Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) - Volume 13, Issue 1, 2013

Regular consumption of fruit and vegetables is associated with reduced risks of cancer, cardiovascular disease and other aging-related diseases. Convincing evidence exists suggesting that an increased fruit, vegetables, and grains consumption is a relatively easy and practical strategy to significantly reduce the incidence of chronic diseases. Cancer chemoprevention intends to interrupt the carcinogenesis process, which includes initiation, promotion and progression of otherwise normal cells to reduce cancer. The development of diet-derived constituents represents one of the major goals in cancer chemoprevention. A key question is whether a purified phytochemical has the same protective effects as does the whole food or mixture of foods in which the phytochemical is present. Putative chemopreventive agents are identified on the basis of epidemiological and in vitro and in vivo studies. All these compounds present tumor-suppressing properties in animal models of carcinogenesis, and they interfere with cellular processes involved in tumor formation. Phase I clinical trials have been completed only for few of these phytochemicals, and pilot phase II-III trials are planned. In the revised version of this review originally published in 2005 on this journal (Russo et al., Dietary Phytochemicals in Chemoprevention of Cancer. Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry, 2005, 5, 61-72), we updated data regarding the description of the mechanisms by which these compounds exert their biological activities. Finally, we also reviewed in details data regarding well-known and promising chemopreventive phytochemicals.

Diabetic retinopathy remains the most frequent cause of new cases of blindness among adults aged 20-74 years. A number of large trials have validated that laser photocoagulation is a useful treatment but the disease continues to progress in approximately 50% of eyes treated by photocoagulation. Current treatment of diabetic retinopathy is only available for advanced stages of the disease and is given independently of the diabetes disease status itself and metabolic status. Other forms of therapy targeted at the earliest stages of retinal disease are needed. Proposals for defining and accepting surrogate outcomes that appropriately evaluate the earlier stages of the retinopathy are presented in this review. The most likely candidates for surrogate outcomes are: mean difference in ETDRS retinopathy scale, 2 steps per eye, microaneurysm turnover and reduction in macular thickening.

The purpose of this article is to compare and evaluate the advantages and benefits of the cognitive screening technique Virtual Scanning with contemporary diagnostic and screening techniques, in particular genetic screening and biomarkers. In the last 50 years biomarker techniques and more recently genetic screening have been developed to characterise the onset, progression and regression of pathologies. Nevertheless the scientific picture is not yet complete. It does not yet include an understanding of relationship between genotype and phenotype; the regulatory function of the autonomic nervous system; or the rate or level of the expressed protein, protein conformation, the rate at which proteins react, and the reaction conditions such as pH, levels of minerals and cofactors, and temperature. By contrast, Virtual Scanning is based upon the light absorbing and emitting properties of proteins and how this bioluminescence influences colour perception. It provides a measure of the level of expressed protein and the rate at which such expressed protein subsequently reacts with its reactive substrate. The article highlights the limitations of genetic screening and biomarkers and the perceived advantages which Virtual Scanning may have for routine mass screening e.g. of diabetes, cardiovascular disease, cancers, depression, migraine, etc.

Extranuclear or nongenomic actions of thyroid hormones are unaffected by the inhibitors of protein synthesis, their site of action has been localized at the plasma membrane but also in the cytoplasm and organelles such as the mitochondria. This review takes into account recent major advances in nongenomic effects of thyroid hormones in nervous system, immune system and cardiovascular tissue, with a particular focus on the plasma membrane receptor integrin αvβ3. In nerve cells nongenomic effects of thyroid hormones point mainly to a direct modulation of several channels/receptors for the major neurotransmitters, even though more complex pathways have also been demonstrated. Certain neuroprotective actions have recently been described for thyronamines, and this may be relevant to Alzheimer's disease and multiple sclerosis. The immune system is also modulated nongenomically by thyroid hormones, through potentiation of the effects of cytokines such as IFN-γ or lipopolysaccharide, or through activators of STAT protein leading to activation of the mammalian target of rapamycin (mTOR) pathway, a highly conserved kinase downstream target of nongenomic actions of thyroid hormone. The mTOR system is also involved in the cardioprotection mechanisms, where thyroid hormone signaling through the receptor integrin αvβ3 may play an important role that needs to be further studied. The identification of integrin αvβ3 as a plasma membrane receptor for thyroid hormones has provided a new perspective on the role of these hormones in cellular defense. Analogs of thyroid hormones, inhibitors and agonists at the integrin receptor for the hormone and mTOR inhibitors are evaluated as areas of emphasis for therapeutic research.

