This study investigates how firms in the gambling industry manage their corporate social disclosures (CSDs) about controversial issues. We performed thematic content analysis of CSDs about ...responsible gambling, money laundering prevention and environmental protection in the annual reports and stand-alone CSR reports (2009–2016) of four USA-based multinational gambling firms and their four Macao counterparts. This study draws on impression management theory, camouflage theory and corporate integrity theory to examine the gambling firms’ CSDs. We infer that the CSD strategies of gambling firms in Macao and the USA did not serve as vehicles for reflexivity about social responsibility or social responsiveness. Instead, the firms camouflaged legitimacy gaps about sensitive topics by adopting assertive or defensive façades, disclaiming ethical responsibility, curtailing disclosure, or offering zero disclosure. Differences between CSD strategies according to topic, location, time, and reporting channel appear to reflect four factors: pressure to report, availability of good news, whether a firm was assuming ethical responsibility for addressing the topic, and the prospective readership. This study extends our understanding of the contextual and topic-specific factors affecting the quantity and character of CSDs by firms in a contested industry.
Over two decades of research on venom peptides derived from cone snails ("conopeptides or conotoxins") has led to several compounds that have reached human clinical trials, most of them for the ...treatment of pain. Remarkably, none of the conopeptides in clinical development mediate analgesia through the opioid receptors, underlying the diverse and novel neuropharmacology evolved by Conus snails. These predatory animals produce an estimated approximately 100,000 distinct conotoxins, a vast majority yet to be discovered and characterized. The conopeptides studied to-date in animal models, have exhibited antinociceptive, antiepileptic, neuroprotective or cardioprotective activities. Screening results also suggest applications of conotoxins in cancer, neuromuscular and psychiatric disorders. Additional potentially important applications of conotoxin research are the discovery and validation of new therapeutic targets, also defining novel binding sites on already validated molecular targets. As the structural and functional diversity of conotoxins is being investigated, the Conus venoms continue to surprise with the plethora of neuropharmacological compounds and potential new therapeutics. This review summarizes recent efforts in the discovery of conopeptides, and their preclinical and clinical development.
Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) ...rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB₁Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB₁R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB₁R-deficient (Cnr1(-/-)) or Nlrp3(-/-) mice, with the endocannabinoid anandamide. Peripheral CB₁R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB₁R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB₁R as a therapeutic target in T2DM.
Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Current systemic therapies result only in modest benefits and new therapeutic options are critically ...needed. Some patients show promising clinical responses to immune checkpoint inhibitors, however, additional immunotherapeutic approaches, such as adoptive cell therapies (ACT), need to be developed. This review summarizes recent ACT studies and discusses the promise and obstacles of this approach. We further discuss ways of improving the efficacy of ACT in HCC including the use of combination therapies and locoregional delivery methods.
This paper attempts to investigate how and why organisations in Macao's gambling industry engage in corporate social responsibility (CSR). It is based on an indepth investigation of Macao's gambling ...industry with 49 semi-structured interviews, conducted in 2011. We found that firms within the industry were emphasising pragmatic legitimacy based on both economic and non-economic contributions, in order to project positive images of the industry, while glossing over two domains of adverse externalities: problem gambling among visitors, and the pollution and despoliation of the environment. By engaging symbolically rather than substantively in CSR, the gambling firms were diverting attention away from issues of moral legitimacy, in order to be allowed to continue to pursue "business as usual" as a means of obtaining substantial financial returns in a social, cultural and sociopolitical context that was exerting relatively little public pressure to improve corporate social and environmental performance. We conjecture that the gambling firms were feeding on borrowed time.
The μ-conotoxin KIIIA is a three disulfide-bridged blocker of voltage-gated sodium channels (VGSCs). The Lys7 residue in KIIIA is an attractive target for manipulating the selectivity and efficacy of ...this peptide. Here, we report the design and chemical synthesis of μ-conopeptoid analogues (peptomers) in which we replaced Lys7 with peptoid monomers of increasing side-chain size: N-methylglycine, N-butylglycine and N-octylglycine. In the first series of analogues, the peptide core contained all three disulfide bridges; whereas in the second series, a disulfide-depleted selenoconopeptide core was used to simplify oxidative folding. The analogues were tested for functional activity in blocking the Nav1.2 subtype of mammalian VGSCs exogenously expressed in Xenopus oocytes. All six analogues were active, with the N-methylglycine analogue, Sar7KIIIA, the most potent in blocking the channels while favouring lower efficacy. Our findings demonstrate that the use of N-substituted Gly residues in conotoxins show promise as a tool to optimize their pharmacological properties as potential analgesic drug leads.
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•Two series of peptoid–peptide chimeras of μ-conotoxin KIIIA were synthesized.•Oxidative folding of μ-KIIIA peptomers was simplified using selenocysteines.•All peptomer analogues blocked mammalian Nav1.2 sodium channels.•One of the peptomer analogues presented unique pharmacological properties.
