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Objective: Pyogenic liver abscess (PLA) is a common surgical infectious disease caused by various pathogens. Klebsiella pneumoniae is a relatively recent cause, often affecting patients with low immunity. Endogenous endophthalmitis (EE), a rare and serious complication of PLA, may appear with eye symptoms before PLA. By reviewing a case of Klebsiella pneumoniae‐induced PLA complicated with EE, we want to summarize the information about the characteristics, causes, and complications of PLA based on the literature review. Methods: This case report describes a 37‐year‐old male who had fever high to 39°C for 10 days experienced blurred vision followed by nonlight perception vision. He reported a history of diabetes irregularly taking oral medications and insulin therapy. Imaging examination found a large low‐density area in the right lobe of the liver with an unclear border and vague surrounding fat gap. The blood culture was not positive. The culture of the drainage fluid from the liver puncture showed Klebsiella pneumonia. Blood and liver puncture drainage fluid were sent for microbial high‐throughput gene detection with next‐generation sequencing technology (NGS), which confirmed the diagnosis of Klebsiella pneumoniae‐induced PLA complicated with EE. Results: The patient's surgical incision had healed well at discharge, and he could feel light at his left eye. But the patient was lost to follow‐up since the third month after discharge. Conclusion: By reviewing this case and summarize the information about the characteristics, causes, and complications of PLA based on the literature review, we concluded that it is necessary to promptly perform liver puncture drainage and empirically use antibiotics for patients with PLA, especially those with poor glycemic control, to avoid serious complications such as EE. [ABSTRACT FROM AUTHOR]

Voltage-gated sodium channels (VGSC) are essential for triggering and relaying action potentials (AP), which perform critical functions in a variety of physiological processes, such as controlling muscle contractions and facilitating the release of neurotransmitters. In this study, we used a mouse C2C12 cell differentiation model to study the molecular expression and channel dynamics of VGSC and to investigate the exact role of VGSC in the development of muscle regeneration. Immunofluorescence, Real-time quantitative polymerase chain reaction, Western blot, and whole-cell patch clamp were employed for this purpose in mouse myoblasts. The findings revealed an increase in intracellular sodium concentration, Na V 1.4 gene expression, and protein expression with the progress of differentiation (days 0, 1, 3, 5 and 7). Furthermore, VGSC dynamics exhibit the following characteristics: ① The increase of sodium current (I Na); ② The decrease in the activation threshold and the voltage trigger maximum of I Na ; ③ A positive shift in the steady-state inactivation curve; ④ The recovery of I Na during repolarization is delayed, the activity-dependent decay rate of I Na was accelerated, and the proportionate amount of the fraction of activated channels was reduced. Based on these results, it is postulated that the activation threshold of AP could be decreased, and the refractory period could be extended with the extension of differentiation duration, which may contribute to muscle contraction. Taken together, VGSC provides a theoretical and empirical basis for exploring potential targets for neuromuscular diseases and other therapeutic muscle regeneration dysfunctions. The present research employed a differentiation model (D0、D1、D3、D5、D7)utilizing mouse myoblast C2C12 cells to investigate the expression of Na V 1.4 and channel kinetics. [Display omitted] • It is the first time to confirm the electrophysiological changes of VGSC in myoblast at different stages of differentiation. • It is the first elucidation of functional changes in Na V 1.4 with differentiation time in myoblast. • The increase of sodium ions in myoblasts makes the cells more sensitive to electrical excitation. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a common and multiple endocrine metabolic disease. When pancreatic β cell in case of dysfunction, the synthesis and secretion of insulin are reduced. This study is to explore the effect of cordycepin (the molecular formula C 10 H 13 N 5 O 3), a natural adenosine isolated from Cordyceps militaris , on high glucose/lipid-induced glucotoxicity and lipotoxicity in INS-1 cells. Our results showed that cordycepin improved cell viability, improved cell energy metabolism and promoted insulin synthesis and secretion. The mechanism may be related to that cordycepin reduces intracellular reactive oxygen species (ROS), increases ATP content in cells, causes membrane depolarization and balances the steady state of Ca2+ concentration, cordycepin inhibits cell apoptosis, which may be related to the downregulation of proteins level of c-Jun N-terminal kinases (JNK) phosphorylation, cytochrome c (Cyt-c), Cleaved Capase-3, the mRNA level of JNK, Cyt-c, Capase-3 and upregulation of proteins/mRNA level of pancreatic and duodenal homeobox factor-1 (PDX-1). These results suggest that cordycepin can inhibit cell apoptosis and protect cell number by downregulating ROS/JNK mitochondrial apoptosis pathway under high glucose/lipid environment, thereby improving the function of pancreatic islet cells, providing a theoretical basis for the related research on the prevention and control of cordycepin on T2DM. [Display omitted] • Cordycepin protects INS-1 cells viability and energy metabolism against glucolipotoxicity. • Cordycepin inhibits INS-1 cells apoptosis exposed to a glucolipotoxicity environment. • Cordycepin improved insulin secretion and synthesis under glucolipotoxicity environment. [ABSTRACT FROM AUTHOR]

