A series of novel, saccharin-based antagonists have been identified for the interferon signaling pathway. Through in vitro high-throughput screening with the Colorado Center for Drug Discovery (C2D2) Pilot Library, we identified hit compound 1, which was the basis for extensive structure–activity relationship studies. Our efforts produced a lead anti-inflammatory compound, tert-butyl N-(furan-2-ylmethyl)-N-{4-[(1,1,3-trioxo-2,3-dihydro-1λ6,2-benzothiazol-2-yl)methyl]benzoyl}carbamate CU-CPD103 (103), as a potent inhibitor using an established nitric oxide (NO) signaling assay. With further studies of its inhibitory mechanisms, we demonstrated that 103 carries out this inhibition through the JAK/STAT1 pathway, providing a drug-like small molecule inflammation suppressant for possible therapeutic uses.

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The objectives of this study were to determine whether plane of nutrition (PON) of milk replacer previously provided to calves, and dosage level of Mannheimia haemolytica (MH), influenced inflammatory responses to a combined viral-bacterial respiratory challenge. Holstein calves (1 d of age; n = 30) were assigned to treatments in a 2 × 3 factorial with preweaning PON and MH dose as main effects (n = 5 per treatment). Calves were fed either a low (LPN; n = 15) or a high PON (HPN; n = 15) from birth through weaning. Calves fed LPN were fed 436 g of dry matter (DM) per day of milk replacer until weaning, and HPN calves were fed 797 g of DM per day of milk replacer from d 1 to 10 and 1,080 g of DM per day from d 11 until weaning. Calf starter and water were offered ad libitum. Calves were step-down weaned beginning at d 54 and moved into an enclosed barn at d 70. Indwelling rectal temperature (RT) recording devices and jugular catheters were inserted at d 80. Calves were challenged with 1.5 × 10 8 plaque-forming units (pfu) per mL of bovine herpesvirus-1 (BHV-1) in each nostril at d 81 and with either 10 6 , 10 7 , or 10 8 cfu of MH at d 84. Blood samples were collected at varying intervals relative to BHV-1 and MH challenges. Four LPN calves either died or were euthanized soon after the 144-h observation period, whereas all HPN calves survived the entire observation period. As dosage of MH administered increased, acute and systemic inflammatory responses increased. Higher doses of MH resulted in increased leukocyte, neutrophil, and haptoglobin concentrations in infected calves. Data from the current study suggest that the highest dose, 10 8 cfu, triggered weaned calves' acute disease response, whereas the lower doses, 10 6 and 10 7 cfu, caused more moderate inflammation and disease. The effects of PON on inflammation responses to the disease challenge indicated that calves previously fed the LPN diet had more severe pathophysiological responses. Calves fed LPN showed higher peripheral neutrophil and leukocyte counts and serum haptoglobin concentrations following the BHV-1 challenge. Additionally, following the MH challenge, LPN calves had higher peripheral neutrophil counts, neutrophil-tolymphocyte ratios, and serum tumor necrosis factor-α concentrations. These data demonstrate that higher doses of MH increase the acute inflammatory response and prolong inflammation, and that calves previously fed LPN responded more severely to the combined viral-bacterial respiratory challenge.

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The objective of this study was to determine the effects of supplementing a commercial porous ceramic clay particle, with or without a blend of preservatives, on the performance and nutrient digestibility of weanling pigs. Fifteen weanling pigs of the Yorkshire, Landrace, and Duroc breeds were blocked by breed and randomly assigned to one of three treatments (n = 5): (1) Control, non-medicated diet with no additional feed additives (CON); (2) PowerGuard, basal diet with 0.25% of the DM consisting of a ceramic particle mixed into the pelleted feed (PG; MB Nutritional Sciences, Lubbock, TX, 79403); or (3) Power Guard + a blend of preservatives, basal diet with 0.3% of the DM consisting of the ceramic clay and preservatives mixed into the pelleted feed (PG-D). The facility was temperature controlled with an average temperature of 28.5 °C. Pigs were offered ad libitum access to feed and water and were housed individually in elevated crates. Body weights were collected upon enrollment on day 0 and at the end of the observation period on day 18. On day 15 , a 72-h total feed and fecal collection period began. Feed and fecal samples were analyzed for DM, CP, Ash, OM, ADF, NDF, zinc, copper, thiamin (vitamin B1), and retinol (vitamin A). Liver samples were collected immediately after harvest and frozen for later mineral analysis. Data were analyzed using Proc Mixed in SAS with dietary group as the main effect and block as the random effect (SAS 9.4, Cary, NC). There were no treatment differences in performance measures including final BW, ADG, or G:F (P ≥ 0.701). There were no treatment differences in diet nutrient digestibility for DM, CP, Ash, OM, ADF, or NDF (P ≥ 0.312). Additionally, there were no treatment effects on zinc, copper, or retinol digestibility (P ≥ .298); however, thiamin inclusion rate was increased for the PG-D treatment, thus leading to an increased digestibility for thiamin (P = 0.018) in the PG-D treatment. There were no treatment differences in hepatic mineral concentrations (P ≥ 0.532); however, there was a tendency for pigs fed PG-D to have increased hepatic concentrations of lead and mercury when compared with both PG and CON pigs (P ≤ 0.066). In summary, supplementation of a commercial ceramic particle with or without a blend of preservatives to weaned pigs did not affect performance or apparent nutrient digestibility.