Iron and Porphyrin Trafficking in Heme Biogenesis

Iron is an essential element for diverse biological functions. In mammals, the majority of iron is enclosed within a single prosthetic group: heme. In metazoans, heme is synthesized via a highly conserved and coordinated pathway within the mitochondria. However, iron is acquired from the environment and subsequently assimilated into various cellular pathways, including heme synthesis. Both iron and heme are toxic but essential cofactors. How is iron transported from the extracellular milieu to the mitochondria? How are heme and heme intermediates coordinated with iron transport? Although recent studies have answered some questions, several pieces of this intriguing puzzle remain unsolved.     

Heterogeneous effects of cholecystokinin on neuronal response properties in deep layers of rat barrel cortex

Abstract

Cholecystokinin (CCK) is one of the most studied neuropeptides in the brain. In this study, we investigated the effects of CCK-8s and LY225910 (CCK₂ receptor antagonist) on properties of neuronal response to natural stimuli (whisker deflection) in deep layers of rat barrel cortex. This study was done on 20 male Wistar rats, weighing 230–260?g. CCK-8s (300?nmol/rat) and LY225910 (1?µmol/rat) were administered intracerebroventricularly (ICV). Neuronal responses to deflection of principal (PW) and adjacent (AW) whiskers were recorded in the barrel cortex using tungsten microelectrodes. Computer controlled mechanical displacement was used to deflect whiskers individually or in combination at 30?ms inter-stimulus intervals. ON and OFF responses for PW and AW deflections were measured. A condition-test ratio (CTR) was computed to quantify neuronal responses to whisker interaction. ICV administration of CCK-8s and LY225910 had heterogeneous effects on neuronal spontaneous activity, ON and OFF responses to PW and/or AW deflections, and CTR for both ON and OFF responses. The results of this study demonstrated that CCK-8s can modulate neuronal response properties in deep layers of rat barrel cortex probably via CCK₂ receptors.     

Age‐specific reference intervals for routine biochemical parameters in healthy neonates,infants, and young children in Iran

Age and sex need to be considered in the establishment of reference intervals (RIs), especially in early life when there are dynamic physiological changes. Since data for important biomarkers in healthy neonates and infants are limited, particularly in Iranian populations, we have determined age‐specific RIs for 7 laboratory biochemical parameters. This cross‐sectional study comprised a total of 344 paediatric participants (males: 158, females: 186) between the ages of 3 days and 30 months (mean age: 12.91 ± 7.15 months). Serum levels of creatinine, urea, uric acid, calcium, phosphate, vitamin D and high‐sensitivity C‐reactive protein (hs‐CRP) were measured using an Alpha classic‐AT plus auto‐analyser. We determined age‐specific RIs using CLSI Ep28‐A3 and C28‐A3 guidelines. No sex partitioning was required for any of the biomarkers. Age partitioning was required for kidney function tests and phosphate. The serum concentration of urea and creatinine increased with age, while phosphate and uric acid decreased with age. Age partitioning was not required for serum calcium, vitamin D, and hs‐CRP, which remained relatively constant throughout the age range. Age‐specific RIs for 7 routine biochemical markers were determined to address critical gaps in RIs in early life to help improve clinical interpretation of blood test results in young children, including neonates. Established age partitions demonstrate the biochemical changes that take place during child growth and development. These novel data will ultimately better disease management in the Iranian paediatric population and can be of value to clinical and hospital laboratories with similar populations.     