Abstract: All eight stereoisomers of saxagliptin have been synthesized and evaluated for their inhibitory activity against DPP-IV. It was unambiguously confirmed that the configuration of saxagliptin was critical to potent inhibition of DPP-IV. Docking study was performed to elucidate the configuration–activity relationship of saxagliptin stereoisomers. Tyr662 and Tyr470 have been suggested as the key residues of DPP-IV interacting with the inhibitors. This work provides valuable information for further inhibitor design against DPP-IV. [Copyright &y& Elsevier]

Cordycepin (known as 3-deoxyadenosine, CRD), a natural product from the valuable traditional Chinese medicine Cordyceps militaris , has been reported to improve cognitive function and modulate neuroprotective effects on the central nervous system (CNS). However, the modulating mechanisms of cordycepin on information processing in hippocampal CA1 pyramidal neurons are not fully understood. To clarify how cordycepin modulates synaptic responses of pyramidal neurons in rat hippocampal CA1 region, we conducted an electrophysiological experiment using whole-cell patch-clamp technique. The spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs, respectively) and the spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs, respectively) recorded by this technique evaluated pure single or multi-synapse responses and enabled us to accurately quantify how cordycepin influenced the pre and postsynaptic aspects of synaptic transmission. The present results showed that cordycepin significantly decreased the frequency of both glutamatergic and GABAergic postsynaptic currents without affecting the amplitude, while these inhibitory effects were antagonized by the A 1 adenosine receptor antagonist (DPCPX), but not the A 2A (ZM 241385), A 2B (MRS1754) and A 3 (MRS1191) adenosine receptor antagonists. Taken together, our results suggested that cordycepin had a clear presynaptic effect on glutamatergic and GABAergic transmission, and provided novel evidence that cordycepin suppresses the synaptic transmission through the activation of A 1 AR. [Display omitted] • Cordycepin decreased the frequency of glutamatergic postsynaptic currents. • Cordycepin decreased the frequency of GABAergic postsynaptic currents. • Cordycepin suppressed the synaptic transmission through the activation of A 1 AR. [ABSTRACT FROM AUTHOR]

A systemical modulation on the frequency of the surface plasmon resonance (SPR) band of high density silver nanoparticle arrays is demonstrated by depositing gas phase silver clusters on substrate surface with a controlled particle coverage under in-situ SPR spectra monitoring. With increasing the density of the Ag nanoparticles, the SPR wavelength shows a redshift from less than 400 nm to more than 570 nm. The tuning of the SPR wavelength is found to correlate to the increase of the fraction of closely spaced nanoparticle pairs that are near-field coupled with the deposition mass. The coverage dependent SPR properties are also compared with the results from discrete dipole approximation (DDA) calculations. [ABSTRACT FROM AUTHOR]

