. Following the subthreshold US re-exposure, we observed the upregulation of pro- IL-1β as well as pro-receptor for advanced glycation end products (RAGE). Toll-like receptor 4 (TLR-4) was not. We also observed an increase in RAGE mRNA expression when mice were exposed to US prior to the start of the CUS paradigm. Importantly, a primary exposure to US, was sufficient to increase RAGE mRNA expression. We found that polyphenol administration significantly improved CUS-induced depressive-like phenotypes and also reversed neuroinflammation in mice. Treatment with dietary flavonoids prevented upregulation of IL-1β, RAGE mRNA, which reflects the ability of polyphenols that may have begun following the primary exposure to US. Conclusions Taken all together, the results provide evidence of the role of dietary polyphenols in preventing persistent microglial activation, which has been shown to result in reduced long term vulnerability to depressive-like behaviors following expose to chronic stress. Funding Sources This study was supported by a P50 CARBON Center grant from the NCCIH/ODS.

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Polyphenolic Compounds Ameliorate Stress-induced Depression by Preventing NLRP3 Inflammasome Priming (P19-011-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz049.p19-011-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Tal Frolinger ◽

Giulio Pasinetti

Keyword(s):

Mrna Expression ◽

Chronic Stress ◽

Nlrp3 Inflammasome ◽

Polyphenolic Compounds ◽

Dietary Polyphenols ◽

Funding Sources ◽

Glycation End Products ◽

Molecular Patterns

Abstract Objectives Chronic stress activates danger-associated molecular patterns (DAMPs), which then stimulate the NLRP3 inflammasome. NLRP3 activation triggers the released of the pro-inflammatory cytokine IL‐1β.The activity of the NLRP3 inflammasome propagates pro-inflammatory signaling cascades implicated in the onset of depression. In previous studies conducted in our lab, polyphenolic compounds were found to ameliorate stress induced depression in mouse models. However, the mechanism by which they do so has not been identified. This study examined the effect of administering polyphenols on DAMP signaling in enriched mice microglia. Methods This study examined the effect of administering polyphenols on DAMP signaling in mice microglia. To recapitulate stress-induced depression, mice underwent chronic unpredictable stress (CUS). Microglia were isolated at various time points throughout the CUS protocol. We also assessed long-term persistent changes after CUS and susceptibility to subthreshold unpredictable stress (US) re-exposure. Results Interestingly, the development of US - induced depression and anxiety depended upon a previous exposure to CUS. We found that CUS caused robust upregulation of IL-1β mRNA in enriched microglia, an effect that persists for up to 4 weeks following CUS exposure. Following the subthreshold US re-exposure, we observed the upregulation of pro- IL-1β as well as pro-receptor for advanced glycation end products (RAGE). Toll-like receptor 4 (TLR-4) was not. We also observed an increase in RAGE mRNA expression when mice were exposed to US prior to the start of the CUS paradigm. Importantly, a primary exposure to US, was sufficient to increase RAGE mRNA expression. We found that polyphenol administration improved CUS-induced depressive-like phenotypes and also reversed neuroinflammation in mice. Treatment with dietary polyphenols prevented upregulation of IL-1β, RAGE mRNA, which reflects the ability of polyphenols that may have begun following the primary exposure to US. Conclusions Taken all together, the results provide evidence of the role of polyphenols in preventing persistent microglial activation, which has been shown to result in reduced long term vulnerability to depressive-like behaviors following expose to chronic stress. Funding Sources This study was supported by a P50 CARBON Center grant from the NCCIH and ODS.

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Role of Glucose-Lowering Medications in Erectile Dysfunction

Journal of Clinical Medicine ◽

10.3390/jcm10112501 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2501

Author(s):

Angelo Cignarelli ◽

Valentina Annamaria Genchi ◽

Rossella D’Oria ◽

Fiorella Giordano ◽

Irene Caruso ◽

...

