ß-Nicotinamide mononucleotide supplementation prolongs the lifespan of prematurely aged mice and protects colon function in ageing mice.

Ageing is defined as the degeneration of physiological functions in numerous tissues and organs of an organism, which occurs with age. As we age, the gut undergoes a series of changes and weaknesses that may contribute to overall ageing. Emerging evidence suggests that ß-nicotinamide mononucleotide (NMN) plays a role in regulating intestinal function, but there is still a lack of literature on its role in maintaining the colon health of ageing mice. In our research, Zmpste24-/- mice proved that NMN prolonged their life span and delayed senescence. This study was designed to investigate the effects of long-term intervention on regulating colon function in ageing mice. Our results indicated that NMN improved the pathology of intestinal epithelial cells and intestinal permeability by upregulating the expression of intestinal tight junction proteins and the number of goblet cells, increasing the release of anti-inflammatory factors, and increasing beneficial intestinal bacteria. NMN increased the expression of the proteins SIRT1, NMNAT2, and NMNAT3 and decreased the expression of the protein P53. It also regulated the activity of ISCs by increasing Wnt/ß-catenin and Lgr5. Our findings also revealed that NMN caused a significant increase in the relative abundance of Akkermansia muciniphila and Bifidobacterium pseudolongum and notable differences in metabolic pathways related to choline metabolism in cancer. In summary, NMN supplementation can delay frailty in old age, aid healthy ageing, and delay gut ageing.

Cu-Based Thermocompression Bonding and Cu/Dielectric Hybrid Bonding for Three-Dimensional Integrated Circuits (3D ICs) Application.

Advanced packaging technology has become more and more important in the semiconductor industry because of the benefits of higher I/O density compared to conventional soldering technology. In advanced packaging technology, copper-copper (Cu-Cu) bonding has become the preferred choice due to its excellent electrical and thermal properties. However, one of the major challenges of Cu-Cu bonding is the high thermal budget of the bonding process caused by Cu oxidation, which can result in wafer warpage and other back-end-of-line process issues in some cases. Thus, for specific applications, reducing the thermal budget and preventing Cu oxidation are important considerations in low-temperature hybrid bonding processes. This paper first reviews the advancements in low-temperature Cu-based bonding technologies for advanced packaging. Various low-temperature Cu-Cu bonding techniques such as surface pretreatment, surface activation, structure modification, and orientation control have been proposed and investigated. To overcome coplanarity issues of Cu pillars and insufficient gaps for filling, low-temperature Cu-Cu bonding used, but it is still challenging in fine-pitch applications. Therefore, low-temperature Cu/SiO2, Cu/SiCN, and Cu/polymer hybrid bonding have been developed for advanced packaging applications. Furthermore, we present a novel hybrid bonding scheme for metal/polymer interfaces that achieves good flatness and an excellent bonding interface without the need for the chemical mechanical polishing (CMP) process.

Initial dosage optimisation of cyclosporine in Chinese paediatric patients undergoing allogeneic haematopoietic stem cell transplantation based on population pharmacokinetics: a retrospective study.

OBJECTIVE: Improved understanding of cyclosporine A (CsA) pharmacokinetics in children undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT) is crucial for effective prevention of acute graft-versus-host disease and medication safety. The aim of this study was to establish a population pharmacokinetic (Pop-PK) model that could be used for individualised therapy to paediatric patients undergoing allo-HSCT in China. DESIGN, SETTING AND PARTICIPANTS: A retrospective analysis of 251 paediatric HSCT patients who received CsA intravenously in the early post transplantation period at Women and Children's Medical Center in Guangzhou was conducted. ANALYSIS MEASURES: The model building dataset from 176 children was used to develop and analyse the CsA Pop-Pk model by using the nonlinear mixed effect model method. The basic information was collected by the electronic medical record system. Genotype was analysed by matrix-assisted time-of-flight mass spectrometry. The stability and predictability of the final model were verified internally, and a validation dataset of 75 children was used for external validation. Monte Carlo simulation is used to adjust and optimise the initial dose of CsA in paediatric allo-HSCT patients. RESULTS: The typical values for clearance (CL) and volume of distribution ([Formula: see text]) were 14.47 L/hour and 2033.53 L, respectively. The body weight and haematocrit were identified as significant variables for V, while only body weight had an impact on CL. The simulation based on the final model suggests that paediatrics with HSCT required an appropriate intravenous dose of 5 mg/kg/day to reach the therapeutic trough concentration. CONCLUSIONS: The CsA Pop-PK model established in this study can quantitatively describe the factors influencing pharmacokinetic parameters and precisely predict the intrinsic exposure to CsA in children. In addition, our dosage simulation results can provide evidence for the personalised medications TRIAL REGISTRATION NUMBER: ChiCTR2000040561.

