Endotoxin antagonists appear to slow metabolism.

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rockarolla

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Toll-Like Receptors in Antiviral Innate Immunity
Toll-Like Receptors in Antiviral Innate Immunity
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The TLR1 family encompasses TLR1, TLR2, TLR6, and TLR10. These reside on plasma membranes and recognize components of microbial cell walls and membranes such as lipoproteins and peptidoglycans. They function as a heterodimeric receptor, with TLR2 paired with one of the rest of the TLR1 family members. TLR4 and TLR5 also localize to plasma membrane and engage bacterial lipopolysaccharide (LPS) and flagellin, respectively [2]. On the contrary, members of the TLR3, TLR7, and TLR11 families are intracellular TLRs expressed in endosomes and lysosomes. Initially localizing to the endoplasmic reticulum after their synthesis, these TLRs depend on UNC93B1, a polytopic membrane protein for transport to endolysosomal compartments where they are processed by proteases to become functional receptors [11]. TLR3 recognizes double-stranded RNA (dsRNA) [12]. TLR7, TLR8, and TLR9 make up the TLR7 family, with TLR7 and TLR8 detecting single-stranded RNA (ssRNA) while TLR9 engaging unmethylated CpG DNA [2]. In the TLR11 family, TLR11 and TLR12 operate as a heterodimer for sensing profilin from the parasite Toxoplasma gondii [13], while TLR13 detects bacterial 23S ribosomal RNA.
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Furthermore, initiating antiviral immune responses with TLR3 agonists has been shown to provide protection from many different viruses including hepatitis B virus, influenza virus, certain human immunodeficiency virus (HIV) strains, and coronaviruses...
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Of the TLRs characterized to date, several have been linked to antiviral immunity. Among these, TLR3, TLR7, TLR8, and TLR9 detect distinct forms of viral nucleic acids and are critical in the recognition of viral genetic materials in endolysosomal compartments and initiate antiviral responses. TLR2 and TLR4 are two additional TLR family members that have been implicated in the recognition of viral structural and nonstructural proteins leading to inflammatory cytokine production [20], [21], [22], [23]. There is also evidence that TLR13 may recognize viral infection such as that by vesicular stomatitis virus (VSV), although the exact PAMP sensed by TLR13 in this case remains unknown [24]. In this review, we summarize recent advances in the roles of TLRs and their pathways in innate antiviral immunity. We discuss examples of TLR-mediated viral recognition and describe strategies evolved by viruses to circumvent host antiviral innate immune responses triggered by TLRs.
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In response to invading pathogens such as viruses, a powerful antiviral innate immune system is rapidly activated in the host. TLRs are important constituents of this system and recognize a wide variety of PAMPs that are conserved molecular signatures of bacteria and viruses. Of the TLRs that have been identified, six represent a subclass that recognizes viral ligands. TLRs are predominately expressed in immune cells but also found in a variety of cell types. TLR3, TLR7/TLR8, and TLR9 are intracellular receptors located in endosomal compartments in which they detect viral dsRNA, ssRNA, and unmethylated CpG DNA, respectively. TLR2 and TLR4 reside on the cell surface and are stimulated by viral glycoproteins and, in some cases, nonstructural proteins released to extracellular milieu. The signaling mechanisms leading to the induction of antiviral innate immune responses are dependent on the particular TLR activated, its stimulus, and cell type. Through MyD88-dependent and/or TRIF-dependent pathways, TLRs elicit the production of proinflammatory cytokines and/or type I and type III IFNs via activation of the essential transcription factors NF-κB and IRF family members, tailoring the innate immune responses and shaping the subsequent, antigen-specific adaptive immunity. These immune responses often contribute to viral clearance and disease resolution but sometimes can be harmful to the host. In the past decade and a half, much has been learned concerning TLR structures, ligand recognition, signaling mechanisms, and viral countermeasures of TLR signaling, but our knowledge of the precise roles TLRs play in antiviral immunity and viral disease pathogenesis in vivo falls short. Clearly, progresses in these areas using animal infection models that recapitulate viral diseases in humans are urgently needed and will unequivocally help develop novel therapeutic and preventive approaches against viral infections.