Abstract: First nucleoside aminooxy acids were synthesized from furanoid sugar phthalimidooxy acids by N-glycosylation with uracil, thymine, N-benzoylcytosine, 6-N-benzoyladenine and 2-N-acetyl-6-O-diphenylcarbamoylguanine. Boc or Fmoc protected uridine aminooxy acid derivatives have also been prepared. As oxyamine protecting group, the phthalimido group was shown to be instable in MeOH, leading to the imide ring-opening product in a reversible way. This reaction was accelerated under acid or basic conditions. A uridine dimer linked by N-oxy amide has also been prepared by coupling of uridine aminooxy ester with uridine phthalimidooxy acid. These nucleoside aminooxy acids might constitute useful building blocks for the development of novel RNA mimics and conjugates with other biomolecules or reporter compounds. [Copyright &y& Elsevier]

The gas dynamics of pulsed laser ablation of silicon target in the helium gas ambient is investigated via direct simulation Monte Carlo method with a real physical scale of target-substrate configuration. A shock driven process is clearly observed. It is shown that the interaction of the shock front with the target surface and the vapor front induce significant backward flux of ablated particles and oscillating behavior of vapor front. A confined layer mixed with high density Si and He atoms is formed around the contact front. Its behavior is important to the nanoparticle formation and deposition. [Copyright &y& Elsevier]

The advent of small molecule modulators targeting the cystic fibrosis transmembrane conductance regulator (CFTR) has revolutionized the treatment of persons with cystic fibrosis (CF) (pwCF). Presently, these small molecule CFTR modulators have gained approval for usage in approximately 90 % of adult pwCF. Ongoing drug development endeavors are focused on optimizing the therapeutic benefits while mitigating potential adverse effects associated with this treatment approach. Based on their mode of interaction with CFTR, these drugs can be classified into two distinct categories: specific CFTR modulators and non-specific CFTR modulators. Specific CFTR modulators encompass potentiators and correctors, whereas non-specific CFTR modulators encompass activators, proteostasis modulators, stabilizers, reader-through agents, and amplifiers. Currently, four small molecule modulators, all classified as potentiators and correctors, have obtained marketing approval. Furthermore, numerous novel small molecule modulators, exhibiting diverse mechanisms of action, are currently undergoing development. This review aims to explore the classification, mechanisms of action, molecular structures, developmental processes, and interrelationships among small molecule CFTR modulators. The current review is kept forth to compile a summary of the structure, classification, and mechanism of small molecule modulators of CFTR. [Display omitted] • Small molecule modulators targeting the cystic fibrosis transmembrane conductance regulator (CFTR) have significantly improved cystic fibrosis (CF) treatment. • Various mechanisms categorize those modulators. • Modulators within the same class share Structural similarities. • Medicinal chemistry optimization of modulators reveals potential structure-activity relationships. [ABSTRACT FROM AUTHOR]