Effects of Dietary Flavonoids on the Metabolism of Vortioxetine and its Potential Mechanism

INTRODUCTION: Quercetin and apigenin are two common dietary flavonoids widely found in foods and fruits. Quercetin and apigenin can act as the inhibitors of CYP450 enzymes, which may affect the pharmacokinetics of clinical drugs. Vortioxetine (VOR), approved for marketing by the Food and Drug Administration (FDA) in 2013, is a novel clinical drug for treating major depressive disorder (MDD). OBJECTIVE: This study aimed to evaluate the effects of quercetin and apigenin on the metabolism of VOR in in vivo and in vitro experiments. METHOD: Firstly, 18 Sprague-Dawley rats were randomly divided into three groups: control group (VOR), group A (VOR + 30 mg/kg quercetin) and group B (VOR + 20 mg/kg apigenin). We collected the blood samples at different time points before and after the final oral administration of 2 mg/kg VOR. Subsequently, we further used rat liver microsomes (RLMs) to investigate the half-maximal inhibitory concentration (IC50) of the metabolism of vortioxetine. Finally, we evaluated the inhibitory mechanism of two dietary flavonoids on VOR metabolism in RLMs. RESULTS: In animal experiments, we found AUC (0-∞) (area under the curve from 0 to infinity) and CLz/F (clearance) to be obviously changed. Compared to controls, AUC (0-∞) of VOR in group A and group B was 2.22 and 3.54 times higher, respectively, while CLz/F of VOR in group A and group B was significantly decreased down to nearly two-fifth and one-third. In in vitro studies, the IC50 value of quercetin and apigenin in the metabolic rate of vortioxetine was 5.322 µM and 3.319 µM, respectively. Ki value of quercetin and apigenin was found to be 0.279 and 2.741, respectively, and the αKi value of quercetin and apigenin was 0.066 and 3.051 µM, respectively. CONCLUSION: Quercetin and apigenin exhibited inhibitory effects on the metabolism of vortioxetine in vivo and in vitro. Moreover, quercetin and apigenin non-competitively inhibited the metabolism of VOR in RLMs. Thus, we should pay more attention to the combination between these dietary flavonoids and VOR in the future clinical use.

Effects of different doses glimepiride intake on the pharmacokinetics of benzbromarone in rats.

Benzbromarone (BNR) is prescribed for the management of hyperuricemia, whereas glimepiride (GLM) for the treatment of Type 2 Diabetes Mellitus. Both drugs are certified to be mainly metabolized via cytochrome P450 (CYP) 2C9 in vivo and may have the potential drug-drug interactions. This study aims to investigate the possible influence of orally administered low- and high-dose glimepiride (GLM) on pharmacokinetic characteristics (PK) of benzbromarone (BNR) in rats. Fifteen rats were randomly assigned to group A, B and C (n=5) and administered 0.5% sodium carboxymethyl cellulose (CMC), 0.5mg/kg GLM (low-dose) and 1.0 mg/kg GLM (high-dose) once daily for 8 days, respectively, which were all followed with a single oral dose of BNR (9.0 mg/kg) on the day 8th. Blood samples were obtained from retro orbital plexus at the time points of 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24h and BNR in plasma was quantitated by HPLC-MS/MS assay. Resultantly a slight influence of GLM on PK of BNR could be found in rats. When compared with Group A, the half-life time (t1/2z) of BNR in Group B and C significantly decreased 52.39% and 73.49%, respectively, although other major PK parameters were negligibly changed by co-administration of GLM. On the whole, the combinational therapy of GLM at low or high dose would notably alter the elimination of BNR and the effect was dose-dependent.

Research progress of natural silk fibroin and the application for drug delivery in chemotherapies.