Sensing of RNA Viruses: a Review of Innate Immune Receptors Involved in Recognizing RNA Virus Invasion
https://jvi.asm.org/content/86/6/2900
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... Individual TLRs and the RNA viruses recognized by them:
... https://jvi.asm.org/highwire/markup/62553/expansion

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Targeting the PXR-TLR4 signaling pathway to reduce intestinal inflammation in an experimental model of necrotizing enterocolitis
Targeting the PXR-TLR4 signaling pathway to reduce intestinal inflammation in an experimental model of necrotizing enterocolitis
There is substantial evidence that signaling through Toll-like receptor 4 (TLR4) contributes to the pathogenesis of necrotizing enterocolitis (NEC). Pregnane X receptor (PXR), a xenobiotic sensor and signaling intermediate for certain host-bacterial metabolites, has been shown to negatively regulate TLR4 signaling. Here we investigated the relationship between PXR and TLR4 in the developing murine intestine and explored the capacity of PXR to modulate inflammatory pathways involved in experimental NEC.
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We found a reciprocal relationship between the developmental expression of PXR and TLR4 in wild-type murine intestine, with PXR acting to reduce TLR4 expression by decreasing TLR4 mRNA stability. In addition, PXR−/− mice exhibited a remarkably heightened severity of disease in experimental NEC. Moreover, LCA attenuated intestinal proinflammatory responses in the early stages of experimental NEC.

Activation of PXR inhibits LPS-induced NF-κB activation by increasing IκBα expression in HepG2 cells
Activation of PXR inhibits LPS-induced NF-κB activation by increasing IκBα expression in HepG2 cells - Molecular & Cellular Toxicology
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In this study, we found that rifampicin-activated pregnane X receptor (PXR) plays an important role in the suppression of lipopolysaccharide-activated nuclear factor kappa B (NF-κB) activity by increasing the expression of the inhibitor of κBα (IκBα) in HepG2 cells.
 
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TLR4 agonism via polysaccharides from "Cordyceps militaris":

Cordyceps militaris polysaccharide converts immunosuppressive macrophages into M1-like phenotype and activates T lymphocytes by inhibiting the PD-L1/PD-1 axis between TAMs and T lymphocytes.
Cordyceps militaris polysaccharide converts immunosuppressive macrophages into M1-like phenotype and activates T lymphocytes by inhibiting the PD-L1/PD-1 axis between TAMs and T lymphocytes.,International Journal of Biological Macromolecules - X-MOL

Immunostimulatory Effects of Cordyceps militaris on Macrophages through the Enhanced Production of Cytokines via the Activation of NF-κB
Immunostimulatory Effects of Cordyceps militaris on Macrophages through the Enhanced Production of Cytokines via the Activation of NF-κB
In conclusion, together with these facts of our finding suggest that CME might be useful as a therapeutic agent for the treatment of the immune deficiency diseases.

in-10-55-g003.jpg


^ CME = Cordyceps militaris; LPS = endotoxin

Outcomes as dose dependent increase in:

- production of NO
- proinfl. cytokines IL-1β, IL-6, TNF-α, and PGE2
- protein levels of: iNOS, COX-2


Cordlan polysaccharide isolated from mushroom Cordyceps militaris induces dendritic cell maturation through TLR4 signalings
Cordlan polysaccharide isolated from mushroom Cordyceps militaris induces dendritic cell maturation through toll-like receptor 4 signalings

Cordyceps militaris Enhances MHC-restricted Antigen Presentation via the Induced Expression of MHC Molecules and Production of Cytokines
Cordyceps militaris Enhances MHC-restricted Antigen Presentation via the Induced Expression of MHC Molecules and Production of Cytokines

...

but not "Cordyceps sinensis":

[Immunosuppressive effect of cultured Cordyceps sinensis on cellular immune response] - PubMed