Cordycepin (with a molecular formula of C 10 H 13 N 5 O 3), a natural adenosine isolated from Cordyceps militaris , has an important regulatory effect on skeletal muscle remodelling and quality maintenance. The aim of this study was to investigate the effect of cordycepin on myoblast differentiation and explore the underlying molecular mechanisms of this effect. Our results showed that cordycepin inhibited myogenesis by downregulating myogenic differentiation (MyoD) and myogenin (MyoG), preserved undifferentiated reserve cell pools by upregulating myogenic factor 5 (Myf5) and retinoblastoma-like protein p130 (p130), and enhanced energy reserves by decreasing intracellular reactive oxygen species (ROS) and enhancing mitochondrial membrane potential, mitochondrial mass, and ATP content. The effect of cordycepin on myogenesis was associated with increased phosphorylation of extracellular signal-regulated kinase 1/2 (p-ERK1/2). PD98059 (a specific inhibitor of p-ERK1/2) attenuated the inhibitory effect of cordycepin on C2C12 differentiation. The present study reveals that cordycepin inhibits myogenesis through ERK1/2 MAPK signalling activation accompanied by an increase in skeletal muscle energy reserves and improving skeletal muscle oxidative stress, which may have implications for its further application for the prevention and treatment of degenerative muscle diseases caused by the depletion of depleted muscle stem cells. [Display omitted] • Cordycepin improved oxidative stress and enhanced energy reserve in C2C12 myoblasts. • Cordycepin preserved reserve of the satellite cell pool in vitro. • Cordycepin inhibited the myogenic differentiation of C2C12 myoblasts. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) represents a cluster of diseases that includes diabetes and insulin resistance. A combination of these metabolic disorders damages liver function. We hypothesized here that histone deacetylase 1 (HDAC1) inhibits fibroblast growth factor 21 (FGF21) expression through histone deacetylation, thereby accentuating liver injury in rats with MetS. MetS rats induced by a high-fat diet were monitored weekly for blood pressure and body weight measurement. The changes of hepatic injury parameters were also measured. The pathological changes in the liver were observed by HE staining and oil red O staining. We found that HDAC1 was increased in the liver of rats with MetS, while sh-HDAC1 reduced blood pressure, body weight, and hepatic injury parameters. Improvement of structural pathological alterations and reduction of lipid deposition were observed after HDAC1 inhibition. Notably, HDAC1 inhibited FGF21 expression through histone deacetylation. The hepatoprotective effects of sh-HDAC1 on rats were reversed by adenovirus-mediated knockdown of FGF21. Moreover, methyltransferase-like 3 (METTL3) mediated the N6-methyladenosine (m6A) modification of HDAC1 mRNA and increased its binding to IGF2BP2. Consistently, sh-METTL3 inhibited HDAC1 and increased FGF21 expression, thereby ameliorating liver injury in MetS rats. This study discovered that HDAC1 is capable of managing liver injury in MetS. Targeting HDAC1 may be an optimal treatment for MetS-related liver injury. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) has recently become one of the major diseases that have received attention. Cordycepin (molecular formula: C 10 H 13 N 5 O 3), is one of the major bioactive components of Cordyceps militaris , decreases blood glucose levels. In this study, the effect and mechanism of cordycepin in normal and oxidative-damaged INS-1 cells were explored by using cell and molecular biology methods. Results showed that cordycepin could enhance insulin synthesis and secretion. The mechanism is possibly related to the elevated ATP content induced membrane depolarisation and increased Ca2+ concentration. At the genetic level, cordycepin upregulated the mRNA level of insulin, pancreatic duodenal homeobox factor-1 (PDX-1) and glucose transporter 1 (GLUT1). At the protein level, cordycepin promoted the expression of PDX-1, GLUT1, serine threonine kinase (Akt) and phosphorylated Akt (P-Akt). These effects may also contribute to the enhancement of insulin synthesis and secretion. Further analysis revealed that cordycepin protected against H 2 O 2 -induced damage on INS-1 cells and improved their viability and insulin synthesis/secretion. This effect should be attributed to the reduced intracellular reactive oxygen species (ROS), enhanced mitochondrial membrane potential (MMP), increased activity of superoxide dismutase (SOD) and upregulated genetic and protein expression of catalase (CAT), PDX-1, GLUT1 and P-Akt. In conclusion, cordycepin promotes insulin synthesis and secretion in normal islet β cells and improves this function in oxidative-damaged islet β cells. Given that islet β cells are vulnerable to oxidative stress, the improving effect of cordycepin on the antioxidant capacity and insulin synthesis/secretion of INS-1 cells may be an important mechanism for its hypoglycaemic effect. [Display omitted] [ABSTRACT FROM AUTHOR]