Keyword(s):

Erectile Dysfunction ◽

Current Knowledge ◽

Smooth Muscle Contractility ◽

Glucose Lowering ◽

Glycation End Products ◽

Altered Metabolism

Erectile dysfunction (ED) is a long-term complication of type 2 diabetes (T2D) widely known to affect the quality of life. Several aspects of altered metabolism in individuals with T2D may help to compromise the penile vasculature structure and functions, thus exacerbating the imbalance between smooth muscle contractility and relaxation. Among these, advanced glycation end-products and reactive oxygen species derived from a hyperglycaemic state are known to accelerate endothelial dysfunction by lowering nitric oxide bioavailability, the essential stimulus of relaxation. Although several studies have explained the pathogenetic mechanisms involved in the generation of erectile failure, few studies to date have described the efficacy of glucose-lowering medications in the restoration of normal sexual activity. Herein, we will present current knowledge about the main starters of the pathophysiology of diabetic ED and explore the role of different anti-diabetes therapies in the potential remission of ED, highlighting specific pathways whose activation or inhibition could be fundamental for sexual care in a diabetes setting.

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Hypoactivity of the Hypothalamo-Pituitary-Adrenocortical Axis during Recovery from Chronic Variable Stress

Endocrinology ◽

10.1210/en.2005-1041 ◽

2006 ◽

Vol 147 (4) ◽

pp. 2008-2017 ◽

Cited By ~ 113

Author(s):

Michelle M. Ostrander ◽

Yvonne M. Ulrich-Lai ◽

Dennis C. Choi ◽

Neil M. Richtand ◽

James P. Herman

Keyword(s):

Mrna Expression ◽

Chronic Stress ◽

Hpa Axis ◽

Male Rats ◽

Plasma Acth ◽

Novel Environment ◽

Systemic Hypoxia ◽

Delayed Recovery ◽

Chronic Variable Stress

Chronic stress induces both functional and structural adaptations within the hypothalamo-pituitary-adrenocortical (HPA) axis, suggestive of long-term alterations in neuroendocrine reactivity to subsequent stressors. We hypothesized that prior chronic stress would produce persistent enhancement of HPA axis reactivity to novel stressors. Adult male rats were exposed to chronic variable stress (CVS) for 1 wk and allowed to recover. Plasma ACTH and corticosterone levels were measured in control or CVS rats exposed to novel psychogenic (novel environment or restraint) or systemic (hypoxia) stressors at 16 h, 4 d, 7 d, or 30 d after CVS cessation. Plasma ACTH and corticosterone responses to psychogenic stressors were attenuated at 4 d (novel environment and restraint) and 7 d (novel environment only) recovery from CVS, whereas hormonal responses to the systemic stressor were largely unaffected by CVS. CRH mRNA expression was up-regulated in the paraventricular nucleus of the hypothalamus (PVN) at 16 h after cessation of CVS, but no other alterations in PVN CRH or arginine vasopressin mRNA expression were observed. Thus, in contrast to our hypothesis, reductions of HPA axis sensitivity to psychogenic stressors manifested at delayed recovery time points after CVS. The capacity of the HPA axis to respond to a systemic stressor appeared largely intact during recovery from CVS. These data suggest that chronic stress selectively targets brain circuits responsible for integration of psychogenic stimuli, resulting in decreased HPA axis responsiveness, possibly mediated in part by transitory alterations in PVN CRH expression.

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BDNF-induced TrkB activation down-regulates the K+–Cl− cotransporter KCC2 and impairs neuronal Cl− extrusion

The Journal of Cell Biology ◽

10.1083/jcb.200209011 ◽

2002 ◽

Vol 159 (5) ◽

pp. 747-752 ◽

Cited By ~ 316

Author(s):

Claudio Rivera ◽

Hong Li ◽

Judith Thomas-Crusells ◽

Hannele Lahtinen ◽

Tero Viitanen ◽

...

