Search

Purpose: Individuals with chronic ankle instability (CAI) have deficits in closed kinetic chain dorsiflexion that may perpetuate injury. Determining the characteristics of muscle stiffness in the plantar flexors of individuals with CAI may help in developing appropriate treatments. We aimed to highlight the characteristics of static muscle stiffness in ankle plantar flexor muscles during the passive dorsiflexion of the ankle joint in individuals with CAI., Methods: A total of 30 patients were included in the study based on the International Ankle Consortium criteria. The patients were categorized evenly into healthy, coper, and CAI groups (i.e., 10 patients in each group). After measuring the dorsiflexion range of motion (non-weight-bearing/weight-bearing) of the ankle joint, the static muscle stiffness measurements of the medial gastrocnemius, lateral gastrocnemius, soleus, and peroneus longus were obtained. The measurements were performed during the knee joint's extension and 50° flexion and passive dorsiflexion between the range of 40° plantar flexion and 20° dorsiflexion., Results: The dorsiflexion range of motion of the CAI group was significantly smaller than that of the healthy and coper groups in the weight-bearing position. No interaction was observed for muscle stiffness in both the knee flexion and extension positions, and no significant differences were identified among the three groups. The shear modulus of the soleus at 20° ankle dorsiflexion with knee flexion had a significant negative correlation with the weight-bearing range of motion of the ankle., Conclusion: The limitation in the weight-bearing dorsiflexion range of motion in CAI was largely due to factors other than the increased elasticity of the ankle plantar flexor muscles., (© 2023. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

This study evaluated the solubility of piperine (PP) in biorelevant media and the effect of its ground mixtures (GMs) and coprecipitates (CPs) on intestinal contractions when presented in inclusion complexes with α-, β-, and γ-cyclodextrins (CDs). In the powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) measurements, CP (PP/αCD) and CP (PP/γCD) suggest the formation of inclusion complexes. The 1 H-nuclear magnetic resonance (NMR) analysis showed the integrated intensity ratios of CP (PP/αCD) and CP (PP/γCD) protons to be 1/2 and 1/1, the same as the respective molar ratios in the respective GM inclusion complexes. The intestinal contraction test confirmed that the intestinal contraction rate of carbachol (CCh) in the presence of 2.0 × 10 -5 M PP was comparable to that in the absence of PP. On the other hand, CP (PP/αCD), GM (PP/αCD = 1/2), and GM (PP/βCD = 1/1) formed inclusion complexes that significantly suppressed the intestinal contractility at PP 1.0 × 10 -8 M. No significant differences were observed between CP and GM. The solubility of the PP/αCD inclusion complex was 6-7 times higher than that of PP in the fasted-state-simulated intestinal fluid (FaSSIF, pH 6.5). PP functioned to suppress intestinal contraction by forming an inclusion complex. Based on this result, PP/αCD might be expected to be effective as an antidiarrheal., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

A series of high-entropy superconductors, ROBiS 2 (R = La + Ce + Pr + Nd + Sm), have been successfully grown in the form of single crystals using CsCl flux. The obtained single crystals have a platelike shape with a size of 0.5-2.0 mm and a thickness of 70-450 μm, and they are cleavable along the c -plane. The c -axis lattice constants of the obtained ROBiS 2 single crystals have similar values of 13.47-13.57 Å. The Ce in the obtained ROBiS 2 single crystals was in a mixed-valence state, comprising both Ce 3+ and Ce 4+ . On the other hand, Pr and Sm showed only the trivalent state. The superconducting transition temperatures of ROBiS 2 single crystals were approximately 2-4 K. The superconducting transition temperature and superconducting anisotropies of R-site mixed high-entropy samples increased with a decrease in the mean ionic radius of the R-site. Moreover, a deviation in the tendency to exhibit superconducting properties was observed based on the difference in the R-site mixed entropy. R-site mixed entropy in ROBiS 2 superconductors may affect their superconducting properties., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Cross-metathesis (CM) and Keck asymmetric allylation, which allows access to defined stereochemistry of a remote side chain hydroxyl group, are the key steps in a versatile synthesis of broussonetine M ( 3 ) from the d-arabinose-derived cyclic nitrone 14 . By a similar strategy, ent -broussonetine M ( ent -3 ) and six other stereoisomers have been synthesized, respectively, starting from l- arabino -nitrone ( ent -14 ), l- lyxo -nitrone ( ent -3- epi -14 ), and l- xylo -nitrone ( 2- epi -14 ) in five steps, in 26%-31% overall yield. The natural product broussonetine M ( 3 ) and 10'- epi -3 were potent inhibitors of β-glucosidase (IC 50 = 6.3 μM and 0.8 μM, respectively) and β-galactosidase (IC 50 = 2.3 μM and 0.2 μM, respectively); while their enantiomers, ent -3 and ent -10'- epi -3 , were selective and potent inhibitors of rice α-glucosidase (IC 50 = 1.2 μM and 1.3 μM, respectively) and rat intestinal maltase (IC 50 = 0.29 μM and 18 μM, respectively). Both the configuration of the polyhydroxylated pyrrolidine ring and C-10' hydroxyl on the alkyl side chain affect the specificity and potency of glycosidase inhibition., Competing Interests: The authors declare no conflict of interest.