Recent studies have emphasized the role of vascular adventitia inflammation and immune response in hypertension. It has been reported that stromal cell-derived factor-1 (SDF-1) plays various biological functions through its receptors C-X-C motif chemokine receptor 4 (CXCR4) and CXCR7 in tumor growth and tissue repair. However, it is unclear that whether SDF-1/CXCR4/CXCR7 axis is involved in hypertensive vascular remodeling. In the present study, the involvement of SDF-1/CXCR4/CXCR7 axis was evaluated with lentivirus-mediated shRNA of SDF-1 and CXCR7, CXCR4 antagonist AMD3100 and CXCR7 agonist VUF11207 in angiotensin II (AngII)-induced hypertensive mice and in cultured adventitial fibroblasts (AFs). Results showed that AngII infusion markedly increased SDF-1 expressed in vascular adventitia, but not in media and endothelium. Importantly, blockade of SDF-1/CXCR4 axis strikingly potentiated AngII-induced adventitial thickening and fibrosis, as indicated by enhanced collagen I deposition. In contrast, CXCR7 shRNA largely attenuated AngII-induced adventitial thickness and fibrosis, whereas CXCR7 activation with VUF11207 significantly potentiated AngII-induced adventitial thickening and fibrosis. In consistent with these in vivo study, CXCR4 inhibition with AMD3100 and CXCR7 activation with VUF11207 aggravated AngII-induced inflammation, proliferation and migration in cultured AFs. In summary, these results suggested that SDF-1 exerted opposing effects through CXCR4 and CXCR7 in AngII-induced vascular adventitial remodeling. • AngII infusion results in marked increase of SDF-1 levels in thoracic adventitia, but not in media and endothelium. • Blocking SDF-1/CXCR4 axis promotes thoracic adventitial thickening and fibrosis in AngII-induced hypertensive mice。. • CXCR7 plays a detrimental role in AngII-induced thoracic adventitial thickening and fibrosis. [ABSTRACT FROM AUTHOR]

Thermal energy has been considered to propagate by wave-like phonons with well-defined wave vectors in crystalline materials. In this work, we demonstrate a completely different thermal conduction scenario in crystalline rare earth niobates, RE 3 NbO 7 (RE=La, Nd, Sm, Eu, Gd), having ultralow thermal conductivities of 1.0–1.5 Wm-1K-1. Especially, the rare earth niobates exhibit glass-like temperature dependence of thermal conductivity from room temperature to 1273 K, indicating significant suppression of both phonon and radiation heat transfer. According to Cahill model based on amorphous theory, minimum thermal conductivity of rare earth niobate was calculated. It is shown that the glass-like thermal conductivity result from a wide range of amorphous solids due to phonon scattering by multiple lattice imperfections. Furthermore, phonon mean free path of RE 3 NbO 7 is comparable to the atomic spacing of crystal indicating that energy carried by phonons can only transmission between a few atomic spacings leading to the ultralow thermal conductivity. The mechanical properties of rare earth niobates are also discussed. [ABSTRACT FROM AUTHOR]

Aims: We investigated the impacts of CYP2C19 polymorphisms on pharmacokinetics and pharmacodynamics of vicagrel in healthy Chinese subjects. Methods: CYP2C19 extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs; 16 subjects/group) participated in a randomized, open‐label, 2‐period cross‐over study. Each study period lasted 7 days, with a loading dose of 24 mg of vicagrel or 300 mg of clopidogrel on day 1, and maintenance doses of 6 mg of vicagrel or 75 mg of clopidogrel daily from day 2 to day 7. The pharmacokinetics and pharmacodynamics were assessed on day 1 and day 7. Results: After a loading dose, the AUC0‐t of the active metabolite H4 by vicagrel was slightly lower in IMs and PMs (decreased by 21 and 27%, respectively) compared to EMs. Similar results were found after maintenance doses. In EMs, the AUC0‐t of H4 by vicagrel was somewhat higher than clopidogrel after the loading dose, and comparable with clopidogrel (90% confidence interval 0.94, 1.21) after the maintenance doses. However, it was much higher than clopidogrel in PMs, with a 1.28‐fold (loading dose) and a 73% (maintenance doses) increases compared to clopidogrel (P < 0.001). Consequently, the inhibition of platelet aggregation by vicagrel was greater than clopidogrel after both loading dose (28.2 vs 12.4% at 4 hours, P < 0.01) and maintenance doses (42.8 vs 24.6% at 4 hours, P < 0.001) in PMs. Conclusions: CYP2C19 polymorphisms have less impact on vicagrel as compared to clopidogrel. Drug exposure and response to vicagrel in PMs were even higher than to clopidogrel in IMs. [ABSTRACT FROM AUTHOR]

