Current Issue : July - September Volume : 2011 Issue Number : 3 Articles : 9 Articles
Artemisinin based drugs have in this decade been made the first line antimalarial drugs for Africa3, 8. Artemisinin based antimalarials are therefore consumed daily by millions of Africans. A disturbing feature of malaria treatment with artemisinin drugs is that although they are highly efficacious in eliminating clinical malaria symptoms, malaria treated with artemisinin drugs has high recrudescence rate of sometimes over 50% especially with 7 day oral treatments1, 3. A review of the results we obtained in a study on the effects of dihydroartemisinin 5 days and 7 days oral (DHA) treatments on the blood of Wistar albino rats showed that 5 days treatments produced the maximal effects of DHA on the blood (elevation of the packed cell volume (PCV) and the total white blood cell (WBC) count). The intense physiological effects of 5 days DHA treatments produced an auto-inhibitory feed-back effect on the DHA Effects on the blood cells. This inhibitory feed-back effect of DHA on itself caused all the stimulatory effects of DHA on the blood to be slowed down. The net effect of the negative feed-back effect of DHA on its own maximal effects was that the pharmacological effects of 7 days DHA treatments were lower than those of 5 days DHA treatments and the effects of 80mg/ Kg DHA was lower than those of 60mg/ Kg and 2mg/ Kg DHA. The study also showed that effects of DHA on the PCV and the WBC of treated albino rats were increased by repetition of the same dosage regimen after an interval of one week. Five dosage regimen of DHA were used in the study. The doses of DHA administered were 1mg/Kg, a repeated 1mg/Kg dose, 2 mg/ Kg, 60mg/ Kg and 80 mg/Kg. The response curve for 5 days and 7 days DHA treatments were similar and the maximal response dose for the 5 days and 7 days treatments was the same (2 mg/ Kg). The results of the study showed that the effects of DHA were dose, repetition and time dependent. The findings of the study suggest that a self regulating negative feed-back effect of DHA on its own effects on the body is responsible for the safety and high recrudescence of oral dihydroartemisinin....
The regulation of appetite relies on complex hypothalamic neurocircuitry in which the arcuate nucleus and the hormone leptin, ghrelin play important roles. Excess body fat is stored in adipose tissue which forms over 10% of total body weight, but it is now clear that adipocytes have functions other than simple storage cells. The most significant of these appears to be the secretory. Obesity is the result of a sustained disequilibrium between energy intake and energy expenditure. If energy intake is too high or energy expenditure too low, an increase in body weight will develop over time. While in the past the contribution of an increased consumption of high-calorie food has been thought to be the primary factor in the pathogenesis of obesity, reduced physical activity is now thought to be equally or even more important. Even a small difference between these parameters becomes relevant if it is maintained over a prolonged period. It is clear to people living in the Western world that obesity is increasing, probably as a consequence of easily available, fat-rich food and an increasingly sedentary lifestyle and due to this obesity is fast becoming a global epidemic and a potential financial problem for the developing countries. The present review mainly focuses on basic neurological basis of eating behavior and its relation in the pathogenesis of obesity....
To investigate the biological effect of adenosine A2b receptor (A2bR) on the human hepatocellular carcinoma cell line HepG2, three A2bR siRNA constructs were transiently transfected into HepG2 cells. The results showed that A2bR siRNA reduced the levels of A2bR mRNA and protein. In order to further detect the function of A2bR, we established a stable hepatocellular carcinoma cell line (HepG2) expressing siRNA targeting the adenosine A2b receptor. Targeted RNAi significantly inhibited tumor cell growth in vitro, and flow cytometry (FCM) showed that significantly more cells expressing A2bR siRNA were in the G0/G1 phase compared to the untransfected group ((8 9 . 5 6 % �± 3 . 1 5 %) versus (5 6 . 1 9 % �± 1 . 5 8 %), ?? < 0 . 0 1). These results indicated that silencing the expression of adenosine A2b receptor in HepG2 cells can suppress cell growth effectively by blocking the cell cycle. Downregulation of adenosine A2b receptor gene expression with RNA interference could be a new approach to hepatocellular carcinoma therapy....
Background\r\nAdenosine is involved in several neurological and behavioral disorders including alcoholism. In cultured cell and animal studies, type 1 equilibrative nucleoside transporter (ENT1, slc29a1), which regulates adenosine levels, is known to regulate ethanol sensitivity and preference. Interestingly, in humans, the ENT1 (SLC29A1) gene contains a non-synonymous single nucleotide polymorphism (647 T/C; rs45573936) that might be involved in the functional change of ENT1.\r\nPrincipal Findings\r\nOur functional analysis showed that prolonged ethanol exposure increased adenosine uptake activity of mutant cells (ENT1-216Thr) compared to wild-type (ENT1-216Ile) transfected cells, which might result in reduced extracellular adenosine levels. We found that mice lacking ENT1 displayed increased propensity to ethanol withdrawal seizures compared to wild-type littermates. We further investigated a possible association of the 647C variant with alcoholism and the history of alcohol withdrawal seizures in subjects of European ancestry recruited from two independent sites. Analyses of the combined data set showed an association of the 647C variant and alcohol dependence with withdrawal seizures at the nominally significant level.\r\nConclusions\r\nTogether with the functional data, our findings suggest a potential contribution of a genetic variant of ENT1 to the development of alcoholism with increased risk of alcohol withdrawal-induced seizures in humans....