Silk fibroin has been widely used in biological fields due to its biocompatibility, mechanical properties, biodegradability, and safety. Recently, silk fibroin as a drug carrier was developed rapidly and achieved remarkable progress in cancer treatment. The silk fibroin-based delivery system could effectively kill tumor cells without significant side effects and drug resistance. However, few studies have been reported on silk fibroin delivery systems for antitumor therapy. The advancement of silk fibroin-based drug delivery systems research and its applications in cancer therapy are highlighted in this study. The properties, applications, private opinions, and future prospects of silk fibroin carriers are discussed to understand better the development of anti-cancer drug delivery systems, which may also contribute to advancing silk fibroin innovation.

The Effect of Single-Dose Ougan Juice Application on the Pharmacokinetics of Erlotinib.

The aim of our study was to investigate the effects of single-dose Ougan (Citrus reticulata cv. Suavissima) juice application on the pharmacokinetics of erlotinib in vivo. Twelve Sprague-Dawley rats were randomly divided into the Ougan juice and control groups (n = 6 each). The rats were given a single dose of 1 mL/100 g Ougan juice or 1 mL/100 g normal saline (NS) by intragastric administration, followed by a single oral administration of 20 mg/kg erlotinib. The plasma concentration of erlotinib in rats was determined using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Erlotinib-d6 was used as the internal standard for chromatographic analysis on the UPLC BEH C18 analysis column (2.1 mm × 50 mm, 1.7 µm). The mobile phase was composed of acetonitrile and 0.1% formic acid eluting by gradient. Different pharmacokinetic (PK) parameters of erlotinib were calculated. The Ougan juice promoted the absorption of erlotinib and reduced the clearance of the drug. The area under the curve of erlotinib in the single-dose Ougan juice pretreatment group was approximately 1.87 times higher, and the maximum blood concentration (Cmax) was approximately 1.34 times higher than that in the control group. The mean residence time of erlotinib in the Ougan juice group was larger, and the clearance rate was smaller than those in the control group; the difference was statistically significant (P < 0.05). Ougan juice affected the PK spectrum of erlotinib in rats by improving the bioavailability of the drug and significantly increasing its plasma concentration.

Clinical efficacy of anti-vascular endothelial growth factor versus panretinal photocoagulation for patients with proliferative diabetic retinopathy: A protocol for systematic review and meta-analysis.

BACKGROUND: The argument on the optimal treatment for patients with proliferative diabetic retinopathy (PDR) remains to be resolved. Therefore, the primary objective of the present study was to evaluate the clinical efficacy of anti-vascular endothelial growth factor (anti-VEGF) therapy versus panretinal photocoagulation (PRP) for patients with PDR. METHODS: Two independent investigators followed The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines and the recommendations of the Cochrane Collaboration to conduct this meta-analysis. The electronic databases of EMBASE, PubMed, Cochrane Library, and Web of Science were searched from the inception to April 2021 using the following key terms: "proliferative diabetic retinopathy," "anti-vascular endothelial growth factor," and "panretinal photocoagulation," for all relevant studies. We identified literature that met the following inclusion criteria: patients with PDR; studies focusing on assessing anti-VEGF therapy and PRP; the following outcome measures must be shown: anatomical outcomes, including complete regression and recurrence of neovascularization, mean change in best corrected vision acuity from baseline to the end of follow-up period. The Cochrane risk of bias tool was used to evaluate the risk of bias of included randomized clinical trials by 2 independent reviewers. RESULTS: This protocol will provide a reliable theoretical basis for the following research. TRIAL REGISTRATION NUMBER: 10.17605/OSF.IO/UHYDR.

Micro RNA-1298 opposes the effects of chronic oxidative stress on human trabecular meshwork cells via targeting on EIF4E3.

