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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. Key words: METTL3, IGF2BP2, HDAC1, FGF21, metabolic syndrome, liver injury, Introduction Metabolic syndrome (MetS), also known as syndrome X, insulin resistance (IR), etc., is defined by World Health Organization as a pathological condition characterized by abdominal obesity, hypertension, as well [...]

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]

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]

Background: Vicagrel is a novel anti-platelet drug and hydrolyzed to the same intermediate as clopidogrel via esterase, instead of CYP2C19. Here we report the first clinical trial on the tolerability, pharmacokinetics and pharmacodynamics of different doses of vicagrel, and comparison with clopidogrel in healthy Chinese volunteers. Methods: This study was conducted in two parts. Study I was a dose-escalating (5–15 mg) study. For each dose, 15 participants were randomized into three groups (total n = 45); nine participants were given vicagrel, three were given clopidogrel, and three were given a placebo. Study II was conducted to assess interactions between vicagrel and aspirin in 15 healthy participants. The plasma concentrations of the metabolites of vicagrel and clopidogrel were determined using a LC-MS/MS method. Platelet aggregation was assessed using the VerifyNow-P2Y12 assay. Results: Vicagrel (5–15 mg per day) dosing for 10 days or addition of aspirin was well tolerated in healthy volunteers. The exposure of the active metabolite increased proportionally across the dose range and was higher (~10-fold) than clopidogrel. The levels of IPA dosing 75 mg clopidogrel were between the responses of 5 mg and 10 mg vicagrel. After a single loading dose of vicagrel (30 mg) and a once-daily maintenance dose (7.5 mg) for 8 days, the maximum inhibition of platelet aggregation was similar to that seen with the combined use of vicagrel and aspirin (100 mg/day). Conclusion: Oral vicagrel demonstrated a favorable safety profile and excellent anti-platelet activity, which could be a promising P2Y12 antagonist as anti-platelet drug and can be further developed in phase II/III studies, and marketing for the unmet medical needs of cardiovascular diseases. The study was registered at http://www.chictr.org.cn (ChiCTR-IIR-16009260). [ABSTRACT FROM AUTHOR]

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]

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]

Germanium nanoclusters are prepared by means of the inert-gas condensation method. The growth, coalescence, and aggregation processes are investigated by means of TEM. It is found that the clusters can be either nanocrystals or amorphous-like. Furthermore, during the deposition, they can either randomly land on surface, keep isolated and finally form a cluster-assembled uniform film or aggregate with fractal structures and then form porous film, depending on their preparation condition. Spectropho-tometric measurements are recorded for these samples at room temperature in the ultraviolet, visible, and near-IR region, and show obvious blueshift of the band gap as large as 1.0-2.0 eV in comparison with those for the bulk specimens, which may be related to the quantum-confinement effect. [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]

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]

[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]

• 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]

P2Y 12 receptor inhibitors are commonly used in clinical antiplatelet therapy, typically alongside other medications. Vicagrel, a promising P2Y 12 receptor inhibitor, has submitted a new drug marketing application to the U.S. FDA. Its primary metabolites and some metabolic pathways are identical to those of clopidogrel. The aim of this study was to investigate the effects of the thiol methyltransferase inhibitor ({plus minus})-2,3-dichloro-α-methylbenzylamine (DCMB) on the metabolism and pharmacokinetics of vicagrel. In vitro incubation with human and rat liver microsomes revealed that DCMB significantly inhibited the methylation of vicagrel's thiol metabolite M15-1. Rats were orally administered 6 mg/kg [ 14 C]vicagrel (100 μCi/kg) 1 h after peritoneal injection with or without DCMB (80 mg/kg). Compared to the control group, the plasma of DCMB-pretreated rats exhibited C max decrease and T max delay for all vicagrel-related substances, the methylation product of the thiol metabolite (M9-2) and the derivatization product of the active thiol metabolite (MP-M15-2). However, no significant changes in AUC or t 1/2 were observed. DCMB had negligible effect on the total radiological recovery of vicagrel within 72 h, although the rate of vicagrel excretion slowed down within 48 h. DCMB had a negligible impact on the metabolic pathway of vicagrel. Overall, the present study found that DCMB did not significantly affect the total exposure, metabolic pathways, metabolite profiles, or total excretion rates of vicagrel-related metabolites in rats, but led to C max decrease, T max delay, and slower excretion rate within 48 h. Significance Statement This study used LC-MS/MS combined with radiolabeling technology to investigate the effects of the TMT inhibitor DCMB on the absorption, metabolism and excretion of vicagrel in rats. This work helps to better understand the in vivo metabolism of active thiol metabolites of P2Y 12 inhibitors such as clopidogrel and vicagrel, etc., (Copyright © 2024 American Society for Pharmacology and Experimental Therapeutics.)