The affinity of a series of iminosugar-based inhibitors exhibiting various ring sizes toward Hex A and their essential interactions with the enzyme active site were investigated. All the Hex A-inhibiting iminosugars tested formed hydrogen bonds with Arg178, Asp322, Tyr421 and Glu462 and had the favorable cation-π interaction with Trp460. Among them, DMDP amide (6) proved to be the most potent competitive inhibitor with a K i value of 0.041 μM. We analyzed the dynamic properties of both DMDP amide (6) and DNJNAc (1) in aqueous solution using molecular dynamics (MD) calculations; the distance of the interaction between Asp322 and 3-OH and Glu323 and 6-OH was important for stable interactions with Hex A, reducing fluctuations in the plasticity of the active site. DMDP amide (6) dose-dependently increased intracellular Hex A activity in the G269S mutant cells and restored Hex A activity up to approximately 43% of the wild type level; this effect clearly exceeded the border line treatment for Tay-Sachs disease, which is regarded as 10-15% of the wild type level. This is a significantly greater effect than that of pyrimethamine, which is currently in Phase 2 clinical trials. DMDP amide (6), therefore, represents a new promising pharmacological chaperone candidate for the treatment of Tay-Sachs disease.

This study shows that the cyclization of l-DMDP thioureas to bicyclic l-DMDP isothioureas improved α-l-rhamnosidase inhibition which was further enhanced by increasing the length of the alkyl chain. The addition of a long alkyl chain, such as decyl or dodecyl, to the nitrogen led to the production of highly potent inhibitors of α-l-rhamnosidase; it also caused broad inhibition spectrum against β-glucosidase and β-galactosidase. In contrast, the corresponding N-benzyl-l-DMDP cyclic isothioureas display selective inhibition of α-l-rhamnosidase; 3',4'-dichlorobenzyl-l-DMDP cyclic isothiourea (3r) was found to display the most potent and selective inhibition of α-l-rhamnosidase, with IC 50 value of 0.22μM, about 46-fold better than the positive control 5-epi-deoxyrhamnojirimycin (5-epi-DRJ; IC 50 =10μM) and occupied the active-site of this enzyme (K i =0.11μM). Bicyclic isothioureas of ido-l-DMDP did not inhibit α-l-rhamnosidase. These new mimics of l-rhamnose may affect other enzymes associated with the biochemistry of rhamnose including enzymes involved in progression of tuberculosis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The first total synthesis of (+)-broussonetine W (4), a naturally-occurring pyrrolidine iminosugar isolated from the traditional Chinese medical plant Broussonetia kazinoki SIEB (Moraceae), has been completed through a concise synthetic route starting from the readily available d-arabinose derived cyclic nitrone 10 in 11 steps and 31% overall yield, with regioselective installation of the α,β-unsaturated ketone functional group by the elimination of HBr from α-bromoketone as the key step. A number of analogs of (+)-broussonetine W (4) with variable side chain length, different polyhydroxylated pyrrolidine core configurations or saturated cyclohexanones have also been prepared to explore the glycosidase inhibition and the preliminary structure-activity relationship of this intriguing class of compounds. Glycosidase inhibition studies identified the natural product (+)-broussonetine W (4) as a selective and potent inhibitor of β-galactosidase (IC50 = 0.03 μM), while its enantiomer was a selective and potent inhibitor of α-glucosidase (IC50 = 0.047 μM). It was found that the configuration of the polyhydroxylated pyrrolidine ring played a key role on their glycosidase inhibitory activities. The length of side chain and α,β-unsaturated ketone functional group also exhibited some effect on their glycosidase inhibition.

The key step in the concise syntheses of calystegine B2 and its C-2 epimer calystegine B3 was the construction of cycloheptanone 8via an intramolecular Nozaki-Hiyama-Kishi (NHK) reaction of 9, an aldehyde containing a Z-vinyl iodide. Vinyl iodide 9 was obtained by the Stork olefination of aldehyde 10, derived from carbohydrate starting materials. Calystegines B2 (3) and B3 (4) were synthesized from d-xylose and l-arabinose derivatives respectively in 11 steps in excellent overall yields (27% and 19%).

