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Nathan Goodyear

The Complex Role of Estrogens in Inflammation - 0 views

  • These studies suggest inflammation-dependent up-regulation of ERβ relative to ERα.
  • up-regulation of ERβ relative to ERα under hypoxic conditions, which might lead to a preponderance of signaling through ERβ pathways
  • it seems that E2 at periovulatory to pregnancy levels inhibited proinflammatory cytokines from PBMCs
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  • it is clear that E2 can stimulate antibody production by B cells, probably by inhibiting T cell suppression of B cells
  • In cycling women, the largest quantities of Ig were detected before ovulation
  • In contrast, E2 at high concentrations leads to a suppression of B-lymphocyte lineage precursors
  • E2 at periovulatory to pregnancy serum levels is able to stimulate antibody secretion under healthy conditions but also in autoimmune diseases, whereas similar serum levels of E2 lead to a suppression of bone marrow B cell lineage precursors
  • In chronic inflammatory disorders, where B cells play a decisive role, E2 would promote the disease when autoaggressive B cells are already present, whereas chronically elevated E2 would inhibit initiation of an autoimmune disease when no such B cells are available. This might be a good reason why particularly B cell-dependent diseases such as SLE, mixed connective tissue disease (Sharp syndrome), IgA nephropathy, dermatitis herpetiformis, gluten sensitive enteropathy, myasthenia gravis, and thyroiditis appear in women in the reproductive years, predominantly, in the third or fourth decades of life
  • Th17 cells are thought to be the main responsible cells for chronic inflammatory tissue destruction in autoimmune diseases
  • IFN-γ, IL-12, and TNF were allocated to Th1 reactions
  • IL-4, IL-5, and IL-10 to Th2 responses
  • antiinflammatory T regulatory cells producing TGF-β and proinflammatory T helper type 17 cells (Th17) producing IL-17
  • no direct effects of estrogens on Th17 cells or IL-17 secretion have been described until now.
  • So-called Th17 cells producing IL-17 are the main T cells responsible for chronic inflammation.
  • Because IFN-γ has been allocated a Th17-inhibiting role (Fig. 1⇑), its increase by E2 at pregnancy doses and the E2-mediated inhibition of TNF must be viewed as a favorable effect in chronic inflammation
  • in humans and mice, E2 at periovulatory to pregnancy levels stimulates IL-4, IL-10, and IFN-γ but inhibits TNF from CD4+ T cells
  • In humans and mice, E3 and E2, respectively, at pregnancy levels inhibit T cell-dependent delayed type hypersensitivity
  • increased IL-4, IL-10, and IFN-γ in the presence of low TNF support an antiaggressive immune response
  • secretion of IL-1β is increased at periovulatory/proestrus to early pregnancy levels, whereas IL-1 secretion is inhibited at high pregnancy levels
  • The dichotomous effect of E2 on IL-1β and TNF at high and low concentrations is most probably due to inhibition of NF-κB at high concentrations
  • experiments with mouse and rat macroglial and microglial cells demonstrate that E2 at proestrus to pregnancy levels exerts neuroprotective effects by increasing TGF-β and by inhibiting iNOS and NO release, and reducing expression of proinflammatory cytokines and prostaglandin E2 production.
  • E2 at periovulatory to pregnancy levels inhibits NF-κB activation, which must be viewed as an antiinflammatory signal
  • It was shown that E2 concentrations equal to or above 10−10 m are necessary to inhibit NF-κB activation
  • important proinflammatory cytokines are typically inhibited at periovulatory (proestrus) to pregnancy levels of E2, which is evident for IL-6, IL-8, and TNF
  • low E2 concentrations were demonstrated to have no or even stimulatory effects
  • This renders a woman in the postmenopausal phase to a more proinflammatory situation
  • most in vitro studies demonstrated a stimulatory effect of E2 on secretion of IL-4, IL-10, and TGF-β typically at periovulatory to pregnancy levels
  • E2 at periovulatory to pregnancy levels has an ameliorating effect on chronic inflammatory diseases as long as B cell-dependent immunity or an overshooting fibrotic tissue repair process do not play a crucial pathogenic role. However, when the B cell plays an important role, E2 might even stimulate the disease process as substantiated by flare-ups in SLE during pregnancy
    • Nathan Goodyear
       
      SLE, mixed connective tissue disease (Sharp syndrome), IgA nephropathy, dermatitis herpetiformis, gluten sensitive enteropathy, myasthenia gravis, and thyroiditis
  • Short-term administration of E2 at pregnancy levels was shown to induce an inflammatory response specific to the lateral prostate of the castrated male rat
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    great review of the complex interaction between Estrogens and inflammation.  Reference here is in females.
Nathan Goodyear

Glutathione Redox Regulates Airway Hyperresponsiveness and Airway Inflammation in Mice ... - 0 views

