Nicotinic--serotonergic interactions in brain and behaviour

This review focuses on nicotinic--serotonergic interactions in the central nervous system (CNS). Nicotine increases 5-hydroxytryptamine (5-HT) release in the cortex, striatum, hippocampus, dorsal raphé nucleus (DRN), hypothalamus, and spinal cord. As yet, there is little firm evidence for nicotinic receptors on serotonergic terminals and thus nicotine's effects on 5-HT may not necessarily be directly mediated, but there is strong evidence that the 5-HT tone plays a permissive role in nicotine's effects. The effects in the cortex, hippocampus, and DRN involve stimulation of 5-HT(1A) receptors, and in the striatum, 5-HT(3) receptors. The 5-HT(1A) receptors in the DRN play a role in mediating the anxiolytic effects of nicotine and the 5-HT(1A) receptors in the dorsal hippocampus and lateral septum mediate its anxiogenic effects. The increased startle and anxiety during nicotine withdrawal is mediated by 5-HT(1A) and 5-HT(3) receptors. The locomotor stimulant effect of acute nicotine is mediated by 5-HT(1A) receptors and 5-HT(2) receptors may play a role in the expression of a sensitised response after chronic nicotine treatment. Unfortunately, the role of 5-HT(1A) receptors in mediating nicotine seeking has not yet been investigated and would seem an important area for future research. There is also evidence for nicotinic--serotonergic interactions in the acquisition of the water maze, passive avoidance, and impulsivity in the five-choice serial reaction task.     

Seroepidemiological surveillance of Burkholderia pseudomallei in Bangladesh

Melioidosis (Burkholderia pseudomallei infection) has yet to be demonstrated systematically in Bangladesh. A prospective, cross-sectional serological survey was conducted in 2010 at six Bangladeshi hospitals. Age, gender, occupation and residential address were recorded. Of 1244 patients, 359 (28.9%) were positive for B. pseudomallei by indirect haemagglutination assay. Farmers had an increased risk of seropositivity (risk ratio=1.4, 95% CI 1.0-1.8; p=0.03). There was no clear geographic clustering of seropositives. Melioidosis should be considered as a possible cause of febrile illness in Bangladesh. Further studies are needed to establish the incidence of clinical disease and distribution of environmental risk.     

Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer

Human breast tumors comprise a minor sub-population of tumor-initiating cells (TICs), commonly termed cancer stem cells. TICs are thought to sustain tumor growth and to confer resistance to current anticancer therapies. Hence, targeting TIC may be essential to achieving durable cancer cures. To identify molecular targets in breast TIC, we employed a transgenic mouse model of ERBB2 breast cancer; tumors arising in this model comprise a very high frequency of TIC, which is maintained in tumor cell populations propagated in vitro as non-adherent tumorspheres. The Notch pathway is dysregulated in human breast tumors and overexpression of constitutively active Notch proteins induces mammary tumors in mice. The Notch pathway has also been implicated in stem cell processes including those of mammary epithelial stem cells. Hence, we investigated the potential that the Notch pathway is required for TIC activity. We found that an antagonist of Notch signaling, a gamma (γ)-secretase inhibitor termed MRK-003, inhibited the survival of tumorsphere-derived cells in vitro and eliminated TIC as assessed by cell transplantation into syngeneic mice. Whereas MRK-003 also inhibited the self-renewal and/or proliferation of mammosphere-resident cells, this effect of the inhibitor was reversible thus suggesting that it did not compromise the survival of these cells. MRK-003 administration to tumor-bearing mice eliminated tumor-resident TIC and resulted in rapid and durable tumor regression. MRK-003 inhibited the proliferation of tumor cells, and induced their apoptosis and differentiation. These findings suggest that MRK-003 targets breast TIC and illustrate that eradicating these cells in breast tumors ensures long-term, recurrence-free survival.     

Inflammatory bowel disease-related colorectal cancer: Past,present and future perspectives

Inflammatory bowel disease-related colorectal cancer (IBD-CRC) is one of the most serious complications of IBD contributing to significant mortality in this cohort of patients. IBD is often associated with diet and lifestyle-related gut microbial dysbiosis, the interaction of genetic and environmental factors, leading to chronic gut inflammation. According to the “common ground hypothesis”, microbial dysbiosis and intestinal barrier impairment are at the core of the chronic inflammatory process associated with IBD-CRC. Among the many underlying factors known to increase the risk of IBD-CRC, perhaps the most important factor is chronic persistent inflammation. The persistent inflammation in the colon results in increased proliferation of cells necessary for repair but this also increases the risk of dysplastic changes due to chromosomal and microsatellite instability. Multiple pathways have been identified, regulated by many positive and negative factors involved in the development of cancer, which in this case follows the ‘inflammation-dysplasia-carcinoma’ sequence. Strategies to lower this risk are extremely important to reduce morbidity and mortality due to IBD-CRC, among which colonoscopic surveillance is the most widely accepted and implemented modality, forming part of many national and international guidelines. However, the effectiveness of surveillance in IBD has been a topic of much debate in recent years for multiple reasons — cost-benefit to health systems, resource requirements, and also because of studies showing conflicting long-term data. Our review provides a comprehensive overview of past, present, and future perspectives of IBD-CRC. We explore and analyse evidence from studies over decades and current best practices followed globally. In the future directions section, we cover emerging novel endoscopic techniques and artificial intelligence that could play an important role in managing the risk of IBD-CRC.     

