Curative effects of crocin in ulcerative colitis via modulating apoptosis and inflammation.

Ulcerative colitis (UC) is an inflammatory bowel disease with characteristic inflammation to mucosal cells in rectum and colon leading to lesions in mucosa and submucosa. Moreover, crocin is a carotenoid compound among active constituents of saffron with many pharmacological effects as antioxidant, anti-inflammatory and anticancer activities. Therefore, we aimed to investigate therapeutic effects of crocin against UC through affecting the inflammatory and apoptotic pathways. For induction of UC in rats, intracolonic 2 ml of 4% acetic acid was used. After induction of UC, part of rats was treated with 20 mg/kg crocin. cAMP was measured using ELISA. Moreover, we measured gene and protein expression of B-cell lymphoma 2 (BCL2), BCL2-associated X (BAX), caspase-3/8/9, NF-κB, tumor necrosis factor (TNF)-α and IL-1ß/4/6/10. Colon sections were stained with hematoxylin-eosin and Alcian blue or immune-stained with anti-TNF-α antibodies. Microscopic images of colon sections in UC group revealed destruction of intestinal glands associated with infiltration of inflammatory cell and severe hemorrhage. While images stained with Alcian blue showed damaged and almost absent intestinal glands. Crocin treatment ameliorated morphological changes. Finally, crocin significantly reduced expression levels of BAX, caspase-3/8/9, NF-κB, TNF-α, IL-1ß and IL-6, associated with increased levels of cAMP and expression of BCL2, IL-4 and IL-10. In conclusion, protective of action of crocin in UC is proved by restoration of normal weight and length of colon as well as improvement of morphological structure of colon cells. The mechanism of action of crocin in UC is indicated by activation of anti-apoptotic and anti-inflammatory effects.

The Unusual Architecture of RNA-Dependent RNA Polymerase (RdRp)'s Catalytic Chamber Provides a Potential Strategy for Combination Therapy against COVID-19.

The unusual and interesting architecture of the catalytic chamber of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) was recently explored using Cryogenic Electron Microscopy (Cryo-EM), which revealed the presence of two distinctive binding cavities within the catalytic chamber. In this report, first, we mapped out and fully characterized the variations between the two binding sites, BS1 and BS2, for significant differences in their amino acid architecture, size, volume, and hydrophobicity. This was followed by investigating the preferential binding of eight antiviral agents to each of the two binding sites, BS1 and BS2, to understand the fundamental factors that govern the preferential binding of each drug to each binding site. Results showed that, in general, hydrophobic drugs, such as remdesivir and sofosbuvir, bind better to both binding sites than relatively less hydrophobic drugs, such as alovudine, molnupiravir, zidovudine, favilavir, and ribavirin. However, suramin, which is a highly hydrophobic drug, unexpectedly showed overall weaker binding affinities in both binding sites when compared to other drugs. This unexpected observation may be attributed to its high binding solvation energy, which disfavors overall binding of suramin in both binding sites. On the other hand, hydrophobic drugs displayed higher binding affinities towards BS1 due to its higher hydrophobic architecture when compared to BS2, while less hydrophobic drugs did not show a significant difference in binding affinities in both binding sites. Analysis of binding energy contributions revealed that the most favorable components are the ΔEele, ΔEvdw, and ΔGgas, whereas ΔGsol was unfavorable. The ΔEele and ΔGgas for hydrophobic drugs were enough to balance the unfavorable ΔGsol, leaving the ΔEvdw to be the most determining factor of the total binding energy. The information presented in this report will provide guidelines for tailoring SARS-CoV-2 inhibitors with enhanced binding profiles.