CD4+ T Cell Depletion in Human Immunodeficiency Virus (HIV) Infection: Role of Apoptosis

Human immunodeficiency virus (HIV) infection is principally a mucosal disease and the gastrointestinal (GI) tract is the major site of HIV replication. Loss of CD4+ T cells and systemic immune hyperactivation are the hallmarks of HIV infection. The end of acute infection is associated with the emergence of specific CD4+ and CD8+ T cell responses and the establishment of a chronic phase of infection. Abnormal levels of immune activation and inflammation persist despite a low steady state level of viremia. Although the causes of persistent immune hyperactivation remain incompletely characterized, physiological alterations of gastrointestinal tract probably play a major role. Failure to restore Th17 cells in gut-associated lymphoid tissues (GALT) might impair the recovery of the gut mucosal barrier. This review discusses recent advances on understanding the contribution of CD4+ T cell depletion to HIV pathogenesis

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Péptidos sintéticos o naturales que unen la proteína fosfatasa 2A, procedimiento de identificación y usos

Péptidos sintéticos o naturales que unen la proteína fosfatasa 2A, procedimiento de identificación y usos. La presente invención se refiere a nuevos péptidos, sintéticos o naturales, útiles en particular en el tratamiento de las infecciones víricas o parasitarias o en el tratamiento de tumores, siendo dicho péptidos de un tamaño inferior a 30 aminoácidos, preferentemente inferior a 20 aminoácidos, en particular de 15 a 20 aminoácidos, y caracterizados porque ligan, in vitro, de manera específica, una holoenzima proteína fosfatasa de tipo 2A o una de sus sub-unidades. La invención se refiere asimismo a un procedimiento de identificación de dichos péptidos, y a sus usos.Institut Pasteur, Institut National de la Recherche Agronomique, Consejo Superior de Investigaciones Científicas (España), Centre National de la Recherche Scientifique (CNRS)T3 Traducción de patente europe

Role of Akt and c-Jun N-terminal Kinase 2 in Apoptosis Induced by Interleukin-4 Deprivation

El copyright pertenece a The American Society for Cell Biology. The final versión of the paper is available at http://www.pubmedcentral.nih.govWe have shown previously that interleukin-4 (IL-4) protects TS1ab cells from apoptosis, but very little is known about the mechanism by which IL-4 exerts this effect. We found that Akt activity, which is dependent on phosphatidylinositol 3 kinase, is reduced in IL-4-deprived TS1ab cells. Overexpression of wild-type Akt or a constitutively active Akt mutant protects cells from IL-4 deprivation-induced apoptosis. Readdition of IL-4 before the commitment point is able to restore Akt activity. We also show expression and c-Jun N-terminal kinase 2 activation after IL-4 deprivation. Overexpression of the constitutively activated Akt mutant in IL-4-deprived cells correlates with inhibition of c-Jun N-terminal kinase 2 activity. Finally, TS1ab survival is independent of Bcl-2, Bcl-x, or Bax.Peer reviewe

Evaluation of Caspase-9b and PP2Acα2 as potential biomarkers for chronic lymphocytic leukemia

International audienceBackground: Disruption of alternative splicing in apoptotic factors has been associated to chronic lymphocytic leukemia among other cancers and hematological malignancies. The proapoptotic proteins Caspase-9 and PP2Acα are functionally related in a direct interaction, which constitutes a promising target for cancer therapy. Both proteins present aberrant mRNA splicing variants that are antiapoptotic (Caspase-9b) and catalytically inactive (PP2Acα2), respectively. Results: In this work we have analyzed the relative abundance of the aberrant spliced forms Caspase-9b and PP2Acα2 in several cell lines and chronic lymphocytic leukemia patients and correlated it with several parameters of the disease. Despite 40 % of the patients presented Caspase-9b dysregulation, there was no direct association between alterations in Caspase-9b relative abundance and the parameters analyzed in medical records. More importantly, PP2Acα2 dysregulation was observed in 88 % of CLL patients and was related with advanced stages of the malignancy. Conclusions: Caspase-9b dysregulation seemed to be associated with the disease, although the differences between healthy donors and CLL patients were not statistically significant. However, PP2Acα2 dysregulation was significantly different between healthy donors and CLL patients and correlated with Binet B and C stages; therefore, we propose the use of PP2Acα2 dysregulation as a potential biomarker for advanced stages of chronic lymphocytic leukemia

Peptides derived from Plasmodium falciparum leucine-rich repeat 1 bind to serine/threonine phosphatase type 1 and inhibit parasite growth in vitro.

