Targeted drug delivery of magnetic microbubble for abdominal aortic aneurysm: an in silico study

Biomechanics and Modeling in Mechanobiology - Targeted drug delivery (TDD) to abdominal aortic aneurysm (AAA) using a controlled and efficient approach has recently been a significant challenge. In...     

Targeted-nanoliposomal combretastatin A4 (CA-4) as an efficient antivascular candidate in the metastatic cancer treatment

A number of antiangiogenic drugs have been approved by the Food and Drug Administration which are used in cancer therapy, and variety of other agents in several stages of clinical development or in preclinical assessment. Among these, combretastatin A4 (CA-4) is an under-researched inhibitor of angiogenesis that shows potential activity in the treatment of advanced tumors with migration capacity. However, its clinical application has been limited due to poor water solubility, low bioavailability, rapid metabolism, and systemic elimination. During the last decade, numerous investigations have been done to overcome these problems by using different CA-4 delivery systems or developing produgs of CA-4 or its structural analogs. Nevertheless, these strategies could not be efficient out of the undesired side effects on normal tissues. Nanoliposomal CA-4 not only benefits from the advantage of using liposomal drugs as opposed to free drugs but also can accumulate in the tumor site via specific targeting ligands, which leads to efficient targeting and enhancement of bioavailability. To the best of our knowledge, we consider an important attempt to understand different factors that might influence the CA-4 loading and release pattern of liposomes and the consequent results in tumor therapy. In this review, we shed light on various studied liposomal CA-4 formulations showing application thereof in cancer treatment.     

Light and electron microscope studies of effects of 50 Hz electromagnetic fields on preincubated chick embryo

We investigated the effects of an electromagnetic field (EMF) of 50 Hz, 1.33-7.32 mT on sections of preincubated white leghorn chicken embryos using light, SEM and TEM microscopes. Five hundred healthy, fresh, and fertilized eggs (55-65 g) were divided into three groups of experimental (n = 18-20), control (n = 60), and sham (n = 50). Experimental eggs (inside the coil) were exposed to 15 different intensities (1.33-7.32 mT) for morphological surveys and to the known most effective intensities for light, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) studies. Sham groups were located inside the same coil with no exposure for 24 h before incubation. Control, sham, and experimental groups were then incubated in an incubator (38 +/- 0.5 degrees C, 60% humidity) for 4 days. At the end of this period, embryos were removed from their shells, prepared for morphometric, light, and SEM/TEM studies. Results of light microscopic studies (serial sections, 6mu) and morphometric data showed significant differences between different groups (P < 0.005). Larger and abnormal brain cavities, spina bifida, monophthalmia, microphthalmia, anophthalmia, and growth retardation were shown on SEM. TEM sections demonstrated that the nucleus was condensed, the nuclear envelope disappeared, and mitochondria degenerated. Golgi apparatus and endoplasmic reticulum were the least affected organelles. The Telencephlon was the most affected region, and the retina was altered more than the lens. We conclude that EMFs affect the brain, especially the Telencephalon and eye of preincubated-exposed chick embryo at the morphological and cellular level, nuclei are the most affected part, and our data agrees with "Ubeda's windows effects" of EMFs on preincubated chick embryos.     

Early patterned stimulation leads to changes in adult behavior and gene expression in C. elegans

Across phylogeny, early experience plays a critical role in nervous system development. In these experiments, we investigated the long-term effects that specific patterns of sensory experience during development had on the biology and function of the Caenorhabditis elegans nervous system. The delivery of a specific pattern of mechanosensory stimulation in the first larval stage (L1) produced significant enhancement in the tap withdrawal behavioral response, expression patterns of an ionotropic glutamate receptor (iGluR) subunit and mRNA levels for that receptor in 3-day-old adult worms and a depression of these same three measures in 5-day-old adult worms. A critical period for the 3-day enhanced behavior and GLR distribution was observed in L1, whereas there was no critical period for the depressed effects observed in 5-day-old worms. The spaced pattern of stimulation was essential for expression of this effect: Various forms of massed training produced neither the enhancement at 3 days nor the depression at 5 days. The 5-day depressed behavioral response had many features in common with long-term memory, including sensitivity to disruption following retrieval. The different behavioral and molecular effects that early patterned mechanosensory stimulation produced in 3 and 5-day-old worms led us to hypothesize that separate cellular phenomena produced the enhanced 3-day and depressed 5-day behaviors and molecular effects.     

A novel mechanism of iron-core formation by Pyrococcus furiosus archaeoferritin, a member of an uncharacterized branch of the ferritin-like superfamily

Storage of iron in a nontoxic and bioavailable form is essential for many forms of life. Three subfamilies of the ferritin-like superfamily, namely, ferritin, bacterioferritin, and Dps (DNA-binding proteins from starved cells), are able to store iron. Although the function of these iron-storage proteins is constitutive to many organisms to sustain life, the genome of some organisms appears not to encode any of these proteins. In an attempt to identify new iron-storage systems, we have found and characterized a new member of the ferritin-like superfamily of proteins, which unlike the multimeric storage system of ferritin, bacterioferritin, and Dps is monomeric in the absence of iron. Monomers catalyze oxidation of Fe(II) and they store the Fe(III) product as they assemble to form structures comparable to those of 24-meric ferritin. We propose that this mechanism is an alternative method of iron storage by the ferritin-like superfamily of proteins in organisms that lack the regular preassociated 24-meric/12-meric ferritins.     

