Bound to shock: protection from lethal endotoxemic shock by a novel, nontoxic, alkylpolyamine lipopolysaccharide sequestrant

Lipopolysaccharide (LPS), or endotoxin, a structural component of gram-negative bacterial outer membranes, plays a key role in the pathogenesis of septic shock, a syndrome of severe systemic inflammation which leads to multiple-system organ failure. Despite advances in antimicrobial chemotherapy, sepsis continues to be the commonest cause of death in the critically ill patient. This is attributable to the lack of therapeutic options that aim at limiting the exposure to the toxin and the prevention of subsequent downstream inflammatory processes. Polymyxin B (PMB), a peptide antibiotic, is a prototype small molecule that binds and neutralizes LPS toxicity. However, the antibiotic is too toxic for systemic use as an LPS sequestrant. Based on a nuclear magnetic resonance-derived model of polymyxin B-LPS complex, we had earlier identified the pharmacophore necessary for optimal recognition and neutralization of the toxin. Iterative cycles of pharmacophore-based ligand design and evaluation have yielded a synthetically easily accessible N(1),mono-alkyl-mono-homologated spermine derivative, DS-96. We have found that DS-96 binds LPS and neutralizes its toxicity with a potency indistinguishable from that of PMB in a wide range of in vitro assays, affords complete protection in a murine model of LPS-induced lethality, and is apparently nontoxic in vertebrate animal models.     

Scrotal ulceration during induction therapy of acute promyelocytic leukemia with ATRA

All-trans-Retinoic acid (ATRA) has been shown to improve survival in patients with acute promyelocytic leukemia (APML). It is a well-tolerated drug except for the serious side effect of ATRA syndrome. Dryness of the skin, cheilitis, and xerostomia are the common mucocutaneous side effects. Occurrence of scrotal ulceration is very rare. We report a 13-year-old boy who had scrotal ulceration caused by ATRA during the induction therapy of APML.     

Polycationic sulfonamides for the sequestration of endotoxin

Lipopolysaccharides (LPS) play a key role in the pathogenesis of septic shock, a major cause of mortality in the critically ill patient. We had previously shown that monoacylated polyamine compounds specifically bind to and neutralize the activity of LPS with high in vitro potency and afford complete protection in a murine model of endotoxic shock. Fatty acid amides of polyamines may be rapidly cleared from systemic circulation due to their susceptibility to nonspecific serum amidases and, thus, would be predicted to have a short duration of action. In a systematic effort to increase the likelihood of better bioavailability properties together with structural modifications that may result in gains in activity, we now report structure-activity relationships pertaining to endotoxin-binding and -neutralizing activities of homologated polyamine sulfonamides.     

Hypolipidemic, hepato-protective and renal damage recovering effects of catechin isolated from the methanolic extract of Cassia fistula stem bark on Streptozotocin-induced diabetic Wistar rats: a biochemical and morphological analysis

Traditional systems of medicine and medicinal plants research are the most promising areas of research in the modern drug discovery technologies. Today, drugs have taken their roots from the phytoconstituents. This study is aimed at the establishment of the hypolipidemic, hepatoprotective, and renal damage restoring efficacies of catechin isolated from Cassia fistula using bioassay guided fractionation on streptozotocin (STZ)-induced diabetic male albino Wistar rats. Catechin was administered to STZ (60?mg/kg b.?wt)-induced diabetic male Wistar rats at 20 mg/kg b.?wt for 45?days. Plasma glucose level was significantly reduced when compared with the control. In addition, oral administration of catechin significantly decreased glycosylated hemoglobin (HbA1C), serum total cholesterol, triglyceride, LDL-cholesterol, urea, uric acid, and creatinine, and at the same time, markedly increased hemoglobin, HDL-cholesterol, and serum protein. Catechin also restored the altered plasma enzymes (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and acid phosphatase) levels to near normal. Histological studies reveal that oral administration of catechin recovered the hepatic and renal damages. Results of this experimental study indicated that catechin possessed hypolipidemic, hepato-protective, and renal damage restoring efficacies, and hence, this could be used as an oral drug for treating diabetes and related diseases.     

Age dependent phosphorylation and deregulation of p53 in human vestibular schwannomas

Tumor-specific alterations at the p53 gene locus in 30 human vestibular schwannomas (VS) comprising 10 confirmed NF2 cases and 20 sporadic cases were analyzed. We found loss of heterozygosity (LOH) at the first intron of the p53 gene locus in 54% of the informative cases. This is the first report showing LOH at the p53 gene locus in a significant number of human VS and both sporadic and NF2 cases show the LOH event. Increased levels of normal size p53 mRNA and p53 protein were found in all the tumors analyzed. Thus p53 appears to be deregulated in all the tumors suggesting that p53 alterations may be associated with tumor progression in VS. There was a negative significant correlation of patients' age and percentage of Ser 392 phosphorylated p53 protein. The tumor samples obtained from younger patients of 35 yr and below showed higher percentage of Ser 392 phosphorylated p53 protein compared to the tumors of older patients. The increased percentage of Ser 392 phosphorylated p53 protein indicates that it could be involved in the acceleration of tumor growth in the younger patients. Our results suggest that age dependent phosphorylation of p53 protein and deregulation of p53 gene has a role in the development of human vestibular schwannomas.     

Inability of mitogen-induced liver hyperplasia to support the induction of enzyme-altered islands induced by liver carcinogens

Experiments were designed to determine whether liver cell proliferation induced by direct mitogens is as effective as compensatory cell proliferation consequent to previous cell loss, in supporting the growth of enzyme-altered islands in the liver induced by chemical carcinogens. Male Wistar rats were given injections of a single nonnecrogenic dose of N-methyl-N-nitrosourea or benzo(a)pyrene during the S phase following the administration of four different liver mitogens, namely, lead nitrate, ethylene dibromide, nafenopin, and cyproterone acetate, or during compensatory cell proliferation following partial hepatectomy or a necrogenic dose of CCl4. The carcinogen-altered hepatocytes were monitored as gamma-glutamyltransferase- or placental glutathione S-transferase-positive foci using a 2-wk promoting regimen consisting of 0.03% 2-acetylaminofluorene coupled with a necrogenic dose of CCl4. The results indicate that, unlike compensatory cell proliferation induced by partial hepatectomy or CCl4, the mitogen-induced cell proliferation did not result in a significant number of enzyme-altered islands, despite the fact that the extent of cell proliferation at the time of carcinogen administration, as monitored by the examination of labeled cells, is similar with both types of proliferative stimuli.     

The role of hMSH3 and hMSH6 in ovarian endometrioid carcinoma and relationship with microsatellite instability phenotype

Frequent frameshift mutations in the DNA mismatch repair genes hMSH3, and hMSH6, have been reported in colorectal and endometrial cancers with microsatellite instability, however, it is unclear whether they are similarly altered in ovarian endometrioid carcinoma. In this study, we examined frequency of frameshift mutation and protein expression in hMSH3 and hMSH6 in ovarian endometrioid carcinoma with or without microsatellite instability. Only 1 frameshift mutation of the 16 cases with microsatellite instability-high phenotype (6%) was detected in poly(A)8 tract of the hMSH3, but not in poly(C)8 tract of hMSH6 genes. In addition, none of the 6 microsatellite instability-low or 20 microsatellite-stable tumors showed mutations in these regions in either gene. These results indicate that mutations in the mono-nucleotide tracts of hMSH3 and hMSH6 are infrequent in ovarian endometrioid adenocarcinomas, other mechanisms may play a more important role in the development of these tumors.