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Trypanosoma cruzi (T. cruzi), the causative agent of Chagas disease, has infected 6 million people, putting 70 million people at risk worldwide. Presently, very limited drugs are available, and these have severe side effects. Hence, there is an urgency to delve into other pathways and targets for novel drugs. Trypanosoma cruzi (T. cruzi) expresses a number of different cyclic AMP (cAMP)-specific phosphodiesterases (PDEs). cAMP is one of the key regulators of mammalian cell proliferation and differentiation, and it also plays an important role in T. cruzi growth. Very few studies have demonstrated the important role of cyclic nucleotide-specific PDEs in T. cruzi’s survival. T. cruzi phosphodiesterase C (TcrPDEC) has been proposed as a potential new drug target for treating Chagas disease. In the current study, we screen several analogs of xanthine for potency against trypomastigote and amastigote growth in vitro using three different strains of T. cruzi (Tulahuen, Y and CA-1/CL72). One of the potent analogs, GVK14, has been shown to inhibit all three strains of amastigotes in host cells as well as axenic cultures. In conclusion, xanthine analogs that inhibit T. cruzi PDE may provide novel alternative therapeutic options for Chagas disease.

Claudin-4 is part of the Claudin family of transmembrane tight junction (TJ) proteins found in almost all tissues and, together with adherens junctions and desmosomes, forms epithelial and endothelial junctional complexes. Although the distribution of Claudin-4 occurs in many cell types, the level of expression is cell-specific. Claudin proteins regulate cell proliferation and differentiation by binding cell-signaling ligands, and its expression is upregulated in several cancers. As a result, alterations in Claudin expression patterns or distribution are vital in the pathology of cancer. Profiling the genetic expression of Claudin-4 showed that Claudin-4 is also a receptor for the clostridium perfringens enterotoxin (CPE) and that Claudin-4 has a high sequence similarity with CPE’s high-affinity receptor. CPE is cytolytic due to its ability to form pores in cellular membranes, and CPE treatment in breast cancer cells have shown promising results due to the high expression of Claudin-4. The C-terminal fragment of CPE (c-CPE) provides a less toxic alternative for drug delivery into breast cancer cells, particularly metastatic tumors in the brain, especially as Claudin-4 expression in the central nervous system (CNS) is low. Therefore, c-CPE provides a unique avenue for the treatment of breast–brain metastatic tumors.

Glial cells play a critical role in shaping neuronal development, structure, and function. In a screen for Caenorhabditis elegans mutants that display dopamine (DA)-dependent, Swimming-Induced Paralysis (Swip), we identified a novel gene, swip-10, the expression of which in glia is required to support normal swimming behavior. swip-10 mutants display reduced locomotion rates on plates, consistent with our findings of elevated rates of presynaptic DA vesicle fusion using fluorescence recovery after photobleaching. In addition, swip-10 mutants exhibit elevated DA neuron excitability upon contact with food, as detected by in vivo Ca(2+) monitoring, that can be rescued by glial expression of swip-10. Mammalian glia exert powerful control of neuronal excitability via transporter-dependent buffering of extracellular glutamate (Glu). Consistent with this idea, swip-10 paralysis was blunted in mutants deficient in either vesicular Glu release or Glu receptor expression and could be phenocopied by mutations that disrupt the function of plasma membrane Glu transporters, most noticeably glt-1, the ortholog of mammalian astrocytic GLT1 (EAAT2). swip-10 encodes a protein containing a highly conserved metallo-β-lactamase domain, within which our swip-10 mutations are located and where engineered mutations disrupt Swip rescue. Sequence alignments identify the CNS-expressed gene MBLAC1 as a putative mammalian ortholog. Together, our studies provide evidence of a novel pathway in glial cells regulated by swip-10 that limits DA neuron excitability, DA secretion, and DA-dependent behaviors through modulation of Glu signaling.