  • γ-GCE reduced levels of IL-4, IL-5, IL-10, and the chemokines eotaxin and RANTES (regulated on activation, normal T cell expressed and secreted) in bronchoalveolar lavage fluid, whereas it enhanced the production of IL-12 and IFN-γ.
  • γ-GCE suppressed eosinophils infiltration
  • γ-GCE directly inhibited chemokine-induced eosinophil chemotaxis
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  • these findings suggest that changing glutathione redox balance, increase in GSH level, and the GSH/GSSG ratio by γ-GCE, ameliorate bronchial asthma by altering the Th1/Th2 imbalance through IL-12 production from APC and suppressing chemokine production and eosinophil migration itself.
  • Bronchial asthma is a typical helper T cell type 2 (Th2) disease
  • Through the release of Th2 cytokines, such as IL-4, IL-5, and IL-13, orchestrate the recruitment and activation of the primary effector cells of the allergic response: the mast cells and the eosinophils
  • Glutathione is the most abundant nonprotein sulfhydryl compound in almost all cells. This tripeptide plays a significant role in many biological processes. It also constitutes the first line of the cellular defense mechanism against oxidative injury along with SOD, ascorbate, vitamin E, and catalase, and is the major intracellular redox buffer in ubiquitous cell types
  • We have shown that glutathione redox status, namely the balance between intracellular reduced (GSH) and oxidized (GSSG) glutathione, in murine antigen-presenting cells (APC) plays a central role in determining which of the reductive and oxidative APC predominate during immune status, and the balance between reductive and oxidative APC regulates Th1/Th2 balance through production of IL-12
  • we have also shown that exposure of human alveolar macrophages to the Th1 cytokine IFN-γ or the Th2 cytokine IL-4 either increases or decreases the GSH/GSSG ratio, respectively, which regulates Th1/Th2 balance through IL-12 production
  • the ability to generate a Th1 or Th2 type response has turned out to depend not only on T cells but also on the intracellular glutathione redox status of APC
  • Th1 cytokine IFN-γ and Th2 cytokine IL-4 increases and decreases the GSH/GSSG ratio, respectively, and that this ratio influences LPS-induced IL-12 production from alveolar macrophages
  • the ability to generate a Th1 or Th2 response is dependent on glutathione redox status of APC
  • administration of γ-GCE elevates GSH level and GSH/GSSG ratio in the lung, and ameliorates AHR and eosinophilic airway inflammation by altering the Th1/Th2 balance and suppressing chemokine production and eosinophil migration in a mouse asthma model
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    glutathione redox reaction plays an important role in the ability to balance Th1 and Th2 and thus disease potential i.e. asthma as this study example.  
Nathan Goodyear

How is the Immune System Suppressed by Cancer - 1 views

  • nitric oxide (NO) released by tumor cells
  • Excellent work by Prof de Groot of Essen, indicated by adding exogenous xanthine oxidase ( XO) in hepatoma cells, hydrogen peroxide was produced to destroy the hepatoma cells
  • NO from eNOS in cancer cells can travel through membranes and over long distances in the body
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  • NO also is co linked to VEGF which in turn increases the antiapoptotic gene bcl-2
  • The other important influence of NO is in its inhibition of the proapoptoic caspases cascade. This in turn protects the cells from intracellular preprogrammed death.
  • nitric oxide in immune suppression in relation to oxygen radicals is its inhibitory effect on the binding of leukocytes (PMN) at the endothelial surface
  • Inhibition of inducible Nitric Oxide Synthase (iNOS)
  • NO from the tumor cells actually suppresses the iNOS, and in addition it reduces oxygen radicals to stop the formation of peroxynitrite in these cells. But NO is not the only inhibitor of iNOS in cancer.
  • Spermine and spermidine, from the rate limiting enzyme for DNA synthases, ODC, also inhibit iNOS
  • tolerance in the immune system that decreases the immune response to antigens on the tumors
  • Freund’s adjuvant
  • increase in kinases in these cells which phosphorylate serine, and tyrosine
  • responsible for activation of many growth factors and enzymes
  • phosphorylated amino acids suppress iNOS activity
  • Hexokinase II
  • Prostaglandin E2, released from tumor cells is also an inhibitor of iNOS, as well as suppressing the immune system
  • Th-1 subset of T-cells. These cells are responsible for anti-viral and anti-cancer activities, via their cytokine production including Interleukin-2, (IL-2), and Interleukin-12 which stimulates T-killer cell replication and further activation and release of tumor fighting cytokines.
    • Nathan Goodyear
       
      Th1 cells stimulate NK and other tumor fighting macrophages via IL-2 and IL-12; In contrast, Th2, which is stimulated in allergies and parasitic infections, produce IL-4 and IL-10.  IL-4 and IL-10 inhibit TH-1 activation and the histamine released from mast cell degranulation upregulates T suppressor cells to further immune suppression.
  • Th-2 subset of lymphocytes, on the other hand are activated in allergies and parasitic infections to release Interleukin-4 and Interleukin-10
  • These have respectively inhibitory effects on iNOS and lymphocyte Th-1 activation
  • Mast cells contain histamine which when released increases the T suppressor cells, to lower the immune system and also acts directly on many tumor Histamine receptors to stimulate tumor growth
  • Tumor cells release IL-10, and this is thought to be one of the important areas of Th-1 suppression in cancer patients
  • IL-10 is also increased in cancer causing viral diseases such as HIV, HBV, HCV, and EBV
  • IL-10 is also a central regulator of cyclooxygenase-2 expression and prostaglandin production in tumor cells stimulating their angiogenesis and NO production
  • nitric oxide in tumor cells even prevents the activation of caspases responsible for apoptosis
    • Nathan Goodyear
       
      NO produced by cancer cells inhibits proapoptotic pathways such as the caspases.
  • early stages of carcinogenesis, which we call tumor promotion, one needs a strong immune system, and fewer oxygen radicals to prevent mutations but still enough to destroy the tumor cells should they develop
  • later stages of cancer development, the oxygen radicals are decreased around the tumors and in the tumor cells themselves, and the entire cancer fighting Th-1 cell replication and movement are suppressed. The results are a decrease in direct toxicity and apoptosis, which is prevented by NO, a suppression of the macrophage and leukocyte toxicity and finally, a suppression of the T-cell induced tumor toxicity
  • cGMP is increased by NO
  • NO in cancer is its ability to increase platelet-tumor cell aggregates, which enhances metastases
  • the greater the malignancies and the greater the metastatic potential of these tumors
  • The greater the NO production in many types of tumors,
  • gynecological
  • elevated lactic acid which neutralizes the toxicity and activity of Lymphocyte immune response and mobility
  • The lactic acid is also feeding fungi around tumors and that leads to elevated histamine which increases T-suppressor cells.  Histamine alone stimulates many tumor cells.
    • Nathan Goodyear
       