Background: The associations of cardiovascular autonomic neuropathy (CAN) with diabetic nephropathy and heart disease remain elusive. The aim of this study was to explore the correlations of CAN with urinary albumin excretion rate (UAER) and cardiac function in patients with type 2 diabetes mellitus (T2DM)., Methods: A total of 225 T2DM patients were assigned into CAN and non-CAN groups using cardiovascular reflex tests (CARTs). They were divided into macroalbuminuria, microalbuminuria and normoalbuminuria groups according to urinary albumin/creatinine ratio (UACR), or left ventricular diastolic dysfunction and normal groups based on left ventricular peak E/A velocity ratio (E/A). The correlations of CAN with albuminuria and left ventricular diastolic dysfunction, and the predictive values of UACR and E/A were analyzed., Results: Compared with non-CAN group, CAN group had older age, longer T2DM duration, higher serum urine acid (SUA) level, UACR, systolic and diastolic pressure differences between supine and standing positions, and lower other CARTs parameters and E/A (P<0.001). Macroalbuminuria group had largest positional systolic and diastolic pressure differences, and lowest other CARTs parameters (P<0.001). Compared with normal group, left ventricular diastolic dysfunction group had larger positional systolic and diastolic pressure differences, and lower other CARTs parameters (P<0.001). CAN in T2DM patients was positively correlated with albuminuria and left ventricular diastolic dysfunction (P<0.001). Age, SUA, UACR and E/A were independent predictive factors (P=0.031, P=0.005, P<0.001, P<0.001). UACR and E/A had high predictive values., Conclusions: In T2DM patients, CAN is positively correlated with declined UAER and cardiac function. UACR and E/A have high predictive values.