Abstract Background and objectives Vicagrel, a novel thienopyridine antiplatelet agent, is an analogue of clopidogrel in development for the treatment of acute coronary syndromes. This study investigated the pharmacokinetic properties of vicagrel after single oral dosing with a direct comparison with clopidogrel in healthy Chinese subjects in the first two phase I clinical studies. The relationship between the exposure to the active metabolite and the platelet reactivity was also assessed for vicagrel. Methods Study A was a single-ascending-dose study of vicagrel (5–75 mg) compared with clopidogrel (75 mg) in 67 healthy volunteers. Study B was a randomized, two-period, crossover, loading-dose study of vicagrel 20 mg compared with clopidogrel 300 mg in 12 healthy subjects. Plasma concentrations of three common metabolites of vicagrel and clopidogrel, the active thiol metabolite H4, the inactive thiol metabolite H3, and the S -methylated form of H3 (SM3, the major metabolite of vicagrel), were determined using a validated UHPLC–MS/MS method. The relationship between the AUC 0−t of active H4 and the P2Y 12 reaction units at 4 h after administration of vicagrel was investigated. Blood concentrations of vicagrel were determined after a single oral administration of vicagrel 25 mg to two healthy Chinese subjects. Results In the single-ascending-dose study, vicagrel was metabolized rapidly with the median t max for the three metabolites, namely, H4, H3, and SM3, ranging from 0.25–1.75 h. The pharmacokinetics of the three metabolites for vicagrel were linear across the dose range of 5–75 mg, with the mean C max and AUCs for H4 and H3 increasing in an approximately 1:1 dose-proportional manner and for SM3 increasing in a <1:1 dose-proportional manner. The median t max for active H4 in the vicagrel 5 mg group was slightly shorter than that in the clopidogrel 75 mg group (0.50 versus 0.75 h). The mean AUC 0−t for H4 in the vicagrel 5 mg group was similar to that in the clopidogrel 75 mg group (11.7 versus 11.8 ng∙h/mL). The AUC 0−t of active H4 was apparently associated with the P2Y 12 reaction units at 4 h for vicagrel. In the loading-dose study, for active H4, the median t max was slightly shorter (0.50 versus 0.75 h) and the mean AUC 0−t was 29% higher in the vicagrel 20 mg group than those in the clopidogrel 300 mg group. After a single oral administration of vicagrel 25 mg to 2 subjects, vicagrel was detected in blood but in very low concentrations. Conclusions Vicagrel was rapidly and extensively metabolized, and the levels of the parent drug in circulation were very low. The pharmacokinetics of the three metabolites of vicagrel were linear and predictable across the dose range of 5–75 mg. The AUC of active H4 was apparently associated with the P2Y 12 reaction units for vicagrel. For active H4, vicagrel 5 mg produced similar exposure (AUC) with more rapid appearance compared with clopidogrel 75 mg, and vicagrel 20 mg produced even slightly higher exposure (AUC) with more rapid appearance compared with clopidogrel 300 mg in humans. Trial Registration: CTR20150346, CTR20160379. Graphical abstract (A) Metabolic pathways of clopidogrel and vicagrel in humans. (B) Mean plasma concentrations of active H4 after a single oral administration of vicagrel 5 mg or clopidogrel 75 mg in healthy Chinese subjects. (C) Assessment of dose proportionality for AUC 0−t of active H4 after single oral administration of vicagrel. Unlabelled Image [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Oxidative stress cytotoxicity was involved in Aβ 25–35 -induced apoptosis and this damage was rescued by cordycepin. • Cordycepin can inhibit the Aβ 25–35 -induced increased p-Tau expression and AChE overactivity. • The cytoprotection of cordycepin could be prevented by the A 1 AR antagonist (DPCPX). Abstract In Alzheimer's disease (AD), β-amyloid (Aβ) protein toxicity increases the formation of reactive oxygen species (ROS) and intracellular calcium levels, resulting in neuronal dysfunction, neurodegenerative disorders, and cell death. Cordycepin is a derivative of the nucleoside adenosine; also, it is speculated to exert neuroprotective effects against Aβ-induced oxidative toxicity in hippocampal neurons. In the present study, the fluorescence detection method and whole-cell patch-clamp recordings were used to study the neuroprotective effects against Aβ-induced toxicity in the primary hippocampal cultured neurons. The results revealed that Aβ 25–35 toxicity causes increased cellular ROS production and abnormal calcium homeostasis in hippocampal neurons. Moreover, Aβ 25–35 -induced cytotoxicity led to a series of downstream events, including the activation of acetylcholinesterase, increased p-Tau expression, and increased apoptosis. Cordycepin inhibits ROS production, elevated levels of Ca2+ induced by Aβ 25–35 , and the activation of acetylcholinesterase; all these are involved in oxidative-induced apoptosis. In addition, it decreases the increased p-Tau expression that plays a key role in the initiation of the AD. Results showed that the anti-apoptotic effects of cordycepin are partially dependent on the activation of adenosine A 1 receptor, whereas an antagonist selectively attenuated the neuroprotective effects of cordycepin. Collectively, these results suggest that cordycepin could be a potential future therapeutic agent for neuronal disorders, such as AD. [ABSTRACT FROM AUTHOR]

