Antidiabetic activity and molecular docking of fructooligosaccharides produced by Aureobasidium pullulans in poloxamer-407-induced T2DM rats

This study evaluated the beneficial effects of fructooligosaccharide (FOS) intake from Aureobasidium pullulans using poloxamer-407 (PX-407) induced type 2 diabetes mellitus (T2DM) in rat. Administration of FOS enhanced enzymatic activities of catalase and glutathione reductase in a dose-dependent manner. Significant reduction in fasting plasma triacylglycerol and very low-density lipoprotein level coupled with slight increase in fasting plasma insulin level was observed. Significant decrease in severe glucosuria, proteinuria, blood creatinine, urea and advanced glycation end products was also observed. Supplementation of FOS increased glucagon like peptide-1 content as well as Bifidobacteria and Lactobacilli populations in the caecum. Molecular docking by Gold and Glide software revealed that three sugar types present in the FOS (1-kestose, nystose, and 1-β-fructofuranosyl nystose) are potent dipeptidyl peptidase-IV inhibitors as well as peroxisome proliferator-activated receptor-gamma agonists. This work indicates that FOS can be positioned as a nutraceutical product, beneficial in diabetes-associated metabolic abnormalities.     

Role of Thrombopoietin Receptor Agonists in Inherited Thrombocytopenia

In the last decade, improvements in genetic testing have revolutionized the molecular diagnosis of inherited thrombocytopenias (ITs), increasing the spectrum of knowledge of these rare, complex and heterogeneous disorders. In contrast, the therapeutic management of ITs has not evolved in the same way. Platelet transfusions have been the gold standard treatment for a long time. Thrombopoietin receptor agonists (TPO-RA) were approved for immune thrombocytopenia (ITP) ten years ago and there is evidence for the use of TPO-RA not only in other forms of ITP, but also in ITs. We have reviewed in the literature the existing evidence on the role of TPO-RAs in ITs from 2010 to February 2021. A total of 24 articles have been included, 4 clinical trials, 3 case series and 17 case reports. A total of 126 patients with ITs have received TPO-RA. The main diagnoses were Wiskott–Aldrich syndrome, MYH9-related disorder and ANKRD26-related thrombocytopenia. Most patients were enrolled in clinical trials and were treated for short periods of time with TPO-RA as bridging therapies towards surgical interventions, or other specific approaches, such as hematopoietic stem cell transplantation. Here, we have carried out an updated and comprehensive review about the efficacy and safety of TPO-RA in ITs.     

Peptide Architecture: Adding an α‐Helix to the PYY Lysine Side Chain Provides Nanomolar Binding and Body‐Weight‐Lowering Effects

The gut hormone PYY3‐36 influences food intake and body weight via interaction with hypothalamic presynaptic Y2 receptors (Y2R). Novel Y2R‐selective analogues of PYY3‐36 are therefore potential drug candidates for the treatment of obesity. It has been hypothesized that PYY3‐36 and possibly also the related PP‐fold peptides, NPY and PP, bind to the membrane via their amphipathic α‐helix prior to receptor interaction. The PYY3‐36 amphipathic α‐helix causes the peptide to associate with the membrane, making it essential for Y receptor potency as it potentially guides the C‐terminal pentapeptide into the correct conformation for receptor activation. Based on this hypothesis, the importance of the amphipathic nature of PYY3‐36, as well as the ability of amphipathic α‐helices to interact in solution to form di‐ and tetramers, we redesigned the peptide architecture by addition of an amphipathic α‐helix via the Lys 4 side chain of PYY3‐36. Two different amphipathic sequences were introduced; first, PYY17‐31, the native α‐helix of PYY, and secondly, its retro counterpart, PYY31‐17, which is also predicted to form an α‐helix. Moreover, several different turn motifs between the branching point and the additional α‐helix were tested. Several novel peptides with nanomolar Y2R binding affinities, as well as increased Y receptor selectivity, were identified. CD experiments showed the modifications to be well accepted, and an increase in mean ellipticity (ME) signifying an increased degree of α‐helicity was observed. Receptor binding experiments indicated that the direction of the additional α‐helix is less important, in contrast to the turn motifs, which greatly affect the Y1R binding and thus determine the Y1R activity. Conversely, the structure–activity relationships from in vivo data showed that the peptide containing the retro‐sequence was inactive, even though the binding data demonstrated high affinity and selectivity. This demonstrates that radical redesign of peptide architecture can provide nanomolar binding with improved subtype selectivity and with in vivo efficacy.     

盐酸地匹福林合成工艺

对盐酸地匹福林合成工艺进行研究,并对其进行纯度检测和结构确证。以邻苯二酚为主要起始原料,与氯乙酰氯发生傅克酰化反应得到3,4-二羟基-2'-氯苯乙酮,经特戊酰氯酯化得到4-（2-氯乙酰基）-1,2-二特戊酸苯酯,与N-甲基苄胺亲核取代得到1-（3,4-二特戊酰氧苯基）-2-（N-苄基甲基氨基）-1-酮,再经羰基还原、氢化脱苄、重结晶制得盐酸地匹福林。改进后的路线总收率为43.4%,显著提高了原工艺收率（23.6%）,HPLC纯度达到98.98%,并通过MS、IR、¹H-NMR、¹³C-NMR进行了结构确证。     

Delay-dependent modulation of memory retrieval by infusion of a dopamine D? agonist into the rat medial prefrontal cortex.

Dopamine (DA) in the medial prefrontal cortex (PFC) can modulate the short-term retention of information and other executive functions. The present study examined whether administration of a DA D? agonist into the PFC could have differential effects on memory retrieval in circumstances in which memory was either excellent or poor. Separate groups of rats were trained on a delayed version of the radial maze task. On the test day, the delay between the phases was either 30 min or 12 hr. Infusions of the D? receptor agonist SKF 81297 (0.05, 0.10, or 0.20 Ag/0.5 P1) into the PFC before the test phase improved memory retrieval after a 12-hr delay but disrupted performance after a 30-min delay. These data suggest that D? receptor activity can exert differential effects over PFC function, depending on the strength of the memory trace. When memory is decremented by an extended delay, activation of PFC DA D? receptors by an agonist can improve cognitive function. (PsycINFO Database Record (c) 2010 APA, all rights reserved)