Blockade of Glial Connexin 43 Hemichannels Reduces Food Intake.

The metabolic syndrome, which comprises obesity and diabetes, is a major public health problem and the awareness of energy homeostasis control remains an important worldwide issue. The energy balance is finely regulated by the central nervous system (CNS), notably through neuronal networks, located in the hypothalamus and the dorsal vagal complex (DVC), which integrate nutritional, humoral and nervous information from the periphery. The glial cells' contribution to these processes emerged few year ago. However, its underlying mechanism remains unclear. Glial connexin 43 hemichannels (Cx43 HCs) enable direct exchange with the extracellular space and can regulate neuronal network activity. In the present study, we sought to determine the possible involvement of glial Cx43 HCs in energy balance regulation. We here show that Cx43 is strongly expressed in the hypothalamus and DVC and is associated with glial cells. Remarkably, we observed a close apposition of Cx43 with synaptic elements in both the hypothalamus and DVC. Moreover, the expression of hypothalamic Cx43 mRNA and protein is modulated in response to fasting and diet-induced obesity. Functionally, we found that Cx43 HCs are largely open in the arcuate nucleus (ARC) from acute mice hypothalamic slices under basal condition, and significantly inhibited by TAT-GAP19, a mimetic peptide that specifically blocks Cx43 HCs activity. Moreover, intracerebroventricular (i.c.v.) TAT-GAP19 injection strongly decreased food intake, without further alteration of glycaemia, energy expenditures or locomotor activity. Using the immediate early gene c-Fos expression, we found that i.c.v. TAT-GAP19 injection induced neuronal activation in hypothalamic and brainstem nuclei dedicated to food intake regulation. Altogether, these results suggest a tonic delivery of orexigenic molecules associated with glial Cx43 HCs activity and a possible modulation of this tonus during fasting and obesity.

Generation and testing of engineered multimeric Fabs of trastuzumab.

Recombinant antibodies fragments in several new formats are routinely investigated and used in diagnostic and therapeutic applications as anti-cancers molecules. New antibody formats are generated to compensate the need for multispecificity and site-specific introduction of fluorescent dyes, cytotoxic payloads or for generating semisynthetic multimeric molecules. Fabs of trastuzumab bearing transglutaminase (MTG) reactive sites were generated by periplasmic expression in E. coli and purified. Multimeric Fabs were generated by either disulfide bridge formation or by using MTG-sensitive peptide linkers. Binding to receptor was assessed by ELISA and SPR methods. Internalization and growth inhibition assays were performed on BT-474 and SKBR3 Her2+ cells. Fabs were successfully produced and dimerized or trimerized using MTG and suitably designed peptide linkers. Site-specific derivatizations with fluorophores were similarly achieved. The monomeric, dimeric and trimeric variants bind the receptor with affinities similar or superior to the full antibody. Fab and Fab2 are rapidly internalized in Her2+ cells and exhibit growth inhibition abilities similar to the full antibody. Altogether, the data show that the recombinant Fabs can be produced in E. coli and converted into multimeric variants by MTG-based bioconjugation. Similar approaches are extendable to the introduction of cytotoxic payloads for the generation of novel Antibody Drug Conjugates.

SP94 Peptide-Functionalized PEG-PLGA Nanoparticle Loading with Cryptotanshinone for Targeting Therapy of Hepatocellular Carcinoma.

To achieve improved drug delivery efficiency to hepatocellular carcinoma (HCC), biodegradable poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PEG-PLGA) nanoparticles (NP), surface-modified with SP94 peptide, were designed for the efficient delivery of cryptotanshinone to the tumor for the treatment of HCC. Cryptotanshinone NP and SP94-NP were prepared by using nanoprecipitation. The physicochemical and pharmaceutical properties of the NP and SP94-NP were characterized, and the release kinetics suggested that both NP and SP94-NP provided continuous, slow release of cryptotanshinone for 48 h. The in vitro cellular experiment demonstrated that SP94-NP significantly enhanced the cellular uptake of cryptotanshinone and induced high cytotoxicity and cellular apoptosis of hepatocellular carcinoma (HepG2) cells. The in vivo detecting results of targeting effect using the Cy5.5 probe evidenced that SP94-NP showed an accumulation in tumor more efficiently than that of unconjugated ones. Meanwhile, SP94-NP exhibited the smallest tumor size than other groups and showed no toxicity to body. The results of this study provide a promising nanoplatform for the targeting of HCC.