      The warburg effect in cancer cells results in the increase in local lactic acid production which suppresses lymphocyte activity and toxicity as well as stimulates histamine production with further stimulates tumor cell growth.
  • T-regulatory cells (formerly,T suppressor cells) down regulate the activity of Natural killer cells
  • last but not least, the Lactic acid from tumor cells and acidic diets shifts the lymphocyte activity to reduce its efficacy against cancer cells and pathogens in addition to altering the bacteria of the intestinal tract.
  • intestinal tract bacteria in cancer cells release sterols that suppress the immune system and down regulate anticancer activity from lymphocytes.
  • In addition to the lactic acid, adenosine is also released from tumors. Through IL-10, adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state
  • Adenosine up regulates the PD1 receptor in T-1 Lymphocytes and inhibits their activity
  • Adenosine is a purine nucleoside found within the interstitial fluid of solid tumors at concentrations that are able to inhibit cell-mediated immune responses to tumor cells
  • Adenosine appears to up-regulate the PD1 receptor in T-1 Lymphocytes and inhibits the immune system further
  • Mast cells with their release of histamine lower the immune system and also stimulate tumor growth and activate the metalloproteinases involved in angiogenesis and metastases
  • COX 2 inhibitors or all trans-retinoic acid
  • Cimetidine, an antihistamine has been actually shown to increase in apoptosis in MDSC via a separate mechanism than the antihistamine effect
    • Nathan Goodyear
       
      cimetidine is an H2 blocker
  • interleukin-8 (IL-8), a chemokine related to invasion and angiogenesis
  • In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNF-alpha)
  • these data raise the possibility that the majority of CAFs in CLM originate from resident LFs. TNF-alpha-induced up-regulation of IL-8 via nuclear factor-kappaB in CAFs is an inflammatory pathway, potentially permissive for cancer invasion that may represent a novel therapeutic target
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    Great review of the immunosuppression in cancer driven by the likes of NO.
Nathan Goodyear

Cytokine profiles in localized scleroderma and relationship to clinical features - 0 views

  • Evaluation of the literature reveals a Th2 predominant cytokine profile in the biological specimens (sera, PBMCs, and tissue) of those with SSc
  • the literature available from studies in LS show that Th1, Th2, and Th17 cytokines may contribute equally to the pathogenesis of the disease
  • Classically, Th1 cells have been known to secrete IL-2, IFN-γ, and TNF-α, and are stimulated by IL-2 and IL-12
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  • Th2 cells have been shown to be activated by IL-4 and produce IL-4, IL-5, IL-10 and IL-13
  • Th17 cells, a more recently identified Th cell subset that has altered the classic Th1/Th2 paradigm, produce IL-17 A/F, IL-21, and IL-22. IL-1, IL-6, IL-23, and TGF-β are now known to play important roles in the differentiation and propagation of the Th17 cell lineage
  • there is an overall notion that pro-inflammatory Th1 and Th17 associated cytokines are elevated during the early stages of scleroderma, whereas Th2 cytokines mainly correlate with disease damage and fibrosis extent
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    morphea
Nathan Goodyear

IL-2: The First Effective Immunotherapy for Human Cancer | The Journal of Immunology - 0 views

  • IL-2 is a 15.5-kDa cytokine secreted predominately by Ag-simulated CD4+ T cells, but it can also be produced by CD8+ cells, NK cells, and activated dendritic cells
  • IL-2 is the predominant factor responsible for the maintenance of CD4+ regulatory T cells
  • A generalized capillary leak syndrome was induced by IL-2 in vivo that resulted in interstitial pulmonary infiltrates and substantial weight gain in patients
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  • The side effects were transient and returned to baseline following treatment
  • Tumors do not express IL-2 receptors and thus the antitumor activity was the result of IL-2 stimulation of immune cell
  • Patients with metastatic melanoma or metastatic renal cell cancer were uniquely responsive to high-dose IL-2 administration, and except for patients with advanced non-Hodgkin’s lymphomas (35) only rare responses were seen in patients with other tumor types
  • The underlying toxicity of IL-2 results from a capillary leak that leads to fluid extravasation into visceral organs that can compromise their function
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    Great review of the history of IL-2 in the treatment of cancer.  IL-2 stimulates the immune system to attack cancer.  Don't reinvent the wheel; use what is already present and available.
Nathan Goodyear

Low testosterone elevates interleukin family cyto... [J Surg Res. 2014] - PubMed - NCBI - 0 views

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    low Testosterone associated with increased inflammatory cytokines in animal model.  The cytokines IL-2, IL-6, IL-10, Il-12, and IL-13 were specifically found to be elevated.  Translated, in animal model, low T equals increased inflammation.
Nathan Goodyear

