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Nathan Goodyear

Toll-like Receptor Status in Obesity and Metabolic Syndrome: A Translational Perspectiv... - 0 views

press.endocrine.org/...jc.2013-3092

toll like receptors toll-like receptors TLRs TLR-4 TLR4 inflammation metabolic syndrome MetS insulin resistance IR Diabetes obesity

shared by Nathan Goodyear on 06 Jan 14 - No Cached
  • Nathan Goodyear on 06 Jan 14
     
    Only the abstract is available publicly.   Toll-like receptors, particularly TLR-4 has been shown to be associated with insulin resistance.  These TLRs have specific pathogen recognition sites.  TLRs are stimulated by fatty acids (FA) and endotoxemia from bacteria.  Thus, dietary intake of high trans fats, inflammation originating from the gut can be the source of insulin receptor dysfunction through TLRs.
Nathan Goodyear

Toll-like receptors in innate immunity - 0 views

intimm.oxfordjournals.org/...1.full

Toll-like receptors Toll-like receptors TLRs innate immune system immunity

shared by Nathan Goodyear on 15 Jun 14 - No Cached
  • Nathan Goodyear on 15 Jun 14
     
    Great review of Toll-like receptors.
Nathan Goodyear

Pattern recognition receptors (PRRs): toll-like receptors | British Society for Immunology - 0 views

www.immunology.org/...ern-recognition-receptors-prrs

immune system pattern recognition receptors TLR PPR toll-like receptors

shared by Nathan Goodyear on 22 Aug 20 - No Cached
  • Nathan Goodyear on 22 Aug 20
     
    Not an article, but a good review of TLRs and their immunologic role
Nathan Goodyear

Toll-like receptor signaling links dietary fatty acids to the metabolic syndrome - 0 views

www.ncbi.nlm.nih.gov/...PMC3099529

TLR toll-like receptors toll-like receptors fatty acids fat metabolic syndrome obesity overweight inflammation dietary

shared by Nathan Goodyear on 08 Oct 12 - No Cached
  • Activation of the innate immune system controls macronutrient metabolism
  • the innate immune response is the first line of defense against invading pathogens, wherein highly conserved pathogen-associated molecular patterns (PAMPs) are recognized by cognate pattern recognition receptors (PRRs
  • many studies have supported the idea that cytokine signaling directly promotes insulin resistance
  • ...10 more annotations...
  • innate immune system may be causally linked to obesity
  • adipose tissue contains a substantial population of macrophages, and macrophage-driven adipose inflammation contributes significantly to the pathogenesis of obesity
  • Collectively, activation of the innate immune system is strongly associated with ASCVD, insulin resistance, and obesity, and recent evidence suggests that much of this association can be traced to a unique family of PRRs known as TLRs
  • TLRs are a family of type I transmembrane receptors, currently thought to comprise at least 13 members in mammals, that specifically recognize a variety of microbial PAMPs and trigger host cellular responses
  • Free SFAs have indeed been demonstrated to elicit TLR4-dependent and TLR2-dependent responses in several cell types.
  • Endogenous SFAs released from adipocytes activate cocultured macrophages via TLR4 [18], indicating the potential for cellular crosstalk in adipose tissue. Collectively, there is a growing body of evidence that SFAs promote, whereas long chain PUFA antagonize, TLR4-dependent and TLR2-dependent signaling in multiple cell models
  • In an elegant study, Shi et al. [16] demonstrated that SFAs activate TLR4-dependent signaling in both macrophages and adipocytes, and mice lacking TLR4 are protected against insulin resistance driven by intravenous lipid infusion
  • In addition to effects in macrophages and adipocytes, SFAs can activate TLR4 in the hypothalamus, which triggers a central inflammatory response that results in resistance to anorexigenic signals
  • endogenous SFAs can indeed promote innate immunity and inflammatory disease
  • This finding strongly supports the work of Hwang and coworkers [19–22] demonstrating that ω-3 PUFAs can effectively counteract SFA-induced TLR4 activation in cultured macrophages and dendritic cells.
  • Nathan Goodyear on 08 Oct 12
     
    high dietary fatty acids linked to metabolic syndrome through TLR.
Nathan Goodyear