Previous work in this laboratory has indicated that 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] inhibits rapid, 1,25-dihuydroxyvitamin D3 [1,25(OH)2D3] stimulated phosphate uptake in isolated intestinal cells and perfused duodenal loops. Studies were undertaken to determine if 24,25(OH)2D3 had a similar effect in vivo. 24,25(OH)2D3 has two isomers which are 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] and 24S,25-dihydroxyvitamin D3 [24S,25(OH)2D3]., which we studied separately and tested over a time course of 1, 5, 10, 15 and 18 hours after steroid using chicks on regular diet, but fasted, and chicks on a lower vitamin D diet. All chicks were anesthetized prior to surgical exposure of the duodenal loop and injection of a solution containing H3 32PO4 into the lumen. Blood was then collected and serum prepared to determine transport of the radionuclide by liquid scintillation counting. An initial time course study of phosphate transport determined that 3 to 9 min of absorption in vivo was in a linear range, as judged by serum levels of radioactivity. Chicks were then injected with either 200 μg 24R,25(OH)2D3, 20 μg 24S,25(OH)2D3 or vehicle for control groups within the same time course studies. We found that the isomers had different effects on phosphate absorption. 24R,25(OH)2D3 had a hypophosphatemic effect in vivo. The serum levels of radionuclide revealed hypophosphatemic effects at 1, 5, 15 and 18 hours time points with a decrease of 56%, 42%, 39% and 43%, respectively, (P< 0.05) compared with controls. In contrast, 24S,25(OH)2D3 stimulated intestinal phosphate absorption at the five hour time point by 64%, but had no other effects at the other time points tested. We conclude that 24R,25(OH)2D3, which is made when dietary vitamin D levels are high, inhibits phosphate transport from the intestine, while 24S,25(OH)2D3 lacks activity in vivo.

Several studies have revealed that lower hepatic expression of microsomal triglyceride transfer protein (MTP) plays an important role in the development of nonalcoholic steatohepatitis (NASH). The aim of this study was to clarify the relationship between MTP and apoptosis using Fatty Liver Shionogi mice (FLS). We checked the phenotypes including the degree of apoptosis and performed molecular biological examinations in 16- and 48-week-old FLS and C57BL/6J mice (B6). The influence of MTP induction on apoptosis was examined using vector-mediated hepatic expression of MTP. The degree of hepatic apoptosis indicated by TUNEL staining, the gene expression of Bax and Bcl-2 and the protein expression of Bax and cleaved caspase3 were markedly increased in 48-week-old FLS compared to 48-week-old B6. TUNEL-positive cells and the protein expression of Bax, Bcl-2 and cleaved caspase3 were markedly increased in 48- week-old FLS compared to 16-week-old FLS. Hepatocyte apoptosis was increased in 16-week-old FLS with increased TUNEL-positive cells and upregulation of the protein expression of Bax compared to those in 16-week-old B6. The pAKT/AKT ratio was decreased in 48-week-old FLS compared to 16-week-old FLS and 48-week-old B6. Hepatic induction of MTP resulted in not only amelioration of steatosis as well as insulin resistance, but also prevention of the progression to hepatic apoptosis via inhibition of the expression of Bax and cleaved caspase3 accompanied by restoration of the pAKT/AKT ratio. Our findings suggested that MTP might play a pivotal role in preventing the progression to hepatic apoptosis in the development of NASH via improvement of hepatic insulin resistance.

Although the linkage between vascular dysfunction and Alzheimer's disease has received much attention, the influence of beta-amyloid (Aβ) deposits on microcirculation in the chronic stage of ischemic brain injury is unknown. To examine the relationship of Aβ with the microcirculation around Aβ deposits in the chronic stage of cerebral infarction, Wistar rats were exposed to permanent middle cerebral artery occlusion (MCAo). Microangiography using albuminfluorescein isothiocyanate was performed 3 months after MCAo, followed by immunohistochemistry with GFAP and Aβ. Two types of atrophic changes were observed in the thalamus of ischemic brains: mild atrophy and severe atrophy with tissue defects. In both types, the deposition of Aβ was observed in the ventroposterior lateral and ventroposterior medial nuclei of the thalamus. Although various patterns of microcirculation were observed in the thalamus, a high density of enlarged microvessels with reactive gliosis was often observed around Aβ deposits. Conversely, enlarged low-density microvessels with less reactive gliosis were observed in the Aβ deposits. Because the regions with reactive gliosis without Aβ deposits showed no changes in microcirculation and previous reports showed the proangiogenic and anti-angiogenic effects of Aβ in in vitro studies, we hypothesize that continuous Aβ deposits act directly on microvessels, rather than via reactive gliosis. Although further studies are necessary, therapeutic approaches to reduce Aβ deposits might be a promising approach to improve microcirculation in the thalamus in the chronic stage of ischemic stroke.