16α-Hydroxycleroda-3,13 (14)Z-dien-15,16-olide from Polyalthia longifolia: a safe and orally active antileishmanial agent

Background and purpose:

New antileishmanials from natural products are urgently needed due to the emergence of drug resistance complicated by severe cytotoxic effects. 16α-Hydroxycleroda-3,13 (14)Z-dien-15,16-olide (Compound 1) from Polyalthia longifolia was found to be a potential antileishmanial and non-cytotoxic, as evidenced by long-term survival (>6 months) of treated animals. This prompted us to determine its target and, using molecular modelling, identify the interactions responsible for its specific antileishmanial activity.

Experimental approach:

In vitro activity of compound was assessed using intracellular transgenic green fluorescent protein-stably expressed Leishmania donovani parasites. In vivo activity and survival of animals post-treatment were evaluated in L. donovani-infected hamsters. Known property of clerodane diterpenes as potent human DNA topoisomerase inhibitors led us to evaluate the inhibition of recombinant L. donovani topoisomerase I using relaxation assay. Mode of cell death induced by Compound 1 was assessed by phosphotidylserine exposure post-treatment. Molecular modelling studies were conducted with DNA topoisomerase I to identify the binding interactions responsible for its activity.

Key results:

Bioassay-guided fractionation led to isolation of Compound 1 as a non-cytotoxic, orally active antileishmanial. Compound 1 inhibited recombinant DNA topoisomerase I which, ultimately, induced apoptosis. Molecular docking studies indicated that five strong hydrogen-bonding interactions and hydrophobic interactions of Compound 1 with L. donovani DNA-topoisomerase are responsible for its antileishmanial activity.

Conclusions and implications:

The data reveal Compound 1 is a potent and safe antileishmanial. The study further exploited the structural determinants responsible for its non-cytotoxic and potent activity, to raise the feasibility of specifically targeting the target enzyme responsible for its activity through rational drug design.     

Oxidative stress in inflammatory cells of patient with rheumatoid arthritis: clinical efficacy of dietary antioxidants

Rheumatoid arthritis (RA) is an autoimmune disease responsible for significant human morbidity in modern life. However, oxidative stress is one of the key markers for determining pathophysiology of patients with RA. The interaction between cellular immune system and body’s endogenous and/or exogenous antigens produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) in autoimmune disease like RA. ROS and RNS include highly toxic superoxide (O₂ ^?) and peroxynitrite (ONOO^?) radicals, which activate the signaling cascades of inflammatory cells to synthesize pro-inflammatory cytokines and chemokines. Previous studies reported that Th1 cytokines could promote the development of autoimmune disorders like RA, whereas the Th2 cytokines may attenuate the same diseases. An increased awareness of the relationship between food and health led to a tremendous increase of antioxidant research in the last decade. Evaluation of the efficacy of dietary antioxidants is also becoming highly acceptable in RA research. A number of dietary phytomolecules are already established as having antioxidant activity in isolated synovial cellular infiltrate or peripheral blood neutrophils and lymphocytes. This review aims to highlight the oxidative stress in inflammatory cells of patients with RA and to summarize the clinical relevance of dietary antioxidants as a first step in assessing beneficial effect, safety and dose safety ratio in patients with RA.     

A prostatic intraepithelial neoplasia-dependent p27 Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression

Transgenic expression of activated AKT1 in the murine prostate induces prostatic intraepithelial neoplasia (PIN) that does not progress to invasive prostate cancer (CaP). In luminal epithelial cells of Akt-driven PIN, we show the concomitant induction of p27(Kip1) and senescence. Genetic ablation of p27(Kip1) led to downregulation of senescence markers and progression to cancer. In humans, p27(Kip1) and senescence markers were elevated in PIN not associated with CaP but were decreased or absent, respectively, in cancer-associated PIN and in CaP. Importantly, p27(Kip1) upregulation in mouse and human in situ lesions did not depend upon mTOR or Akt activation but was instead specifically associated with alterations in cell polarity, architecture, and adhesion molecules. These data suggest that a p27(Kip1)-driven checkpoint limits progression of PIN to CaP.     

Effect of hydrocortisone on the metabolism of L-ascorbic acid in rats

Adrenalectomy causes a significant decrease in the tissue levels of l-ascorbic acid. The ascorbic acid concentration is raised when adrenalectomized animals receive hydrocortisone. Various enzymes of l-ascorbic acid metabolism have been measured in rats after adrenalectomy and subsequent treatment with hydrocortisone and/or actinomycin D. Hydrocortisone stimulates the activity of liver gulono-oxidase responsible for the synthesis of l-ascorbic acid from l-gulonolactone. A slight increase in the activity of dehydroascorbatase is also observed in the adrenalectomized rats. Little change was observed in uronolactonase, l-gulonate dehydrogenase and l-gulonate decarboxylase activities.