Toll-like receptor 4 as a predictor of clinical outcomes of estrogen receptor-negative ... - 0 views

www.ncbi.nlm.nih.gov/...PMC5338938

NF-kapppB TLR-4 toll-like receptors inflammation NF-κB NF-KappaB toll like receptors metastasis TLRs TLR4 NFKB recurrence cancer

shared by Nathan Goodyear on 21 Jul 22 - No Cached
  • Nathan Goodyear on 21 Jul 22
     
    TLR4 promotes tumor progression, aggression, and resistance in ER-
Nathan Goodyear

Toll-Like Receptor-4 Mediates Vascular Inflammation and Insulin Resistance in Diet-Indu... - 0 views

circres.ahajournals.org/...1589.short

inflammation insulin resistance obesity FFA saturated fat TLR4 NF-kappaB IKK-Beta

shared by Nathan Goodyear on 21 Dec 11 - No Cached
  • Nathan Goodyear on 21 Dec 11
     
    high saturated fat intake (excess FFA) shown to contribute to obesity through TLR4 receptors.  TLR4 receptors are mediators in the innate immunity.   The result will be both IKK-Beta and NF-KappaB.
Nathan Goodyear

Role of toll-like receptor 4 on the immune escape of human oral squamous cell carcinoma... - 0 views

www.ncbi.nlm.nih.gov/...PMC3496658

toll-like receptors TLR-4 chemoresistance TLR4 chemotherapy cancer

shared by Nathan Goodyear on 12 Jun 20 - No Cached
  • Nathan Goodyear on 12 Jun 20
     
    TLR-4 receptor increase increases chemotherapy resistance.
Nathan Goodyear

Toll-like Receptors, Infection | Learn Science at Scitable - 0 views

www.nature.com/...that-detect-infection-14396559

toll-like receptors TLRs inflammation immune system

shared by Nathan Goodyear on 01 Oct 12 - No Cached
  • Nathan Goodyear on 01 Oct 12
     
    basic summary of TLRs
Nathan Goodyear

Saturated Fatty Acids, but Not Unsaturated Fatty Acids, Induce the Expression of Cycloo... - 0 views

www.jbc.org/...16683.long

TLR-4 TLR4 TLR DHA EPA toll like receptors Toll-like receptors omega 3 omega-3 inflammation NF-kappaB lkappaB-alpha lkkb

shared by Nathan Goodyear on 11 Sep 14 - No Cached
  • Nathan Goodyear on 11 Sep 14
     
    OMega-3 inhibits inflammation via decreased phosphorylation of lkappaBalpha and resultant decreased disassociation of NF-kappaB and decreased cytokine production.  This occurs through TLR-4.
Nathan Goodyear

Toll-like receptors in innate immunity | International Immunology | Oxford Academic - 0 views

academic.oup.com/...721976

immunotherapy toll-like receptors toll like receptors TLR immune system

shared by Nathan Goodyear on 22 May 20 - No Cached
  • Nathan Goodyear on 22 May 20
     
    good review of TLRs
Nathan Goodyear

Suppressive effects of sunitinib on a TLR activation-induced cytokine storm - ScienceDi... - 0 views

www.sciencedirect.com/...S0014299919302870

cytokine storm TLR4 cancer toll-like receptors

shared by Nathan Goodyear on 14 May 20 - No Cached
  • Nathan Goodyear on 14 May 20
     
    Toll-like receptors trigger cytokine storm.
Nathan Goodyear

The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic... - 0 views

www.ncbi.nlm.nih.gov/...PMC3962576

microglia LDN low dose naltrexone pain inflammation

shared by Nathan Goodyear on 05 Jul 17 - No Cached
  • orally active competitive opioid receptor antagonist
  • 4.5 mg, though the dosage can vary a few milligrams below or above that common value
  • At the low dosage level, naltrexone exhibits paradoxical properties, including analgesia and anti-inflammatory actions
  • ...10 more annotations...
  • LDN may be an effective treatment for FM
  • In addition to the antagonist effect on mu-opioid and other opioid receptors, naltrexone simultaneously has an antagonist effect on non-opioid receptors (Toll-like receptor 4 or TLR4) that are found on macrophages such as microglia
  • It is via the non-opioid antagonist path that LDN is thought to exert its anti-inflammatory effects
  • Once activated, microglia produce inflammatory and excitatory factors that can cause sickness behaviors such as pain sensitivity, fatigue, cognitive disruption, sleep disorders, mood disorders, and general malaise
  • The neuroprotective action appears to result when microglia activation in the brain and spinal cord is inhibited
  • By suppressing microglia activation, naloxone reduces the production of reactive oxygen species and other potentially neuroexcitatory and neurotoxic chemicals
  • suppressed TNF-alpha, IL-6, MCP-1, and other inflammatory agents in peripheral macrophages
  • individuals with greater ESR at baseline experienced a greater drop in pain when taking LDN
  • LDN has been reported to reduce not only self-reported pain in that condition but also objective markers of inflammation and disease severity
  • Naltrexone has also shown some promise in improving disease severity in multiple sclerosis
  • Nathan Goodyear on 05 Jul 17
     
