The Meta-Position of Phe4 in Leu-Enkephalin Regulates Potency, Selectivity, Functional Activity, and Signaling Bias at the Delta and Mu Opioid Receptors

This work is licensed under a Creative Commons Attribution 4.0 International License.As tool compounds to study cardiac ischemia, the endogenous δ-opioid receptors (δOR) agonist Leu5-enkephalin and the more metabolically stable synthetic peptide (d-Ala2, d-Leu5)-enkephalin are frequently employed. However, both peptides have similar pharmacological profiles that restrict detailed investigation of the cellular mechanism of the δOR’s protective role during ischemic events. Thus, a need remains for δOR peptides with improved selectivity and unique signaling properties for investigating the specific roles for δOR signaling in cardiac ischemia. To this end, we explored substitution at the Phe4 position of Leu5-enkephalin for its ability to modulate receptor function and selectivity. Peptides were assessed for their affinity to bind to δORs and µ-opioid receptors (µORs) and potency to inhibit cAMP signaling and to recruit β-arrestin 2. Additionally, peptide stability was measured in rat plasma. Substitution of the meta-position of Phe4 of Leu5-enkephalin provided high-affinity ligands with varying levels of selectivity and bias at both the δOR and µOR and improved peptide stability, while substitution with picoline derivatives produced lower-affinity ligands with G protein biases at both receptors. Overall, these favorable substitutions at the meta-position of Phe4 may be combined with other modifications to Leu5-enkephalin to deliver improved agonists with finely tuned potency, selectivity, bias and drug-like properties

Evaluation of kratom opioid derivatives as potential treatment option for alcohol use disorder

Background and Purpose: Mitragyna speciosa extract and kratom alkaloids decrease alcohol consumption in mice at least in part through actions at the δ-opioid receptor (δOR). However, the most potent opioidergic kratom alkaloid, 7-hydroxymitragynine, exhibits rewarding properties and hyperlocomotion presumably due to preferred affinity for the mu opioid receptor (µOR). We hypothesized that opioidergic kratom alkaloids like paynantheine and speciogynine with reduced µOR potency could provide a starting point for developing opioids with an improved therapeutic window to treat alcohol use disorder. Experimental Approach: We characterized paynantheine, speciociliatine, and four novel kratom-derived analogs for their ability to bind and activate δOR, µOR, and κOR. Select opioids were assessed in behavioral assays in male C57BL/6N WT and δOR knockout mice. Key Results: Paynantheine (10 mg∙kg(−1), i.p.) produced aversion in a limited conditioned place preference (CPP) paradigm but did not produce CPP with additional conditioning sessions. Paynantheine did not produce robust antinociception but did block morphine-induced antinociception and hyperlocomotion. Yet, at 10 and 30 mg∙kg(−1) doses (i.p.), paynantheine did not counteract morphine CPP. 7-hydroxypaynantheine and 7-hydroxyspeciogynine displayed potency at δOR but limited µOR potency relative to 7-hydroxymitragynine in vitro, and dose-dependently decreased voluntary alcohol consumption in WT but not δOR in KO mice. 7-hydroxyspeciogynine has a maximally tolerated dose of at least 10 mg∙kg(−1) (s.c.) at which it did not produce significant CPP neither alter general locomotion nor induce noticeable seizures. Conclusion and Implications: Derivatizing kratom alkaloids with the goal of enhancing δOR potency and reducing off-target effects could provide a pathway to develop novel lead compounds to treat alcohol use disorder with an improved therapeutic window

Dependence of Initial Value on Pattern Formation for a Logistic Coupled Map Lattice.

The logistic coupled map lattices (LCML) have been widely investigated as well as their pattern dynamics. The patterns formation may depend on not only fluctuations of system parameters, but variation of the initial conditions. However, the mathematical discussion is quite few for the effect of initial values so far. The present paper is concerned with the pattern formation for a two-dimensional Logistic coupled map lattice, where any initial value can be linear expressed by corresponding eigenvectors, and patterns formation can be determined by selecting the corresponding eigenvectors. A set of simulations are conducted whose results demonstrate the fact. The method utilized in the present paper could be applied to other discrete systems as well

Spatial pattern of the time evolution at different instants.