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TLR-4 may mediate signaling pathways of Astragalus polysaccharide RAP induced cytokine expression of RAW264.7 cells
TLR-4 may mediate signaling pathways of Astragalus polysaccharide RAP induced cytokine expression of RAW264.7 cells - PubMed
Results: It has been found that RAP itself did not have any cytotoxic effect on mouse mammary carcinoma 4T1 cells, but it significantly enhanced cytotoxicity of the supernatant of RAW264.7cells on 4T1 cells. Furthermore, RAP enhanced the production of NO and cytokines in RAW264.7 cells, and significantly up-regulated gene expressions of TNF-α, IL-6, iNOS. All these bioactivities were blocked by the inhibitor of TLR4 (Toll-like receptor 4), suggesting that TLR4 is a receptor of RAP and mediates its immunomodulating activity. Further analyses demonstrated that RAP rapidly activated TLR4-related MAPKs, including phosphorylated ERK, phosphorylated JNK, and phosphorylated p38, and induced translocation of NF-κB as well as degradation of IκB-α. These results are helpful to better understand the immunomodulating effects of Radix Astragali.
 
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Mycobacterium tuberculosis inhibits human innate immune responses via the production of TLR2 antagonist glycolipids
Mycobacterium tuberculosis inhibits human innate immune responses via the production of TLR2 antagonist glycolipids

To secure their colonization and survival, pathogens have evolved tactics to undermine host immune responses. Most particularly, Mycobacterium tuberculosis inhibits the activation of macrophages, one of whose roles is to recognize and kill invading microorganisms. Here, we used a library of M. tuberculosis mutants to infect macrophages and uncover molecular mechanisms by which the pathogen modulates the function of these immune cells. We found that M. tuberculosis produces cell envelope glycolipids that are antagonists of a macrophage receptor, named TLR2, which is dedicated to the recognition of pathogens, thereby preventing its efficient recognition by the immune system.

A highly successful intracellular pathogen, Mycobacterium tuberculosis has evolved numerous strategies to evade clearance by the immune system and most particularly the innate immune system (1). Notably, M. tuberculosis has adapted to replicate within macrophages and to subvert their function. It is able to inhibit phagosome maturation, to evade autophagy, or to dampen the production of proinflammatory cytokines. However, the molecular mechanisms by which M. tuberculosis circumvents host defenses are not completely understood.
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We show that sulfoglycolipids are able to inhibit NF-κB activation and subsequent cytokine production or costimulatory molecule expression, by acting as competitive antagonists of Toll-like receptor 2. Our study uncovers a strategy used by M. tuberculosis to undermine innate immunity, as well as a mechanism by which sulfoglycolipids may contribute to M. tuberculosis virulence.

The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens
The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens - PubMed

Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signalling
Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signalling

Anti-inflammatory effect of lycopene on endotoxin-induced uveitis in rats
Anti-inflammatory effect of lycopene on endotoxin-induced uveitis in rats - PubMed

Methods:: Endotoxin-induced uveitis (EIU) was induced in Sprague-Dawley rats by a single subcutaneous injection of 200 μg lipopolysaccharide (LPS). Induction of EIU was preceded by daily intraperitoneal injection of 10 mg/kg lycopene for three consecutive days (Lycopene + LPS group) or equivolume vehicle (Vehicle + LPS group). A positive control group received 1 mg/kg dexamethasone pretreatment (DEX + LPS), and a negative control group received daily vehicle injection but no LPS (Vehicle Control). Twenty-four hours after LPS or final vehicle administration, eyes were enucleated, and aqueous humor was collected for measurement of the number of infiltrating cells, total protein concentration, and levels of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and oxidative stress markers. Inflammatory response severity was compared among groups clinically and histopathologically.

Results:: Infiltrating cell number, total protein concentration, and NO, TNF-α, and IL-6 levels were significantly elevated in the aqueous humor of Vehicle + LPS group rats compared to Vehicle Controls. Compared to the Vehicle + LPS group, lycopene pretreatment significantly reduced aqueous humor concentrations of oxidative stress markers, NO (0.29 ± 0.1 μM vs. 0.19 ± 0.1 μM, p=0.003), TNF-α (71.0 ± 22.3 ng/ml vs. 50.1 ± 2.1 ng/ml, p=0.043), and IL-6 (121.6 ± 3.0 pg/ml vs. 111.1 ± 5.6 pg/ml, p=0.008). Inflammatory score was also reduced (2.0 ± 0.0 vs. 0.4 ± 0.5, p=0.001). Lycopene reduced the infiltrating cell count and protein concentration, but differences did not reach significance. Most lycopene effects were equivalent to dexamethasone.