Background: Using targeted liposomes to encapsulate and deliver drugs has become a hotspot in biomedical research. Folated Pluronic F87/D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) co-modified liposomes (FA-F87/TPGS-Lps) were fabricated for curcumin delivery, and intracellular targeting of liposomal curcumin was investigated., Methods: FA-F87 was synthesized and its structural characterization was conducted through dehydration condensation. Then, cur-FA-F87/TPGS-Lps were prepared via thin film dispersion method combined with DHPM technique, and their physicochemical properties and cytotoxicity were determined. Finally, the intracellular distribution of cur-FA-F87/TPGS-Lps was investigated using MCF-7 cells., Results: Incorporation of TPGS in liposomes reduced their particle size, but increased the negative charge of the liposomes as well as their storage stability, and the encapsulation efficiency of curcumin was improved. While, modification of liposomes with FA increased their particle size, and had no impact on the encapsulation efficiency of curcumin in liposomes. Among all the liposomes (cur-F87-Lps, cur-FA-F87-Lps, cur-FA-F87/TPGS-Lps and cur-F87/TPGS-Lps), cur-FA-F87/TPGS-Lps showed highest cytotoxicity to MCF-7 cells. Moreover, cur-FA-F87/TPGS-Lps was found to deliver curcumin into the cytoplasm of MCF-7 cells., Conclusion: Folate-Pluronic F87/TPGS co-modified liposomes provide a novel strategy for drug loading and targeted delivery., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: Vicagrel, a novel antiplatelet prodrug to overcome the residual high platelet reactivity of clopidogrel induced by inactive metabolism and cytochrome P450 (CYP) 2C19 polymorphisms, provides favourable antiplatelet inhibition in healthy volunteers. However, its antiplatelet effect and safety in patients with coronary artery disease (CAD) are unclear., Methods and Results: This was a multicentre, randomized, double-blind, triple-dummy, dose-exploring phase II trial comparing the antiplatelet activity and safety of vicagrel at different doses vs. those of clopidogrel in patients with CAD undergoing percutaneous coronary intervention (PCI). The primary endpoint was inhibition of adenosine diphosphate (ADP)-induced platelet aggregation (%IPA) after loading and maintenance doses (LD/MD) at 28 days. Safety endpoints included adverse events (AEs) and Bleeding Academic Research Consortium-defined any bleeding. Pharmacokinetic (PK) profiles and the influence of CYP2C19 polymorphisms were explored in subgroup analysis. Two hundred and seventy-nine patients diagnosed with stable CAD (51.97%), unstable angina (40.86%), and myocardial infarction (7.17%) were randomized to receive vicagrel 20/5 mg (LD/MD), 24/6 mg, or 30/7.5 mg or clopidogrel 300/75 mg in combination with aspirin. %IPAs on Day 28 were 30.19%, 35.02%, 45.61%, and 32.55% for vicagrel 20/5, 24/6, and 30/7.5 mg and clopidogrel, respectively, and were comparable across all groups (P = 0.0694). The plasma concentration of the vicagrel active metabolite M15-2 had a similar area under curve and Tmax to those of clopidogrel. There were no significant differences in AEs (4.35%, 0%, 1.45%, and 5.56% for vicagrel 20/5, 24/6, and 30/7.5 mg and clopidogrel, P = 0.6667) or any bleeding (13.04%, 14.06%, 11.59%, and 11.11% for vicagrel 20/5, 24/6, and 30/7.5 mg and clopidogrel, respectively, P = 0.95) across four groups. %IPAs and PK profiles of vicagrel did not vary significantly among different CYP2C19 metabolizers., Conclusion: Vicagrel had comparable antiplatelet effect and safety to clopidogrel in patients with CAD undergoing PCI., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aim: Folate-conjugated Pluronic F87-poly(lactic-co-glycolic acid) block copolymer (FA-F87-PLGA) was synthesized to encapsulate anticancer drug Paclitaxel (PTX) for targeted drug delivery. To further improve the curative effect, D-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS or Vitamin E TPGS) was added to form FA-F87-PLGA/TPGS mixed NPs., Methods: FA-F87-PLGA was synthesized by the ring-opening polymerization, and the structure was characterized. PTX-loaded nanoparticles were prepared with the nanoprecipitation method. The physicochemical characteristics were studied to determine the appropriate dose ratio of the FA-F87-PLGA to TPGS. The cytotoxicity against Ovarian Cancer Cells (OVCAR-3) was determined by MTT assay. The Area Under the Curve (AUC) and half-life were measured in the in vivo pharmacokinetic studies., Results: Based on the optimization of particle size and embedding rate of PTX-loaded mixed NPs, the appropriate dosage ratio of FA-F87-PLGA to TPGS was finally determined to be 5:3. According to in vitro release studies, the cumulative release rate of PTX-loaded FA-F87-PLGA/TPGS mixed NPs was 92.04%, which was higher than that of nanoparticles without TPGS. The cytotoxicity studies showed that the IC50 value of PTX-loaded FA-F87-PLGA/TPGS decreased by 75.4 times and 19.7 times after 72 h treatment compared with free PTX injections and PTX-loaded FA-F87- PLGA NPs, respectively. In vivo pharmacokinetic studies indicated that FA-F87-PLGA/TPGS mixed NPs had a longer drug metabolism time and a larger Area Under the Curve (AUC) compared with free PTX injections., Conclusion: FA-F87-PLGA/TPGS mixed NPs are potential candidates for targeted drug delivery systems., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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 AUC 0-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 AUC 0-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., (© 2020 The British Pharmacological Society.)

Long non-coding RNAs (lncRNAs) have emerged as new gene regulators and prognostic markers in various cancers. Although the lncRNA nuclear enriched abundant transcript 1 (NEAT1) has been associated with tumorigenesis, its functions in renal cell carcinoma (RCC) have not been elucidated. We determined that NEAT1 is up-regulated in RCC tissue compared to corresponding non-tumor tissue. High NEAT1 expression was associated with tumor progression and poor survival in RCC patients. NEAT1 knockdown suppressed RCC cell proliferation by inhibiting cell cycle progression, and inhibited RCC cell migration and invasion by reversing the epithelial-to-mesenchymal transition phenotype. Down-regulation of NEAT1 increased the sensitivity of RCC cells to sorafenib in vitro . Mechanistic analysis revealed that NEAT1 acts as a competitive sponge for miR-34a, which prevents inhibition of c-Met. Thus, NEAT1 promotes RCC progression through the miR-34a/c-Met axis., Competing Interests: CONFLICTS OF INTEREST The authors declare that there are no conflicts of interest.

Periodic nanoring arrays are prepared by self-assembled poly styrene-block-polymethylmethacrylate (PS-b-PMMA) diblock copolymer under rapid solvent-annealing. The dimension of the nanorings can be modified by controlling the solvent-annealing time.