Testosterone: a vascular hormone in health and disease - 0 views

  • Testosterone has beneficial effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation
  • In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart failure.
  • testosterone is an L-calcium channel blocker and induces potassium channel activation in vascular smooth muscle cells
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  • Animal studies have consistently demonstrated that testosterone is atheroprotective, whereas testosterone deficiency promotes the early stages of atherogenesis
  • there is no compelling evidence that testosterone replacement to levels within the normal healthy range contributes adversely to the pathogenesis of CVD (Carson & Rosano 2011) or prostate cancer (Morgentaler & Schulman 2009)
  • bidirectional effect between decreased testosterone concentrations and disease pathology exists as concomitant cardiovascular risk factors (including inflammation, obesity and insulin resistance) are known to reduce testosterone levels and that testosterone confers beneficial effects on these cardiovascular risk factors
  • Achieving a normal physiological testosterone concentration through the administration of testosterone replacement therapy (TRT) has been shown to improve risk factors for atherosclerosis including reducing central adiposity and insulin resistance and improving lipid profiles (in particular, lowering cholesterol), clotting and inflammatory profiles and vascular function
  • It is well known that impaired erectile function and CVD are closely related in that ED can be the first clinical manifestation of atherosclerosis often preceding a cardiovascular event by 3–5 years
  • no decrease in the response (i.e. no tachyphylaxis) of testosterone and that patient benefit persists in the long term.
  • free testosterone levels within the physiological range, has been shown to result in a marked increase in both flow- and nitroglycerin-mediated brachial artery vasodilation in men with CAD
  • Clinical studies, however, have revealed either small reductions of 2–3 mm in diastolic pressure or no significant effects when testosterone is replaced within normal physiological limits in humans
  • Endothelium-independent mechanisms of testosterone are considered to occur primarily via the inhibition of voltage-operated Ca2+ channels (VOCCs) and/or activation of K+ channels (KCs) on smooth muscle cells (SMCs)
  • Testosterone shares the same molecular binding site as nifedipine
  • Testosterone increases the expression of endothelial nitric oxide synthase (eNOS) and enhances nitric oxide (NO) production
  • Testosterone also inhibited the Ca2+ influx response to PGF2α
  • one of the major actions of testosterone is on NO and its signalling pathways
  • In addition to direct effects on NOS expression, testosterone may also affect phosphodiesterase type 5 (PDE5 (PDE5A)) gene expression, an enzyme controlling the degradation of cGMP, which acts as a vasodilatory second messenger
  • the significance of the action of testosterone on VSMC apoptosis and proliferation in atherosclerosis is difficult to delineate and may be dependent upon the stage of plaque development
  • Several human studies have shown that carotid IMT (CIMT) and aortic calcification negatively correlate with serum testosterone
  • t long-term testosterone treatment reduced CIMT in men with low testosterone levels and angina
  • neither intracellular nor membrane-associated ARs are required for the rapid vasodilator effect
  • acute responses appear to be AR independent, long-term AR-mediated effects on the vasculature have also been described, primarily in the context of vascular tone regulation via the modulation of gene transcription
  • Testosterone and DHT increased the expression of eNOS in HUVECs
  • oestrogens have been shown to activate eNOS and stimulate NO production in an ERα-dependent manner
  • Several studies, however, have demonstrated that the vasodilatory actions of testosterone are not reduced by aromatase inhibition
  • non-aromatisable DHT elicited similar vasodilation to testosterone treatment in arterial smooth muscle
  • increased endothelial NOS (eNOS) expression and phosphorylation were observed in testosterone- and DHT-treated human umbilical vein endothelial cells
  • Androgen deprivation leads to a reduction in neuronal NOS expression associated with a decrease of intracavernosal pressure in penile arteries during erection, an effect that is promptly reversed by androgen replacement therapy
  • Observational evidence suggests that several pro-inflammatory cytokines (including interleukin 1β (IL1β), IL6, tumour necrosis factor α (TNFα), and highly sensitive CRP) and serum testosterone levels are inversely associated in patients with CAD, T2DM and/or hypogonadism
  • patients with the highest IL1β concentrations had lower endogenous testosterone levels
  • TRT has been reported to significantly reduce TNFα and elevate the circulating anti-inflammatory IL10 in hypogonadal men with CVD
  • testosterone treatment to normalise levels in hypogonadal men with the MetS resulted in a significant reduction in the circulating CRP, IL1β and TNFα, with a trend towards lower IL6 compared with placebo
  • parenteral testosterone undecanoate, CRP decreased significantly in hypogonadal elderly men
  • Higher levels of serum adiponectin have been shown to lower cardiovascular risk
  • Research suggests that the expression of VCAM-1, as induced by pro-inflammatory cytokines such as TNFα or interferon γ (IFNγ (IFNG)) in endothelial cells, can be attenuated by treatment with testosterone
  • Testosterone also inhibits the production of pro-inflammatory cytokines such as IL6, IL1β and TNFα in a range of cell types including human endothelial cells
  • decreased inflammatory response to TNFα and lipopolysaccharide (LPS) in human endothelial cells when treated with DHT
  • The key to unravelling the link between testosterone and its role in atherosclerosis may lay in the understanding of testosterone signalling and the cross-talk between receptors and intracellular events that result in pro- and/or anti-inflammatory actions in athero-sensitive cells.
  • testosterone functions through the AR to modulate adhesion molecule expression
  • pre-treatment with DHT reduced the cytokine-stimulated inflammatory response
  • DHT inhibited NFκB activation
  • DHT could inhibit an LPS-induced upregulation of MCP1
  • Both NFκB and AR act at the transcriptional level and have been experimentally found to be antagonistic to each other
  • As the AR and NFκB are mutual antagonists, their interaction and influence on functions can be bidirectional, with inflammatory agents that activate NFκB interfering with normal androgen signalling as well as the AR interrupting NFκB inflammatory transcription
  • prolonged exposure of vascular cells to the inflammatory activation of NFκB associated with atherosclerosis may reduce or alter any potentially protective effects of testosterone
  • DHT and IFNγ also modulate each other's signalling through interaction at the transcriptional level, suggesting that androgens down-regulate IFN-induced genes
  • (Simoncini et al. 2000a,b). Norata et al. (2010) suggest that part of the testosterone-mediated atheroprotective effects could depend on ER activation mediated by the testosterone/DHT 3β-derivative, 3β-Adiol
  • TNFα-induced induction of ICAM-1, VCAM-1 and E-selectin as well as MCP1 and IL6 was significantly reduced by a pre-incubation with 3β-Adiol in HUVECs
  • 3β-Adiol also reduced LPS-induced gene expression of IL6, TNFα, cyclooxygenase 2 (COX2 (PTGS2)), CD40, CX3CR1, plasminogen activator inhibitor-1, MMP9, resistin, pentraxin-3 and MCP1 in the monocytic cell line U937 (Norata et al. 2010)
  • This study suggests that testosterone metabolites, other than those generated through aromatisation, could exert anti-inflammatory effects that are mediated by ER activation.
  • The authors suggest that DHT differentially effects COX2 levels under physiological and pathophysiological conditions in human coronary artery smooth muscle cells and via AR-dependent and -independent mechanisms influenced by the physiological state of the cell
  • There are, however, a number of systematic meta-analyses of clinical trials of TRT that have not demonstrated an increased risk of adverse cardiovascular events or mortality
  • The TOM trial, which was designed to investigate the effect of TRT on frailty in elderly men, was terminated prematurely as a result of an increased incidence of cardiovascular-related events after 6 months in the treatment arm
  • trials of TRT in men with either chronic stable angina or chronic cardiac failure have also found no increase in either cardiovascular events or mortality in studies up to 12 months
  • Evidence may therefore suggest that low testosterone levels and testosterone levels above the normal range have an adverse effect on CVD, whereas testosterone levels titrated to within the mid- to upper-normal range have at least a neutral effect or, taking into account the knowledge of the beneficial effects of testosterone on a series of cardiovascular risk factors, there may possibly be a cardioprotective action
  • The effect of testosterone on human vascular function is a complex issue and may be dependent upon the underlying androgen and/or disease status.
  • the majority of studies suggest that testosterone may display both acute and chronic vasodilatory effects upon various vascular beds at both physiological and supraphysiological concentrations and via endothelium-dependent and -independent mechanisms
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    Good deep look into the testosterone and CVD link.
Nathan Goodyear