Conclusions:: Lycopene may aid in the clinical management of uveitis by suppressing inflammation and oxidative stress.

Single-Dose Pharmacokinetic Study of Lycopene Delivered in a Well-Defined Food-Based Lycopene Delivery System (Tomato Paste-Oil Mixture) in Healthy Adult Male Subjects
Single-Dose Pharmacokinetic Study of Lycopene Delivered in a Well-Defined Food-Based Lycopene Delivery System (Tomato Paste-Oil Mixture) in Healthy Adult Male Subjects
Lycopene displayed the shortest half-life of elimination after carotenoid withdrawal (12–33 days) compared to other common carotenoids.

Antimicrobial efficacy of lycopene compound aganist some pathogens:
https://www.journalcra.com/sites/default/files/issue-pdf/22695.pdf

TLR2 and TLR4 mediated host immune responses in major infectious diseases: a review
TLR2 and TLR4 mediated host immune responses in major infectious diseases: a review | The Brazilian Journal of Infectious Diseases

During the course of evolution, multicellular organisms have been orchestrated with an efficient and versatile immune system to counteract diverse group of pathogenic organisms. Pathogen recognition is considered as the most critical step behind eliciting adequate immune response during an infection. Hitherto Toll-like receptors (TLRs), especially the surface ones viz. TLR2 and TLR4 have gained immense importance due to their extreme ability of identifying distinct molecular patterns from invading pathogens. These pattern recognition receptors (PRRs) not only act as innate sensor but also shape and bridge innate and adaptive immune responses. In addition, they also play a pivotal role in regulating the balance between Th1 and Th2 type of response essential for the survivability of the host. In this work, major achievements rather findings made on the typical signalling and immunopathological attributes of TLR2 and TLR4 mediated host response against the major infectious diseases have been reviewed. Infectious diseases like tuberculosis, trypanosomiasis, malaria, and filariasis are still posing myriad threat to mankind. Furthermore, increasing resistance of the causative organisms against available therapeutics is also an emerging problem. Thus, stimulation of host immune response with TLR2 and TLR4 agonist can be the option of choice to treat such diseases in future.

Plant lectins are novel Toll-like receptor agonists
https://pubmed.ncbi.nlm.nih.gov/21420389/

The T cell mitogen and plant glycoprotein, phytohaemagglutinin (PHA), is commonly used to stimulate peripheral blood mononuclear cell (PBMC) preparations to produce IL-2, IL-5, GM-CSF and IFN-γ and so provide an assay to detect immunosuppressants like FK506 and anti-inflammatories such as PDE IV inhibitors. During the early discovery of novel TLR agonists for the treatment of asthma we initially showed that PHA-L is a specific human TLR4 agonist, devoid of effects on equivalent TLR4 null cells. This TLR4 agonism was not due to LPS contamination of PHA-L, as polymyxin B was ineffective and unlike PHA-L, LPS did not stimulate TLR5 or TLR2/6. Also this specific PHA-L agonism of TLR4 was shown for different PHA forms, for example, PHA-P. This TLR lectin pharmacology finding was further explored by testing a broader panel of plant lectin representatives for agonism against a suite of hrTLR cell reporter assays (2/6, 3, 4, 5, 7, 8 and 9). Soybean agglutinin (SBA), concanavalin A (ConA) and PHA lectin family members only stimulated extracellular TLRs (2/6, 4 and 5) probably due to lack of intracellular access, whilst other lectins were either pan-active (WGA) or inactive (AIL). Interestingly SBA only stimulated TLR4, ConA, TLR2/6 and PHA-L, TLR2/6, 4 and 5. As each lectin family exhibits different sugar ligand specificity for interaction, these results suggest that the pharmacology of this TLR agonism is encoded by the lectin's carbohydrate recognition motifs and the appropriate surface presentation of these motifs on different TLRs.

