cis-Aconitic Acid, a Constituent of Echinodorus grandiflorus Leaves, Inhibits Antigen-Induced Arthritis and Gout in Mice.

cis-Aconitic acid is a constituent from the leaves of Echinodorus grandiflorus, a medicinal plant traditionally used in Brazil to treat inflammatory conditions, including arthritic diseases. The present study aimed to investigate the anti-arthritic effect of cis-aconitic acid in murine models of antigen-induced arthritis and monosodium urate-induced gout. The possible underlying mechanisms of action was evaluated in THP-1 macrophages. Oral treatment with cis-aconitic acid (10, 30, and 90 mg/kg) reduced leukocyte accumulation in the joint cavity and C-X-C motif chemokine ligand 1 and IL-1ß levels in periarticular tissue. cis-Aconitic acid treatment reduced joint inflammation in tissue sections of antigen-induced arthritis mice and these effects were associated with decreased mechanical hypernociception. Administration of cis-aconitic acid (30 mg/kg p. o.) also reduced leukocyte accumulation in the joint cavity after the injection of monosodium urate crystals. cis-Aconitic acid reduced in vitro the release of TNF-α and phosphorylation of IκBα in lipopolysaccharide-stimulated THP-1 macrophages, suggesting that inhibition of nuclear factor kappa B activation was an underlying mechanism of cis-aconitic acid-induced anti-inflammatory effects. In conclusion, cis-aconitic acid has significant anti-inflammatory effects in antigen-induced arthritis and monosodium urate-induced arthritis in mice, suggesting its potential for the treatment of inflammatory diseases of the joint in humans. Additionally, our findings suggest that this compound may contribute to the anti-inflammatory effect previously reported for E. grandiflorus extracts.

Microenvironment-Induced In Situ Self-Assembly of Polymer-Peptide Conjugates That Attack Solid Tumors Deeply.

In cancer treatment, the unsatisfactory solid-tumor penetration of nanomaterials limits their therapeutic efficacy. We employed an in vivo self-assembly strategy and designed polymer-peptide conjugates (PPCs) that underwent an acid-induced hydrophobicity increase with a narrow pH-response range (from 7.4 to 6.5). In situ self-assembly in the tumor microenvironment at appropriate molecular concentrations (around the IC50 values of PPCs) enabled drug delivery deeper into the tumor. A cytotoxic peptide KLAK, decorated with the pH-sensitive moiety cis-aconitic anhydride (CAA), and a cell-penetrating peptide TAT were conjugated onto poly(ß-thioester) backbones to produce PT-K-CAA, which can penetrate deeply into solid tumors owing to its small size as a single chain. During penetration in vivo, CAA responds to the weak acid, leading to the self-assembly of PPCs and the recovery of therapeutic activity. Therefore, a deep-penetration ability for enhanced cancer therapy is provided by this in vivo assembly strategy.

Unexpected anthracycline-mediated alterations in iron-regulatory protein-RNA-binding activity: the iron and copper complexes of anthracyclines decrease RNA-binding activity.

Anthracyclines are effective antineoplastic agents. However, the interaction of these drugs with iron (Fe) is an important cause of myocardial toxicity, limiting their therapeutic use (J Lab Clin Med 122:245-251, 1993). To overcome this limitation, it is crucial to understand how anthracyclines interact with the Fe metabolism of myocardial and neoplastic cells. Iron-regulatory proteins (IRPs) play vital roles in regulating cellular Fe metabolism via their mRNA-binding activity. We showed that doxorubicin (DOX) and its analogs interfere with tumor and myocardial cell Fe metabolism by affecting the RNA-binding activity of IRPs. Unexpectedly, experiments with the free radical scavengers, catalase, superoxide dismutase, ebselen, and Mn(III) tetrakis (4-benzoic acid) porphyrin complex, suggested that the effects of DOX on IRP-RNA-binding activity were not due to anthracycline-mediated free radical production. In contrast to previous studies, we showed that the DOX metabolite, doxorubicinol, had no effect on IRP-RNA-binding activity. Rather, the anthracycline-Fe and -copper (Cu) complexes decreased IRP-RNA-binding activity, indicating that formation of anthracycline-metal complexes may affect cellular Fe metabolism. In addition, anthracyclines prevented the response of IRPs to the depletion of intracellular Fe by chelators. This information may be useful in designing novel therapeutic strategies against tumor cells by combining chelators and anthracyclines. Interestingly, the effect of DOX on primary cultures of cardiomyocytes was similar to that observed using neoplastic cells, and particularly notable was the decrease in IRP2-RNA-binding activity. Our results add significant new information regarding the effects of anthracyclines on Fe metabolism that may lead to the design of more effective treatments.

Evaluation of antileishmanial activity of trans-aconitic acid.

TAA, an inhibitor of the enzyme aconitase, inhibits the growth of L. donovani promastigotes. Morphogenic transformation of the amastigote to the promastigote (table; see text) form in vitro was also inhibited by 2 mM TAA. TAA also reduced multiplication of the parasite in macrophage culture. In the hamster model of leishmania, TAA significantly reduced the parasitic burden of liver. In acute toxicity tests with BALB/c mice no deaths were recorded even at a dose level of 2 g/kg body wt/day.

Regulation of progesterone biosynthesis in human placental mitochondria by Krebs cycle metabolites.

1. 2-Oxoglutarate, succinate, fumarate, malate and citrate, cis-aconitate and isocitrate stimulate conversion of cholesterol to progesterone in human placental mitochondria. 2. The stimulatory effect of dicarboxylic and tricarboxylic acids depends on the activity of malate dehydrogenase (decarboxylating) (NADP+) (EC 1.1.1.40) and isocitrate dehydrogenase (NADP+) (EC 1.1.1.42), respectively.