    LDN maybe useful in treating chronic pain via anti-inflammatory effects on microglia.
Nathan Goodyear

Obesity - Inducible Toll-like Receptor and NF-[kappa]B Regulatory Pathway Expression in... - 0 views

www.nature.com/...oby200825a.html

TLR-4 TLR Toll-like receptors NF-kapppB inflammation obesity

shared by Nathan Goodyear on 19 Jan 12 - No Cached
  • TLRs are functionally inducible and associated with downstream NF-B activation and proinflammatory cytokine production.
  • TLRs represent a family of receptors that are critical to the innate immune response against foreign pathogens and microorganisms
  • LPS has been shown to induce proinflammatory chemokine gene expression in differentiated human adipocytes through TLR and NF-B action
  • ...2 more annotations...
  • Stimulation of TLRs initiates intracellular signaling cascades resulting in downstream NF-B and mitogen-activated protein kinase activation and production of proinflammatory chemokines associated with mechanisms of metabolic dysfunction and cardiovascular disease progression.
  • Elevated fatty acids levels associated with obesity activate TLR4 signaling in fat cells and macrophages, and induce insulin resistance in murine models
  • Nathan Goodyear on 19 Jan 12
     
    TLR, especially TLR-4, is directly involved in NF-KappaB activation and release of inflammatory cytokines
Nathan Goodyear

NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond - PMC - 0 views

www.ncbi.nlm.nih.gov/...PMC8924116

cancer NETosis SARS-CoV-2 COVID COVID-19 COVID19 platelets

shared by Nathan Goodyear on 18 Apr 23 - No Cached
  • Pneumonia is a typical symptom of COVID-19 infection, while acute respiratory distress syndrome (ARDS) and multiple organ failure are common in severe COVID-19 patients
  • NETs are important for preventing pathogen invasion, their excessive formation can result in a slew of negative consequences, such as autoimmune inflammation and tissue damage
  • SARS-CoV-2 infection has also been linked to increased neutrophil-to-lymphocyte ratios, which is associated with disease severity and clinical prognosis
  • ...40 more annotations...
  • NETosis is a special form of programmed cell death in neutrophils, which is characterized by the extrusion of DNA, histones, and antimicrobial proteins in a web-like structure known as neutrophil extracellular traps (NETs)
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Definition
  • increased generation of reactive oxygen species (ROS) is a crucial intracellular process that causes NETosis
  • Another indirect route of SARS-CoV-2-induced NET production is platelet activation
  • When NETs are activated in the circulation, they can also induce hypercoagulability and thrombosis
  • In COVID-19, major NET protein cargos of NETs (i.e., NE, MPO, and histones) are significantly elevated.
  • SARS-CoV-2 can also infect host cells through noncanonical receptors such as C-type lectin receptors
  • Immunopathological manifestations, including cytokine storms and impaired adaptive immunity, are the primary drivers behind COVID-19, with neutrophil infiltration being suggested as a significant cause
  • NETosis and NETs are increasingly recognized as causes of vascular injury
  • SARS-CoV-2 and its components (e.g., spike proteins and viral RNA) attach to platelets and increase their activation and aggregation in COVID-19, resulting in vascular injury and thrombosis, both of which are linked to NET formation
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Connects SARS-CoV-2 to TLR on Platelets to NETosis to metastasis.
  • NET formation may be caused by activated platelets rather than SARS-CoV-2 itself
  • NETosis, leading to aberrant immunity such as cytokine storms, autoimmune disorders, and immunosuppression.
  • early bacterial coinfections were more prevalent in COVID-19 patients than those infected with other viruses
  • NETosis and NETs may also have a role in the development of post COVID-19 syndromes, including lung fibrosis, neurological disorders, tumor growth, and worsening of concomitant disease
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      NETosis-> tumor growth
  • NETs and other by-products of NETosis have been shown to act as direct inflammation amplifiers. Hyperinflammation
  • “cytokine storm”
  • SARS-CoV-2 drives NETosis and NET formation to allow for the release of free DNA and by-products (e.g., elastases and histones). This may trigger surrounding macrophages and endothelial cells to secrete excessive proinflammatory cytokines and chemokines, which, in turn, enhance NET formation and form a positive feedback of cytokine storms in COVID-19
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Cycle of hyperinflammation
  • NET release enables self-antigen exposure and autoantibody production, thereby increasing the autoinflammatory response
  • patients with COVID-19 who have higher anti-NET antibodies are more likely to be detected with positive autoantibodies [e.g., antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA)]
  • COVID-19 NETs may act as potential inducers for autoimmune responses
  • have weakened adaptive immunity as well as a high level of inflammation
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Immunomodulation
  • tumor-associated NETosis and NETs promote an immunosuppressive environment in which anti-tumor immunity is compromised
  • NETs have also been shown to enhance macrophage pyroptosis in sepsis
  • facilitating an immunosuppressive microenvironment
  • persistent immunosuppression may result in bacterial co-infection or secondary infection
  • can enhance this process by interacting with neutrophils through toll-like receptor 4 (TLR4), platelet factor 4 (PF4), and extracellular vesicle-dependent processes
  • NET-induced immunosuppression in COVID-19 in the context of co-existing bacterial infection
  • Following initial onset of COVID-19, an estimated 50% or more of COVID-19 survivors may develop multi-organ problems (e.g., pulmonary dysfunction and neurologic impairment) or have worsening concomitant chronic illness
  • NETs in the bronchoalveolar lavage fluid of severe COVID-19 patients cause EMT in lung epithelial cells
  • decreased E-cadherin (an epithelial marker) expression
    • Nathan Goodyear
      Nathan Goodyear on 23 Apr 23
       