Effect of a Mediterranean-Style Diet on Endothelial Dysfunction and Markers of Vascular... - 0 views

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    Mediterranean diet shown to reduce hs-CRP, IL-6, IL-7, IL-18, and decreases insulin resistance in those with metabolic syndrome
Nathan Goodyear

PLOS ONE: Probiotic Microbes Sustain Youthful Serum Testosterone Levels and Testicular ... - 0 views

  • Studies in both humans and rodents, however, suggest that low testosterone is due to age-related lesions in testes rather than irregular luteinizing hormone metabolism
  • Various dietary factors and diet-induced obesity have been shown to increase the risk for late onset male hypogonadism and low testosterone production in both humans and mice
  • Testosterone deficiency and metabolic diseases such as obesity appear to inter-digitate in complex cause-and-effect relationships
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  • dietary supplementation of aged mice with the probiotic bacterium Lactobacillus reuteri makes them appear to be younger than their matched untreated sibling mice
  • These results indicate that gut microbiota induce modulation of local gastrointestinal immunity resulting in systemic effects on the immune system which activate metabolic pathways that restore tissue homeostasis and overall health
  • all these studies we consistently observed that young and aged mice consuming purified L. reuteri organisms had particularly large testes and a dominant male behavior.
  • The testes of probiotic-fed aged mice were rescued from both seminiferous tubule atrophy and interstitial Leydig cell area reduction typical of the normal aging process. Preservation of testicular architecture despite advanced age or high-fat diet coincided with remarkably high levels of circulating testosterone. The beneficial effects of probiotic consumption were recapitulated by the depletion of the pro-inflammatory cytokine Il-17.
  • feeding of L. reuteri consistently increased the gonadal weights, consumption of a non-pathogenic strain of Escherichia coli (E. coli) K12 organisms did not affect testicular weight
  • mice with dietary L. reuteri supplements were rescued from diet-induced obesity and had normal body weight and lean physique
  • Despite the comparable numbers of ST profiles, we determined that testes from L. reuteri-treated mice had increased ST cross-sectioned profiles
  • the probiotic organism induced prominent Leydig cell accumulations in the interstitial tissue between the ST's
  • The probiotic-associated increase of interstitial Leydig cell areas was sustained with advancing age at 7 (CD vs CD+LR, P = 0.0025; CD+E.coli vs CD+LR, P = 0.0251) and 12 months
  • mice eating L. reuteri had profoundly increased levels of circulating testosterone regardless of the type of diet they consumed
  • blocking pro-inflammatory Il-17 signaling entirely recapitulates the beneficial effects of probiotics
  • previous studies we found that dietary probiotics counteract obesity [19] and age-related integumentary pathology [18] at least in part by down-regulating systemic pro-inflammatory IL-17A-dependent signaling
  • Testes histomorphometry and serum androgen concentration data were both suggestive of a probiotic-associated up-regulation of spermatogenesis in mice
  • Lactobacillus reuteri we discovered that aging male animals had larger testes compared to their age-matched controls
  • xamined testes of probiotic microbe-fed mice and found that they had less testicular atrophy coinciding with higher levels of circulating testosterone compared to their age-matched controls
  • Similar testicular health benefits were produced using systemic depletion of the pro-inflammatory cytokine Il-17 alone, implicating a chronic inflammatory pathway in hypogonadism
  • One specific aspect of this paradigm is reciprocal activities of pro-inflammatory Th-17 and anti-inflammatory Treg cells
  • Feeding of L. reuteri organisms was previously shown to up-regulate IL-10 levels and reduce levels of IL-17 [19] serving to lower systemic inflammation
  • insufficient levels of IL-10 may increase the risk for autoimmunity, obesity, and other inflammatory disease syndromes
  • Westernized diets are also low in vitamin D, a nutrient that when present normally works together with IL-10 to protect against inflammatory disorders
  • Physiological feedback loops apparently exist between microbes, host hormones, and immunity
  • The hormone testosterone has been shown to act directly through androgen receptors on CD4+ cells to increase IL-10 expression
  • studies in both humans and rodents suggest that hypogonadism is due to age-related lesions in testes rather than irregular LH metabolism
  • We postulate that probiotic gut microbes function symbiotically with their mammalian hosts to impart immune homeostasis to maintain systemic and testicular health [34]–[35] despite suboptimal dietary conditions.
  • Dietary factors and diet-induced obesity were previously shown to increase risk for age-associated male hypogonadism, reduced spermatogenesis, and low testosterone production in both humans and mice [2]–[4], [8]–[11], [14]–[17], phenotypic features that in this study were inhibited by oral probiotic therapy absent milk sugars, extra protein, or vitamin D supplied in yogurt.
  • Similar beneficial effects of probiotic microbes on testosterone levels and sperm indices were reported in male mice that had been simultaneously supplemented with selenium
  • L. reuteri-associated prevention of age- and diet-related testicular atrophy correlates with increased numbers and size of Leydig cells
  • the initial changes of testicular atrophy begin to occur in mice from the age of 6 moths onwards [7] and indicates that the trophic effect of L. reuteri on Leydig cells is a key event which precedes and prevents age-related changes in the testes of mice. This effect is reminiscent of earlier studies describing Leydig cell hyperplasia and/or hypertrophy in the mouse and the rat testis that were achievable by the administration of gonadotropins, including human chorionic gonadotropin, FSH and LH
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    Fascinating study on how the addition of Lactobacillus reuteri increased Testicular size, prevented testicular atrophy, increased serum Testosterone production and protected against diet-induced/obesity-induced hypogonadism.  This was a mouse model
Nathan Goodyear