Keyword(s):

Hippocampal Slice ◽

Neuronal Excitability ◽

Epileptic Activity ◽

Signaling Cascades ◽

Gabaergic Inhibition ◽

Long Term Effects ◽

Mouse Hippocampus

Pathophysiological activity and various kinds of traumatic insults are known to have deleterious long-term effects on neuronal Cl− regulation, which can lead to a suppression of fast postsynaptic GABAergic responses. Brain-derived neurotrophic factor (BDNF) increases neuronal excitability through a conjunction of mechanisms that include regulation of the efficacy of GABAergic transmission. Here, we show that exposure of rat hippocampal slice cultures and acute slices to exogenous BDNF or neurotrophin-4 produces a TrkB-mediated fall in the neuron-specific K+–Cl− cotransporter KCC2 mRNA and protein, as well as a consequent impairment in neuronal Cl− extrusion capacity. After kindling-induced seizures in vivo, the expression of KCC2 is down-regulated in the mouse hippocampus with a spatiotemporal profile complementary to the up-regulation of TrkB and BDNF. The present data demonstrate a novel mechanism whereby BDNF/TrkB signaling suppresses chloride-dependent fast GABAergic inhibition, which most likely contributes to the well-known role of TrkB-activated signaling cascades in the induction and establishment of epileptic activity.

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Prevalence of IgG antibodies to SARS-CoV-2 in Wuhan – implications for the ability to produce long-lasting protective antibodies against SARS-CoV-2

10.1101/2020.06.13.20130252 ◽

2020 ◽

Cited By ~ 10

Author(s):

Tao Liu ◽

Sanyun Wu ◽

Huangheng Tao ◽

Guang Zeng ◽

Fuling Zhou ◽

...

Keyword(s):

Healthcare Workers ◽

Healthcare Providers ◽

Significant Proportion ◽

Development Program ◽

Data Access ◽

Igg Antibodies ◽

Funding Sources ◽

Protective Antibodies

AbstractBackgroundIt is to be determined whether people infected with SARS-CoV-2 will develop long-term immunity against SARS-CoV-2 and retain long-lasting protective antibodies after the infection is resolved. This study was to explore to explore the outcomes of IgG antibodies to SARS-CoV-2 in four groups of individuals in Wuhan, China.MethodsWe included the following four groups of individuals who received both COVID-19 IgM/IgG tests and RT-PCR tests for SARS-CoV-2 from February 29, 2020 to April 29, 2020: 1470 hospitalized patients with COVID-19 from Leishenshan Hospital, Zhongnan Hospital of Wuhan University, and Wuhan No. 7 Hospital, 3832 healthcare providers without COVID-19 diagnosis, 19555 general workers, and 1616 other patients to be admitted to the hospital (N=26473). COVID-19 patients who received IgM/IgG tests <21 days after symptom onset were excluded.ResultsIgG prevalence was 89.8% (95% CI 88.2-91.3%) in COVID-19 patients, 4.0% (95% CI 3.4-4.7%) in healthcare providers, 4.6 (95% CI 4.3-4.9 %) in general workers, and 1.0% in other patients (p all <0.001 for comparisons with COVID-19 patients). IgG prevalence increased significantly by age among healthcare workers and general workers. Prevalence of IgM antibodies to SARS-CoV-2 was 31.4% in COVID-19 patients, 1.5% in healthcare providers, 1.3% in general workers, and 0.2% in other patients.ConclusionsVery few healthcare providers had IgG antibodies to SARS-CoV-2, though a significant proportion of them had been infected with the virus. After SARS-CoV-2 infection, people are unlikely to produce long-lasting protective antibodies against this virus.Primary Funding SourcesPart of the study was supported by National Key Research and Development Program of China (2020YFC0845500). The content is solely the responsibility of the authors and does not necessarily represent the official views of the sponsors.Role of the Funder/SponsorThe sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication.Data and code availability statementData and analyses codes are available from the corresponding authors on request. All request for raw and analyzed data and materials will be reviewed by the corresponding authors to verify whether the request is subject to any intellectual property or confidentiality obligations. Access will be granted after a signed data access agreement is attained.

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Introducing Gordonibacter urolithinfaciens into Gut Ecosystems to Study Its Role in Mediating the Metabolic Benefits of Dietary Polyphenols

Current Developments in Nutrition ◽

10.1093/cdn/nzaa062_051 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1594-1594

Author(s):

Ashley Toney ◽

Yibo Xian ◽

Jing Shao ◽

Robert Schmaltz ◽

Virginia Chaidez ◽

...

