GRP78 enabled micelle-based glioma targeted drug delivery.

GRP78, a specific cancer cell-surface marker, is implicated in cancer cells proliferation, apoptosis resistance, metastasis and drug resistance. l-VAP (SNTRVAP) is a tumor homing peptide exhibiting high binding affinity in vitro to GRP78 protein overexpressed on glioma, glioma stem cells, vasculogenic mimicry and neovasculature. Even though short peptides are often non-immunogenic and demonstrate high affinity to tumor cells, their targeting efficacy is always undermined by rapid blood clearance and enzymatic degradation. In the present study, two d peptides RI-VAP (retro inverso isomer of l-VAP) and d-VAP (retro isomer of l-VAP) were developed by structure-guided peptide design and retro-inverso isomerization technique for glioma targeting. RI-VAP and d-VAP were predicted to bind their receptor GRP78 protein with similar binding affinity, which was experimentally confirmed. The results of in vivo imaging demonstrated that RI-VAP and d-VAP had remarkably advantage over l-VAP for tumor accumulation. In addition, RI-VAP and d-VAP modified paclitaxel-loaded polymeric micelle had better anti-tumor efficacy in comparison to taxol, paclitaxel-loaded plain micelles and l-VAP modified micelles. Overall, the VAP modified micelles suggested in the present study could effectively achieve glioma-targeted drug delivery, validating the potential of the stable VAP peptides in improving the therapeutic efficacy of paclitaxel for glioma.

Effect of royal jelly on serum trace elements in rats undergoing head and neck irradiation.

OBJECTIVES: This study aims to investigate the effects of radiation on serum trace elements and the changes in these elements as induced by royal jelly in rats undergoing head and neck irradiation. MATERIALS AND METHODS: Thirty-two Sprague-Dawley male rats at the age of eight weeks with a mean weight of 275±35 g were included in the study. Subjects were divided into four groups with eight rats in each group: group 1: controls (C), group 2: radiation-only (RT), group 3: radiation plus royal jelly 50 mg/kg (RT+RJ50) and group 4: royal jelly 50 mg/kg-only (RJ50). Radiotherapy was applied to the head and neck area by single fraction at a dose of 22 Gy. The royal jelly was given once daily for seven days. The subjects were sacrificed on the seventh day of the study. Trace elements in blood samples were measured using ICP/MS method. RESULTS: When the trace element levels among the groups were compared using ANOVA test, a statistically significant difference was found in Al, As, Ca, Cd, Cr, K, Mg, Pb, Se, and Sn levels (p<0.05). No significant difference was found in the levels of Ag, Ba, Co, Cs, Cu, Fe, Ga, Hg, Mn, Na, Ni, Rb, Sr, Ti, U, V, and Zn (p>0.05). It was observed that oxidative stress was reduced in the radiation plus royal jelly group, compared to the radiation-only group. CONCLUSION: Our study results suggest that head and neck irradiation increases oxidative stress, leading to some changes in the trace element levels, while royal jelly exhibits a protective effect against the oxidative stress induced by radiation.

Evidence for a role of GABA and Mas-allatotropin in photic entrainment of the circadian clock of the cockroach Leucophaea maderae.

Accumulating evidence suggests that the accessory medulla is the location of the circadian pacemaker in the fruit fly Drosophila melanogaster and the cockroach Leucophaea maderae. gamma-Aminobutyric acid (GABA) and Mas-allatotropin are two putative neurotransmitters, in the accessory medulla in the cockroach Leucophaea maderae. Neurons immunoreactive to the neuropeptide Mas-allatotropin are local neurons with arborizations in the noduli of the accessory medulla, while GABA-immunoreactive neurons connect the noduli of the accessory medulla to the medulla and to the lamina via processes in the distal tract. Injections of GABA and Mas-allatotropin into the vicinity of the accessory medulla resulted in stable phase-dependent resetting of the circadian locomotor activity of the cockroach. The resulting phase response curves closely matched light-dependent phase response curves, suggesting that both substances play a role in circuits relaying photic information from circadian photoreceptors to the central pacemaker.

Adipokinetic hormone stimulates neurones in the insect central nervous system.

A simple preparation designed to screen and compare the central action of putative neuroactive agents in the moth Manduca sexta is described. This approach combines microinjections into the central nervous system with myograms recorded from a pair of spontaneously active mesothoracic muscles. Pressure injection of either octopamine or Manduca adipokinetic hormone (M-AKH) into the mesothoracic neuropile increases the monitored motor activity. Under the conditions used, the excitatory effects of M-AKH exceed those of the potent neuromodulator octopamine. This suggests that M-AKH plays a role in the central nervous system in addition to its known metabolic functions and supports recent evidence that neuropeptides in insects can be multifunctional.