Introduction\r\nThe objective of this study is to determine if multiple systemic autoimmune diseases (SAID) share gene expression pathways that could provide insights into pathogenic mechanisms common to these disorders.\r\nMethods\r\nRNA microarray analyses (Agilent Human 1A(V2) 20K oligo arrays) were used to quantify gene expression in peripheral blood cells from 20 monozygotic (MZ) twin pairs discordant for SAID. Six affected probands with systemic lupus erythematosus (SLE), six with rheumatoid arthritis (RA), eight with idiopathic inflammatory myopathies (IIM), and their same-gendered unaffected twins, were enrolled. Comparisons were made between discordant twin pairs and these were also each compared to 40 unrelated control subjects (matched 2:1 to each twin by age, gender and ethnicity) using statistical and molecular pathway analyses. Relative quantitative PCR was used to verify independently measures of differential gene expression assessed by microarray analysis.\r\n\r\nResults\r\nProbands and unrelated, matched controls differed significantly in gene expression for 104 probes corresponding to 92 identifiable genes (multiple-comparison adjusted P values < 0.1). Differentially expressed genes involved several overlapping pathways including immune responses (16%), signaling pathways (24%), transcription/translation regulators (26%), and metabolic functions (15%). Interferon (IFN)-response genes (IFI27, OASF, PLSCR1, EIF2AK2, TNFAIP6, and TNFSF10) were up-regulated in probands compared to unrelated controls. Many of the abnormally expressed genes played regulatory roles in multiple cellular pathways. We did not detect any probes expressed differentially in comparisons among the three SAID phenotypes. Similarly, we found no significant differences in gene expression when comparing probands to unaffected twins or unaffected twins to unrelated controls. Gene expression levels for unaffected twins appeared intermediate between that of probands and unrelated controls for 6535 probes (32% of the total probes) as would be expected by chance. By contrast, in unaffected twins intermediate ordering was observed for 84 of the 104 probes (81%) whose expression differed significantly between probands and unrelated controls.\r\nConclusions\r\nAlterations in expression of a limited number of genes may influence the dysregulation of numerous, integrated immune response, cell signaling and regulatory pathways that are common to a number of SAID. Gene expression profiles in peripheral blood suggest that for genes in these critical pathways, unaffected twins may be in a transitional or intermediate state of immune dysregulation between twins with SAID and unrelated controls, perhaps predisposing them to the development of SAID given the necessary and sufficient environmental exposures....
Induction of tolerance against grafted organs is achieved by the immunosuppressive agent cyclosporine, a prominent member of the calcineurin inhibitors. Unfortunately, its lifetime use is associated with hypertension and nephrotoxicity. Several mechanism for cyclosporine induced hypertension have been proposed, i.e. activation of the sympathetic nervous system, endothelin-mediated systemic vasoconstriction, impaired vasodilatation secondary to reduction in prostaglandin and nitric oxide, altered cytosolic calcium translocation, and activation of the renin-angiotensin system (RAS). In this regard the molecular basis for undue RAS activation and an increased signaling of the vasoactive oligopeptide angiotensin II (AngII) remain elusive. Notably, angiotensinogen (AGT) is the precursor of AngII and transcriptional regulation of AGT is controlled by the hepatic nuclear factor HNF4alpha. To better understand the molecular events associated with cyclosporine induced hypertension, we investigated the effect of cyclosporine on HNF4alpha expression and activity and searched for novel HNF4alpha target genes among members of the RAS cascade. Using bioinformatic algorithm and EMSA bandshift assays we identified angiotensin II receptor type 1 (AGTR1), angiotensin I converting enzyme (ACE), and angiotensin I converting enzyme 2 (ACE2) as genes targeted by HNF4alpha. Notably, cyclosporine represses HNF4alpha gene and protein expression and its DNA-binding activity at consensus sequences to AGT, AGTR1, ACE, and ACE2. Consequently, the gene expression of AGT, AGTR1, and ACE2 was significantly reduced as evidenced by quantitative real-time RT-PCR. While RAS is composed of a sophisticated interplay between multiple factors we propose a decrease of ACE2 to enforce AngII signaling via AGTR1 to ultimately result in vasoconstriction and hypertension. Taken collectively we demonstrate cyclosporine to repress HNF4alpha activity through calcineurin inhibitor mediated inhibition of nuclear factor of activation of T-cells (NFAT) which in turn represses HNF4alpha that leads to a disturbed balance of RAS....
