Cancer cachexia, one of the metabolic syndromes caused by cancer, is a devastating and miserable condition encountered in more than 50% of terminal cancer patients presenting with significant weight loss associated with skeletal muscle atrophy and fat loss. Though cachexia may account for up to 20% of cancer deaths, no significant treatment is still lacking and is of urgent unmet medical need in cancer treatment. Therefore, understanding the underlying molecular mechanisms is essential for anticipating therapeutic approaches. Since the primary events driving cachexia are mediated via either the central nervous system relatedor inflammation related-anorexia, hypoanabolism, and hypercatabolism, therapy usually targets nutritional support to compensate reduced food intake along with some anti-inflammatory agents to cover specific inflammation-related metabolic derangement, and encourages exercise to supplement reduced physical activity, but all proven to be not so effective so far. Therefore, combination therapies such as a standard multi-modal package including an anorexic agent, megestrol acetate, and anti-inflammatory agent coupled with the development of potential novel therapeutics promise a new era in rescuing patients from cancer cachexia. In this review, we propose the potential application of BPC157, one of the active cytoprotective agents isolated from gastric juices for cancer cachexia. Before clinical trial, we introduced the evidence showing BPC157 rescued from cancer cachexia supported with explored mode of actions.

S100B is an EF-hand containing calcium-binding protein of the S100 protein family that exerts its biological effect by binding and affecting various target proteins. A consensus sequence for S100B target proteins was published as (K/R)(L/I)xWxxIL and matches a region in the actin capping protein CapZ (V.V. Ivanenkov, G.A. Jamieson, Jr., E. Gruenstein, R.V. Dimlich, Characterization of S-100b binding epitopes. Identification of a novel target, the actin capping protein, CapZ, J. Biol. Chem. 270 (1995) 14651-14658). Several additional S100B targets are known including p53, a nuclear Dbf2 related (NDR) kinase, the RAGE receptor, neuromodulin, protein kinase C, and others. Examining the binding sites of such targets and new protein sequence searches provided additional potential target proteins for S100B including Hdm2 and Hdm4, which were both found to bind S100B in a calcium-dependent manner. The interaction between S100B and the Hdm2 and/or the Hdm4 proteins may be important physiologically in light of evidence that like Hdm2, S100B also contributes to lowering protein levels of the tumor suppressor protein, p53. For the S100B-p53 interaction, it was found that phosphorylation of specific serine and/or threonine residues reduces the affinity of the S100B-p53 interaction by as much as an order of magnitude, and is important for protecting p53 from S100B-dependent down-regulation, a scenario that is similar to what is found for the Hdm2-p53 complex.

Background: Valproic acid (VPA), a commonly used mood stabilizer that promotes neuronal differentiation, regulates multiple signaling pathways involving extracellular signal-regulated kinase (ERK) and glycogen synthase kinase3β (GSK3β). However, the mechanism by which VPA promotes differentiation is not understood.

Abstract-In this study, we examined the signaling pathways activated by Wnt5a in endothelial differentiation of embryonic stem (ES) cells and the function of Wnt5a during vascular development. We first found that Wnt5a Ϫ/Ϫ mouse embryonic stem (mES) cells exhibited a defect in endothelial differentiation, which was rescued by addition of Wnt5a, suggesting that Wnt5a is required for endothelial differentiation of ES cells. Involvement of both ␤-catenin and protein kinase (PK)C␣ pathways in endothelial differentiation of mES cells requiring Wnt5a was indicated by activation of both ␤-catenin and PKC␣ in Wnt5a ϩ/Ϫ but not in Wnt5a Ϫ/Ϫ mES cells. We also found that ␤-catenin or PKC␣ knockdowns inhibited the Wnt5a-induced endothelial differentiation of ES cells. Moreover, the lack of endothelial differentiation of Wnt5a Ϫ/Ϫ mES cells was rescued only by transfection of both ␤-catenin and PKC␣, indicating that both genes are required for Wnt5a-mediated endothelial differentiation. Wnt5a was also found to be essential for the differentiation of mES cells into immature endothelial progenitor cells, which are known to play a role in repair of damaged endothelium. Furthermore, a defect in the vascularization of the neural tissue was detected at embryonic day 14.5 in Wnt5a Ϫ/Ϫ mice, implicating Wnt5a in vascular development in vivo. Thus, we conclude that Wnt5a is involved in the endothelial differentiation of ES cells via both Wnt/␤-catenin and PKC signaling pathways and regulates embryonic vascular development. Key Words: Wnt5a Ⅲ embryonic stem cells Ⅲ ␤-catenin Ⅲ PKC␣ Ⅲ endothelial differentiation T he Wnt family of proteins comprises a large family of cysteine-rich secreted proteins that control multiple processes, including embryonic patterning, growth, migration, and cell differentiation. 1 Wnts are known to activate several different pathways. One of them, the canonical pathway, is characterized by in stabilization of ␤-catenin as a result of the transmission of the signal through cell surface receptors and in subsequent transcriptional activation of target genes. In other pathways, often called noncanonical pathways, Wnt proteins function via cell surface receptors to stimulate the Wnt/Ca 2ϩ pathway through the activation of protein kinase (PK)C 2 or the Wnt/PCP pathway through the activation of c-Jun N-terminal kinase (JNK). 3,4 Wnt5a has been reported to function through the both noncanonical pathway involving PKC 5 and the canonical pathway involving ␤-catenin. 1,6 At a functional level, Wnt5a has been implicated in the regulation of development, proliferation, and cell differentiation. [7][8][9][10][11][12] During development, Wnt5a is involved in the differentiation of chondrocytes, 13 as well as dopaminergic neuron differentiation of ventral midbrain. 14 -16 Wnt5a is also highly expressed in human primary endothelial cells 17 Materials and Methods Culture of ES CellsWnt5a ϩ/Ϫ and Wnt5a Ϫ/Ϫ mouse ES cells were generated as described previously. 20 EPC CultureTo collect EPCs, the Sca-1 ϩ cells were sorted f...