A Fluorescence Anisotropy-Based Comprehensive Method for the In Vitro Screening of COI1-JAZs Agonists and Antagonists.

The phytohormone (+)-7-iso-jasmonoyl-L-isoleucine (JA-Ile) causes protein-protein interactions (PPI) between F-box Protein CORONATINE INSENSITIVE 1 (COI1) and JASMONATE ZIM DOMAIN (JAZ) transcriptional repressor. A total of 13 JAZ subtypes are encoded in the genome of Arabidopsis thaliana; however, their genetic redundancy obfuscates the individual function of each JAZ. One approach to decipher this redundant signaling network is chemical genetics, using small molecules specific to individual JAZ subtype, for which a reliable and high-throughput screening system of the ligands for all combinations of COI1-JAZs would be indispensable. In this chapter, we describe a fluorescence anisotropy-based quantitative screening system for the ligands of COI1-JAZ co-receptors. Our method is applicable to agonists and antagonists of the COI1-JAZs.

Synthesis, characterization and nociceptive screening of new VV-hemorphin-5 analogues.

In the present study, some new analogues of VV-hemorphin-5, modified at position 1 and 7 by the non-proteinogenic and/or natural amino acids followed the structures Xxx-Val-Val-Tyr-Pro-Trp-Thr-Gln-NH2 and Val-Val-Tyr-Pro-Trp-Thr-Yyy-NH2, where Xxx is Ile or Aib and Yyy is Lys/Orn/Dap/Dab were synthesized to investigate their potential antinociceptive activities. We report also the redox potentials and the acid/base properties as pKa values of these peptide analogues which were compared toward electrochemical behaviour of tryptophan containing peptides. All analogues showed a short lasting initial antinociceptive effect, however H2 hemorphin analogue is characterized with prolong and strong antinociceptive effect, while the other peptide analogues exerted more variable effects on the visceral nociception depending on the dose or time after the intracerebral injection.

Pharmacokinetic and Chemical Synthesis Optimization of a Potent d-Peptide HIV Entry Inhibitor Suitable for Extended-Release Delivery.

Peptides often suffer from short in vivo half-lives due to proteolysis and renal clearance that limit their therapeutic potential in many indications, necessitating pharmacokinetic (PK) enhancement. d-Peptides, composed of mirror-image d-amino acids, overcome proteolytic degradation but are still vulnerable to renal filtration due to their small size. If renal filtration could be slowed, d-peptides would be promising therapeutic agents for infrequent dosing, such as in extended-release depots. Here, we tether a diverse set of PK-enhancing cargoes to our potent, protease-resistant d-peptide HIV entry inhibitor, PIE12-trimer. This inhibitor panel provides an opportunity to evaluate the PK impact of the cargoes independently of proteolysis. While all the PK-enhancing strategies (PEGylation, acylation, alkylation, and cholesterol conjugation) improved in vivo half-life, cholesterol conjugation of PIE12-trimer dramatically improves both antiviral potency and half-life in rats, making it our lead anti-HIV drug candidate. We designed its chemical synthesis for large-scale production (CPT31) and demonstrated that the PK profile in cynomolgous monkeys supports future development of monthly or less frequent depot dosing in humans. CPT31 could address an urgent need in both HIV prevention and treatment.

D-Cateslytin, a new antimicrobial peptide with therapeutic potential.

The rise of antimicrobial resistant microorganisms constitutes an increasingly serious threat to global public health. As a consequence, the efficacy of conventional antimicrobials is rapidly declining, threatening the ability of healthcare professionals to cure common infections. Over the last two decades host defense peptides have been identified as an attractive source of new antimicrobials. In the present study, we characterized the antibacterial and mechanistic properties of D-Cateslytin (D-Ctl), a new epipeptide derived from L-Cateslytin, where all L-amino acids were replaced by D-amino acids. We demonstrated that D-Ctl emerges as a potent, safe and robust peptide antimicrobial with undetectable susceptibility to resistance. Using Escherichia coli as a model, we reveal that D-Ctl targets the bacterial cell wall leading to the permeabilization of the membrane and the death of the bacteria. Overall, D-Ctl offers many assets that make it an attractive candidate for the biopharmaceutical development of new antimicrobials either as a single therapy or as a combination therapy as D-Ctl also has the remarkable property to potentiate several antimicrobials of reference such as cefotaxime, amoxicillin and methicillin.