Distribution of drugs into the brain is strictly regulated by the presence of the blood-brain barrier that is formed by brain capillary endothelial cells. Since the endothelial cells are connected to each other by tight junctions and lack pores and/or fenestrations, compounds must cross the membranes of the cells to enter the brain from the bloodstream. The blood–brain barrier forms an interface between the circulating blood and the brain and possesses various carrier-mediated transport systems for small molecules to support and protect central nervous system functions. For example, the blood-to-brain influx transport systems supply nutrients, such as glucose and amino acids. Consequently, xenobiotic drugs recognized by influx transporters are expected to have high permeability across the blood brain barrier. On the other hand, efflux transporters, including ATP-binding cassette transporters such as P-glycoprotein located at the luminal membrane of endothelial cells, function as clearance systems for metabolites and neurotoxic compounds produced in the brain. Drugs recognized by these transporters are expected to show low Blood Brain Barrier permeability and low distribution to the brain. Because of the physiological nature of the blood brain barrier, transport of chemical compounds between blood and brain has been widely believed to occur by means of passive diffusion, depending upon the lipophilicity of the compounds. However, discrepancies exist between the lipophilicity and apparent blood brain barrier permeation properties in many cases, such as hydrophilic drugs and these discrepancies can be ascribed to the existence of multiple mechanisms of drug transport through the blood brain barrier. So, for efficient supply of drugs and endogenous substances, the blood brain barrier is equipped with membrane transport systems and some of those transporter proteins have been shown to accept drug molecules and transport them into brain. Molecular identification and functional analysis of influx transport proteins (from blood to brain) and efflux transport proteins (from brain to blood) have progressed rapidly. Therefore, the blood brain barrier is now considered to be a dynamic interface that controls the influx and efflux of a wide variety of substances, including endogenous nutrients and exogenous compounds such as drugs, to maintain a favorable environment for the central nervous system. This review describes mainly the transporters that are involved in drug transfer across the blood brain barrier and have been molecularly identified. The transport systems described include transporters for amino acids, monocarboxylic acids, organic cations, hexoses, nucleosides, and peptides, as well as on strategies to increase drug delivery into the brain by blocking efflux transport protein function, or to reduce central nervous system side effects by modulating blood brain barrier transport processes. This review also will discuss the role of the blood brain barrier in various neuroinflammatory diseases....
5-fluorouracil (5-FU) is widely used in chemotherapy for gastric and colorectal cancer, but gemcitabine (GEM), and not 5-FU, is approved as a standard drug for use in pancreatic cancer. Interindividual variation in the enzyme activity of the GEM metabolic pathway can affect the extent of GEM metabolism and the efficacy of GEM chemotherapy. Human equilibrative nucleoside transporter 1 (hENT1) is recognized as a major transporter of GEM into cells. In addition, a factor that activates hENT1 is the inhibition of thymidylate synthase (TS), one of the 5-FU metabolic enzymes; TS inhibition mediates depleting intracellular nucleotide pools, resulting in the activation of the salvage pathway mediated through hENT1. In this paper, the role of 5-FU in GEM-based chemotherapy for pancreatic cancer is discussed with special emphasis on enzymes involved in the 5-FU and GEM metabolic pathways and in the correlation between GEM responsiveness and the expression of 5-FU and GEM metabolic enzymes....
Since the approval of artemisinin-based therapies for the treatment of uncomplicated and severe malaria in Africa by World Health organization in 20041, millions of people in Africa and elsewhere in the world especially in Asia use artemisinin based antimalarial drugs to treat malaria2, 4. The Canadian recommendations for the prevention and treatment of malaria among international travelers noted that by the year 2000 there have been two human cases of complete heart block associated with the use of artemisinin but most volunteer and clinical studies have found no evidence of cardiac or other toxicity1. The present study evaluated the effect of orally administered dihydroartemisinin (DHA) on the activities of serum alanine amino transferase, serum aspartate amino transferase and alkaline phosphatase.The effect of Dihydroartemisinin administration on the activities of these three serum enzymes were investigated with 5 oral dosage regiments of DHA which were 1mg/kg, 2mg/kg, 60mg/kg, 80mg/kg and a dosage of 1mg/kg which was given twice to a group of rat with a one week resting interval.. The results obtained from the assay of the three enzymes with the whole blood collected from the DHA-treated and control rats showed that the activities of these three enzymes were neither elevated nor depressed by DHA treatment. Histopathological examination of the liver and heart of these DHA treated rats confirmed that DHA treatment did not adversely affect the liver and heart of the rats5. The study concludes that dihydroartemisinin does not interfere with the activities of serum enzymes and this is one of the attributes that contribute to the safety of oral dihydroartemisinin....
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