Evaluation of known and novel inhibitors of Orai1-mediated store operated Ca2+ entry in MDA-MB-231 breast cancer cells using a Fluorescence Imaging Plate Reader assay

The Orai1 Ca²⁺ permeable ion channel is an important component of store operated Ca²⁺ entry (SOCE) in cells. It’s over-expression in basal molecular subtype breast cancers has been linked with poor prognosis, making it a potential target for drug development. We pharmacologically characterised a number of reported inhibitors of SOCE in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader (FLIPR) assay, and show that the rank order of their potencies in this assay is the same as those reported in a wide range of published assays. The assay was also used in a screening project seeking novel inhibitors. Following a broad literature survey of classes of calcium channel inhibitors we used simplified ligand structures to query the ZINC on-line database, and following two iterations of refinement selected a novel Orai1-selective dichlorophenyltriazole hit compound. Analogues of this were synthesized and evaluated in the FLIPR assay to develop structure–activity relationships (SAR) for the three domains of the hit; triazole (head), dichlorophenyl (body) and substituted phenyl (tail). For this series, the results suggested the need for a lipophilic tail domain and an out-of-plane twist between the body and tail domains.     

Apolipoprotein E gene polymorphism and the risk of left ventricular dysfunction among Egyptian β-thalassemia major

In Egypt, β-thalassemia is the most common hereditary hemolytic anemia. Cardiac dysfunction, secondary to iron overload with formation of oxygen free radicals, is the most common cause of death in β-thalassemia patients. This study was designed to determine whether the allelic genotype of apolipoprotein E (Apo E), which exhibits antioxidant properties, could represent a genetic risk factor for the development of left ventricular (LV) dysfunction in β-thalassemia major. Fifty Egyptian β-thalassemia major patients were subjected to echocardiography to assess LV function. Apo E genotyping by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was done for all patients in addition to 50 age and sex matched healthy control subjects. Patients were classified into three groups. Group I and II were clinically asymptomatic. Group II subjects had evidence of LV dilatation, while Group III patients had clinical and echocardiographic findings of LV failure. Apo E4 allele was significantly higher among Group II and III than in controls. In conclusion, Apo E4 allele can be considered as a genetic risk factor for LV dysfunctions in β-thalassemic patients. It could be used as predictive indicator for additional risk of LV failure, particularly in asymptomatic patients with LV dilatation, requiring a closer follow-up, to prevent further disease progression.     

Seasonal patterns of egg parasitism and natural biological control of rice brown planthopper in Indonesia

1 Egg mortality is known to be an important factor in brown planthopper (BPH) (Nilaparvata lugens) population dynamics in tropical Asia, but few quantitative data are available on the role of egg parasitoids. 2 Field studies are reported at two sites in Java, Indonesia, over a period of 4 years in both wet and dry seasons, where no chemical pesticides were used. Rice plants previously infested in the laboratory with BPH eggs were exposed to natural parasitism and predation in experimental fields for periods of 5 days. 3 Egg batches were dissected from both experimental and control plants after field exposure at seven fortnightly intervals through the rice growing season and BPH nymphs and adult parasitoids were allowed to emerge. 4 Parasitism by species of Oligosita (Hymenopera, Trichogrammatidae) and Anagrus (Hym., Mymaridae) varied between 18% and 61% in dry, and from 1% to 65% in wet, seasons. There was generally a trend from low to higher rates through wet seasons, contrasting with more uniform higher levels through dry seasons. 5 Reduction in BPH survival as a result of egg parasitism varied between 29% and 91%. Generally parasitism was density independent. 6 It is suggested that lower initial levels of parasitism in dry seasons may be due to the longer fallow period between dry and wet, than between wet and dry, resulting in lower local populations of appropriate natural enemies. 7 Unlike previous studies in Asia, little evidence was found for egg predation as an important mortality factor. 8 The conservation of egg parasitoids should form part of any rice pest management programmes in tropical Asia.     

A novel ABCB11 mutation in an Iranian girl with progressive familial intrahepatic cholestasis

Progressive familial intrahepatic cholestasis is an autosomal recessive liver disorder caused by (biallelic) mutations in the ATP8B1 of ABCB11 gene. A nine-year-old girl with cholestasis was referred for genetic counseling. She had a family history of cholestasis in two previous expired siblings. Genetic analysis of the ABCB11 gene led to the identification of a novel homozygous mutation in exon 25. The mutation 3593- A > G lead to a missense mutation at the amino acid level (His1198Arg). This mutation caused PFIC2 due to abnormal function in the bile salt export pump protein (BSEP).