Cutting Edge: IL-12 Induces CD4+CD25− T Cell Activation in the Presence of T ... - 0 views

  • Whereas IL-12 instigates Th1 immune responses, CD4+CD25+ regulatory T cells (Treg)3 actively restrain them
  • Following engagement of their TCR, Treg suppress the proliferation of conventional CD4+CD25− T responder cells in vitro
  • Furthermore, they inhibit the development of CD4+ T cell responses against alloantigens, tumor, microbial, and self-Ags in vivo.
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  • Treg act to prevent spontaneous autoimmunity and to limit collateral damage to healthy tissues during adaptive immunity. However, these cells also have the potential to sabotage protective antimicrobial responses
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    Great T cell activiation review: Il-2 stimulates NK cells primarily release from TH1 cells and T cytotoxic lymphocytes are under the control of IL-12 released primarily from dendritic cells.  Inflammatory cytokines in the presence of Treg to stimulate CD4+CD25- T cell activation.
Nathan Goodyear

PLOS ONE: Microbial Dysbiosis in Colorectal Cancer (CRC) Patients - 0 views

  • differences in the colon microbiota in individuals with colon cancer versus those with a normal colonoscopy
  • qPCR revealed significant elevation of the Bacteroides/Prevotella population in cancer patients that appeared to be linked with elevated IL17 producing cells in the mucosa of individuals with cancer.
  • Bacteroides genus populations and more specifically those of Bacteroides fragilis, have recently been shown to produce a metalloprotease in colon cancer patients, but not in controls [12] suggesting this species sub population might favor carcinogenesis
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  • It is noteworthy that among the many mechanisms that may mediate associations between microbiota and human health [21]–[22], pro-inflammatory and immune cell activation in colon mucosa are of great importance in relation to malignancy
  • B. fragilis has been shown to induce mucosal regulatory T-cell responses in the intestine involving TH17 cell recruitment in experimental models
  • the elevations of Bacteroides in the stool and/or IL17 immunoreactive cells in the normal mucosa appear to be promising sensitive markers
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    A relationship between dysbiosis and colon cancer appears to be present.  Particularly an increase in Bacteroidetes and Prevotella species were found in those with colon cancer versus those without.  An inflammatory up regulation of IL-17 appears to be involved.  Whether this is a cause or effect is yet to be determined, but the presence of elevated Bacteroidetes species with increased IL17 could be used as sensitive biomarkers.
Nathan Goodyear

The psychoneuroendocrine-immunotherapy of cancer: Historical evolution and clinical res... - 0 views

  • It is known that immune system-induced destruction of cancer cells is mainly mediated by T cytotoxic lymphocytes (CD8+) and NK cells (CD16+), respectively, through an antigen-specific and an antigen nonspecific cytotoxicity
  • NK cells are mainly stimulated by IL-2 released by T helper-1 (TH1) lymphocytes (CD4+) while T cytotoxic lymphocytes (CD8+) are namely under a stimulatory control released by IL-12 produced by the dendritic cells
  • On the other hand, the anticancer immunity is inhibited by the activation of the macrophage system through the production of suppressive cytokines, such as IL-6 and T regulatory (T reg) lymphocytes (CD4+CD25+), which counteract the anticancer immunity by producing immunosuppressive cytokines inhibiting the secretion of both IL-2 and IL-12, including TGF-beta and IL-10, or by a direct cell-cell contact
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    to be read review of melatonin in cancer treatment.
Nathan Goodyear

Immune Modulation in Multiple Sclerosis Patients Treated with the Pregnancy Hormone Est... - 0 views