Embryogenic callus culture of Tribulus terrestris L. a potential source of harmaline, harmine and diosgenin

In the present study, a simple one medium formulation protocol for callus culture, somatic embryogenesis and in vitro production of β-carboline alkaloids and diosgenin in Tribulus terrestris L. was developed. Extensive callus induction and proliferation was obtained in leaf explant on Murashige and Skoog (MS) medium supplemented with 5.0 μM 6 benzyl adenine (BA) and 2.5 μM α-naphthaleneacetic acid (NAA). The embryogenic callus was maintained on subculture to fresh parental medium at 4-week intervals over a period of 28 months. The frequency of embryo formation was at a maximum (18.1 ± 0.9 per g of callus) on MS medium containing 5.0 μM BA and 2.5 μM NAA together with 75 mg l⁻¹ casein hydrolysate. Globular embryo developed into torpedo stage embryo under the influence of starvation. The accumulation of β-carboline alkaloids (harmaline and harmine) and steroidal saponin (diosgenin) in non-embryogenic and embryogenic callus culture derived from leaf explant was compared with root, leaf, stem, and fruit of the mother plant. The embryogenic callus accumulated equivalent amounts of harmaline (66.4 ± 0.5 μg/g dry weight), harmine (82.7 ± 0.6 μg/g dry weight), and diosgenin (170.7 ± 1.0 μg/g dry weight) to that of the fruit of T. terrestris. The embryogenic callus culture of this species might offer a potential source for production of important pharmaceuticals.     

Heterologous expression,purification and characterization of the influenza A virus <Emphasis Type="Italic">M2e</Emphasis> gene fused to <Emphasis Type="Italic">Mycobacterium tuberculosis</Emphasis> HSP70<Subscript>359–610</Subscript> in prokaryotic system as a fusion protein

One of the concerns about influenza A vaccine based on M2e protein is their limited potency; hence, optimal approaches to enhance immunogenicity of M2e protein immunization remain to be established. It seems by linking this M2e-peptide to an appropriate carrier such as mycobacterium tuberculosis C-terminal 28-kDa domain of HSP70 (HSP70_359–610), we can render it very immunogenic. According to previous reports, this study was designed to produce a novel influenza A virus recombinant fusion protein consisted of M2e, a potent immunogenic protein from influenza A virus, fused to C-terminal domain of mycobacterium tuberculosis HSP70, HSP70_359–610, as a carrier and adjuvant. We fused the genes of M2e and HSP70 _359–610 then inserted in pQE-60, prokaryotic expression vector. This recombinant fusion protein with a 6xHis-tag was successfully over expressed in Escherichia coli M-15. The recombinant fusion protein was purified by Ni–NTA affinity chromatography under denaturing conditions, followed by urea gradient dialysis. The purified fusion protein was analyzed on SDS–PAGE. Western blot assay was used to examine the immunoreaction of the expressed protein using commercial penta-His HRP conjugate antibody. The antigenicity and biological activity of the recombinant protein was also qualitatively detected on the infected MDCK cells surface by immunofluorescence and cell-ELISA assay using rabbit’s immunized antiserum. This observation suggest that the expressed fusion protein is useful as a universal recombinant vaccine for overcoming highly mutational influenza virus, but more immunological study in animal lab remains to be evaluated.     

Novel rearranged abietane diterpenoids from the roots of Salvia sahendica

Two naphthoquinone diterpenoids, 1 and 2, one tricyclic, and one tetracyclic rearranged abietane ('4,5-seco-10,5-friedo-abietane') diterpenoids, 3 and 4, respectively, together with horminone (5) have been isolated from the roots of Salvia sahendica. Compounds 2 and 3 are new, and the 13C-NMR assignment for compound 4 was modified using ' Heteronuclear Multiple-Bond Correlation' (HMBC) spectroscopic data. The structures of the compounds have been established by using different spectral data including 1D- and 2D-NMR, IR, UV, and MS. The elemental composition for the major peaks of 3 and 4 were determined by ' High-Resolution Electron Impact Mass Spectrometry' (HR-EI-MS). The relative configurations of the new compounds were determined by 1H-NMR and 'Rotating-Frame NOES' (ROESY) spectroscopy. Compounds 1, 2, and 5 showed antifungal activities when tested on Blakeslea trispora. Lapachol, a prelynated naphthoquinone, was used as a positive control. The biological activities of the related naphthoquinones and abietane diterpenoids were discussed.     

(-)-Epigallocatechin-3-gallate induced apoptosis by dissociation of c-FLIP/Ku70 complex in gastric cancer cells

Anti-cancer properties of (-)-epigallocatechin-3-gallate (EGCG) are mediated via apoptosis induction, as well as inhibition of cell proliferation and histone deacetylase. Accumulation of stabilized cellular FLICE-inhibitory protein (c-FLIP)/Ku70 complex in the cytoplasm inhibits apoptosis through interruption of extrinsic apoptosis pathway. In this study, we evaluated the anti-cancer role of EGCG in gastric cancer (GC) cells through dissociation of c-FLIP/Ku70 complex. MKN-45 cells were treated with EGCG or its antagonist MG149 for 24 h. Apoptosis was evaluated by flow cytometry and quantitative RT-PCR. Protein expression of c-FLIP and Ku70 was analysed using western blot and immunofluorescence. Dissociation of c-FLIP/Ku70 complex as well as Ku70 translocation were studied by sub-cellular fractionation and co-immunoprecipitation. EGCG induced apoptosis in MKN-45 cells with substantial up-regulation of P53 and P21, down-regulation of c-Myc and Cyclin D1 as well as cell cycle arrest in S and G2/M check points. Moreover, EGCG treatment suppressed the expression of c-FLIP and Ku70, decreased their interaction while increasing the Ku70 nuclear content. By dissociating the c-FLIP/Ku70 complex, EGCG could be an alternative component to the conventional HDAC inhibitors in order to induce apoptosis in GC cells. Thus, its combination with other cancer therapy protocols could result in a better therapeutic outcome.