Drug targeting to the brain using avidin-biotin technology in the mouse; (blood-brain barrier, monoclonal antibody, transferrin receptor, Alzheimer's disease)

A beta1-40 peptide radiopharmaceuticals could be used to image A beta brain amyloid in transgenic mouse models of Alzheimer's disease should the A beta peptide radiopharmaceutical be made transportable through the blood-brain barrier (BBB) in vivo. The present studies used the RI7-217 rat monoclonal antibody to the mouse transferrin receptor as a BBB drug targeting vector for the delivery to brain of A beta1-40 radiolabeled with either 125-Iodine or 111-Indium. The A beta peptide radiopharmaceutical is conjugated to the RI7 MAb using avidin biotin technology, wherein the A beta1-40 peptide radiopharmaceutical is monobiotinylated (bio) and bound to a conjugate of the RI7 MAb and streptavidin (SA). The [125 I]-bio-A beta1-40 or the [111 In]-bio-A beta1-40 either free or bound to the RI7/SA conjugate was injected intravenously into anesthetized adult mice and plasma pharmacokinetics and organ uptake were measured over the next 60 minutes. The A beta1-40 peptide radiopharmaceutical radiolabeled with 111-Indium was the preferred formulation, compared to peptide labeled with 125-Iodine, because there was a greater metabolic stability and reduced artifactual organ uptake of metabolites associated with the use of the 111-Indium nuclide. However, biotinylated A beta1-40 peptide radiopharmaceuticals conjugated to the RI7/SA brain drug targeting system were metabolically unstable in mice in vivo owing to active biotinidase activity. Future work involving brain drug targeting in mice that utilizes avidin biotin technology will need to incorporate biotin analogues that are resistant to biotinidase.     

The beneficial effect of ATP-MgCl(2) on hepatic ischemia/reperfusion-induced mitochondrial dysfunction

The present study was undertaken to determine whether ATP-MgCl(2) administration in rats could protect hepatic mitochondrial function and improve energy metabolism during hepatic ischemia and subsequent reperfusion. Global hepatic ischemia was produced for 60 min followed by reperfusion. The rats then received 0.5 ml of saline or ATP-MgCl(2) intravenously. In saline-treated ischemic rats, serum alanine-aminotransferase levels peaked at 5 h. The aminotransferase level was significantly reduced in the ATP-MgCl(2) treatment group. The wet weight-to-dry weight ratio of the liver was significantly increased by ischemia/reperfusion. ATP-MgCl(2) treatment minimized the increase in this ratio. The ketone body ratio in blood, which reflects the mitochondrial free NAD(+)/NADH ratio, decreased after ischemia and at 1 h following reperfusion. This decrease was somewhat improved by ATP-MgCl(2) infusion. At 1 and 5 h after reperfusion, mitochondrial monoamine oxidase and glutamate dehydrogenase activities decreased. ATP-MgCl(2) infusion following ischemia restored the lost activities. Hepatic ATP levels in saline-treated rats were found to be 50% lower 5 h following reperfusion; however, treatment with ATP-MgCl(2) resulted in significantly higher ATP levels and energy charge. The accumulation of purine catabolites in ischemic tissues was reduced during reperfusion. ATP-MgCl(2) infusion resulted in accumulation of adenosine in reperfused liver. Mitochondrial lipid peroxidation was elevated in the saline-treated ischemic group, but this elevation was inhibited by ATP-MgCl(2) infusion. The present results lead us to conclude that the amelioration of liver function which occurs with ATP-MgCl(2) infusion following ischemia may be mediated through improvement in ischemia-induced mitochondrial energy metabolism.     

Comparison of IY81149 with omeprazole in rat reflux oesophagitis

1. This study was aimed at evaluating the effects of IY81149[2-[[(4methoxy-3-methyl)-2-pyridinyl]methylsulfinyl]-5-(1H-pyrrol-1-yl)-1H-benzimidazole], a new proton pump inhibitor, on the development of the surgically induced reflux oesophagitis, on gastric secretion and on lipid peroxidation which is a marker of oxidative stress. Omeprazole was used as a reference drug. We furthermore investigated the influence of quercetin and desferrioxamine (DFO) on the development of the surgically induced reflux oesophagitis in rats on gastric secretion and on lipid peroxidation. 2. IY81149 and omeprazole significantly prevented the development of reflux oesophagitis and gastric secretion in a dose-dependent manner. The ED50 values of IY81149 for inhibition of oesophagitis and volume of gastric secretion were lower than of omeprazole (5.7 vs. 14.2 micromol, 15.3 vs. 24.0 micromol, respectively). IY81149 was also more potent in the acid output inhibition with an ED50 of 6.8 micromol compared with 20.8 micromol of omeprazole. 3. Malonyldialdehyde (MDA) content, the end product of lipid peroxidation, increased significantly in the oesophageal mucosa after the induction of reflux oesophagitis. IY81149 and omeprazole significantly and dose-dependently prevented lipid peroxidation. Quercetin (200 mg kg-1, p.o.) and DFO (800 mg kg-1, i.d.) significantly prevented the development of reflux oesophagitis and inhibited the lipid peroxidation independent of their actions on gastric secretion. 4. This result suggests that IY81149 is comparable with omeprazole in the treatment of reflux oesophagitis.     