  • A beneficial effect of pregnancy on clinical symptoms has been observed in MS and other Th1-mediated autoimmune diseases, including rheumatoid arthritis (RA), psoriasis, uveitis, and thyroiditis
  • In general, Th1 lymphocytes secrete proinflammatory cytokines (e.g., IL-2, IL-12, IFN-γ, and TNF-α) that promote cellular immunity, while Th2 lymphocytes produce anti-inflammatory cytokines (e.g., IL-4, IL-5, IL-6, and IL-10) that promote humoral immunity
  • Th2 cytokines are associated with the down-regulation of Th1 cytokines and may confer protection from Th1-mediated autoimmune diseases
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  • During pregnancy, there is a shift from Th1 to Th2 that occurs both locally, at the fetal maternal interface, (23, 24, 25), and systemically
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    MS is in part a Th1 autoimmune disease.  Estriol therapy induces a shift to Th2 through increase in Th10.  Estriol also decreases TNF-alpha cytokine production.
Nathan Goodyear

Interleukin-2 enhances the response of natural killer cells to interleukin-12 through u... - 1 views

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    low dose IL-2 induces increase NK cell activity.
Nathan Goodyear

Testosterone: a metabolic hormone in health and disease - 0 views

  • E2 and the inflammatory adipocytokines tumour necrosis factor α (TNFα) and interleukin 6 (IL6) inhibit hypothalamic production of GNRH and subsequent release of LH and FSH from the pituitary
  • Leptin, an adipose-derived hormone with a well-known role in regulation of body weight and food intake, also induces LH release under normal conditions via stimulation of hypothalamic GNRH neurons
  • In human obesity, whereby adipocytes are producing elevated amounts of leptin, the hypothalamic–pituitary axis becomes leptin resistant
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  • there is evidence from animal studies that leptin resistance, inflammation and oestrogens inhibit neuronal release of kisspeptin
  • Beyond hypothalamic action, leptin also directly inhibits the stimulatory action of gonadotrophins on the Leydig cells of the testis to decrease testosterone production; therefore, elevated leptin levels in obesity may further diminish androgen status
  • increasing insulin resistance assessed by glucose tolerence test and hypoglycemic clamp was shown to be associated with a decrease in Leydig cell testosterone secretion in men
  • ADT for the treatment of prostatic carcinoma in some large epidemiological studies has been shown to be associated with an increased risk of developing MetS and T2DM
  • Non-diabetic men undergoing androgen ablation show increased occurrence of new-onset diabetes and demonstrate elevated insulin levels and worsening glycaemic control
  • Prostate cancer patients with pre-existing T2DM show a further deterioration of insulin resistance and worsening of diabetic control following ADT
  • The response to testosterone replacement of insulin sensitivity is in part dependent on the androgen receptor (AR)
  • Low levels of testosterone have been associated with an atherogenic lipoprotein profile, characterised by high LDL and triglyceride levels
  • a positive correlation between serum testosterone and HDL has been reported in both healthy and diabetic men
  • up to 70% of the body's insulin sensitivity is accounted for by muscle
  • Testosterone deficiency is associated with a decrease in lean body mass
  • relative muscle mass is inversely associated with insulin resistance and pre-diabetes
  • GLUT4 and IRS1 were up-regulated in cultured adipocytes and skeletal muscle cells following testosterone treatment at low dose and short-time incubations
  • local conversion of testosterone to DHT and activation of AR may be important for glucose uptake
  • inverse correlation between testosterone levels and adverse mitochondrial function
  • orchidectomy of male Wistar rats and associated testosterone deficiency induced increased absorption of glucose from the intestine
  • (Kelley & Mandarino 2000). Frederiksen et al. (2012a) recently demonstrated that testosterone may influence components of metabolic flexibility as 6 months of transdermal testosterone treatment in aging men with low–normal bioavailable testosterone levels increased lipid oxidation and decreased glucose oxidation during the fasting state.
  • Decreased lipid oxidation coupled with diet-induced chronic FA elevation is linked to increased accumulation of myocellular lipid, in particular diacylglycerol and/or ceramide in myocytes
  • In the Chang human adult liver cell line, insulin receptor mRNA expression was significantly increased following exposure to testosterone
  • Testosterone deprivation via castration of male rats led to decreased expression of Glut4 in liver tissue, as well as adipose and muscle
  • oestrogen was found to increase the expression of insulin receptors in insulin-resistant HepG2 human liver cell line
  • FFA decrease hepatic insulin binding and extraction, increase hepatic gluconeogenesis and increase hepatic insulin resistance.
  • Only one, albeit large-scale, population-based cross-sectional study reports an association between low serum testosterone concentrations and hepatic steatosis in men (Völzke et al. 2010)
  • This suggests that testosterone may confer some of its beneficial effects on hepatic lipid metabolism via conversion to E2 and subsequent activation of ERα.
  • hypogonadal men exhibiting a reduced lean body mass and an increased fat mass, abdominal or central obesity
  • visceral adipose tissue was inversely correlated with bioavailable testosterone
  • there was no change in visceral fat mass in aged men with low testosterone levels following 6 months of transdermal TRT, yet subcutaneous fat mass was significantly reduced in both the thigh and the abdominal areas when analysed by MRI (Frederiksen et al. 2012b)
  • ADT of prostate cancer patients increased both visceral and subcutaneous abdominal fat in a 12-month prospective observational study (Hamilton et al. 2011)
  • Catecholamines are the major lipolysis regulating hormones in man and regulate adipocyte lipolysis through activation of adenylate cyclase to produce cAMP
  • deficiency of androgen action decreases lipolysis and is primarily responsible for the induction of obesity (Yanase et al. 2008)
  • may be some regional differences in the action of testosterone on subcutaneous and visceral adipose function
  • proinflammatory adipocytokines IL1, IL6 and TNFα are increased in obesity with a downstream effect that stimulates liver production of CRP
  • observational evidence suggests that IL1β, IL6, TNFα and CRP are inversely associated with serum testosterone levels in patients
  • TRT has been reported to significantly reduce these proinflammatory mediators
  • This suggests a role for AR in the metabolic actions of testosterone on fat accumulation and adipose tissue inflammatory response
  • testosterone treatment may have beneficial effects on preventing the pathogenesis of obesity by inhibiting adipogenesis, decreasing triglyceride uptake and storage, increasing lipolysis, influencing lipoprotein content and function and may directly reduce fat mass and increase muscle mass
  • Early interventional studies suggest that TRT in hypogonadal men with T2DM and/or MetS has beneficial effects on lipids, adiposity and parameters of insulin sensitivity and glucose control
  • Evidence that whole-body insulin sensitivity is reduced in testosterone deficiency and increases with testosterone replacement supports a key role of this hormone in glucose and lipid metabolism
  • Impaired insulin sensitivity in these three tissues is characterised by defects in insulin-stimulated glucose transport activity, in particular into skeletal muscle, impaired insulin-mediated inhibition of hepatic glucose production and stimulation of glycogen synthesis in liver, and a reduced ability of insulin to inhibit lipolysis in adipose tissue
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    Great review of the Hypogonadal-obesity-adipocytokine hypothesis.
Nathan Goodyear