In mice, administration of lectins stimulates IgG and IgA production, similar to that of the cholera toxin:

Mucosal immunogenicity of plant lectins in mice
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2327126/

Antibodies and Lectins in Glycan Analysis
https://www.ncbi.nlm.nih.gov/books/NBK1919/

Natural human antibodies to dietary lectins
https://pubmed.ncbi.nlm.nih.gov/8955334/

Natural antibodies to self and non-self proteins, including dietary proteins, are a significant part of the immune repertoire of humans. Antibodies to three structurally related legume lectins (Erythrina corallodendron lectin (ECorL), peanut agglutinin (PNA), and soybean agglutinin (SBA)) and to one cereal lectin (wheat germ agglutinin (WGA)) were purified by affinity chromatography from human sera and their binding specificity examined. The anti-SBA, anti-ECorL and anti-WGA antibodies exhibited high specificity, whereas the anti-PNA antibodies were polyreactive. Although the anti-WGA antibodies were highly specific for WGA, they also crossreacted slightly toward some other proteins. The anti-ECorL antibodies bound to native SBA, but the anti-SBA antibodies failed to bind to the native ECorL. Although the anti-SBA and anti-ECorL antibodies both exhibited specificity when interacting with native lectins, they bound to a wider range of denatured lectins, indicating a common or universal epitope which is recognized by many natural antibodies. Interestingly, the natural antibodies did not interfere with the agglutination properties of the lectins. These findings may provide a basis for studying the in vivo biological effects of anti-dietary protein antibodies, including those against carbohydrate-binding proteins.

Mistletoe lectins enhance immune responses to intranasally co-administered herpes simplex virus glycoprotein D2
https://pubmed.ncbi.nlm.nih.gov/12383207/

The identification of plant lectins with mucosal adjuvant activity
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1783150/

Modulation of immune function by dietary lectins in rheumatoid arthritis
https://pubmed.ncbi.nlm.nih.gov/10884708/

Despite the almost universal clinical observation that inflammation of the gut is frequently associated with inflammation of the joints and vice versa, the nature of this relationship remains elusive. In the present review, we provide evidence for how the interaction of dietary lectins with enterocytes and lymphocytes may facilitate the translocation of both dietary and gut-derived pathogenic antigens to peripheral tissues, which in turn causes persistent peripheral antigenic stimulation. In genetically susceptible individuals, this antigenic stimulation may ultimately result in the expression of overt rheumatoid arthritis (RA) via molecular mimicry, a process whereby foreign peptides, similar in structure to endogenous peptides, may cause antibodies or T-lymphocytes to cross-react with both foreign and endogenous peptides and thereby break immunological tolerance. By eliminating dietary elements, particularly lectins, which adversely influence both enterocyte and lymphocyte structure and function, it is proposed that the peripheral antigenic stimulus (both pathogenic and dietary) will be reduced and thereby result in a diminution of disease symptoms in certain patients with RA.

How to Remove Arsenic, Lectins and Phytic Acid From Rice:

View: https://www.youtube.com/watch?v=4AISEnGISyI


The truth about rice: Why brown rice isn't always better:
https://www.euronews.com/2018/12/07/truth-about-rice-brown-rice-really-better-you-t144165
 
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rockarolla

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Results from our previous studies demonstrated that saturated fatty acids activate TLR4 and polyunsaturated fatty acids (PUFA) inhibit both saturated fatty acid- and LPS-induced activation of TLR4 (15, 16).

In the current study, our goal was to first identify the activeingredient in the supplementation by comparing three prepa-rations of PUFA,i.e.AA and DHA, egg phospholipids, andDHA alone in preterm formula on the development of NEC.Secondly, we sought to determine the underlying mechanismsresponsible for the effects of PUFA on intestinal injury inNEC using thein vivoneonatal rat model andin vitrointes-tinal epithelial cells. We report here that all PUFA supple-mentations reduced the incidence of NEC in our neonatal ratmodel of NEC. The pathomechanisms may include the abilityof PUFA to suppress TLR4 and PAFR gene expression inepithelial cells


Toll-like receptors (TLRs) are one of the major pattern recognition receptor families that recognize pathogen associated molecular patterns (PAMPs) and mount innate immune responses for host defense against invading pathogens. However, certain TLRs can be activated by non-microbial endogenous molecules leading to induction of sterile inflammation. TLR4 and TLR2 can be activated by saturated fatty acids (SFAs), but inhibited by omega-3 polyunsaturated fatty acids (PUFAs) in particular docosahexaenoic acid (DHA). Receptor dimerization is a prerequisite and sufficient to induce the activation of TLRs.