Vicagrel, an analog of clopidogrel, is a novel thienopyridine P2Y 12 antagonist in clinical development in China for the treatment of acute coronary syndromes. Vicagrel and clopidogrel are prodrugs requiring metabolic activation to produce a pharmacologically active thiol metabolite (H4) in vivo. The formation of H4 from vicagrel in humans is promising more efficient and consistent than that from clopidogrel. After oral dosing of vicagrel or clopidogrel to humans, the active thiol metabolite H4 and two inactive metabolites closely related to H4 formation (the thiol metabolite H3 and the S-methylated metabolite SM3) were observed in plasma; SM3 was the most abundant drug-related component of vicagrel in circulation. In this study, a sensitive, rapid, and reliable UHPLC–MS/MS method was developed for the simultaneous determination of derivatized H3 (MP-H3), derivatized H4 (MP-H4), and SM3 in human plasma to investigate the pharmacokinetics of vicagrel in healthy subjects compared with clopidogrel. After extracted from 50 μL of plasma by simple protein precipitation, the analytes and stable isotope-labeled internal standards were separated on an Acquity UPLC BEH C 18 column (100 mm × 2.1 mm, 1.7 μm). The mobile phase was acetonitrile–water–formic acid (45:55:0.0275, v/v/v) delivered at a flow rate of 0.45 mL/min under isocratic elution. The total chromatographic run time was 6 min. MP-H3, MP-H4, and SM3 were separated from their corresponding isomers under the chromatographic conditions. Mass spectrometric detection was conducted in multiple reaction monitoring mode on an AB Sciex Qtrap 5500 System using a positive electrospray ionization interface. The calibration curves were linear in the following ranges: 0.100–200 ng/mL for MP-H3 and MP-H4 and 1.00–1000 ng/mL for SM3. The intra- and inter-day accuracy and precision for each analyte at all concentrations were within acceptable limits (±15%). The validated method was successfully applied to compare the pharmacokinetics of vicagrel and clopidogrel after a single oral administration to healthy subjects in the first-in-human study of vicagrel. [ABSTRACT FROM AUTHOR]