The possibility of independently manipulating the affinity and efficacy of pore-blocking ligands of sodium channels is of interest for the development of new drugs for the treatment of pain. The ...analgesic μ-conotoxin KIIIA (KIIIA), a 16-residue peptide with three disulfide bridges, is a pore blocker of voltage-gated sodium channels, including neuronal subtype NaV1.2 (K d = 5 nM). At saturating concentrations, KIIIA incompletely blocks the sodium current of NaV1.2, leaving a 5% residual current (rI Na). Lys7 is an important residue: the K7A mutation decreases both the efficacy (i.e., increases rI Na to 23%) and the affinity of the peptide (K d = 115 nM). In this report, various replacements of residue 7 were examined to determine whether affinity and efficacy were inexorably linked. Because of their facile chemical synthesis, KIIIA analogues that had as a core structure the disulfide-depleted KIIIAC1A,C2U,C9A,C15U (where U is selenocysteine) or ddKIIIA were used. Analogues ddKIIIA and ddKIIIAK7X, where X represents one of nine different amino acids, were tested on voltage-clamped Xenopus oocytes expressing rat NaV1.2 or NaV1.4. Their affinities ranged from 0.01 to 36 μM and rI Na values from 2 to 42%, and these two variables appeared to be uncorrelated. Instead, rI Na varied inversely with side chain size, and remarkably charge and hydrophobicity appeared to be inconsequential. The ability to manipulate a μ-conopeptide’s affinity and efficacy, as well as its capacity to interfere with subsequent tetrodotoxin binding, greatly expands its scope as a reagent for probing sodium channel structure and function and may also lead to the development of μ-conotoxins as safe analgesics.
Disulfide-rich peptides represent a megadiverse group of natural products with very promising therapeutic potential. To accelerate their functional characterization, high-throughput chemical ...synthesis and folding methods are required, including efficient mapping of multiple disulfide bridges. Here, we describe a novel approach for such mapping and apply it to a three-disulfide-bridged conotoxin, μ-SxIIIA (from the venom of Conus striolatus), whose discovery is also reported here for the first time. μ-SxIIIA was chemically synthesized with three cysteine residues labeled 100% with 15N/13C, while the remaining three cysteine residues were incorporated using a mixture of 70%/30% unlabeled/labeled Fmoc-protected residues. After oxidative folding, the major product was analyzed by NMR spectroscopy. Sequence-specific resonance assignments for the isotope-enriched Cys residues were determined with 2D versions of standard triple-resonance (1H, 13C, 15N) NMR experiments and 2D 13C, 1H HSQC. Disulfide patterns were directly determined with cross-disulfide NOEs confirming that the oxidation product had the disulfide connectivities characteristic of μ-conotoxins. μ-SxIIIA was found to be a potent blocker of the sodium channel subtype NaV1.4 (IC50 = 7 nM). These results suggest that differential incorporation of isotope-labeled cysteine residues is an efficient strategy to map disulfides and should facilitate the discovery and structure−function studies of many bioactive peptides.
Disulfide bridges that stabilize the native conformation of conotoxins pose a challenge in the synthesis of smaller conotoxin analogues. Herein we describe the synthesis of a minimized analogue of ...the analgesic mu-conotoxin KIIIA that blocks two sodium channel subtypes, the neuronal Na(V)1.2 and skeletal muscle Na(V)1.4. Three disulfide-deficient analogues of KIIIA were initially synthesized in which the native disulfide bridge formed between either C1-C9, C2-C15, or C4-C16 was removed. Deletion of the first bridge only slightly affected the peptide's bioactivity. To further minimize this analogue, the N-terminal residue was removed and two nonessential serine residues were replaced by a single 5-amino-3-oxapentanoic acid residue. The resulting "polytide" analogue retained the ability to block sodium channels and to produce analgesia. Until now, the peptidomimetic approach applied to conotoxins has progressed only modestly at best; thus, the disulfide-deficient analogues containing backbone spacers provide an alternative advance toward the development of conopeptide-based therapeutics.
Conantokins are short peptides derived from the venoms of marine cone snails that act as antagonists of the N-methyl-d-aspartate (NMDA) receptor family of excitatory glutamate receptors. These ...peptides contain γ-carboxyglutamic acid residues typically spaced at i,i+4 and/or i,i+7 intervals, which by chelating divalent cations induce and stabilize helical conformation of the peptide. Introduction of a dicarba bridge (or a staple) can covalently stabilize peptide helicity and improve its pharmacological properties. To test the hypothesis that stapling can effectively replace γ-carboxyglutamic acid residues in stabilizing the helical conformation of conantokins, we designed, synthesized, and characterized several stapled analogs of conantokin G (conG), with varying connectivities in terms of staple length and location along the face of the α-helix. NMR studies confirmed that the ring-closing metathesis reaction yielded a single product with the Z configuration of the olefinic bond. Based on circular dichroism and molecular modeling, the stapled analogs exhibited significantly enhanced helicity compared with the native peptide in a metal-free environment. Stapling i,i+4 was benign with respect to effects on in vitro and in vivo pharmacological properties. One analog, namely conG11–15,Si,i+4S(8), blocked NR2B-containing NMDA receptors with IC50 = 0.7 μm and provided significant protection in the 6-Hz psychomotor model of pharmacoresistant epilepsy in mice. Remarkably, unlike native conG, conG11–15,Si,i+4S(8) produced no behavioral motor toxicity. Our results extend the applications of peptide stapling to helical peptides with extracellular targets and provide a means for engineering conantokins with improved pharmacological properties.
Can dicarba bridges (stapling) replace noncovalent interactions that stabilize helical conformation of neuroactive peptides?
A rational design, synthesis, structural, and functional characterization of stapled conG analogs that target NMDA receptors is reported.
Stapled conG analogs are potent antagonists of NMDA receptors and anticonvulsant compounds.
Stapling can be successfully applied to convert neuroactive peptides into drug leads.
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