 
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Inflammatory Responses to Lipopolysaccharide Are Suppressed in 40% Energy-Restricted Mice
Inflammatory Responses to Lipopolysaccharide Are Suppressed in 40% Energy-Restricted Mice
To elucidate the suppressive effects of energy restriction on the inflammatory responses to lipopolysaccharide (LPS), mice were divided into a control group (fed 5.0 g diet/d; 71 kJ/d) and a 40% energy-restricted group (fed 3.0 g diet/d; 43 kJ/d) at 8-wk of age. Four weeks later, 25 μg of LPS was intraperitoneally injected. After the LPS injection, interleukin-1β, interleukin-6 and tumor necrosis factor-α were elevated in serums in the 40% energy-restricted mice and in the controls, but the extent of the elevation was significantly lower in the restricted group. The LPS-induced expression of inducible nitric oxide synthase in the liver was significantly suppressed by the energy restriction. In addition, the LPS-induced elevations of serum aspartate and alanine aminotransferase activities, which are indexes of hepatic injury, were also significantly attenuated in the restricted group. Moreover, the extent of LPS-induced alterations in hepatic structure was less in the restricted mice than in controls. Serum corticosterone level in the restricted mice was higher than that in the controls before LPS treatment (P < 0.05). Furthermore, after LPS injection, the significantly higher level of corticosterone was maintained in the restricted mice, although the LPS treatment significantly enhanced the level even in the control group. These results suggest that the extreme inflammatory responses to endotoxin are prevented in the 40% energy-restricted mice, and corticosterone participates in the preventive effects.

Altered Alveolar Macrophage Function in Calorie-restricted Rats
https://www.atsjournals.org/doi/full/10.1165/ajrcmb.19.3.3114
Alveolar macrophage functions associated with clearance of bacteria from the lung were assessed in male Fischer 344 rats maintained on a 25% calorie-restricted diet. Calorie-restricted and ad libitum-fed (control) rats were exposed to concentrations of ozone known to compromise phagocytic function of alveolar macrophages. Ozone suppressed alveolar macrophage phagocytosis of latex beads in vitro in ad libitum-fed rats, but not in calorie-restricted rats. In fact, caloric restriction enhanced phagocytic function in both control and ozone-exposed animals. Ad libitum-fed rats exposed to ozone and challenged with Streptococcus zooepidemicus experienced a prolonged infection and influx of polymorphonuclear leukocytes (PMN), whereas calorie-restricted rats exposed to ozone cleared the bacteria in 24 h without an inflammatory response. Bacterial endotoxin-stimulated in vitro production of nitric oxide and tumor necrosis factor (TNF)-α as well as expression of TNF-α and interleukin-6 messenger RNAs were all lower in alveolar macrophages isolated from calorie-restricted rats. Together, the data suggest that caloric restriction enhances resistance to gram-positive bacteria, while lowering the production of proinflammatory mediators elicited by endotoxin, a component of gram-negative bacteria. Although increased bacterial resistance is considered beneficial, reduction in the lung's ability to induce inflammatory mediators can have both positive and pathophysiologic consequences.

...

Ample evidence exists that caloric restriction modulates homeostasis and impacts the sensitivity of host responses to various natural and environmental insults. For instance, caloric restriction retards age-associated pathophysiologic changes (1-4) as well as various types of degenerative diseases, including cancer in rodents (5-7). Although the subject has not been extensively investigated, several studies have shown that feed restriction or fasting enhances host defenses against infection in animals and humans. Feed restriction reduced the age-associated decline in antibody production following challenge with influenza virus (8) and dramatically decreased mortality caused by the cerebral malaria parasite in mice (9). Similarly, acute fasting has been shown to increase host resistance against Listeria monocytogenes challenge in mice (10, 11), enhance delayed cutaneous hypersensitivity to Candida albicans, increase serum monocyte bactericidal activity in obese patients (11), and increase the response to influenza vaccine in anorexia nervosa patients (12).

...