[Display omitted] Vicagrel is a novel antiplatelet drug used to mitigate clopidogrel resistance due to CYP2C19 polymorphism. This study aimed to develop a semi-mechanistic population pharmacokinetic (PopPK) model to characterize the pharmacokinetic (PK) profile of M15-2, the active metabolite of vicagrel and clopidogrel, and to evaluate the influence of CYP2C19 polymorphisms and other covariates in healthy subjects and patients with acute coronary syndrome (ACS) after oral administration. The analysis utilized data from 213 subjects, including 178 healthy subjects and 35 patients, from five clinical trials. PopPK modeling and simulation were used to estimate PopPK parameters and evaluate the impact of covariates. The M15-2 PK profiles were well characterized by a model incorporating transit compartments, two-compartment parent models and two-compartment M15-2 models for both vicagrel and clopidogrel. The parameter estimates indicated the dose fraction of vicagrel that formed M15-2 was approximately 20-fold that of clopidogrel. Covariate analysis identified a significant effect of CYP2C19 on M15-2 apparent clearance (CL/F) and apparent volume of distribution (V3/F) for clopidogrel but only CL/F for vicagrel. The analysis suggested that the nonlinear PK of M15-2 for clopidogrel was due the first-step bioactivation of clopidogrel to 2-oxoclopidogrel. The model illustrated the bioactivation of vicagrel is more efficient and less dependent on CYP2C19 than that of clopidogrel. M15-2 is formed in a linear process from vicagrel, versus a nonlinear and less predictable process from clopidogrel. Advantages in both PK and pharmacogenetics suggest that vicagrel may reduce the complexity of currently recommended CYP2C19-based dosage adjustment for clopidogrel. [ABSTRACT FROM AUTHOR]

A series of optically active 2-hydroxytetrahydrothienopyridine derivatives were designed and synthesized as prodrugs of clopidogrel thiolactone in order to overcome clopidogrel resistance. The final compounds were evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats. Compound 9a was selected for further in vitro and in vivo metabolism studies, since its potency was comparable to that of prasugrel and was much higher than that of clopidogrel. Preliminary pharmacokinetic study results showed that the bioavailability of clopidogrel thiolactone generated from 9a was 6-fold higher than that generated from clopidogrel, implying a much lower clinically effective dose for 9a in comparison with clopidogrel. In summary, 9a (vicagrel) holds great promise as a more potent and a safer antiplatelet agent that might have the following advantages over clopidogrel: (1) no drug resistance for CYP2C19 poor metabolizers; (2) lower dose-related toxicity due to a much lower effective dose; (3) faster onset of action. [ABSTRACT FROM AUTHOR]

Abstract: Naturally occurring pentacyclic triterpenes (PT), a novel class of inhibitors against glycogen phosphorylase (GP), hold promise for the treatment of type-2 diabetes and other diseases with disorders in glycogen metabolism. To identify novel and more potent GP inhibitors, the receptor-based comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) approaches were performed to investigate the quantitative structure–activity relationships (QSAR) among 106 PT analogues. The validated models demonstrated that the elongated or bulky substitutions in C17 position and/or C2, C3 positions are favorable. Then based on the structural information extracted from these models, 56 derivatives were synthesized and biochemically tested in this study. The IC50 value of the most potent compound P50 was found to be 1.1μM. [Copyright &y& Elsevier]

• The sIPSC/mIPSCs of RA projection neurons among male and female zebra finches were compared in this work. • The average frequency and amplitude of sIPSCs/mIPSCs in the RA projection neurons of males are higher than females. • The RA PNs in males receive more inhibitory synaptic input than in females. The song control system in the brain of songbirds is important for the production and acquisition of song and exhibits some of the largest neural sex differences observed in vertebrates. The robust nucleus of the arcopallium (RA) is a premotor nucleus, playing a key role in controlling singing. RA projection neurons (PNs) receives denser synapse inputs including excitatory in males than in females. However, the inhibitory synaptic transmission in the RA has not been reported. In the present study, using whole-cell voltage-clamp recording, spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) of the males and females were recorded. The average frequency and amplitude of sIPSCs/mIPSCs in males were higher than females. These results demonstrate the sexually dimorphic of the inhibitory synaptic transmission in the RA PNs and the RA PNs in males receive more inhibitory synaptic transmission. These findings contribute to further illuminate the neural mechanisms under the sexually dimorphism song production of adult zebra finches. [ABSTRACT FROM AUTHOR]