Investigation of Elemental Mass Spectrometry in Pharmacology for Peptide Quantitation at Femtomolar Levels.

In the search of new robust and environmental-friendly analytical methods able to answer quantitative issues in pharmacology, we explore liquid chromatography (LC) associated with elemental mass spectrometry (ICP-MS) to monitor peptides in such complex biological matrices. The novelty is to use mass spectrometry to replace radiolabelling and radioactivity measurements, which represent up-to now the gold standard to measure organic compound concentrations in life science. As a proof of concept, we choose the vasopressin (AVP)/V1A receptor system for model pharmacological assays. The capacity of ICP-MS to provide highly sensitive quantitation of metallic and hetero elements, whatever the sample medium, prompted us to investigate this technique in combination with appropriate labelling of the peptide of interest. Selenium, that is scarcely present in biological media, was selected as a good compromise between ICP-MS response, covalent tagging ability using conventional sulfur chemistry and peptide detection specificity. Applying selenium monitoring by elemental mass spectrometry in pharmacology is challenging due to the very high salt content and organic material complexity of the samples that produces polyatomic aggregates and thus potentially mass interferences with selenium detection. Hyphenation with a chromatographic separation was found compulsory. Noteworthy, we aimed to develop a straightforward quantitative protocol that can be performed in any laboratory equipped with a standard macrobore LC-ICP-MS system, in order to avoid time-consuming sample treatment or special implementation of instrumental set-up, while allowing efficient suppression of all mass interferences to reach the targeted sensitivity. Significantly, a quantification limit of 57 ng Se L-1 (72 femtomoles of injected Se) was achieved, the samples issued from the pharmacological assays being directly introduced into the LC-ICP-MS system. The established method was successfully validated and applied to the measurement of the vasopressin ligand affinity for its V1A receptor through the determination of the dissociation constant (Kd) which was compared to the one recorded with conventional radioactivity assays.

New opportunities for allergen immunotherapy using synthetic peptide immuno-regulatory epitopes (SPIREs).

INTRODUCTION: Allergen immunotherapy (AIT) reduces allergic rhinoconjunctivitis (ARC) symptoms, but long-term efficacy requires treatment for 3-5 years. Synthetic peptide immuno-regulatory epitopes, a new class of AIT, are allergen peptides with a shorter, more convenient treatment regimen that could potentially have benefits on adherence and outcomes. AREAS COVERED: Phase 2 trials of therapies derived from cat, house dust mite, grass, and ragweed allergen peptides demonstrated significant reduction in ARC symptoms after short-course treatment; improvement was sustained for 18-24 months posttreatment. We conducted a PubMed literature search for clinical publications using the search terms AIT; allergen peptides; ARC; cat, grass, house dust mite, and ragweed allergy; SCIT; SLIT; and synthetic peptides. Expert commentary: Long-term disease modification is a realistic goal of AIT. The inconvenience of conventional AIT regimens negatively impacts long-term persistence and, thus, efficacy. In comparison, SPIREs have a more convenient treatment regimen that could potentially have benefits on adherence and outcomes.

Combined Use of Oligopeptides, Fragment Libraries, and Natural Compounds: A Comprehensive Approach To Sample the Druggability of Vascular Endothelial Growth Factor.

The modulation of protein-protein interactions (PPIs) is emerging as a highly promising tool to fight diseases. However, whereas an increasing number of compounds are able to disrupt peptide-mediated PPIs efficiently, the inhibition of domain-domain PPIs appears to be much more challenging. Herein, we report our results related to the interaction between vascular endothelial growth factor (VEGF) and its receptor (VEGFR). The VEGF-VEGFR interaction is a typical domain-domain PPI that is highly relevant for the treatment of cancer and some retinopathies. Our final goal was to identify ligands able to bind VEGF at the region used by the growth factor to interact with its receptor. We undertook an extensive study, combining a variety of experimental approaches, including NMR-spectroscopy-based screening of small organic fragments, peptide libraries, and medicinal plant extracts. The key feature of the successful ligands that emerged from this study was their capacity to expose hydrophobic functional groups able to interact with the hydrophobic hot spots at the interacting VEGF surface patch.

Isobavachalcone and bavachinin from Psoraleae Fructus modulate Aß42 aggregation process through different mechanisms in vitro.

