Effect of Vitamin D3 in Composition of Original Rectal Suppositories on Parameter of Protein Oxidative Modification in Large Intestine in Experimental Ulcerative Colitis.

The effect of vitamin D3 in the composition of original rectal suppositories on the content of products of oxidative modification of proteins in mucous membrane of the large intestine was studied in rats with experimental ulcerative colitis provoked by a two-stage administration of 3% oxazolone. The rectal suppositories with vitamin D3 (1500 IU) were administered every 12 h during 5 days. Condition of the rats was assessed according to disease activity index (DAI), while the content of oxidative modification products of proteins in the homogenate of the mucous membrane was assayed with extraction-spectrophotometric method in the lesion focus of large intestine. DAI increased during entire observation period of ulcerative colitis, which correlated with the level of products of spontaneous and induced oxidative modification of proteins in mucous membrane of the colon. The study examined the pharmaceutical and technological features of novel rectal suppositories of original composition weighing 300 mg, which are based on polyethylene glycol supplemented with aqueous solution of vitamin D3 (10%). The use of rectal suppositories with vitamin D3 reduced DAI and inhibited the oxidative modification of proteins.

Hypoxia as a Factor Involved in the Regulation of the apoA-1, ABCA1, and Complement C3 Gene Expression in Human Macrophages.

Hypoxia plays a critical role in progression of atherosclerosis. Local oxygen deficiency in a plaque creates a specific microenvironment that alters the transcriptome of resident cells, particularly of macrophages. Reverse cholesterol transport from plaque to liver is considered a main mechanism for regression of atherosclerosis. Ubiquitously expressed ATP-binding cassette transporter A1 (ABCA1) and liver- and small intestine-derived apolipoprotein A-1 (ApoA-1) are two main actors in this process. We recently reported endogenous apoA-1 expression in human macrophages. While ABCA1 and ApoA-1 have antiatherogenic properties, the role of complement factor C3 is controversial. Plasma C3 level positively correlates with the risk of cardiovascular diseases. On the other hand, C3 gene knockout in a murine atherosclerosis model increases both plaque size and triglycerides level in blood. In the present study, we show for the first time that a hypoxia-mimicking agent, CoCl2, induces the upregulation of the apoA-1 and C3 genes and the accumulation of intracellular and membrane protein ApoA-1 in THP-1 macrophages. The MEK1/2-Erk1/2 and MKK4/7-JNK1/2/3 cascades are involved in upregulation of ABCA1 and C3 via activation of transcription factor NF-κB, which interacts with the HIF-1α subunit of hypoxia-inducible factor 1 (HIF-1). The three major MAP-kinase cascades (Erk1/2, JNK1/2/3, and p38) and the NF-κB transcription factor are involved in the hypoxia-induced expression of the apoA-1 gene in THP-1 macrophages.