Peptides have great potential as therapeutic agents, however, their clinic applications are severely hampered by their instability and short circulation half-life. Zero-order release carriers could not only extend the circulation lifetime of peptides, but also maintain the plasma drug level constant, and thus maximize their therapeutic efficacy and minimize their toxic effect. Here using PEGylated salmon calcitonin (PEG-sCT)/tannic acid (TA) film as an example, we demonstrated that hydrogen-bonded layer-by-layer films of a PEGylated peptide and a polyphenol could be a platform for zero-order peptide release. The films were fabricated under mild conditions. The second component, TA, is a natural product and presents potential therapeutic activities itself. Unlike common carriers, the new carrier releases the peptide via gradual disintegration of the film because of its dynamic nature. The release of PEG-sCT follows a perfect zero-order kinetics without initial burst release. In addition the release rate could be tuned via external stimuli, such as pH and temperature. When implanted in rats, the films could remain the plasma level of PEG-sCT constant over an extended period. Accordingly, the serum calcium level was reduced and maintained constant over the same period, suggesting an improved therapeutic efficacy of the released drug.

C-Phycocyanin (C-PC), a kind of blue protein isolated from Spirulina platensis, can ameliorate hyperglycemia, but its effects on gluconeogenesis and glycogenesis are unknown. In the present study, we investigated the effects and underlying mechanisms of C-PC on gluconeogenesis and glycogenesis in insulin resistant hepatocytes. Insulin resistance was induced by high glucose (HG) in human hepatocellular carcinoma (HepG2) cells. C-PC ameliorated glucose production and phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) expression in HG-induced insulin resistant HepG2 cells. It also increased glucose uptake, glycogen content and glycogen synthase (GS) activation in HG-induced insulin resistant HepG2 cells. The data revealed the mechanism of C-PC in improving glucose homoeostasis via activating the IRS/PI3 K/Akt and SIRT1/LKB1/AMPK signaling pathway in insulin resistant hepatocytes. C-PC could be a promising leading compound for the development of a hypoglycemic agent.

Nalfurafine, a moderately selective kappa opioid receptor (KOR) agonist, is used in Japan for treatment of itch without causing dysphoria or psychotomimesis. Here we characterized the pharmacology of compound 42B, a 3-dehydroxy analogue of nalfurafine and compared with that of nalfurafine. Nalfurafine and 42B acted as full KOR agonists and partial μ opioid receptor (MOR) agonists, but 42B showed much lower potency for both receptors and lower KOR/MOR selectivity, different from previous reports. Molecular modeling revealed that water-mediated hydrogen-bond formation between 3-OH of nalfurafine and KOR accounted for its higher KOR potency than 42B. The higher potency of both at KOR over MOR may be due to hydrogen-bond formation between nonconserved Y 7.35 of KOR and their carbonyl groups. Both showed modest G protein signaling biases. In mice, like nalfurafine, 42B produced antinociceptive and antiscratch effects and did not cause conditioned place aversion (CPA) in the effective dose ranges. Unlike nalfurafine, 42B caused motor incoordination and hypolocomotion. As both agonists showed G protein biases, yet produced different effects on locomotor activity and motor incoordination, the findings and those in the literature suggest caution in correlating in vitro biochemical data with in vivo behavior effects. The factors contributing to the disconnect, including pharmacodynamic and pharmacokinetic issues, are discussed. In addition, our results suggest that among the KOR-induced adverse behaviors, CPA can be separated from motor incoordination and hypolocomotion.

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Opioid use disorder is a worldwide societal problem and public health burden. Strategies for treating opioid use disorder can be divided into those that target the opioid receptor system and those that target non‐opioid receptor systems, including the dopamine and glutamate receptor systems. Currently, the clinical drugs used to treat opioid use disorder include the opioid receptor agonists methadone and buprenorphine, which are limited by their abuse liability, and the opioid receptor antagonist naltrexone, which is limited by poor compliance. Therefore, the development of effective medications with lower abuse liability and better potential for compliance is urgently needed. Based on recent advances in the understanding of the neurobiological mechanisms underlying opioid use disorder, potential treatment strategies and targets have emerged. This review focuses on the progress made in identifying potential targets and developing medications to treat opioid use disorder, including progress made by our laboratory, and provides insights for future medication development. LINKED ARTICLES This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc

Previous studies have shown that agmatine, a potential neuromodulator or co-transmitter, exhibited antidepressant-like action in animal models, yet its mechanism, especially the receptor mechanism, remains unclear. In the present study, using efaroxan, a preferential antagonist of I imidazoline receptor (IR) and yohimbine, an antagonist of α adrenergic receptor (αAR), we investigated the roles of IR and αAR in agmatine's antidepressant-like effect in acute and sub-acute depression models in mice. We found that in the tail-suspension test (TST) and the forced swimming test (FST), acute administration of agmatine (20 and 40 mg/kg, p.o.) significantly shortened the immobility time. Concurrent administration of efaroxan (1 mg/kg, i.p.) completely abolished the antidepressant-like effects of agmatine (40 mg/kg, p.o.) whereas yohimbine (5 mg/kg, i.p.) failed to exert similar effects, suggesting that the acute antidepressant-like effects of agmatine was mainly mediated by IR but not αAR. Additionally, in the learned helplessness (LH) test, repeated administration of agmatine (20 mg/kg, p.o., q.d.) for 5 days significantly decreased the escape latency and the number of escape failure, and these effects were respectively abolished by concurrent administration of efaroxan (0.5 mg/kg,i.p., q.d.) and yohimbine (3 mg/kg, i.p., q.d.) for 5 days, suggesting that the antidepressant-like action of agmatine in the LH test was achieved via the activation of both IR and αAR. In summary, we found that the antidepressant-like effects of agmatine in the TST and the FST were mediated by activating IR and in the sub-acute LH test were mediated by activating both IR and αAR.