Spontaneous aggregation of Aß is a key factor in the development of Alzheimer's disease. In searching for Aß aggregation inhibitors from traditional Chinese herbal medicines, we identified two active compounds from Psoraleae Fructus, namely isobavachalcone and bavachinin. We further demonstrated that the two compounds modulate Aß42 aggregation process through different mechanisms. Isobavachalcone significantly inhibits both oligomerization and fibrillization of Aß42, whereas bavachinin inhibits fibrillization and leads to off-pathway aggregation. Both of the compounds attenuated Aß42-induced toxicity in a SH-SY5Y cell model. These findings may provide valuable information for new drug development and Alzheimer's therapy in the future.

[In vitro effect of the S3Pvac vaccine against cysticercosis in human mononucleate cells]. / Efecto in vitro de la vacuna S3Pvac contra cisticercosis en celulas mononucleares humanas.

INTRODUCTION: Neurocysticercosis (NCC) is a parasitic infection caused by the establishment of Taenia solium cysticerci in the central nervous system. The larval stage of the parasite also affects the pig, which is the essential intermediate host for transmission. For this reason, many researchers have focused on identifying protective antigens to prevent swine cysticercosis and interrupt the transmission. These include S3Pvac vaccine antigens. Vaccine is constituted by three protective synthetic peptides: KETc1, KETc12 and GK1. AIM. To evaluate the effect of the vaccine peptides KETc1, KETc12 and GK1 in mononuclear cells of patients with neuro-cysticercosis and healthy individuals. SUBJECTS AND METHODS: Comparative, prospective, transverse study. We studied the proliferation and cytokine profile induced by the three peptides in mononuclear cells from three patients with active NCC, 16 patients by calcified NCC and 16 healthy subjects. RESULTS: KETc1 induces low levels of proliferation in cells from patients with active and controlled NCC, both in lymphocytes and in monocytes. KETc12 and GK-1 induce positive proliferation levels of monocytes in healthy subjects. CONCLUSIONS: KETc1 peptide could be used as an adjuvant in the treatment of patients with active NCC, as induced a Th2 response also GK1 peptide as stimulator of monocyte/macrophage in immunizations with other proteins.

TITLE: Efecto in vitro de la vacuna S3Pvac contra cisticercosis en celulas mononucleares humanas.Introduccion. La neurocisticercosis (NCC) es una infeccion parasitaria generada por el establecimiento de cisticercos de Taenia solium en el sistema nervioso central. La fase larvaria del parasito tambien afecta al cerdo, que es el huesped intermediario indispensable para la transmision. Por tal motivo, muchos investigadores se han enfocado en identificar antigenos protectores para prevenir la cisticercosis porcina e interrumpir la transmision. Entre ellos figuran los antigenos de la vacuna S3Pvac, constituida por tres peptidos protectores: KETc1, KETc12 y GK1. Objetivo. Evaluar el efecto de los peptidos vacunales KETc1, KETc12 y GK1 en celulas mononucleares de pacientes con NCC e individuos sanos. Sujetos y metodos. Estudio comparativo, prospectivo y transversal. Se analizo la proliferacion y el perfil de citocinas inducidos por los tres peptidos en celulas mononucleares de tres pacientes con NCC activa, 16 pacientes con NCC calcificada y 16 sujetos sanos. Resultados. KETc1 induce bajos niveles de proliferacion en las celulas de los pacientes con NCC activa y controlada, tanto en linfocitos como en monocitos. KETc12 y GK-1 inducen niveles positivos de proliferacion de monocitos en sujetos sanos. Conclusiones. El peptido KETc1 podria usarse como coadyuvante en el tratamiento de los pacientes con NCC activa, ya que indujo una respuesta Th2; y el peptido GK1, como estimulador del monocito/macrofago en inmunizaciones con otras proteinas.

Characterization of a selective CaMKII peptide inhibitor.

Analogs of potent CaMKinase II inhibitor, CaM-KNtide, were prepared to explore new structural requirements for the inhibitory activity. The full potency of CaMKII inhibition by CaM-KIINα is contained within a minimal region of 19 amino acids. Here, analysis of the homologous CaM-KIINß showed that a 17 mer peptide (CN17ß) was the shortest sequence that still retained useful inhibitory potency. Ala substitution of almost any residue of CN17ß dramatically reduced potency, except for substitution of P3, R14, and V16. Fusion with the tat sequence generated the cell-penetrating inhibitor version tat-5. This tat-5 fusion peptide maintained selectivity for CaMKII over CaMKI and CaMKIV, and appeared to slightly further enhance potency (IC50 ∼30 nM). Within a breast cancer cell line and in primary human fibroblasts, tat-5 inhibited the Erk signaling pathway and proliferation without any measurable cytotoxicity. Structural analysis of CN17ß by CD and NMR indicated an α-helix conformation in the Leu6-Arg11 segment well overlapping with the crystal structure of 21-residue segment of CaM-KNtide bound to the kinase domain of CaMKII.