Cortisol Exerts Bi-Phasic Regulation of Inflammation in Humans - 0 views

  • GCs induce increased cellular expression of receptors for several pro-inflammatory cytokines including interleukin (IL)-1 (Spriggs et al. 1990), IL-2 (Wiegers et al. 1995), IL-4 (Paterson et al. 1994), IL-6 (Snyers et al. 1990), and IFN-g (Strickland et al. 1986), as well as GM-CSF
  • GCs have also been shown to stimulate effector cell functions including phagocytosis by monocytes (van der Goes et al. 2000), effector cell proliferative responses (Spriggs et al. 1990), macrophage activation (Sorrells and Sapolsky 2010), and a delay of neutrophil apoptosis
  • a concentration- and time-dependent range of GC effects that are both pro- and anti-inflammatory
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  • basal (diurnal) concentrations of cortisol do not exert an anti-inflammatory effect on several pro-and anti-inflammatory mediators of the human immune inflammatory response
  • withdrawal of cortisol activity in vivo did not lead to increased inflammatory responsiveness of immune effector cells
  • maximal suppression of inflammation was achieved by a stress-associated, but still physiologic, cortisol concentration. There was no greater anti-inflammatory effect at higher cortisol concentrations (Yeager et al. 2005) although IL-10 concentrations continued to increase with increasing cortisol concentrations as we and others have shown
  • acutely, physiological cortisol concentrations are anti-inflammatory and, as proposed, act to limit over expression of an inflammatory response that could lead to tissue damage
  • Acutely, cortisol has anti-inflammatory effects following a systemic inflammatory stimulus (Figure 4). However, a cortisol concentration that acts acutely to suppress systemic inflammation also has a delayed effect of augmenting the inflammatory response to subsequent, delayed stimulu
  • 1) GCs can exert pro-inflammatory effects on key inflammatory processes and, 2) GC regulation of inflammation can vary from anti- to a pro-inflammatory in a time-dependent manner
  • The immediate in vivo effect of both stress-induced and pharmacological GC concentrations is to suppress concurrent inflammation and protect the organism from an excessive or prolonged inflammatory response
  • GCs alone, in the absence of an inflammatory stimulus, up-regulate monocyte mRNA and/or receptors for several molecules that participate in pro-inflammatory signaling, as noted above and in the studies presented here.
  • In humans, as shown here, if in vivo GC concentrations are elevated concurrent with an inflammatory stimulus, anti-inflammatory effects are observed
  • In sharp contrast, with a time delay of 12 or more hours between an increased GC concentration and the onset of an inflammatory stimulus, enhancing effects on inflammation are observed. These effects have been shown to persist in humans for up to 6 days
  • GC-induced enhancement of inflammatory responses is maximal at an intermediate concentration, in our studies at a concentration that approximates that observed in vivo following a major systemic inflammatory stimulus
  • In addition to enhanced responses to LPS, recently identified pro-inflammatory effects of GCs also show enhanced localization of effector cells at inflammatory sites
  • we hypothesize that pre-exposure to stress-associated cortisol concentrations “prime” effector cells of the monocyte/macrophage lineage for an augmented pro-inflammatory response by; a) inducing preparative changes in key regulators of LPS signal transduction, and b) enhancing localization of inflammatory effector cells at potential sites of injury
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    very interesting read on the effects of inflammation on cortisol and visa versa.
Nathan Goodyear

EVALUATION OF AN ASSOCIATION BETWEEN GASTROINTESTINAL SYMPTOMS AND CYTOKINE PRODUCTION ... - 0 views

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    Food sensitivities found to play a role in elevated TNF-alpha and IL-12 in children with autism.
Nathan Goodyear

Enhancement of cytotoxicity of NK cells by D-Fraction, a polysaccharide from Grifola fr... - 0 views

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    The D-Fraction from maitake mushrooms enhanced the cytotoxicity from NK cells through IL-12 signaling.
Nathan Goodyear

https://www.researchgate.net/publication/12392637_A_phase_II_study_of_neuroimmunotherap... - 0 views

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    only abstract available here, but 20 mg melatonin plus 4 weeks of low-dose IL-2 found to provide partial response in 1 patient and stable disease in 7 other patients in 12 patients with untreatable, advanced hematologic cancers.
Nathan Goodyear

Administration of Dehydroepiandrosterone Suppresses Experimental Allergic Encephalomyel... - 0 views

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    DHEA found to decrease IFN-gamma, IL-12, and TNF-alpha through inhibition of NF-kappaB in animal model of MS.
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