Feed restriction and/or fasting also affects nonspecific phagocytic responses and inflammation. Prolonged fasting decreases serum neutrophil chemotaxis (13) and reduces the intensity of inflammation and levels of proinflammatory cytokines such as tumor necrosis factor (TNF) α and interleukin (IL)-6 in the salivary glands of NZBxNZWF1 mice for an autoimmune disease model (14). Phagocytosis of opsonized sheep red-blood cells by alveolar macrophages (AM) in Fischer rats was studied on fasted or 20– 95% restricted regimens (15). Phagocytosis increased shortly after fasting (2 d), but decreased after prolonged fasting (3–6 d). Increased phagocytosis also occurred in rats fed a 40% restricted diet.

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Alveolar macrophages constitute the first line of defense against respiratory infections and are primarily responsible for clearance of gram-positive bacteria from the lung via phagocytosis and intracellular killing (16). Alveolar macrophages also elaborate proinflammatory mediators including reactive oxygen species, nitric oxide, and cytokines which regulate inflammatory responses (16). Previous studies have demonstrated that ozone exposure suppresses alveolar macrophage function in animals (17-19) and humans (20). Ozone-suppression of alveolar macrophage phagocytosis results in increased mortality in mice challenged with a relatively avirulent Group C Streptococcus. Delayed clearance of the bacteria in the lungs following ozone exposure has been demonstrated in both mice and rats (19, 21, 22). Recently, we have shown that dietary restriction mitigates ozone-induced lung inflammation in rats, in part, via increasing pulmonary storage of ascorbate (23). Thus, we hypothesized that caloric restriction might also mitigate the negative effects of ozone on alveolar macrophage function, enhance bacterial clearance, and prevent increased mortality from streptococcal challenge. In this study, we explored the effects of caloric restriction on alveolar macrophage functions thought to be important in the control of bacterial infections.




rcmb3114.f3.jpeg


Effect of caloric restriction on LPS-induced nitric oxide production. Rat AM (1 × 106 cells per well) were treated with 0, 0.1, 0.25, 0.5, 0.75, or 1 ng/ml LPS for 18 h. Nitric oxide and LDH production were measured as described in Materials and Methods. Values represent means ± SEM of four individual wells (n = 4). Asterisk indicates significant difference between ad libitum (AL)-fed and calorie-restricted (CR) groups (P < 0.05). Open triangle indicates significant difference from the control of AL or CR group (P < 0.05). Dagger indicates significant difference between AL and CR groups after adjustment for the existing difference without LPS treatment (P < 0.05). Results are representative of replicate experiments.

Calorie restriction attenuates LPS-induced sickness behavior and shifts hypothalamic signaling pathways to an anti-inflammatory bias
https://journals.physiology.org/doi/full/10.1152/ajpregu.00057.2011

Calorie restriction attenuates lipopolysaccharide (LPS)-induced microglial activation in discrete regions of the hypothalamus and the subfornical organ
Calorie restriction attenuates lipopolysaccharide (LPS)-induced microglial activation in discrete regions of the hypothalamus and the subfornical organ

Short-Term Dietary Restriction Rescues Mice From Lethalabdominal Sepsis and Endotoxemia, and Reduces the Inflammatory/Coagulant Potential of Adipose Tissue
Short-Term Dietary Restriction Rescues Mice From Lethalabdominal Sepsis and Endotoxemia, and Reduces the Inflammatory/Coagulant Potential of Adipose Tissue

Anti-inflammatory mechanism of dieting and fasting revealed:
Anti-inflammatory mechanism of dieting and fasting revealed

Researchers at Yale School of Medicine have found that a compound produced by the body when dieting or fasting can block a part of the immune system involved in several inflammatory disorders such as type 2 diabetes, atherosclerosis, and Alzheimer's disease.

In their study, published in the Feb. 16 online issue of Nature Medicine, the researchers described how the compound β-hydroxybutyrate (BHB) directly inhibits NLRP3, which is part of a complex set of proteins called the inflammasome. The inflammasome drives the inflammatory response in several disorders including autoimmune diseases, type 2 diabetes, Alzheimer's disease, atherosclerosis, and autoinflammatory disorders.

"These findings are important because endogenous metabolites like BHB that block the NLRP3 inflammasome could be relevant against many inflammatory diseases, including those where there are mutations in the NLRP3 genes," said Vishwa Deep Dixit, professor in the Section of Comparative Medicine at Yale School of Medicine.