Stimulation of glycogenolysis by three locust adipokinetic hormones involves Gs and cAMP.

Insect adipokinetic hormones (AKHs) have been shown to mobilize fat body carbohydrate by glycogen phosphorylase activation. In this study, the signal transduction pathways of AKH-I, -II and -III from the migratory locust are further elucidated. We show that the AKHs enhance fat body cAMP levels in vitro. For all hormones, maximal levels are reached after 1 min and correspond to a 200% increase compared to resting levels. Although cAMP levels induced by massive doses of AKH-I, -II and -III are equal, AKH-III is the most potent when applied in a physiological dose. This difference in potency also applies to glycogen phosphorylase activation. Cholera toxin (CTX) likewise ennhaces cAMP levels and phosphorylase activity, however pertussis toxin (PTX) has no effect. Increases induced by CTX and AKH are not additive, suggesting that they share the same pathway. Phosphorylase activation by the AKHs is strongly attenuated by guanosine-5'-O-(2-thiodiphosphate) (GDP beta S). These results demonstrate a role for cAMP in AKH signal transduction and indicate that the AKH receptor(s) are coupled to cAMP formation and glycogen phosphorylase activation via the stimulatory guanine nucleotide-binding protein (Gs).

Eclosion hormone-stimulated cGMP levels in the central nervous system of Manduca sexta: inhibition by lipid metabolism blockers, increase in inositol(1,4,5)trisphosphate and further evidence against the involvement of nitric oxide.

Previous studies have shown that the neuropeptide, eclosion hormone, stimulates a nitric oxide-independent increase in the levels of cGMP in the nervous system of Manduca sexta. By contrast, recent results in Bombyx mori suggest that eclosion hormone increases cGMP via the production of nitric oxide. In view of these conflicting results we have carried out additional studies to test whether nitric oxide is involved in this process in Manduca. Evidence presented here supports our earlier observations that in Manduca the eclosion hormone-stimulated increase in cGMP is nitric oxide- and carbon monoxide-independent. In addition, we show that a wide variety of inhibitors of lipid metabolism block the eclosion hormone-stimulated cGMP increase. This supports the hypothesis that the activation of the guanylate cyclase is mediated by a lipid messenger. We also show that eclosion hormone stimulates an increase in the levels of inositol(1,4,5)trisphosphate. The time-course of this increase is consistent with the hypothesis that eclosion hormone stimulation of a phospholipase C is an early event in the cascade that results in an increase in cGMP. Receptor-mediated lipid hydrolysis is often mediated by G protein-coupled receptors. Experiments using pertussis toxin show that the eclosion hormone-stimulated increase in cGMP is not mediated by a pertussis toxin-sensitive G protein.

Structure-activity relationships on hyperglycemia by representatives of the adipokinetic/hyperglycemic hormone family in Blaberus discoidalis cockroaches.

Several members of the adipokinetic/hyperglycemic neurohormone family from several different invertebrate species have been prepared by solid-phase peptide synthesis and assayed by a modified in vivo hyperglycemic bioassay in Blaberus discoidalis cockroaches. The hypertrehalosemic hormone (HrTH) is the endogenous hypertrehalosemic factor for B. discoidalis and was the most potent peptide in the assay. The more divergent the sequence of a family member from Blaberus HrTH, the less potent was the bioanalog. Manduca adipokinetic hormone is the most divergent peptide of the family and was totally inactive in the bioassay. Locusta adipokinetic hormone I had reduced maximum activity in the assay, which suggests that Ser5 is an important residue for the transduction of the hyperglycemic response. The direct relation between bioanalog similarity to Blaberus HrTH sequence and potency suggests that the hormone and target cell receptor for HrTH have evolved to maintain an "optimal fit".

Effects of magainins and cecropins on the sporogonic development of malaria parasites in mosquitoes.

Magainins and cecropins are families of peptides with broad antimicrobial and antiparasitic activities derived respectively from the skin of frogs or from giant silk moths. In insects, cecropins function as part of an inducible immune system against a number of bacterial infections. When injected into anopheline mosquitoes previously infected with a variety of Plasmodium species, both magainins and cecropins disrupt sporogonic development by aborting the normal development of oocysts; sporozoites are not formed and the vector cannot transmit the parasite to another host. It may be possible to induce effective transmission-blocking immunity in the mosquito vector by the introduction and expression of genes coding for magainins, cecropins, or similarly acting parasiticidal peptides into the mosquito genome.