Characteristics of intestinal absorption and disposition of glycyrrhizin in mice

As basic studies to apply an intestinal pressure-controlled colon delivery capsule (PCDC) for glycyrrhizin (GZ), the characteristics of intestinal absorption and disposition of GZ were investigated in mice. In the in vivo study, after intravenous (iv) administration of GZ, 10 mg/kg dose, plasma GZ disappeared from the systemic circulation with t(1/2(alpha)) of 0.0063 h, thereafter, it slowly declined with t(1/2(beta)) of 15.23 h. The area under the plasma drug concentration versus time curve (AUC) values of iv (10 mg/kg), intracolonic (50 mg/kg) and intraduodenum (50 mg/kg) administrations were 115.1, 16.7 and 2.7 microgh/mL, respectively. The AUC values of plasma glycyrrhetic acid (GA), a degradation product after intracolonic and intraduodenum administrations were 2.8 and 8.4 microgh/mL, respectively. In the in situ closed loop study, the concentrations of GZ in plasma and liver after intracolonic administration were significantly increased (p<0.05) in comparison with those after intrajejunum or intraileum administration, while the concentration of GA in plasma and liver after intracolonic administration had trends to increase. These observations clearly suggest that the intracolonic administration is a useful way to improve the oral bioavailability of GZ and to enhance its pharmacological efficacy. These pharmacokinetic results of GZ suggest that GZ is a subject drug to be applied for the PCDC system we previously developed. The PCDCs formulation of GZ will enable us to carry GZ to the colon and enhance the oral bioavailability of GZ.     

Hyaluronidase inhibitory active 6H-dibenzo[b,d]pyran-6-ones from the feces of Trogopterus xanthipes

Bioassay-guided fractionation of the MeOH extract of Pteropi faeces (the feces of Trogopterus xanthipes Milne-Edwards) furnished three hyaluronidase inhibitory active 6H-dibenzo[b,d]-pyran-6-ones (1-3), together with a new compound, 3,8,10-trihydroxy-6H-dibenzo[b,d]pyran-6-one (4). Their structures were established on the basis of the spectroscopic methods.     

Retraction: Radio frequency triggered curcumin delivery from thermo and pH responsive nanoparticles containing gold nanoparticles and its in vivo localization studies in an orthotopic breast tumor model

Retraction of ‘Radio frequency triggered curcumin delivery from thermo and pH responsive nanoparticles containing gold nanoparticles and its in vivo localization studies in an orthotopic breast tumor model’ by N. Sanoj Rejinold et al., RSC Adv., 2014, 4, 39408–39427, DOI: 10.1039/C4RA05727A.

We, the named authors, hereby wholly retract this RSC Advances article due to duplication of images in Fig. 9–12, 15, 18 and 19, which affect the reliability of the data and the overall conclusions presented in the published article.Signed: N. Sanoj Rejinold, Reju George Thomas, Muthunarayanan Muthiah, K. P. Chennazhi, In-Kyu Park, K. Manzoor and R. Jayakumar, 24th July 2020.Yong Yeon Jeong was contacted but did not respond.Retraction endorsed by Laura Fisher, Executive Editor, RSC Advances.     

Preoperative evaluation of hepatic arterial and portal venous anatomy using the time resolved echo-shared MR angiographic technique in living liver donors

The purpose of this study was to determine whether MR angiography utilizing the time resolved echo-shared angiographic technique (TREAT) can provide an effective assessment of the hepatic artery (HA) and portal vein (PV) in living donor candidates. MR angiography (MRA)was performed in 27 patients (23 men and 4 women; mean age, 31 years) by using TREAT. Two blinded radiologists evaluated HA anatomy, origin of segment IV feeding artery and PV anatomy in consensus. Qualitative evaluations of MRA images were performed using the following criteria: (a) overall image quality, (b) presence of artifacts, and (c) degree of venous contamination of the arterial phase. Using intraoperative findings as a standard of reference, the accuracy for the HA anatomy, origin of segment IV feeding artery and PV anatomy on TREAT-MRA were 93% (25/27), 85% (23/27), and 96% (26/27), respectively. Overall image qualities were as follows: excellent (n=22, 81%), good (n=4, 15%), and fair (n=1, 4%). Significant artifacts or venous contamination of the arterial phase images was not noted in any patient. TREAT-MRA can provide a complete evaluation of HA and PV anatomy during preoperative evaluation of living liver donors. Furthermore, it provides a more detailed anatomy of the HA without venous contamination.