International audienceThe biogenesis of protein phosphatase 1 (PP1) holoenzyme in eukaryotes requires diverse regulatory subunit proteins (RSPs) that bind to the highly conserved PP1 catalytic subunit (PP1c) and direct its spatiotemporal activity as well as its specificity. Several studies demonstrated that most RSPs share a canonical common binding motif, the RVXF motif, which is present in ~85% of RSPs and is considered as the main contributor for the interaction to PP1c.1 In Plasmodium falciparum (Pf), our earlier studies revealed that leucine-rich repeat 1 (LRR1), one of the major RSPs of PfPP1 and an ortholog of human and yeast Sds22, lacks the RVXF motif. The amino acids sequence of PfLRR1 exhibits nine leucine-rich repeats (LRRs) and a hydrophobic region at the C-terminal end, known as the LRR cap motif.2 In this work, we identified the PP1-binding peptides of PfLRR1 and examined their capacity to affect Pf growth

In Silico and In Vivo Studies of a Tumor-Penetrating and Interfering Peptide with Antitumoral Effect on Xenograft Models of Breast Cancer

The combination of a tumor-penetrating peptide (TPP) with a peptide able to interfere witha given protein–protein interaction (IP) is a promising strategy with potential clinical application.Little is known about the impact of fusing a TPP with an IP, both in terms of internalization andfunctional effect. Here, we analyze these aspects in the context of breast cancer, targeting PP2A/SET interaction, using both in silico and in vivo approaches. Our results support the fact that state-of-theart deep learning approaches developed for protein–peptide interaction modeling can reliably identify good candidate poses for the IP-TPP in interaction with the Neuropilin-1 receptor. The association of the IP with the TPP does not seem to affect the ability of the TPP to bind to Neuropilin-1. Molecular simulation results suggest that peptide IP-GG-LinTT1 in a cleaved form interacts with Neuropilin-1 in a more stable manner and has a more helical secondary structure than the cleaved IP-GG-iRGD.Surprisingly, in silico investigations also suggest that the non-cleaved TPPs can bind the Neuropilin-1 in a stable manner. The in vivo results using xenografts models show that both bifunctional peptides resulting from the combination of the IP and either LinTT1 or iRGD are effective against tumoral growth. The peptide iRGD-IP shows the highest stability to serum proteases degradation while having the same antitumoral effect as Lin TT1-IP, which is more sensitive to proteases degradation.Our results support the development of the TPP-IP strategy as therapeutic peptides against cancerFacultad de Ciencias Médica

New Therapeutic Approach for Targeting Hippo Signalling Pathway

Nuclear localization signals are short amino acid sequences that target proteins for nuclear import. In this manuscript, we have generated a chimeric tri-functional peptide composed of a cell penetrating peptide (CPP), a nuclear localization sequence and an interfering peptide blocking the interaction between TEAD and YAP, two transcription factors involved in the Hippo signalling pathway, whose deregulation is related to several types of cancer. We have validated the cell penetration and nuclear localization by flow cytometry and fluorescence microscopy and shown that the new generated peptide displays an apoptotic effect in tumor cell lines thanks to the specific nuclear delivery of the cargo, which targets a protein/protein interaction in the nucleus. In addition, the peptide has an anti-tumoral effect in vivo in xenograft models of breast cancer. The chimeric peptide designed in the current study shows encouraging prospects for developing nuclear anti- neoplastic drugs.Facultad de Ciencias Médica

Anti-tumoral Effect of a Cell Penetrating and Interfering Peptide Targeting PP2A/SET Interaction

Objective: To test cell penetrating and interfering peptide Mut3DPT-PP2A/SET in interaction between serine threonine phosphatase PP2A and its physiological inhibitor, the oncoprotein SET. Materials and methods: Adult male C3H/S-strain mice, 60 days old, were given a graft of breast adenocarcinoma cells (TN60) into subcutaneous tissue. Mut3DPT-PP2A/SET peptide was used to block PP2A and SET oncoprotein interaction. The graft-bearing animals were divided into a control group (injected with saline buffer), and an intervention group injected intraperitoneally with Mut3DPTPP2A/ SET peptide (5 mg/kg) every day from day 5 to day 37. The variables we used to compare the outcome in both groups were tumor size in mm (length×width) and histological changes. In the statistical analysis we used ANOVA and Student-Keuls multiple comparisons test and Tuckey for the post-test analysis. Results: 48 mice were grafted at day 0 with breast UNLP-C3H/S tumor cells, and after randomization, they were assigned to one of the two study groups. At day 5 all mice were injected either with placebo or with the peptide. The treated group showed significant tumor reduction (p<0.07). Histological changes showed presence of apoptosis and necrosis of tumor in treated group. Conclusion: The peptide Mut3DPT-PP2A/SET has demonstrated anti-tumor activity by reduction in vivo of tumor growth becoming a promising future in anticancer therapy.Facultad de Ciencias Médica