SPH7854, a gut-limited RORγt antagonist, ameliorates TNBS-induced experimental colitis in rat.

Multiple lines of evidence suggest that Retinoic Acid Related Orphan Nuclear Receptor gamma t (RORγt) is a potent therapeutic target for inflammatory bowel disease (IBD). However, systemic blockade of RORγt easily leads to thymic lymphoma and aberrant liver function. Therefore, the development of gut-limited RORγt antagonists may lead to the development of innovative IBD therapeutics that improve safety and retain effectiveness. We discovered SPH7854, a potent and selective RORγt antagonist. The effect of SPH7854 on the differentiation of T helper 1 (Th1)/Th17/regulatory T (Treg) cells was evaluated in mouse and human primary cells. SPH7854 (2-(4-(ethylsulfonyl)phenyl)-N- (6-(2-methyl-2-(pyridin-2-yl) propanoyl)pyridin-3-yl)acetamide) dose-dependently inhibited interleukin-17A (IL-17A) secretion from mouse CD4 + T cells and human peripheral blood mononuclear cells (PBMC). Additionally, SPH7854 strongly suppressed Th17 cell differentiation and considerably promoted Treg cell differentiation while slightly affected Th1 cell differentiation from mouse CD4 + T cells. The pharmacokinetic (PK) studies indicated that SPH7854 was restricted to the gut: the bioavailability and maximal plasma concentration of SPH7854 after oral administration (6 mg/kg) were 1.24 ± 0.33 % and 4.92 ± 11.81 nM, respectively, in rats. Strikingly, oral administration of SPH7854 (5 mg/kg and 15 mg/kg) twice daily significantly alleviated 2, 4, 6-trinitrobenzensulfonic acid (TNBS)-induced colitis in rats. SPH7854, especially at 15 mg/kg, significantly alleviated symptoms and improved macroscopic signs and microscopic structure in rat colitis, with decreased colonic mucosal levels of IL-17A, IL-6, tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and myeloperoxidase (MPO). These evidences indicated that blockade of RORγt activity via a gut-limited antagonist may be an effective and safe therapeutic strategy for IBD treatment.

Characterization of emissions from rubber modified asphalt and their impact on environmental burden: Insights into composition variability and hazard assessment.

Rubber modified asphalt (RMA) is a promising avenue for recycling waste tires but faces concerns over hazardous fumes emission during production and construction. This study employs a specialized apparatus to analyze RMA's emission behavior, focusing on crumb rubber size variations under thermal conditions. Ozone Formation Potential (OFP) and Secondary Organic Aerosol Formation Potential (SOAFP) were quantified to evaluate the environmental burden. Results indicate distinct periods of emission behavior for different pollutants, with H2S emissions primarily occurring within the initial 150 min while volatile organic compounds (VOCs) dominate within the first 270 min. The size of rubber particles and thermal exposure duration influence the VOCs microscopic emission characteristics and environmental burdens. Polycyclic aromatic hydrocarbons (PAHs) emerge as the primary contributors to OFP and SOAFP, accounting for nearly 65 % and 25 %-60 %, respectively. High molecular weight aliphatic hydrocarbons (ALHs) also significantly contribute to SOAFP, with PAHs dominating throughout, while ALHs peak during the middle stage. H2S emissions likely stem from rubber, while early VOC emissions originate from rubber, transitioning to petroleum asphalt during the middle and late stages. Asphalt fractions influence emission behavior and property evolution. These findings inform emission suppression strategies and highlight the need for tailored approaches to mitigate emissions effectively.

[Hemoperfusion alleviated paraquat-induced kidney inflammation injury of rabbit].

OBJECTIVE: To investigate the effect of hemoperfusion on paraquat-Induced kidney inflammation injury of rabbit and the mechanism of it. METHODS: 60 male rabbits were randomly divided into 4 groups, the normal control group (n=6, the rabbits were given NS by gavage) , blank control group (n=18, he rabbits were given 2 hours hemoperfusion once within 1 hour after given NS by gavage), paraquat poisoning group (n=18, the rabbits were given 50 mg/kg 20% paraquat solution by gavage) , hemoperfusion treatment group (n=18, the rabbits were given 2 hours hemoperfusion once within 1 hour after 20% paraquat solution espoused). The last 3 groups were divided into 3 observation time groups (1, 3, 7 day), contained 6 rabbits each group. On days 1, 3, 7 all groups rabbits were anesthetized and sacrificed, and their kidney tissues collected. The levels of NF-κB mRNA by RT-PCR, and the expression of NF-κB protein was measured by Western blotting,The expression levels of TNF-α, IL-6, iNOS measured by chemical colorimetric method to to observe inflammatory injury. RESULTS: Compared with the normal control group rabbits, there were no changes in the TNF-α, IL-6, iNOS, NF-κB mRNA and protein of blank control group (P>0.05), while the expression of TNF-α, IL-6, NF-κB mRNA and protein in the kidney tissue of PQ group and were significantly increased (P<0.05). The pathological results of kidney tissues were no abnormalities onnormal control group and blank control group. CONCLUSION: HP significantly increase resistance to PQ-induced inflammation injury in the rabbit kidney and exert a protective effect on PQ-induced kidney injury.