Keyword(s):

Drinking Water ◽

Ellagic Acid ◽

Improve Insulin Sensitivity ◽

Microbial Conversion ◽

Dietary Polyphenols ◽

Funding Sources ◽

Host Metabolism

Abstract Objectives Dietary polyphenols such as ellagitannins undergo microbial conversion to yield urolithins, which improve insulin sensitivity. However, feeding ellagic acid-containing foods sometimes yields variable levels of metabolic improvements in humans, suggesting that some individuals may not harbor the specific microbes responsible for transforming ellagic acid (EA) into urolithins. One species of gut bacteria, Gordonibacter urolithinfaciens (G. uro), has been shown to convert EA into urolithins in vitro. However, the specific role of G. uro in mediating the metabolic benefits of EA-containing foods in vivo is unknown, in part, because of challenges associated with its engraftment in mouse models. This study aimed to determine whether G. uro could be introduced into an established microbiota as a single dose or daily probiotic to facilitate future studies regarding its role in improving host metabolism via conversion of EA to urolithins. Methods Germ-free (GF) C57BL/6 mice were either: (1) mono-associated with G. uro for 2 wks prior to introduction of one of three conventional mouse microbiotas naturally deficient for G. uro, (2) colonized with both G. uro and a conventional G. uro-deficient microbiota together, (3) colonized with a conventional G. uro-deficient microbiota for 2 wks and then given a single oral gavage of G. uro, or (4) colonized with a conventional G. uro-deficient microbiota for 2 wks and then administered G. uro fresh daily in drinking water. Results G. uro successfully monocolonized a previously GF mouse but was not detectable following introduction of a complex G. uro-deficient microbiota. G. uro also failed to persist when GF mice were first colonized with a conventional G. uro-deficient microbiota and then given a single gavage of G. uro. However, ex-GF mice colonized with a complex G. uro-deficient microbiota and given daily doses of G. uro in their drinking water were able to maintain this organism throughout the study. Conclusions Our studies demonstrate the challenges associated with introducing G. uro into a microbiota even when G. uro is provided prior to microbiota establishment and the microbiota is naturally devoid of G. uro. These results suggest that G. uro may need to be administered as a daily probiotic to provide health benefits to individuals unable to convert ellagic acid foods into beneficial urolithins. Funding Sources USDA NIFA.

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NF-κB-94ins/del ATTG Genotype Contributes to the Susceptibility and Imbalanced Th17 Cells in Patients with Immune Thrombocytopenia

Journal of Immunology Research ◽

10.1155/2018/8170436 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Jie Yu ◽

Mingqiang Hua ◽

Xueyun Zhao ◽

Rui Wang ◽

Chaoqing Zhong ◽

...

Keyword(s):

Mrna Expression ◽

Nlrp3 Inflammasome ◽

Th17 Cells ◽

Immune Thrombocytopenia ◽

Dose Effect ◽

T Helper ◽

Expression Of Genes ◽

Significant Difference ◽

Significant Gene

Background. The NLRP3 inflammasome plays important roles in the pathogenesis of autoimmune diseases. However, the role of the NLRP3 inflammasome in the pathophysiology of immune thrombocytopenia (ITP) remains unclear. Methods. RT-PCR was used to examine the polymorphism and expression of genes involved in the NLRP3 inflammasome in ITP patients. T helper cells and apoptosis of PBMC from ITP patients were analyzed by flow cytometry. The antiplatelet autoantibodies in plasma were determined by modified monoclonal antibody-specific immobilization of platelet antigens (MAIPA). Results. We found that the NF-κB-94ins/del ATTG genotype contributed to the susceptibility of ITP. Furthermore, the platelet counts of ITP patients with the WW genotype or WD genotype were lower than those with the DD genotype of NF-κB-94ins/del ATTG. Compared with controls, NF-κB gene expression was significantly decreased and WW or WD genotype ITP patients displayed higher mRNA expression than DD individuals. Similarly, the mRNA expression of NLRP3 was also increased in the WW genotype. There was a significant gene dose effect of the percentage of Th17 cells for the WW, WD, and DD genotypes (WW < WD < DD) in the unstimulated group and no significant difference was found after being stimulated. The activation of the NLRP3 inflammasome could upregulate Th17 in ITP patients. Conclusion. The NF-κB-94ins/del ATTG genotype might serve as a novel biomarker and potential target for ITP.

