The Effects of Oral Administration of Molybdenum Fertilizers on Immune Function of Nanjiang Brown Goat Grazing on Natural Pastures Contaminated by Mixed Heavy Metal

Abstract Abstract 1727 Genetic ablation of Syk in hematopoietic cells blocks various leukocyte immune functions, and protects mice from immune-complex mediated inflammation. These data have helped to identify Syk as an important therapeutic target for immune-mediated diseases. The next step is to test the hypothesis that low level, and specific, pharmacological inhibition of Syk retains the immunomodulatory potential observed with Syk genetic deficiency. With this goal in mind, we provide an update on the development of P505-15, a highly specific and potent small molecule Syk inhibitor which suppresses signaling and activation of primary human and rodent leukocyte immune function. The specificity of P505-15 was tested in a panel of 270 independent purified kinase assays at 300nM. At this concentration, Syk and 8 other kinases were inhibited by ≥ 80%. Subsequent analysis demonstrated a Syk IC50 of 1nM, whereas the next most potently inhibited kinase required an IC50 of 81nM. In a variety of cellular assays we observed potent inhibition of B cell receptor (BCR) induced Syk signaling, but not of Lyn, phorbol 12-myristate 13-acetate (PMA) induced protein kinase C, T cell receptor induced Zap70, or cytokine induced JAK1 (IL6), JAK2 (GM-CSF), or JAK1/3 (IL4) dependent STAT phosphorylation. Consistently, in Ba/F3 cell lines transformed by various kinases, P505-15 only inhibited proliferation of those cells transformed by Syk (IC50 = 0.12μM), and not by Zap70 or JAK family members (IC50 > 6μM). In human whole blood, P505-15 suppressed BCR-induced Syk signaling and cellular activation with IC50's of 0.383μM and 0.362μM, respectively. FceR1-induced basophil degranulation was similarly suppressed with an IC50 of 0.171μM. Importantly, Syk-independent signaling and cellular activation in human whole blood via PMA (B cell assays) or fMLP (basophil degranulation) was unaffected by this compound at 4μM and 1μM, respectively (the highest concentrations tested), again demonstrating its specificity of action. Oral administration of P505-15 in mice led to a reversible inhibition of Syk, with an IC50 of 0.282μM as determined by an ex vivo whole blood BCR stimulation assay. Finally, we tested the immunomodulatory potential of specific Syk inhibition in vivo using rodent models of rheumatoid arthritis. Oral administration of P505-15 resulted in statistically significant and dose-dependent anti-inflammatory activity in both the mouse collagen antibody-induced arthritis and rat collagen induced arthritis models. In each case, anti-inflammatory effects were achieved at sub-micromolar plasma concentrations in which Syk specificity was maintained. These data support the hypothesis that specific Syk inhibition can modulate immune function in vivo, and provide a therapeutic strategy for the treatment of human inflammatory disease by inhibition of this kinase. P505-15 is currently being evaluated in phase I clinical trials. Disclosures: Coffey: Portola Pharmaceuticals: Employment. Francis:Portola Pharmaceuticals: Employment. Inagaki:Portola Pharmaceuticals: Employment. Pak:Portola Pharmaceuticals: Employment. Delaney:Portola Pharmaceuticals: Employment. Betz:Portola Pharmaceuticals: Employment. Jia:Portola Pharmaceuticals: Employment. Xu:Portola Pharmaceuticals: Employment. Bauer:Portola Pharmaceuticals: Employment. Song:Portola Pharmaceuticals: Employment. Pandey:Portola Pharmaceuticals: Employment. Baker:Portola Pharmaceuticals: Employment. Hollenbach:Portola Pharmaceuticals: Employment. Phillips:Portola Pharmaceuticals: Employment. Sinha:Portola Pharmaceuticals: Employment.

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ChemInform Abstract: A NOVEL APPROACH FOR HEAVY METAL POISONING TREATMENT, A MODEL. MERCURY POISONING BY MEANS OF CHELATING MICROSPHERES: HEMOPERFUSION AND ORAL ADMINISTRATION

Chemischer Informationsdienst ◽

10.1002/chin.198211156 ◽

1982 ◽

Vol 13 (11) ◽

Author(s):

S. MARGEL

Keyword(s):

Heavy Metal ◽

Oral Administration ◽

Mercury Poisoning ◽

Heavy Metal Poisoning ◽

Novel Approach ◽

Metal Poisoning

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Effect of chitosan on blood profile, inflammatory cytokines by activating TLR4/NF-κB signaling pathway in intestine of heat stressed mice

Scientific Reports ◽

10.1038/s41598-021-98931-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sahar Ghulam Mohyuddin ◽

Aftab Qamar ◽

Can-ying Hu ◽

Sheng-Wei Chen ◽

Jia-ying Wen ◽

...

