The helminth-derived peptide GK-1 induces an anti-tumoral CD8 T cell response associated with downregulation of the PD-1/PD-L1 pathway.

CD8 T cells can kill malignant cells in an antigen-specific manner. However, anti-tumoral responses are usually limited by suppressive factors that curb the effector responses of tumor-infiltrating CD8 T cells. Therapeutic strategies to overcome intra-tumoral T cell suppression, for example immune checkpoint inhibition, have been clinically effective in patients with cancer. Here, we provide data that demonstrates that GK-1, a peptide derived from the parasite Taenia crassiceps, promotes an anti-melanoma CD8 T cell response with heightened effector characteristics that leads to an increased amount of tumor-infiltrating CD44+ IFN-γ-producing CD8 T cells. The response induced by GK-1 was associated with a reduction in the expression of PD-1 and PD-L1 on tumor-infiltrating CD8 and dendritic cells, respectively, effects that led to a dramatic decrease in tumor burden. Our results suggest that the immunomodulatory properties of GK-1 may promote a CD8 T cell response that may be therapeutically useful in the setting of cancer.

Description of advanced third-stage larvae of Gnathostoma lamothei Bertoni-Ruiz et al. 2005 (Nematoda: Gnathostomatidae) from experimental hosts and contributions to its life cycle.

The advanced third-stage larvae (AdvL(3)) of Gnathostoma lamothei was obtained from experimental hosts. Frogs Lithobates heckscheri and snakes Nerodia fasciata pictiventris were compatible hosts allowing optimal larval development. AdvL(3) are 4,487.94 µm long, have two lateral cervical papillae between rows 10 and 16 and an excretory pore at row 23. The average counts of the cephalic bulb hooklets from the four rows are 39.3, 43.3, 44.2, and 47.3. Larvae show an esophagus that represents 40 % of the body width. These findings indicate that amphibians and reptiles could be involved as G. lamothei natural hosts; nevertheless, their role as etiological agents of human gnathostomiasis is uncertain. This paper reports for the first time the taxonomic description of G. lamothei AdvL(3) obtained from experimental hosts and contributes to the understanding of its life cycle.

Fyn kinase controls FcepsilonRI receptor-operated calcium entry necessary for full degranulation in mast cells.

IgE-antigen-dependent crosslinking of the high affinity IgE receptor (FcepsilonRI) on mast cells leads to degranulation, leukotriene synthesis and cytokine production. Calcium (Ca(2+)) mobilization is a sine qua non requisite for degranulation, allowing the rapid secretion of stored pro-inflammatory mediators responsible for allergy symptoms. Fyn is a Src-family kinase that positively controls FcepsilonRI-induced mast cell degranulation. However, our understanding of the mechanism connecting Fyn activation to secretion of pre-synthesized mediators is very limited. We analyzed FcepsilonRI-dependent Ca(2+) mobilization in bone marrow-derived mast cells (BMMCs) differentiated from WT and Fyn -/- knock out mice. Fyn -/- BMMCs showed a marked defect in extracellular Ca(2+) influx after FcepsilonRI crosslinking but not after thapsigargin addition. High concentrations of Gadolinium (Gd(3+)) partially blocked FcepsilonRI-induced Ca(2+) influx in WT cells but, in contrast, completely inhibited Ca(2+) mobilization in Fyn -/- cells. Low concentrations of an inhibitor of the canonical transient receptor potential (TRPC) Ca(2+) channels (2-aminoethoxyphenyl-borane, 2-APB) blocked FcepsilonRI-induced maximal Ca(2+) rise in WT but not in Fyn -/- cells. Ca(2+) entry through Fyn-controlled, 2-APB sensitive channels was found to be important for full degranulation and IL-2 mRNA accumulation in WT cells. Immunoprecipitation assays showed that Fyn kinase interacts with TRPC 3/6/7 channels after IgE-antigen stimulation, but its association is not related to protein tyrosine phosphorylation. Results indicate Fyn kinase mediates the receptor-dependent activation of TRPC channels that contribute to degranulation in FcepsilonRI-stimulated mast cells.

Description and development of the early third-stage larva of Gnathostoma turgidum Stossich, 1902 (Nematoda: Gnathostomatidae) and contributions to its life cycle.

The egg and larval stages of Gnathostoma turgidum were examined using light microscopy. Fertilized uterine eggs are 65.97 long and 32.28 wide, oval, brownish, with two cap-like thickenings. The eggshell surface is covered with numerous irregularly shaped pits of various sizes and depths. A sheathed second-stage larva emerges from the egg, measures 178 x 9; the sheath measures 243 x 21. Development to early third-stage larva in the coelomic cavity of cyclopoid copepods is similar to that described for other gnathostome species. After 10 days at 27 degrees C, the larvae undergo a molt (the second for gnathostomes) and develop to early third stage. The body of this stage measures 412.3 x 40.1, with evident hemispherical cephalic bulbs. Cephalic bulbs measure 25 x 40, armed with four transverse rows of sharp hooklets. The average number of hooklets in each row is 31, 34, 37, and 42, respectively. The whole body is covered with 193 transverse rows of small single-pointed cuticular spines. One pair of cervical papillae and an excretory pore are present on the anterior part of the body. On the other hand, potential species-specific features regarding the latter larval stage are discussed. Finally, some G. turgidum life cycle considerations are portrayed.

