Combination with a Defucosylated Anti-HM1.24 Monoclonal Antibody plus Lenalidomide Induces Marked ADCC against Myeloma Cells and Their Progenitors

The immunomodulatory drug lenalidomide (Len) has drawn attention to potentiate antibody-dependent cellular cytotoxicity (ADCC)-mediated immunotherapies. We developed the defucosylated version (YB-AHM) of humanized monoclonal antibody against HM1.24 (CD317) overexpressed in multiple myeloma (MM) cells. In this study, we evaluated ADCC by YB-AHM and Len in combination against MM cells and their progenitors. YB-AHM was able to selectively kill via ADCC MM cells in bone marrow samples from patients with MM with low effector/target ratios, which was further enhanced by treatment with Len. Interestingly, Len also up-regulated HM1.24 expression on MM cells in an effector-dependent manner. HM1.24 was found to be highly expressed in a drug-resistant clonogenic “side population” in MM cells; and this combinatory treatment successfully reduced SP fractions in RPMI 8226 and KMS-11 cells in the presence of effector cells, and suppressed a clonogenic potential of MM cells in colony-forming assays. Collectively, the present study suggests that YB-AHM and Len in combination may become an effective therapeutic strategy in MM, warranting further study to target drug-resistant MM clonogenic cells.     

The effect of 17-N substituents on the activity of the opioid κ receptor in nalfurafine derivatives

We have previously reported the essential structure of the opioid κ receptor agonist nalfurafine hydrochloride (TRK-820) for binding to the κ receptor. In the course of this study, we focused on the effect of the substituent at 17-N in nalfurafine on the binding affinity for the κ receptor. The exchange of the 17-N substituent in nalfurafine from cyclopropylmethyl to fluoro-substituted alkyl groups, which are strong electron withdrawing substituents, almost completely diminished the binding affinities for the μ and δ opioid receptors, but the binding affinity for the κ receptor was still maintained. As a result, nalfurafine derivatives with 17-fluoro-substituted alkyl groups showed higher selectivities for the κ receptor than did nalfurafine itself. With regard to the κ agonistic activities, the conversion of the 17-N substituent in nalfurafine from cyclopropylmethyl to fluoro-substituted alkyl groups led to the gradual decrease of the agonistic activities in the order corresponding to their binding affinities for the κ receptor. In contrast, the derivative with the bulky 17-isobutyl group showed lower affinity and agonistic activity for the κ receptor than the derivatives with the smaller functional groups. This research suggested that both the electronic property and the steric characteristics of the 17-N substituent would have a great influence on the binding property for the κ receptor.     

The most effective influence of 17-(3-ethoxypropyl) substituent on the binding affinity and the agonistic activity in KNT-127 derivatives, δ opioid receptor agonists

We investigated the structure–activity relationship of KNT-127 (opioid δ agonist) derivatives with various 17-substituents which are different in length and size. The 17-substituent in KNT-127 derivatives exerted a great influence on the affinity and agonistic activity for the δ receptor. While the compounds with electron-donating 17-substituents showed higher affinities for the δ receptor than those with electron-withdrawing groups, KNT-127 derivatives with 17-fluoroalkyl groups (the high electron-withdrawing groups) showed high selectivities for the δ receptor among evaluated compounds. In addition, the basicity of nitrogen as well as the structure of the 17-N substituent such as the length and configuration at an asymmetric carbon atom contributed to agonist properties for the δ receptor. Thus, the analog with a 17-(3-ethoxypropyl) group showed the best selectively and potent agonistic activity for the δ receptor among KNT-127 derivatives. These findings should be useful for designing novel δ selective agonists.     

12-hydroxyjasmonic acid glucoside is a COI1-JAZ-independent activator of leaf-closing movement in Samanea saman

Jasmonates are ubiquitously occurring plant growth regulators with high structural diversity that mediate numerous developmental processes and stress responses. We have recently identified 12-O-β-D-glucopyranosyljasmonic acid as the bioactive metabolite, leaf-closing factor (LCF), which induced nyctinastic leaf closure of Samanea saman. We demonstrate that leaf closure of isolated Samanea pinnae is induced upon stereospecific recognition of (-)-LCF, but not by its enantiomer, (+)-ent-LCF, and that the nonglucosylated derivative, (-)-12-hydroxyjasmonic acid also displays weak activity. Similarly, rapid and cell type-specific shrinkage of extensor motor cell protoplasts was selectively initiated upon treatment with (-)-LCF, whereas flexor motor cell protoplasts did not respond. In these bioassays related to leaf movement, all other jasmonates tested were inactive, including jasmonic acid (JA) and the potent derivates JA-isoleucine and coronatine. By contrast, (-)-LCF and (-)-12-hydroxyjasmonic acid were completely inactive with respect to activation of typical JA responses, such as induction of JA-responsive genes LOX2 and OPCL1 in Arabidopsis (Arabidopsis thaliana) or accumulation of plant volatile organic compounds in S. saman and lima bean (Phaseolus lunatus), generally considered to be mediated by JA-isoleucine in a COI1-dependent fashion. Furthermore, application of selective inhibitors indicated that leaf movement in S. saman is mediated by rapid potassium fluxes initiated by opening of potassium-permeable channels. Collectively, our data point to the existence of at least two separate JA signaling pathways in S. saman and that 12-O-β-D-glucopyranosyljasmonic acid exerts its leaf-closing activity through a mechanism independent of the COI1-JAZ module.     