BHB is a metabolite produced by the body in response to fasting, high-intensity exercise, caloric restriction, or consumption of the low-carbohydrate ketogenic diet.

Dixit said it is well known that fasting and calorie restriction reduces inflammation in the body, but it was unclear how immune cells adapt to reduced availability of glucose and if they can respond to metabolites produced from fat oxidation.

Working with mice and human immune cells, Dixit and colleagues focused on how macrophages -- specialized immune cells that produce inflammation -- respond when exposed to ketone bodies and whether that impacts the inflammasone complex.

The team introduced BHB to mouse models of inflammatory diseases caused by NLP3. They found that this reduced inflammation, and that inflammation was also reduced when the mice were given a ketogenic diet, which elevates the levels of BHB in the bloodstream.

"Our results suggest that the endogenous metabolites like BHB that are produced during low-carb dieting, fasting, or high-intensity exercise can lower the NLRP3 inflammasome," said Dixit.

NLRP3 Inflammasome—A Key Player in Antiviral Responses
NLRP3 Inflammasome—A Key Player in Antiviral Responses

NLRP3 recognizes variety of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) generated during viral replication that triggers the NLRP3 inflammasome-dependent antiviral immune responses and facilitates viral eradication. Meanwhile, several viruses have evolved elaborate strategies to evade the immune system by targeting the NLRP3 inflammasome. In this review, we will focus on the crosstalk between the NLRP3 inflammasome and viruses, provide an overview of viral infection-induced NLRP3 inflammasome activation, and the immune escape strategies of viruses through their modulation of the NLRP3 inflammasome activity.

NLRP3 Inflammasome and Host Protection against Bacterial Infection
NLRP3 Inflammasome and Host Protection against Bacterial Infection

Consuming a hypocaloric high fat low carbohydrate diet for 12 weeks lowers C-reactive protein, and raises serum adiponectin and high density lipoprotein-cholesterol in obese subjects
Consuming a hypocaloric high fat low carbohydrate diet for 12 weeks lowers C-reactive protein, and raises serum adiponectin and high density lipoprotein-cholesterol in obese subjects

Relative to the LFHC[low fat high carbohydrate] group, the HFLC[High fat, low carbohydrate] group had greater improvements in blood lipids and systemic inflammation with similar changes in body weight and composition. This small-scale study suggests that HFLC diets may be more beneficial to cardiovascular health and inflammation in free-living obese adults compared to LFHC diets.

Eat up! Calorie restriction may weaken the immune system
Calorie restriction may weaken the immune system
Scientists at Stanford University yesterday published a more realistic approach to calorie restriction in the journal PLoS Biology. Associate professor of microbiology and immunology David Schneider and graduate student Janelle Ayres worked with fruit flies, this time investigating the effects of bacterial infections on organisms with a restricted diet.
They found that eating less can either increase or shorten the lives of infected flies, depending on the disease. Flies given half their normal diet and exposed to a form of the food-poisoning bug salmonella lived almost twice as long as their full-fat brethren, who only lasted for eight days after infection. But when infected with listeria, another food-poisoning bug, the dieting flies died after just four days, compared to the six or seven managed by flies eating normally.

In their paper, the authors suggest that this mixed reaction to infections should "raise a cautionary flag" for those hoping to live longer by eating less.
Although the effects of calorie restriction in humans have yet to be proven, people may be tempted to reduce their food intake radically by the prospect of a few more years of life. The latest research suggests that this might work if you live in a sterile laboratory, but those of us out in the bacteria-ridden real world should probably eat a more hearty diet.
 
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I feel that I have endotoxin symptoms quite often especially in Fall and Winter and I’m looking for a solution.
 

peter88

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I feel that I have endotoxin symptoms quite often especially in Fall and Winter and I’m looking for a solution.
Me too brother. I upped my fiber to see how I feel and it backfired terribly. Lower abdomen bloating and bad gas. Sleep quality plummeted even though I was sh***ing 3-4 times a day.
 
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Me too brother. I upped my fiber to see how I feel and it backfired terribly. Lower abdomen bloating and bad gas. Sleep quality plummeted even though I was sh***ing 3-4 times a day.

For me it’s muscle aches and general malaise.
 

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