Use of tumor-associated antigens for cancer immunotherapy is limited due to their poor in vivo stability and low cellular uptake. Delivery of antigenic peptides using synthetic polymer-based nanostructures has been actively pursued but with limited success. Peptide-based nanostructures hold much promise as delivery vehicles due to their easy design and synthesis and inherent biocompatibility. Here, we report self-assembly of a dipeptide containing a non-natural amino acid, α,β-dehydrophenylalanine (ΔF), into nanotubes, which efficiently entrapped a MAGE-3-derived peptide (M3). M3 entrapped in F-ΔF nanotubes was more stable to a nonspecific protease treatment and both F-ΔF and F-ΔF-M3 showed no cellular toxicity for four cancerous and noncancerous cell lines used. F-ΔF-M3 showed significantly higher cellular uptake in RAW 267.4 macrophage cells compared to M3 alone and also induced in vitro maturation of dendritic cells (DCs). Immunization of mice with F-ΔF-M3 selected a higher number of IFN-γ secreting CD8+ T cells and CD4+ T compared to M3 alone. On day 21, a tumor growth inhibition ratio (TGI, %) of 41% was observed in a murine melanoma model. These results indicate that F-ΔF nanotubes are highly biocompatible, efficiently delivered M3 to generate cytotoxic T lymphocytes responses, and able to protect M3 from degradation under in vivo conditions. The F-ΔF dipeptide-based nanotubes may be considered as a good platform for further development as delivery agents.
Growing evidence suggests that gonadotropin-inhibitory hormone (GnIH) may play a key role in mediating vertebrate reproduction. GnIH inhibits gonadotropin synthesis and release by decreasing the activity of gonadotropin-releasing hormone (GnRH) neurons as well as by directly regulating gonadotropin secretion from the pituitary. Whereas the presence of GnIH has been widely investigated in various classes of vertebrates, there are very few immunohistochemical reports focusing on GnIH in amphibians. The aim of this study was to assess the presence and neuroanatomical distribution of GnIH-like immunoreactivity in the brain of the anuran amphibian Pelophylax (Rana) esculentus (esculenta) and to explore any potential anatomical relationship with mammalian GnRH-immunoreactive (mGnRH-ir) elements. The GnIH-like immunoreactive (GnIH-ir) system constitutes two distinct subpopulations in the telencephalon and diencephalon, with the highest number of immunoreactive cells located in the preoptic and suprachiasmatic areas. GnIH-ir neurons were also observed in the medial septum, the anterior commissure, the dorsal hypothalamus, the periventricular nucleus of the hypothalamus, and the posterior tuberculum. Scattered GnIH-ir fibers were present in all major subdivisions of the brain but only occasionally in the median eminence. mGnRH-ir neurons were distributed in the mediobasal telencephalon, the medial septal area, and the anterior preoptic area. Double-label immunohistochemistry revealed that the GnRH and GnIH systems coexist and have overlapping distributions at the level of the anterior preoptic area. Some GnIH-ir fibers were in close proximity to mGnRH-ir cell bodies. Our results suggest that both the neuroanatomy and the functional regulation of GnRH release are conserved properties of the hypothalamic GnIH-ir system among vertebrate species.
A fusion chimeric vaccine comprising multiple protective domains of different blood-stage Plasmodium falciparum antigens is perhaps necessary for widening the protective immune responses and reducing the morbidity caused by the disease. Here we continue to build upon the prior work of developing a recombinant fusion chimera protein, His-tagged PfMSP-Fu24, by producing it as a tag-free recombinant protein. In this study, tag-free recombinant PfMSPFu24 (rFu24) was expressed in Escherichia coli, and the soluble protein was purified using a three-step purification involving ammonium sulphate precipitation followed by 2-step ion exchange chromatography procedures and shown that it was highly immunogenic with the human-compatible adjuvant Alhydrogel. We further investigated two dipeptides, phenylalanine-α, β-dehydrophenylalanine (FΔF) and Leucine-α, β-dehydrophenylalanine (LΔF) based hydrogels as effective delivery platforms for rFu24. These dipeptides self-assembled spontaneously to form a highly stable hydrogel under physiological conditions. rFu24 was efficiently entrapped in both the F∆F and L∆F hydrogels, and the three-dimensional (3D) mesh-like structures of the hydrogels remained intact after the entrapment of the antigen. The two hydrogels significantly stimulated rFu24-specific antibody titers, and the sera from the immunized mice showed an invasion inhibitory activity comparable to that of Alhydrogel. Easily synthesized dipeptide hydrogels can be used as an effective antigen delivery platform to induce immune responses.
Nitric oxide (NO) is a chemically diffusible molecular messenger playing various roles in both vertebrates and invertebrates. Nitric oxide synthase (NOS) is the key enzyme in synthesis of NO. The neuroanatomical distribution pattern of neuronal nitric oxide synthase (nNOS) was studied and developing stages of Labeo rohita such as hatchlings (10-15mm), frys (15-35mm), semi-fingerlings (35-65mm), fingerlings (65-100mm) and adults (350-370mm) were used. In the telencephalon, nitrergic cells were observed in both pallial and subpallial regions along with entopeduncular nucleus suggesting the involvement of NO in the control of sensory functions throughout the development. In the diencephalon, nNOS positive neurons were localized in the nucleus preopticus periventricularis and preopticus parvocellularis throughout development while nucleus preopticus magnocellularis was found immunopositive only in adult specimens who suggest the involvement of NO in the hormonal regulation. nNOS immunoreaction was also noted in suprachaismatic nucleus, habenula, lateral tuberal nucleus, paraventricular organ and anterior division of preglomerular nucleus throughout development. In the mesencephalic region, nNOS immunoreactivity was seen in the optic tectum, torus longitudinalis, nucleus of median longitudinal fascicle and occulomotor nucleus indicate the role of NO in integration of visual inputs and modulates motor control of the eyes and movements. Caudally, in the rhombencephalon, the cerebellum, the nucleus reticularis, the octaval nucleus and the motor nucleus of vagal nerve were nNOS positive during development. nNOS reactive cells and fibers were noted in the spinal motor column, thus suggesting a role of NO in gestation and startle response from early development.
We studied the role of nitric oxide (NO) and extra-cellular Ca(2+) on the melanophores in Indian snakehead teleost, Channa punctatus. Increase of Ca(2+) level in the external medium causes pigment aggregation in melanophores. This pigment-aggregating effect was found to be inhibited when the external medium contained spontaneous NO donor, sodium nitro prusside (SNP) at all the levels of concentration tested. Furthermore, it has been observed that SNP keeps the pigment in dispersed state even after increasing the amount of Ca(2+). In order to test whether NO donor SNP causes dispersion of pigments or not is checked by adding the inhibitor of nitric oxide synthase, N-omega-Nitro-L-arginine (L-NNA) in the medium. It has been noted that the inhibitor L-NNA blocked the effect of NO donor SNP causing aggregation of pigments. In that way NO is inhibiting the effect of extracellular Ca(2+), keeping the pigment dispersed.
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