Application of Bio‐Impedance Analysis to Estimate the Condition of Yellowtail (Seriola quinqueradiata) Muscle at Different Storage Temperatures

Changes in impedance at 2 kHz, adenosine triphosphate (ATP) content, and muscle contraction were evaluated in yellowtail during 0 (ice), 5, 10, 15, and 20°C storage. Histological changes during ice storage were also measured. At any temperature, although impedance increased with both rigor mortis and ATP consumption during early storage, it began to decrease rapidly when ATP was almost depleted. Moreover, temporarily increasing impedance had a strong relationship with ATP content; decreasing impedance had a significant correlation with storage temperature after ATP depletion. Furthermore, impedance increased with narrowing of intercellular spaces when sarcolemma was intact and decreased with expansion of intercellular spaces when sarcolemma was leaky. Meanwhile, changes of sarcolemma and intercellular spaces were accompanied by ATP change. Thus, ATP is one significant physiological factor for impedance change, and temperature greatly influenced impedance after depletion of ATP. Results suggest that impedance analysis can be used as a convenient and nondestructive method to diagnose condition of tissue at different storage temperatures. Bioelectromagnetics. 2019;40:488–497. © 2019 Bioelectromagnetics Society     

Phytochemical Content,Antidiabetic, Anticholinergic,and Antioxidant Activities of Endemic Lecokia cretica Extracts

The aim of this work was to investigate the enzyme inhibition, antioxidant activity, and phenolic compounds of Lecokia cretica (Lam .) DC. Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α‐glycosidase enzymes were strongly inhibited by the L. cretica extracts. IC₅₀ values for the three enzymes were found as 3.21 mg/mL, 2.1 mg/mL, and 2.07 mg/mL, respectively. Antioxidant activities were examined in both aqueous and ethanol (EtOH) extracts using CUPRAC, FRAP, and DPPH method. Also, the phenolic compounds of the endemic plant were identified and quantified by using HPLC/MS/MS. According to the results, the extracts have remarkable antioxidant activities. The most abundant phenolic acids of L. cretica in EtOH extract were determined as quinic acid (12.76 mg/kg of crude extract), chlorogenic acid (3.39 mg/kg), and malic acid (2.38 mg/kg).     

Serum Procalcitonin Level and SOFA Score at Discharge from the Intensive Care Unit Predict Post-Intensive Care Unit Mortality: A Prospective Study

Purpose

The final decision for discharge from the intensive care unit (ICU) is uncertain because it is made according to various patient parameters; however, it should be made on an objective evaluation. Previous reports have been inconsistent and unreliable in predicting post-ICU mortality. To identify predictive factors associated with post-ICU mortality, we analyzed physiological and laboratory data at ICU discharge.

Methods

Patients admitted to our ICU between September 2012 and August 2013 and staying for critical care>2 days were included. Sequential Organ Failure Assessment (SOFA) score; systemic inflammatory response syndrome score; white blood cell count; and serum C reactive protein, procalcitonin (PCT), interleukin-6 (IL-6), lactate, albumin, and hemoglobin levels were recorded. The primary end point was 90-day mortality after ICU discharge. Two hundred eighteen patients were enrolled (195 survivors, 23 non-survivors).

Results

Non-survivors presented a higher SOFA score and serum PCT, and IL-6 levels, as well as lower serum albumin and hemoglobin levels. Serum PCT, albumin, and SOFA score were associated with 90-day mortality in multiple logistic regression analysis. Hosmer-Lemeshow test showed chi-square value of 6.96, and P value of 0.54. The area under the curve (95% confidence interval) was 0.830 (0.771–0.890) for PCT, 0.688 (0.566–0.810) for albumin, 0.861 (0.796–0.927) for SOFA score, and increased to 0.913 (0.858–0.969) when these were combined. Serum PCT level at 0.57 ng/mL, serum albumin at 2.5 g/dL and SOFA score at 5.5 predict 90-day mortality, and high PCT, low albumin and high SOFA groups had significantly higher mortality. Serum PCT and SOFA score were significantly associated with survival days after ICU discharge in Cox regression analysis.

Conclusions

Serum PCT level and SOFA score at ICU discharge predict post-ICU mortality and survival days after ICU discharge. The combination of these two and albumin level might enable accurate prediction.