Nickel (Ni) metal and Ni compounds are widely used in applications like stainless steel, alloys, and batteries. Nickel is a naturally occurring element in water, soil, air, and living organisms, and is essential to microorganisms and plants. Thus, human and environmental nickel exposures are ubiquitous. Production and use of nickel and its compounds can, however, result in additional exposures to humans and the environment. Notable human health toxicity effects identified from human and/or animal studies include respiratory cancer, non-cancer toxicity effects following inhalation, dermatitis, and reproductive effects. These effects have thresholds, with indirect genotoxic and epigenetic events underlying the threshold mode of action for nickel carcinogenicity. Differences in human toxicity potencies/potentials of different nickel chemical forms are correlated with the bioavailability of the Ni²⁺ ion at target sites. Likewise, Ni²⁺ has been demonstrated to be the toxic chemical species in the environment, and models have been developed that account for the influence of abiotic factors on the bioavailability and toxicity of Ni²⁺ in different habitats. Emerging issues regarding the toxicity of nickel nanoforms and metal mixtures are briefly discussed. This review is unique in its covering of both human and environmental nickel toxicity data.

Heart disease remains the leading cause of death worldwide, highlighting a pressing need to identify novel regulators of cardiomyocyte (CM) function that could be therapeutically targeted. The mammalian Hippo/Tead pathway is critical in embryonic cardiac development and perinatal CM proliferation. However, the requirement of Tead1, the transcriptional effector of this pathway, in the adult heart is unknown. Here, we show that tamoxifen-inducible adult CM–specific Tead1 ablation led to lethal acute-onset dilated cardiomyopathy, associated with impairment in excitation-contraction coupling. Mechanistically, we demonstrate Tead1 is a cell-autonomous, direct transcriptional activator of SERCA2a and SR-associated protein phosphatase 1 regulatory subunit, Inhibitor-1 (I-1). Thus, Tead1 deletion led to a decrease in SERCA2a and I-1 transcripts and protein, with a consequent increase in PP1-activity, resulting in accumulation of dephosphorylated phospholamban (Pln) and decreased SERCA2a activity. Global transcriptomal analysis in Tead1-deleted hearts revealed significant changes in mitochondrial and sarcomere-related pathways. Additional studies demonstrated there was a trend for correlation between protein levels of TEAD1 and I-1, and phosphorylation of PLN, in human nonfailing and failing hearts. Furthermore, TEAD1 activity was required to maintain PLN phosphorylation and expression of SERCA2a and I-1 in human induced pluripotent stem cell–derived (iPS-derived) CMs. To our knowledge, taken together, this demonstrates a nonredundant, novel role of Tead1 in maintaining normal adult heart function.

Nicotinic acetylcholine receptors (nAChRs) of parasitic nematodes are required for body movement and are targets of important “classical” anthelmintics like levamisole and pyrantel, as well as “novel” anthelmintics like tribendimidine and derquantel. Four biophysical subtypes of nAChR have been observed electrophysiologically in body muscle of the nematode parasite Oesophagostomum dentatum, but their molecular basis was not understood. Additionally, loss of one of these subtypes (G 35 pS) was found to be associated with levamisole resistance. In the present study, we identified and expressed in Xenopus oocytes, four O. dentatum nAChR subunit genes, Ode-unc-38, Ode-unc-63, Ode-unc-29 and Ode-acr-8, to explore the origin of the receptor diversity. When different combinations of subunits were injected in Xenopus oocytes, we reconstituted and characterized four pharmacologically different types of nAChRs with different sensitivities to the cholinergic anthelmintics. Moreover, we demonstrate that the receptor diversity may be affected by the stoichiometric arrangement of the subunits. We show, for the first time, different combinations of subunits from a parasitic nematode that make up receptors sensitive to tribendimidine and derquantel. In addition, we report that the recombinant levamisole-sensitive receptor made up of Ode-UNC-29, Ode-UNC-63, Ode-UNC-38 and Ode-ACR-8 subunits has the same single-channel conductance, 35 pS and 2.4 ms mean open-time properties, as the levamisole-AChR (G35) subtype previously identified in vivo. These data highlight the flexible arrangements of the receptor subunits and their effects on sensitivity and resistance to the cholinergic anthelmintics; pyrantel, tribendimidine and/or derquantel may still be effective on levamisole-resistant worms. Parasitic nematode infections of humans and animals are world-wide. In humans, they cause disease and perpetuate a cycle of poverty. In animals, the parasites cause welfare problems and production loss. In developing countries, the debilitating effect of nematode parasites in school children limits their education, and in adults reduces productivity. These two factors, along with the production loss associated with nematode infections of animals that affects human nutrition, sustain poverty. Treatment and prophylaxis of these parasites requires the use of anthelmintic drugs. Here, we employ the Xenopus oocyte expression system to investigate the diversity of anthelmintic receptors in the parasitic nematode Oesophagostomum dentatum. We demonstrate effects of the ‘novel’ anthelmintics tribendimidine and derquantel on these reconstituted receptors, revealing, for the first time, the subunits that make up a tribendimidine- and derquantel-sensitive receptor from a parasitic nematode. We show that the receptor structure and pharmacology can be plastic, and depends on subunit composition and stoichiometry. The factors that affect the diversity of the receptor may contribute to anthelmintic resistance. Our results demonstrate the presence of acetylcholine receptor subtypes that may serve as anthelmintic targets and suggest that pyrantel, tribendimidine and/or derquantel may still be effective on levamisole-resistant worms.