Finding advanced third-stage larvae of Gnathostoma turgidum Stossich, 1902 in Mexico from natural and experimental host and contributions to the life cycle description.

In order to clarify the role of Gnathostoma turgidum as an etiological agent involved in human gnathostomiasis in Mexico, establish the taxonomic identity of the advanced third-stage larvae (AdvL(3)), and contribute to the knowledge of its life cycle, experimental host infections, examination of potential natural hosts, and morphological comparisons were carried out. Examination of ten species of potential hosts at San Pedro las Playas and Tres Palos Lagoon in Guerrero state, Mexico revealed that two (Kinosternon integrum and Rana zweifeli) were infected by 15 AdvL(3) of G. turgidum. A specific identity was obtained comparing these larvae with those recovered from hosts experimentally infected. The AdvL(3) measured 1.6 mm in length, with two cervical papillae (both in 12th row) and an excretory pore on the 19th row. The average of cephalic hooklets, from first to fourth row, was 30.8, 34.0, 36.7, and 39.6, respectively. This is the first record of AdvL(3) of G. turgidum in America, and it represents a significant contribution for the understanding of the life cycle of this species.

Anandamide inhibits FcεRI-dependent degranulation and cytokine synthesis in mast cells through CB2 and GPR55 receptor activation. Possible involvement of CB2-GPR55 heteromers.

Activation of high affinity receptor for IgE (FcεRI) by IgE/antigen complexes in mast cells (MCs) leads to the release of preformed pro-inflammatory mediators stored in granules by a Ca2+-dependent process known as anaphylactic degranulation. Degranulation inhibition has been proposed as a strategy to control allergies and chronic inflammation conditions. Cannabinoids are important inhibitors of inflammatory reactions but their effects on IgE/Ag-mediated MCs responses are not well described. In this study, we analyzed the effect of the endocannabinoid anandamide (AEA), the selective CB2 receptor agonist HU308, and the GPR55 receptor agonist lysophosphatidylinositol (LPI) on FcεRI-induced activation in murine bone marrow-derived mast cells (BMMCs). Our results show that AEA, HU380 and LPI inhibited FcεRI-induced degranulation in a concentration-dependent manner. This effect was mediated by CB2 and GPR55 receptor activation through a mechanism insensitive to pertussis toxin. Degranulation inhibition was prevented by CB2 and GPR55 antagonism, but not by CB1 receptor blockage. AEA also inhibited calcium-dependent cytokine mRNA synthesis induced by FcεRI crosslinking, without affecting early phosphorylation events. In addition, AEA, HU308 and LPI inhibited intracellular Ca2+ rise in response to IgE/Ag. CB2 and GPR55 receptor antagonism could not prevent the inhibition produced by AEA and HU308, but partially blocked the one caused by LPI. These results indicate that AEA inhibits IgE/Ag-induced degranulation through a mechanism that includes the participation of CB2 and GPR55 receptors acting in close crosstalk, and show that CB2-GPR55 heteromers are important negative regulators of FcεRI-induced responses in MCs.

Vesicular trafficking and signaling for cytokine and chemokine secretion in mast cells.

Upon activation mast cells (MCs) secrete numerous inflammatory compounds stored in their cytoplasmic secretory granules by a process called anaphylactic degranulation, which is responsible for type I hypersensitivity responses. Prestored mediators include histamine and MC proteases but also some cytokines and growth factors making them available within minutes for a maximal biological effect. Degranulation is followed by the de novo synthesis of lipid mediators such as prostaglandins and leukotrienes as well as a vast array of cytokines, chemokines, and growth factors, which are responsible for late phase inflammatory responses. While lipid mediators diffuse freely out of the cell through lipid bilayers, both anaphylactic degranulation and secretion of cytokines, chemokines, and growth factors depends on highly regulated vesicular trafficking steps that occur along the secretory pathway starting with the translocation of proteins to the endoplasmic reticulum. Vesicular trafficking in MCs also intersects with endocytic routes, notably to form specialized cytoplasmic granules called secretory lysosomes. Some of the mediators like histamine reach granules via specific vesicular monoamine transporters directly from the cytoplasm. In this review, we try to summarize the available data on granule biogenesis and signaling events that coordinate the complex steps that lead to the release of the inflammatory mediators from the various vesicular carriers in MCs.

Anti-Inflammatory Effects of Hyptis albida Chloroform Extract on Lipopolysaccharide-Stimulated Peritoneal Macrophages.

We examined the effects of a chloroform extract of Hyptis albida (CHA) on inflammatory responses in mouse lipopolysaccharide (LPS) induced peritoneal macrophages. Our findings indicate that CHA inhibits LPS-induced production of tumor necrosis factor (TNF- α ) and interleukin-6 (IL-6). During the process, levels of cyclooxygenase-2 (COX-2), nitric oxide synthase (iNOS), and nitric oxide (NO) increased in the mouse peritoneal macrophages; however, the extract suppressed them significantly. These results provide novel insights into the anti-inflammatory actions of CHA and support its potential use in the treatment of inflammatory diseases.