1. The hypotensive effect of cross-fostering in spontaneously hypertensive rats (SHR) is thought to involve adjustments in renal function. However, its association with renal anti-oxidant/oxidant balance during cross-fostering is not known. 2. The present study examined the effect of cross-fostering and in-fostering of 1-day-old offspring between SHR and Wistar-Kyoto (WKY) dams on renal anti-oxidant/oxidant status and systolic blood pressure (SBP). Renal anti-oxidant/oxidant status and SBP were determined in the offspring from 4-16 weeks of age. 3. Cross-fostered SHR had significantly lower SBP than in-fostered SHR at 6, 8 and 12 weeks, but not at 16 weeks (127 ± 1 vs 144 ± 2, 138 ± 1 vs 160 ± 1, 174 ± 2 vs 184 ± 2 and 199 ± 2 vs 194 ± 3 mmHg at 6, 8, 12 and 16 weeks, respectively). No differences in SBP were evident between cross-fostered and in-fostered WKY rats. There were no significant differences in levels of thiobarbituric acid-reactive substances (TBARS), protein carbonyl and total anti-oxidant status (TAS) or superoxide dismutase, catalase, glutathione peroxidase (GPx), glutathione S-transferase and glutathione reductase activity between cross-fostered and in-fostered SHR or WKY offspring. However, compared with WKY rats, catalase activity was higher at 6 and 16 weeks, TAS was higher at 16 weeks and GPx activity and TBARS were lower at 16 weeks in SHR. 4. It appears that cross-fostering of SHR offspring to WKY dams during the early postnatal period causes a transient delay in the rise in blood pressure in SHR and that this does not involve the renal anti-oxidant/oxidant system.
1. The present study was performed in order to determine the amino acid and fatty acid composition of an aqueous extract of the freshwater fish Channa striatus, obtained by soaking (1:2, w/v) fresh fillets overnight in a chloroform:methanol (2:1, v/v) solvent, to elucidate the mechanism responsible for its antinociceptive activity and to clarify the relationship between the presence of the amino and fatty acids and the expected activity. 2. The aqueous extract was found to contain all amino acids with the major amino acids glycine, alanine, lysine, aspartic acid and proline making up 35.77 +/- 0.58, 10.19 +/- 1.27, 9.44 +/- 0.56, 8.53 +/- 1.15 and 6.86 +/- 0.78% of the total protein, respectively. 3. In addition, the aqueous extract was found to have a high palmitic acid (C16:0) content, which contributed approximately 35.93 +/- 0.63% to total fatty acids. The other major fatty acids in the aqueous extract were oleic acid (C18:1), stearic acid (C18:0), linoleic acid (C18:2) and arachidonic acid (C20:4), contributing 22.96 +/- 0.40, 15.31 +/- 0.33, 11.45 +/- 0.31 and 7.44 +/- 0.83% of total fatty acids, respectively. 4. Furthermore, the aqueous extract was demonstrated to possess concentration-dependent antinociceptive activity, as expected, when assessed using the abdominal constriction test in mice. 5. It is concluded that the aqueous extract of C. striatus contains all the important amino acids, but only some of the important fatty acids, which are suggested to play a key role in the observed antinociceptive activity of the extract, as well as in the traditionally claimed wound healing properties of the extract.
Tumour invasion and metastasis have been recognized as major causal factors in the morbidity and mortality among cancer patients. Many advances in the knowledge of cancer metastasis have yielded an impressive array of attractive drug targets, including enzymes, receptors and multiple signalling pathways. The present review summarizes the molecular pathogenesis of metastasis and the identification of novel molecular targets used in the discovery of antimetastatic agents. Several promising targets have been highlighted, including receptor tyrosine kinases, effector molecules involved in angiogenesis, matrix metalloproteinases (MMPs), urokinase plasminogen activator, adhesion molecules and their receptors, signalling pathways (e.g. phosphatidylinositol 3-kinase, phospholipase Cγ1, mitogen-activated protein kinases, c-Src kinase, c-Met kinases and heat shock protein. The discovery and development of potential novel therapeutics for each of the targets are also discussed in this review. Among these, the most promising agents that have shown remarkable clinical outcome are anti-angiogenic agents (e.g. bevacizumab). Newer agents, such as c-Met kinase inhibitors, are still undergoing preclinical studies and are yet to have their clinical efficacy proven. Some therapeutics, such as first-generation MMP inhibitors (MMPIs; e.g. marimastat) and more selective versions of them (e.g. prinomastat, tanomastat), have undergone clinical trials. Unfortunately, these drugs produced serious adverse effects that led to the premature termination of their development. In the future, third-generation MMPIs and inhibitors of signalling pathways and adhesion molecules could form valuable novel classes of drugs in the anticancer armamentarium to combat metastasis.
1. Andrographis paniculata (Burm. f) Nees, commonly known as 'king of bitters', is a herbaceous plant belonging to the Family Acanthaceae. It has been widely used for centuries in Asian countries like China, India, Thailand and Malaysia for the treatment of sore throat, flu and upper respiratory tract infections. 2. Andrographolide, 14-deoxy-11,12-didehydroandrographolide and neoandrographolide are examples of the major labdane diterpenoids isolated from A. paniculata. These bioactive molecules have exhibited varying degrees of anti-inflammatory and anticancer activities in both in vitro and in vivo experimental models of inflammation and cancer. 3. Extensive libraries of andrographolide analogues have been synthesised mainly by modifying the α,β-unsaturated γ-butyrolactone moiety, the two double bonds Δ(8,(17)) and Δ(12,(13)) and the three hydroxyls at C-3 (secondary), C-14 (allylic) and C-19 (primary). Many of these synthetic analogues exhibit superior anticancer activity over the naturally occurring andrographolides. 4. Andrographolide and its derivatives have been shown to have anti-inflammatory effects in experimental models of asthma, stroke and arthritis, as well as in patients with upper respiratory tract infections. Andrographolide reduces the production of cytokines, chemokines, adhesion molecules, nitric oxide and lipid mediators, probably via inhibition of the nuclear factor (NF)-κB signalling pathway. 5. The anticancer mechanisms for andrographolide include inhibition of Janus tyrosine kinases-signal transducers and activators of transcription, phosphatidylinositol 3-kinase and NF-κB signalling pathways, suppression of heat shock protein 90, cyclins and cyclin-dependent kinases, metalloproteinases and growth factors, and the induction of tumour suppressor proteins p53 and p21, leading to inhibition of cancer cell proliferation, survival, metastasis and angiogenesis. 6. Andrographolide drug discovery is a promising strategy for the development of a novel class of anti-inflammatory and anticancer drugs.
1. A series of experiments were conducted to investigate the effect of endogenous opioids on blood pressure of laboratory rats during stress. 2. Rats subjected to 120 min immobilization showed a significant drop in systolic pressure which could be prevented by pretreatment injections of naloxone. 3. Adrenalectomized rats subjected to the same kind of stress showed a drop in systolic pressure equivalent to only 30% of the systolic pressure drop in the intact animals. This decrease in systolic pressure could also be prevented by pretreatment injections of naloxone. 4. It was concluded that the decrease in systolic pressure in intact rats during immobilization was mostly due to endogenous opioids released from the adrenal glands, whereas opioids of other origins such as the pituitary gland, were also important.