Bone morphogenetic protein-derived peptide promotes chondrogenic differentiation of human mesenchymal stem cells.

Directing chondrogenic differentiation of human mesenchymal stem cells (MSCs) is currently a challenging problem in tissue engineering of cartilage. Short-peptide motifs are promising new tools to aid in controlling chondrogenesis. The aim of this study was to investigate whether a short bone morphogenetic protein-2 (BMP-2)-derived peptide (BMP peptide) stimulates chondrogenesis of human MSCs in the absence of other growth factors. A high-throughput pellet culture system was used to rapidly collect biochemical data such as glycosaminoglycan (GAG), total collagen, and DNA content, as well as alkaline phosphatase (AP) activity. Cells cultured with ≥100 µg/mL of the peptide produced 74% of the GAG content that cells cultured with BMP-2 produced. Comparable levels of GAG production were promoted by the peptide and BMP-2 over 4 weeks of culture. However, histology revealed that the peptide promoted a more homogenous distribution of GAG than BMP-2. The BMP peptide directed human MSCs to increase collagen production after 3 weeks, but at significantly lower levels compared to BMP-2. Treatment with BMP-2 resulted in a large increase in hypertrophic markers such as AP activity and gene expression of type X collagen, whereas treatment with the peptide resulted in little-to-no increase in these markers. These results suggest that the BMP peptide could be an effective new tool for cartilage tissue engineering.

Identification of influenza virus inhibitors which disrupt of viral polymerase protein-protein interactions.

Due to their ability to rapidly mutate, influenza viruses quickly develop resistance against many antiviral substances, leading to an urgent need for new compounds. The trimeric viral polymerase complex, a major target for the development of new inhibitors, must be assembled from the PB1, PB2, and PA subunits for successful infection. Here, we describe ELISA-based assays which allow the identification of peptides which impair polymerase complex formation. Since the protein-protein interaction domains of the viral polymerase are highly conserved, these inhibitors are also predicted to be active against a broad range of influenza strains. Using this method, identification of small molecules and lead compounds against influenza A and B viruses should be feasible.

Design of Factor XIII V34X activation peptides to control ability to interact with thrombin mutants.

Thrombin helps to activate Factor XIII (FXIII) by hydrolyzing the R37-G38 peptide bond. The resultant transglutaminase introduces cross-links into the fibrin clot. With the development of therapeutic coagulation factors, there is a need to better understand interactions involving FXIII. Such knowledge will help predict ability to activate FXIII and thus ability to promote/hinder the generation of transglutaminase activity. Kinetic parameters have been determined for a series of thrombin species hydrolyzing the FXIII (28-41) V34X activation peptides (V34, V34L, V34F, and V34P). The V34P substitution introduces PAR4 character into the FXIII, and the V34F exhibits important similarities to the cardioprotective V34L. FXIII activation peptides containing V34, V34L, or V34P could each be accommodated by alanine mutants of thrombin lacking either the W60d or Y60a residue in the 60-insertion loop. By contrast, FXIII V34F AP could be cleaved by thrombin W60dA but not by Y60aA. FXIII V34P is highly reliant on the thrombin W215 platform for its strong substrate properties whereas FXIII V34F AP becomes the first segment that can maintain its K(m) upon loss of the critical thrombin W215 residue. Interestingly, FXIII V34F AP could also be readily accommodated by thrombin L99A and E217A. Hydrolysis of FXIII V34F AP by thrombin W217A/E217A (WE) was similar to that of FXIII V34L AP whereas WE could not effectively cleave FXIII V34P AP. FXIII V34F and V34P AP show promise for designing FXIII activation systems that are either tolerant of or greatly hindered by the presence of anticoagulant thrombins.

Disconnecting the yin and yang relation of epidermal growth factor receptor (EGFR)-mediated delivery: a fully synthetic, EGFR-targeted gene transfer system avoiding receptor activation.