Acetylcholine is the canonical excitatory neurotransmitter of the mammalian neuromuscular system. However, in the trematode parasite Schistosoma mansoni, cholinergic stimulation leads to muscle relaxation and a flaccid paralysis, suggesting an inhibitory mode of action. Information about the pharmacological mechanism of this inhibition is lacking. Here, we used a combination of techniques to assess the role of cholinergic receptors in schistosome motor function. The neuromuscular effects of acetylcholine are typically mediated by gated cation channels of the nicotinic receptor (nAChR) family. Bioinformatics analyses identified numerous nAChR subunits in the S. mansoni genome but, interestingly, nearly half of these subunits carried a motif normally associated with chloride-selectivity. These putative schistosome acetylcholine-gated chloride channels (SmACCs) are evolutionarily divergent from those of nematodes and form a unique clade within the larger family of nAChRs. Pharmacological and RNA interference (RNAi) behavioral screens were used to assess the role of the SmACCs in larval motor function. Treatment with antagonists produced the same effect as RNAi suppression of SmACCs; both led to a hypermotile phenotype consistent with abrogation of an inhibitory neuromuscular mediator. Antibodies were then generated against two of the SmACCs for use in immunolocalization studies. SmACC-1 and SmACC-2 localize to regions of the peripheral nervous system that innervate the body wall muscles, yet neither appears to be expressed directly on the musculature. One gene, SmACC-1, was expressed in HEK-293 cells and characterized using an iodide flux assay. The results indicate that SmACC-1 formed a functional homomeric chloride channel and was activated selectively by a panel of cholinergic agonists. The results described in this study identify a novel clade of nicotinic chloride channels that act as inhibitory modulators of schistosome neuromuscular function. Additionally, the iodide flux assay used to characterize SmACC-1 represents a new high-throughput tool for drug screening against these unique parasite ion channels. Schistosomiasis is a widespread, chronic disease affecting over 200 million people in developing countries. Currently, there is no vaccine available and treatment depends on the use of a single drug, praziquantel. Reports of reduced praziquantel efficacy, as well as its ineffectiveness against larval schistosomula highlight the need to develop new therapeutics. Interference with schistosome motor function provides a promising therapeutic target due to its importance in a variety of essential biological processes. The cholinergic system has been shown previously to be a major modulator of parasite motility. In this study, we have described a novel clade of schistosome acetylcholine-gated chloride channels (SmACCs) that act as inhibitory modulators of this pathway. Our results suggest that these receptors are absent in the human host and indirectly modulate inhibitory neuromuscular responses, making them an attractive drug-target. We have also validated a new functional assay to characterize these receptors, which may be modified for future use as a high-throughput drug screening method for parasite chloride channels.