Keyword(s):

Heat Stress ◽

Oral Administration ◽

Immune Function ◽

Control Group ◽

Mrna Levels ◽

Protective Effects ◽

Blood Profile ◽

Stress Group ◽

Tnf Α ◽

Body Heat

AbstractHeat stress can significantly affect the immune function of the animal body. Heat stress stimulates oxidative stress in intestinal tissue and suppresses the immune responses of mice. The protecting effects of chitosan on heat stress induced colitis have not been reported. Therefore, the aim of this study was to investigate the protective effects of chitosan on immune function in heat stressed mice. Mice were exposed to heat stress (40 °C per day for 4 h) for 14 consecutive days. The mice (C57BL/6J), were randomly divided into three groups including: control group, heat stress, Chitosan group (LD: group 300 mg/kg/day, MD: 600 mg/kg/day, HD: 1000 mg/kg/day). The results showed that tissue histology was improved in chitosan groups than heat stress group. The current study showed that the mice with oral administration of chitosan groups had improved body performance as compared with the heat stress group. The results also showed that in chitosan treated groups the production of HSP70, TLR4, p65, TNF-α, and IL-10 was suppressed on day 1, 7, and 14 as compared to the heat stress group. In addition Claudin-2, and Occludin mRNA levels were upregulated in mice receiving chitosan on day 1, 7, and 14 of heat stress. Furthermore, the IL-6, IL-10, and TNF-α plasma levels were down-regulated on day 1, 7, and 14 of heat stress in mice receiving the oral administration of chitosan. In conclusion, the results showed that chitosan has an anti-inflammatory ability to tolerate hot environmental conditions.

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Effect of short‐term oral administration of acephate on immune function in mice

The FASEB Journal ◽

10.1096/fasebj.2019.33.1_supplement.542.12 ◽

2019 ◽

Vol 33 (S1) ◽

Author(s):

Yuan‐Ru Chen ◽

Fang‐Yen Chiu ◽

Hsin‐En Wu ◽

Yi‐Xin Lai ◽

Chia‐Yang Li

Keyword(s):

Oral Administration ◽

Immune Function ◽

Short Term

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Oral Administration of Probiotics Inhibits Absorption of the Heavy Metal Cadmium by Protecting the Intestinal Barrier

Applied and Environmental Microbiology ◽

10.1128/aem.00695-16 ◽

2016 ◽

Vol 82 (14) ◽

pp. 4429-4440 ◽

Cited By ~ 62

Author(s):

Qixiao Zhai ◽

Fengwei Tian ◽

Jianxin Zhao ◽

Hao Zhang ◽

Arjan Narbad ◽

...

Keyword(s):

Heavy Metal ◽

Oral Administration ◽

Tight Junctions ◽

Health Effects ◽

Intestinal Barrier ◽

Environmental Pollutant ◽

Content Type ◽

Adverse Health Effects ◽

Adverse Health ◽

Cd Exposure

ABSTRACTThe heavy metal cadmium (Cd) is an environmental pollutant that causes adverse health effects in humans and animals. Our previous work demonstrated that oral administration of probiotics can significantly inhibit Cd absorption in the intestines of mice, but further evidence is needed to gain insights into the related protection mode. The goal of this study was to evaluate whether probiotics can inhibit Cd absorption through routes other than the Cd binding, with a focus on gut barrier protection. In thein vitroassay, both the intervention and therapy treatments ofLactobacillus plantarumCCFM8610 alleviated Cd-induced cytotoxicity in the human intestinal cell line HT-29 and protected the disruption of tight junctions in the cell monolayers. In a mouse model, probiotics with either good Cd-binding or antioxidative ability increased fecal Cd levels and decreased Cd accumulation in the tissue of Cd-exposed mice. Compared with the Cd-only group, cotreatment with probiotics also reversed the disruption of tight junctions, alleviated inflammation, and decreased the intestinal permeability of mice.L. plantarumCCFM8610, a strain with both good Cd binding and antioxidative abilities, exhibited significantly better protection than the other two strains. These results suggest that along with initial intestinal Cd sequestration, probiotics can inhibit Cd absorption by protecting the intestinal barrier, and the protection is related to the alleviation of Cd-induced oxidative stress. A probiotic with both good Cd-binding and antioxidative capacities can be used as a daily supplement for the prevention of oral Cd exposure.IMPORTANCEThe heavy metal cadmium (Cd) is an environmental pollutant that causes adverse health effects in humans and animals. For the general population, food and drinking water are the main sources of Cd exposure due to the biomagnification of Cd within the food chain; therefore, the intestinal tract is the first organ that is susceptible to Cd contamination. Moreover, Cd exposure causes the disruption of the intestinal barrier and further induces the amplification of Cd absorption. The present study confirms that, along with initial intestinal Cd sequestration, oral administration of probiotics can inhibit Cd absorption by protecting the intestinal barrier. A probiotic with both good Cd-binding and antioxidative capacities can be used as a daily supplement for the prevention of oral Cd exposure.

