Eight different di- and tripeptidyl aldehyde derivatives, each having at its C-terminus an aldehyde analog of L-norleucine, L-methionine, or L-phenylalanine with a preceding L-leucine residue, were synthesized and tested for their inhibitory effects on several serine and cysteine endopeptidases. These compounds showed almost no inhibition of trypsin, and only weak inhibition of alpha-chymotrypsin and cathepsin H, while they exhibited marked inhibition of cathepsin B less than calpain II congruent to calpain I less than cathepsin L, being stronger in this order. The mode of inhibition of these cysteine proteinases was competitive for the peptide substrate used and inhibitor constants (Ki) were calculated from the Dixon plot. The best inhibitors found were: 4-phenyl-butyryl-Leu-Met-H for calpain I (Ki, 36 nM) and calpain II (Ki, 50 nM); acetyl-Leu-Leu-nLeu-H for cathepsin L (Ki, 0.5 nM); acetyl-Leu-Leu-Met-H for cathepsin B (Ki, 100 nM).
Changes of portal hemodynamics with the progression of chronic liver disease and changes caused by body posture and physical exercise were investigated using an ultrasonic pulsed Doppler flowmeter in healthy adults and in patients with chronic persistent hepatitis, chronic active hepatitis, and cirrhosis. Portal venous velocity was significantly reduced in patients with chronic active hepatitis, cirrhosis without a large splenorenal shunt, and cirrhosis with a large splenorenal shunt, compared with normal subjects and patients with chronic persistent hepatitis. Portal venous flow, by contrast, was significantly reduced only in patients with cirrhosis and a large splenorenal shunt compared with normal subjects and with the other three groups; there was no significant difference in portal venous flow among the latter four groups. Both portal venous velocity and flow showed a tendency toward further reduction in patients with cirrhosis who had hepatofugal flow of part of the superior mesenteric venous blood into the splenic vein and a large splenorenal shunt. Both exercise and posture change from supine to sitting significantly reduced portal venous velocity and portal venous flow in normal subjects, as well as in the patients with chronic liver disease.
In this study, mice were immunized nasally with surface protein antigen of Streptococcus mutans serotype c (PAc) and a nontoxic A subunit mutant of cholera toxin (mCT) E112K, as a mucosal adjuvant. Immunization with PAc and mCT elicited significant PAc-specific secretory IgA in saliva and in nasal secretions. Antibody-forming cell (AFC) analysis confirmed the antibody (Ab) titers by revealing significant numbers of PAc-specific IgA AFCs in the submandibular gland and nasal passages. Furthermore, CD4(+) T cells from cervical lymph nodes exhibited significant proliferative responses when restimulated with PAc in vitro. Importantly, mice that were nasally immunized with PAc plus mCT E112K exhibited significantly reduced oral colonization by S. mutans. These results show that nasal administration of PAc and mCT E112K is potentially an effective mucosal vaccine against dental caries and reduces the colonization of S. mutans in the oral cavity.
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