The epidermal growth factor receptor (EGFR) is upregulated within a high percentage of solid tumors and hence is an attractive target for tumor-targeted therapies including gene therapy. The natural EGFR ligand epidermal growth factor (EGF) has been used for this purpose, despite the risk of mitogenic effects due to EGFR activation. We have developed a fully synthetic, EGFR-targeted gene delivery system based on PEGylated linear polyethylenimine (LPEI), allowing evaluation of different EGFR-binding peptides in terms of transfection efficiency and EGFR activation. Peptide sequences directly derived from the human EGF molecule enhanced transfection efficiency with concomitant EGFR activation. Only the EGFR-binding peptide GE11, which has been identified by phage display technique, showed specific enhancement of transfection on EGFR-overexpressing tumor cells including glioblastoma and hepatoma, but without EGFR activation. EGFR targeting led to high levels of cell association of fluorescently labeled polyplexes after only 30 min of incubation. EGF pretreatment of cells induced enhanced cellular internalization of all polyplex types tested, pointing at generally enhanced macropinocytosis. EGF polyplexes diminished cell surface expression of EGFR for up to 4 hr, whereas GE11 polyplexes did not. In a clinically relevant orthotopic prostate cancer model, intratumorally injected GE11 polyplexes were superior in inducing transgene expression when compared with untargeted polyplexes.

Epitope selection to male specific antigens for sex selection in swine.

Immunological approaches to gender selection have been contemplated since the discovery of the family of male-specific H-Y antigens found only on the surface of male cells. H-Y antigens are able to elicit an immune reaction when cells or tissues from a male donor are grafted to a female recipient. We describe here the development and testing of an inexpensive approach using polyclonal antibodies against four specific H-Y outer membrane proteins male enhanced antigen 1 (MEA 1), male enhanced antigen 2 (MEA 2), sex determining region Y (SRY) and testis determining factor (TDF). Epitopes based on hydrophilic primary sequences of the proteins were synthesized, N-terminal biotin-labeled, linked to streptavidin and mixed with a Ribi adjuvant prior to immunization in rabbits. The antiserum was tested to determine affinity to swine spermatozoa using anti-motility, flow cytometry and motility and sedimentation chambers. Fluorescent microscopy and fluorescent in situ hybridization (FISH) was used to identify the percentage of motile spermatozoa that contained the Y chromosome. We found that the polyclonal antibodies had high affinity to the spermatozoa leading to a cessation of motility. Furthermore, the majority of these non-motile spermatozoa contained the Y chromosome. We conclude that the use of polyclonal antiserum against synthetic H-Y peptide antigens may be an inexpensive and simple means to inhibit the motility of swine spermatozoa bearing the Y chromosome.

Valproic acid enhances microglial phagocytosis of amyloid-beta(1-42).

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder manifested by memory loss, confusion and changes in mood. A principal pathology of this debilitating disorder is extracellular deposits of amyloid-beta (Abeta) protein. The "amyloid hypothesis" postulates that a build-up of Abeta protein is responsible for neuronal loss and the ensuing symptoms of AD. One possible mechanism of Abeta clearance, and hence AD therapy, is phagocytosis of Abeta protein by microglial cells. Microglia are the brain's resident immune cells and phagocytosis is one of their innate functions. We are interested in identifying molecules that augment microglial-mediated phagocytosis of Abeta protein. We used the rodent BV-2 microglial cell line which readily phagocytose fluorescent latex beads and synthetic Abeta(1-42) peptide. BV-2 cells treated with the neuroactive drug valproic acid (VPA) showed greatly enhanced phagocytic activity for both latex beads and Abeta. VPA also reduced microglial viability by inducing apoptosis, as previously reported. The relevance of these in vitro results to the treatment of AD is unclear but further investigation into the effects of VPA on the clearance of Abeta through enhanced microglial phagocytosis is warranted.

Antitumor effects of snake venom chemically modified Lys49 phospholipase A2-like BthTX-I and a synthetic peptide derived from its C-terminal region.

The present work evaluates both in vitro and in vivo antitumor activity of BPB-modified BthTX-I and its cationic synthetic peptide derived from the 115-129 C-terminal region. BPB-BthTX-I presented cytotoxicity of 10-40% on different tumor cell lines, which were also susceptible to the lytic action of the synthetic peptide. Injection of the modified protein or the peptide in mice, 5 days after transplantation of S180 tumor cells, reduced 30 and 36% of the tumor size on day 14th and 76 and 79% on day 60th, respectively, when compared to the untreated control group. Thus, these antitumor properties might be of interest in the development of therapeutic strategies against cancer.