      Leads to emt
  • COVID-19 also has a long-term influence on tumor progression
  • Patients with tumors have been shown to be more vulnerable to SARS-CoV-2 infection and subsequent development of severe COVID-19
  • patients who have recovered from COVID-19 may have an increased risk of developing cancer or of cancer progression and metastasis
  • awaken cancer cells
  • NETs have been shown to change the tumor microenvironment
  • enhance tumor progression and metastasis
  • vitamin C has been tested in phase 2 clinical trials aimed at reducing COVID-19-associated mortality by reducing excessive activation of the inflammatory response
  • vitamin C is an antioxidant that significantly attenuates PMA-induced NETosis in healthy neutrophils by scavenging ROS
  • vitamin C may also inhibit NETosis and NET production in COVID-19
  • Metformin
  • Vitamin C
  • Nathan Goodyear on 18 Apr 23
     
    NETosis intimately involved in progressive COVID, long COVID, autoimmunity, and cancer
Nathan Goodyear

Inflammation and insulin resistance 10.1016/j.febslet.2007.11.057 : FEBS Letters | Scie... - 0 views

www.sciencedirect.com/...S0014579307012082

inflammation insulin resistance IR PPAR TNF-alpha IL-6 IL-10 IL-1Beta JNK GLT-4 Resistin adiponectin Gherlin NF-kapppB iNOS lkkb obesity TLR-4