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NLRP3-Inflammasome Inhibition during Respiratory Virus Infection Abrogates Lung Immunopathology and Long-Term Airway Disease Development

Viruses ◽

10.3390/v13040692 ◽

2021 ◽

Vol 13 (4) ◽

pp. 692

Author(s):

Carrie-Anne Malinczak ◽

Charles F. Schuler ◽

Angela J. Duran ◽

Andrew J. Rasky ◽

Mohamed M. Mire ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Severe Disease ◽

Critical Role ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Increased Risk ◽

Rsv Infection ◽

Syncytial Virus

Respiratory syncytial virus (RSV) infects most infants by two years of age. It can cause severe disease leading to an increased risk of developing asthma later in life. Previously, our group has shown that RSV infection in mice and infants promotes IL-1β production. Here, we characterized the role of NLRP3-Inflammasome activation during RSV infection in adult mice and neonates. We observed that the inhibition of NLRP3 activation using the small molecule inhibitor, MCC950, or in genetically modified NLRP3 knockout (Nlrp3−/−) mice during in vivo RSV infection led to decreased lung immunopathology along with a reduced expression of the mucus-associated genes and reduced production of innate cytokines (IL-1β, IL-33 and CCL2) linked to severe RSV disease while leading to significant increases in IFN-β. NLRP3-inflammasome inhibition or deletion diminished Th2 cytokines and inflammatory cell infiltration into the lungs. Furthermore, NLRP3 inhibition or deletion during early-life RSV infection led to reducing viral-exacerbated allergic response in a mouse model of RSV-induced allergy exacerbation. Here, we demonstrated the critical role of NLRP3-inflammasome activation in RSV immunopathology and the related long-term airway alteration. Moreover, these findings suggest the NLRP3-inflammasome as a potential therapeutic target to attenuate severe RSV disease and limit childhood asthma development.

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Emerging Role of the Inflammasome and Pyroptosis in Hypertension

International Journal of Molecular Sciences ◽

10.3390/ijms22031064 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1064

Author(s):

Carmen De Miguel ◽

Pablo Pelegrín ◽

Alberto Baroja-Mazo ◽

Santiago Cuevas

Keyword(s):

Blood Pressure ◽

Animal Models ◽

Nlrp3 Inflammasome ◽

Organ Damage ◽

Subsequent Formation ◽

Caspase 1 ◽

Pyrin Domain ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Inflammasomes are components of the innate immune response that have recently emerged as crucial controllers of tissue homeostasis. In particular, the nucleotide-binding domain, leucine-rich-containing (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a complex platform involved in the activation of caspase-1 and the maturation of interleukin (IL)-1β and IL-18, which are mainly released via pyroptosis. Pyroptosis is a caspase-1-dependent type of cell death that is mediated by the cleavage of gasdermin D and the subsequent formation of structurally stable pores in the cell membrane. Through these pores formed by gasdermin proteins cytosolic contents are released into the extracellular space and act as damage-associated molecular patterns, which are pro-inflammatory signals. Inflammation is a main contributor to the development of hypertension and it also is known to stimulate fibrosis and end-organ damage. Patients with essential hypertension and animal models of hypertension exhibit elevated levels of circulating IL-1β. Downregulation of the expression of key components of the NLRP3 inflammasome delays the development of hypertension and pharmacological inhibition of this inflammasome leads to reduced blood pressure in animal models and humans. Although the relationship between pyroptosis and hypertension is not well established yet, pyroptosis has been associated with renal and cardiovascular diseases, instances where high blood pressure is a critical risk factor. In this review, we summarize the recent literature addressing the role of pyroptosis and the inflammasome in the development of hypertension and discuss the potential use of approaches targeting this pathway as future anti-hypertensive strategies.

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