Epimerization of C5 of an N-hydroxypyrrolidine ring by regioselective oxidation to a nitrone followed by diastereoselective reduction provides a new approach to the synthesis of swainsonine and related compounds. The only protection in the synthesis of the potent mannosidase inhibitor DIM (1,4-dideoxy-1,4-imino-d-mannitol) was the acetonation of d-mannose.

The antiviral activity of UV-4 was previously demonstrated against dengue virus serotype 2 (DENV2) in multiple mouse models. Herein, step-wise minimal effective dose and therapeutic window of efficacy studies of UV-4B (UV-4 hydrochloride salt) were conducted in an antibody-dependent enhancement (ADE) mouse model of severe DENV2 infection in AG129 mice lacking types I and II interferon receptors. Significant survival benefit was demonstrated with 10-20 mg/kg of UV-4B administered thrice daily (TID) for seven days with initiation of treatment up to 48 h after infection. UV-4B also reduced infectious virus production in in vitro antiviral activity assays against all four DENV serotypes, including clinical isolates. A set of purified enzyme, in vitro, and in vivo studies demonstrated that inhibition of endoplasmic reticulum (ER) α-glucosidases and not the glycosphingolipid pathway appears to be responsible for the antiviral activity of UV-4B against DENV. Along with a comprehensive safety package, these and previously published data provided support for an Investigational New Drug (IND) filing and Phases 1 and 2 clinical trials for UV-4B with an indication of acute dengue disease., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Gem-difluoromethylated and trifluoromethylated derivatives of DMDP-related iminosugars have been synthesized from cyclic nitrones 12, 13, 18, ent-18 or 23 and nitrone-derived aldehydes 20 or ent-20. The fluorinated iminosugars were assayed against various glycosidases, and ent-8 showed moderate but selective α-l-rhamnosidase inhibition. Difluoro or trifluoro units influenced the inhibitory activities of iminosugars in a more complex manner than single fluoro substitution. This may be correlated with their highly hydrophobic character and strong electron-withdrawing effect.

This paper identifies the required configuration and orientation of α-glucosidase inhibitors, miglitol, α-1-C-butyl-DNJ, and α-1-C-butyl-LAB for binding to ntSI (isomaltase). Molecular dynamics (MD) calculations suggested that the flexibility around the keyhole of ntSI is lower than that of ctSI (sucrase). Furthermore, a molecular-docking study revealed that a specific binding orientation with a CH-π interaction (Trp370 and Phe648) is a requirement for achieving a strong affinity with ntSI. On the basis of these results, a new class of nortropane-type iminosugars, labystegines, hybrid iminosugars of LAB and calystegine, have been designed and synthesized efficiently from sugar-derived cyclic nitrones with intramolecular 1,3-dipolar cycloaddition or samarium iodide catalyzed reductive coupling reaction as the key step. Biological evaluation showed that our newly designed 3(S)-hydroxy labystegine (6a) inherited the selectivity against intestinal α-glucosidases from LAB, and its inhibition potency was 10 times better than that of miglitol. Labystegine, therefore, represents a promising new class of nortropane-type iminosugar for improving postprandial hyperglycemia.

We report the isolation and structural determination of fourteen iminosugars, containing five pyrrolizidines and five indolizidines, from Castanospermum australe. The structure of a new alkaloid was elucidated by spectroscopic methods as 6,8-diepi-castanospermine (13). Our side-by-side comparison between bicyclic and corresponding monocyclic iminosugars revealed that inhibition potency and spectrum against each enzyme are clearly changed by their core structures. Castanospermine (10) and 1-deoxynojirimycin (DNJ) have a common d-gluco configuration, and they showed the expected similar inhibition potency and spectrum. In sharp contrast, 6-epi-castanospermine (12) and 1-deoxymannojirimycin (manno-DNJ) both have the d-manno configuration but the α-mannosidase inhibition of 6-epi-castanospermine (12) was much better than that of manno-DNJ. 6,8-Diepi-castanospermine (13) could be regarded as a bicyclic derivative of talo-DNJ, but it showed a complete loss of α-galactosidase A inhibition. This behavior against α-galactosidase A is similar to that observed for 1-epi-australine (6) and altro-DMDP., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A series of α-1-C-4'-arylbutyl-L-arabinoiminofuranoses 3 with functional groups attached to the phenyl ring, which are potential α-glycosidase inhibitors, was designed and synthesized by using a Negishi cross-coupling reaction as the key reaction. Arylbutyl derivatives 3a-e showed potent inhibitory activities against intestinal maltase. Among them, difluorophenylbutyl derivative 3e showed good inhibition activities against intestinal isomaltase and sucrase as compared to those of 1 and commercial drugs., (Copyright © 2014 Elsevier Ltd. All rights reserved.)