shared by Nathan Goodyear on 10 Jan 12 - No Cached
  • A subsequent study by Yuan et al. showed that Tnf treatment of 3T3L1 adipocytes induces insulin resistance and that this could be prevented by pretreatment of cells with aspirin
  • Activation of the Tnf receptor results in stimulation of NFκB signaling via Ikkb
  • Insulin is a pleiotropic hormone
  • ...25 more annotations...
  • the percentage of macrophages in a given adipose tissue depot is positively correlated with adiposity and adipocyte size
  • Il-10 is an anti-inflammatory cytokine produced by macrophages and lymphocytes
  • Il-10 exerts its anti-inflammatory activity by inhibiting Tnf-induced NFκB activation by reducing IKK activity [38]
  • adipose tissue macrophages are responsible for nearly all adipose tissue Tnf expression and a significant portion of Nos2 and Il6 expression
  • One theory holds that the expansion of adipose tissue leads to adipocyte hypertrophy and hyperplasia and that large adipocytes outstrip the local oxygen supply leading to cell autonomous hypoxia with activation of cellular stress pathways
  • The use of the anti-inflammatory compounds, salicylate and its derivative aspirin, for treating symptoms of T2DM dates back over 100 years
  • elevated levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin (IL-8) have all been reported in various diabetic and insulin resistant states
  • overnutrition and obesity are often accompanied by elevations in tissue and circulating FFA concentrations, and saturated FFAs can directly activate pro-inflammatory responses
  • Adipokines such as resistin, leptin and adiponectin, which are secreted by adipocytes, can also affect inflammation and insulin sensitivity
  • In skeletal muscle insulin promotes glucose uptake by stimulating translocation of the GLUT4 glucose transporter
  • macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the “classically activated” pro-inflammatory macrophage, to the M2 state or the “alternatively activated” non-inflammatory cell
  • saturated fatty acids are the most potent inducers of this inflammatory response
  • Several inducers of insulin resistance, including FFAs, pro-inflammatory cytokines and oxidative stress, activate the expression of Nos2, the gene that encodes iNOS (reviewed in [33]
  • Adipose tissue insulin signaling results in decreased hormone sensitive lipase activity and this anti-lipolytic effect inhibits free fatty acid (FFA) efflux out of adipocytes.
  • In the liver, insulin inhibits the expression of key gluconeogenic enzymes and, therefore, insulin resistance in liver leads to elevated hepatic glucose production
  • elevated JNK activity in liver, adipose tissue and skeletal muscle of obese insulin resistant mice, and knockout of Jnk1 (Jnk1−/−) leads to amelioration of insulin resistance in high fat diet
  • Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance
  • C-reactive protein (CRP)
  • these studies highlight the possibility that increased iNOS activity plays a direct role in the pathogenesis of insulin resistance
  • the important role of Ikkb in the development of obesity and inflammation-induced insulin resistance.
  • It is probable that local concentrations of inflammatory mediators, such as FFAs, Tnf or other cytokines/adipokines contribute to this polarity switch
  • Tnf and other cytokines/chemokines are symptomatic of inflammation, and while they propagate and/or maintain the inflammatory state, they are not the initial cause(s) of inflammation
  • Tlr4, in particular, is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria
  • Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system.
  • Tlr4 stimulation results in the activation of both Ikkb/NFκB and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1, etc. (reviewed in [57
  • Nathan Goodyear on 10 Jan 12
     
    Great review of all the known components in the inflammation, insulin resistance link
Nathan Goodyear

Toll-like receptors, inflammation, metabolism and obesity, Archives of Physiology and B... - 0 views

informahealthcare.com/...13813455.2011.562514

TLR TLR-4 Toll-like Receptors inflammation obesity Diabetes DM

shared by Nathan Goodyear on 19 Jan 12 - No Cached
  • Nathan Goodyear on 19 Jan 12
     
    TLR, inflammation and obesity.  involved in inflammation.
Nathan Goodyear

Increased Toll-Like Receptor Activity in Patients With Metabolic Syndrome - 0 views

care.diabetesjournals.org/...dc11-2375

TLR4 TLR2 toll-like receptors inflammation metabolic syndrome MetS cytokines IL-1Beta IL-6 IL-8 TNF-alpha obesity overweight

shared by Nathan Goodyear on 29 Feb 12 - No Cached
  • Nathan Goodyear on 29 Feb 12
     
    TLR2 and TLR4 are increased in patients with metabolic syndrome.  No surprise that IL-1Beta, IL-6, IL-8, TNF-alpha were increased as well.
Nathan Goodyear

Loss-of-Function Mutation in Toll-Like Receptor 4 Prevents Diet-Induced Obesity and Ins... - 0 views

diabetes.diabetesjournals.org/...1986.long

TLR-4 TLR4 toll like receptors high fat diet LPS endotoxin insulin resistance IR obesity

shared by Nathan Goodyear on 20 Jul 13 - No Cached
  • Nathan Goodyear on 20 Jul 13
     
    HFD and LPS endotoxin induce inflammation through TLR-4 to increase insulin resistance and obesity.
Nathan Goodyear

The Journal of Steroid Biochemistry and Molecular Biology | Vol 141, Pgs 1-170, (May 20... - 0 views

www.sciencedirect.com/...141

toll like receptors Toll-like receptors vitamin D D3 1 25-dihydroxyvitamin

shared by Nathan Goodyear on 24 Jun 14 - No Cached
  • Nathan Goodyear on 24 Jun 14
     
    vitamin D3 associated with down regulation of most TLRs associated with inflammation.  Though, vitamin D3 did increase TLR-10.
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