<p>Snapshots of contour pictures of the time evolution of CML system at some instants with <i>λ</i> = 2.9 and <i>ε</i> = 0.34 in the Turing instability region. (A) <i>t</i> = 0. (B) <i>t</i> = 100. (C) <i>t</i> = 5000. (D) <i>t</i> = 10000. (E) <i>t</i> = 50000. (F) <i>t</i> = 100000.</p

Spatial pattern of the time evolution at different instants.

<p>Snapshots of contour pictures of the time evolution of CML system at some instants with <i>λ</i> = 1.5 and <i>ε</i> = 0.4 in the Turing instability region. (A) <i>t</i> = 0. (B) <i>t</i> = 57. (C) <i>t</i> = 69.</p

Exploring the Peer Effect of Physicians&rsquo; and Patients&rsquo; Participation Behavior: Evidence from Online Health Communities

Background: Little research has studied the peer effect of physicians and patients in online health communities (OHCs) simultaneously. The study investigates the impact of the focal physician&rsquo;s peers (F-peers) on the focal physician (F-physician), and the impact of patients of the focal physician&rsquo;s peers (F-P-patients) on the focal physician&rsquo;s patients (F-patients). Moreover, based on brand extension and accessible&ndash;diagnosable theories, this study explores the moderating effects of the intensity of F-peers&rsquo; knowledge sharing behavior and department reputation. Methods: This study collects data of 3297 physicians and related patients from Haodf.com platform between January 2019 and December 2019. Both two-way fixed effect and panel negative binomial regression are adopted to quantify the effects. Results: Results show that the behavior of F-peers positively affects the behavior of the F-physician, while the behavior of F-P-patients positively affects the behavior of F-patients. Moreover, both the intensity of F-peers&rsquo; knowledge sharing behavior and department reputation have a compound moderating effect. Conclusions: This study contributes to the literature of peer effects by constructing the conceptual framework of different types of individual participation behaviors in OHCs. The findings offer practical guides for establishing an incentive mechanism and formulating peer incentives or competition strategies in OHCs

Study on the Effect of Rock Mass Structure on CO₂ Transient Fissure Excavation

As a new rock breaking method, CO2 transient cracking has been widely used in rock excavation projects in recent years. However, in the actual construction process, there are often situations where the fracturing effect varies due to different rock mass structures. Through theoretical analysis and on-site cracking tests, this article studies the effect of CO2 transient cracking under the control of different rock mass structures. The results show that: (1) the dynamic compressive strength of rock directly determines the number and range of dynamic impact fractures; the original fractures of rock mass and those caused by dynamic impact in the first stage jointly determine the effect of high-pressure gas expansion in the second stage. (2) The arrangement of holes along the strata is conducive to the action of high-pressure expanding gas along the soft structural plane in the rock mass, which is conducive to the fracturing of the rock mass; the amount of crack formation is small, but the influence range is large. (3) The cracking effect of carbon dioxide transient cracking applied to massive rock mass is better than that of monolithic rock mass, while the cracking effect of layered rock mass with soil interlayer is poor. The research results are of great significance for improving the effectiveness of carbon dioxide transient-induced cracking excavation and guiding actual construction

Allelochemicals from the Rhizosphere Soil of Potato (Solanum tuberosum L.) and Their Interactions with the Soilborne Pathogens

To reveal the allelopathic effects of potato, seven compounds were isolated from the rhizosphere soil: 7-methoxycoumarin (1), palmitic acid (2), caffeic acid (3), chlorogenic acid (4), quercetin dehydrate (5), quercitrin (6), and rutin (7). Bioassays showed that compounds 1, 2, 4, and 6 had inhibitory effects on the growth of L. sativa and tissue culture seedlings of potato. The existence of the allelochemicals was confirmed by HPLC, and their contents were quantified with a total concentration of 9.02 &mu;g/g in the rhizosphere soil of replanted potato. Approaches on the interactions of the allelochemicals and pathogens of potato including A. solani, B. cinerea, F. solani, F. oxysporum, C. coccodes, and V. dahlia revealed that compound 1 had inhibitory effects but compounds 2&ndash;4 promoted the colony growth of the pathogens. These findings demonstrated that the autotoxic allelopathy and enhancement of the pathogens caused by the accumulation of the allelochemicals in the continuously cropped soil should be one of the main reasons for the replant problems of potato