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Heat stress inhibits TLR4-NF-κB and TLR4-TBK1 signaling pathways in broilers infected with Salmonella Typhimurium

International Journal of Biometeorology ◽

10.1007/s00484-021-02146-5 ◽

2021 ◽

Author(s):

Wei-Hao Li ◽

Yi-Lei Liu ◽

Jian-Chi Lun ◽

Yong-Ming He ◽

Lu-Ping Tang

Keyword(s):

Immune Response ◽

Global Warming ◽

Heat Stress ◽

Oral Administration ◽

Salmonella Typhimurium ◽

Immune Function ◽

Signaling Pathways ◽

Production Performance ◽

Tnf Α ◽

Ifn Γ

AbstractWith the global warming, the harm of heat stress (HS) to the breeding industry has become more common, which causes the decline of animal production performance and low immunity. This study aimed to analyze the effect of HS on the intestinal immune function of Salmonella-infected chickens. Fourteen-day-old broilers were divided into the following four groups of eight replicates: control (Control), heat stress (HS), Salmonella Typhimurium (ST), and heat stress + Salmonella Typhimurium (HS+ST). The broilers were subjected to a heat stress of 35 °C from 15 to 28 days of age. Salmonella Typhimurium (ST, 14028, 109 cfu/mL) was inoculated, via oral administration at 29 days of age, into ST and HS+ST group birds. On the 4th day after Salmonella Typhimurium administration, an increase in jejunum IgA levels was observed in chickens infected with Salmonella Typhimurium. Mechanistic regulation of TLR4-NFκB-NLRP3 and TLR4-TBK1 signaling by heat stress was evaluated in Salmonella Typhimurium–infected broilers. Heat stress markedly inhibited the expression of cytokines including TNF-α, IL-6, IL-1β, NLRP3, caspase-1, NF-κB-p65, and p-NF-κB-p65, and the TLR4-TBK1 cytokines IFN-α, IFN-γ, p-IRF3, and p-TBK1 in jejunum of broilers infected with Salmonella Typhimurium. Collectively, our results demonstrate that heat stress can inhibit intestinal immune response by downregulating the expression of TLR4-NFκB-NLRP3 and TLR4-TBK1 signaling pathways in broilers infected with Salmonella Typhimurium.

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Complex dietary-polysaccharide modulates gut immune function and microbiota, and promotes protection from autoimmune diabetes

10.1101/492637 ◽

2018 ◽

Cited By ~ 1

Author(s):

Radhika Gudi ◽

Nicolas Perez ◽

Benjamin M. Johnson ◽

M.Hanief Sofi ◽

Robert Brown ◽

...

Keyword(s):

Oral Administration ◽

Immune Function ◽

Ex Vivo ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Prolonged Treatment ◽

Gut Mucosa ◽

The Impact ◽

Pro Inflammatory Cytokines

ABSTRACTSince the dietary supplement and prebiotic value of β-glucan-rich products have been widely recognized and the dietary approaches for modulating autoimmunity have been increasingly explored, we assessed the impact of oral administration of high-pure yeast β-glucan (YBG) on gut immune function, microbiota and type 1 diabetes (T1D) using mouse models. Oral administration of this non-digestible complex polysaccharide caused a Dectin-1-dependent immune response involving increased expression of IL10, retinaldehyde dehydrogenase (Raldh) and pro-inflammatory cytokines in the gut mucosa. YBG-exposed intestinal DCs induced/expanded primarily Foxp3+, IL10+ and IL17+ T cells, ex vivo. Importantly, prolonged oral administration of low-dose YBG at pre-diabetic stage suppressed insulitis and significantly delayed the T1D incidence in non-obese diabetic (NOD) mice. Further, prolonged treatment with YBG showed increased Foxp3+ T cell frequencies, and a significant change in the gut microbiota, particularly an increase in the abundance of Bacteroidetes and a decrease in the Firmicute members. Oral administration of YBG, together with Raldh-substrate and β-cell antigen, resulted in a better protection of NOD mice from T1D. These observations suggest that YBG not only has a prebiotic property, but also has an oral tolerogenic-adjuvant-like effect, and these features could be exploited for modulating autoimmunity in T1D.

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