OBJECTIVE: This study aimed to investigate the effect and potential mechanism of miR-1298 in the progression of human trabecular meshwork (HTM) cells. MATERIAL AND METHODS: Expression of miR-1298 was assessed by quantitative real time PCR (qRT-PCR), as well as in HTM-1 and HTM-2 cells. Mature miR-1298 mimic, miR-1298 inhibitor, and si-EIF4E3 and their corresponding controls were transfected into HTM-1 and HTM-2 to obtain stable HTM cells. Luciferase reporter assay was used to verify regulation between miR-1298 and EIF4E3. Cytotoxicity and Oxidative damage were assessed using commercial kits, and apoptosis was determined using flow cytometry. ECM and apoptosis related factors were determined using qRT-PCR and western blotting, as well as the pathway related factors. RESULTS: The expression of miR-1298 was significantly decreased both in glaucoma and HTM cells. MiR-1298 mimic could significantly inhibit the increase of cytotoxicity, apoptosis, accumulation of carbonylated proteins and ECM induced by COS, but miR-1298 inhibitor could obviously promote the increase effects caused by COS in HTM cells. EIF4E3 was a downstream target of miR-1298. Sliced EIF4E3 could significantly inhibit the increase effects induced miR-1298 inhibitor in HTM cells under COS. The expression levels of TGF-ß2 and Smad4 were significantly increased, and Wnt3a and ß-cantenin were obviously decreased under COS, and miR-1298 inhibitor could markedly promote this increase effect, while sliced EIF4E3 could reverse the effect of miR-1298 under COS. CONCLUSIONS: miR-1298 could protect HTM cells to against damage caused by COS via inhibiting TGF-ß2/Smad4 pathway and activating canonical Wnt pathway.

Inhibitory effect of ketoconazole and voriconazole on the pharmacokinetics of carvedilol in rats.

The aim of this study was to investigate the effect of orally administered ketoconazole and voriconazole on the pharmacokinetics of carvedilol and its metabolites in rats. Fifteen healthy male Sprague-Dawley (SD) rats were randomly divided into three groups: A group (30 mg/kg ketoconazole), B group (30 mg/kg voriconazole) and C group (control group). A single dose of carvedilol was administered orally 30 min after administration of ketoconazole and voriconazole. Carvedilol and its metabolites plasma levels were measured by ultra-high performance liquid chromatography-mass spectrometry method (UPLC-MS/MS), and pharmacokinetic parameters were calculated by DAS 3.0 software. The co-administrated with ketoconazole could significantly increase the maximal plasma concentration (Cmax) and area under the curve (AUC) of carvedilol (p < 0.01). And the Cmax of its three metabolites 4'-hydroxyphenyl carvedilol (4'-HPC), 5'-hydroxyphenyl carvedilol (5'-HPC) and o-desmethyl carvedilol (o-DMC) decreased drastically by 39.4% (p < 0.01), 45.0% (p < 0.01) and 40.8% (p < 0.05), respectively. Following co-administered with voriconazole, Tmax of carvedilol and o-DMC increased, and the Cmax of 5'-HPC decreased by 27.7% (p < 0.05), while other drugs pharmacokinetic parameters performed no significant differences. Therefore, in clinical, when carvedilol was co-administrated with ketoconazole, dose adjustment of carvedilol should be taken into account.

Orientation-controlled growth and optical properties of diverse Ag nanoparticles on Si(100) and Si(111) wafers.

Well-controlled growth of Ag nanoparticles (NPs) on Si substrates is important for next generation Si-based optoelectronic devices, but only randomly oriented Ag NPs have been previously reported. In this work, well-oriented Ag NPs with regular shapes are pseudomorphically grown on Si(100) and Si(111) substrates with crystallographic relationships of {100} mathematical left angle bracket 010 mathematical right angle bracket Ag ∥ {100} mathematical left angle bracket 010 mathematical right angle bracket Si and {111} mathematical left angle bracket 110 mathematical right angle bracket Ag ∥ {111} mathematical left angle bracket 110 mathematical right angle bracket Si, respectively. From a cross-sectional image, the Ag NPs on Si(100) substrates penetrate into Si and generate an inverted pyramid-like structure terminated by {111} planes embedded in Si substrates. In contrast, the Ag NPs on Si(111) substrates show flat morphology with the top plane terminated by Ag {111}. The Si underneath Ag NPs was not penetrated by Ag and a SiO(2) layer was formed between Ag and Si. Photoluminescence spectra of the Ag NPs show ultraviolet emissions centered in the 340-343 nm range. The mathematical left angle bracket 111 mathematical right angle bracket-oriented Ag particles show stronger emissions with an extra peak at 343 nm compared with mathematical left angle bracket 100 mathematical right angle bracket-oriented Ag NPs. Raman spectra show that the mathematical left angle bracket 100 mathematical right angle bracket - and mathematical left angle bracket 111 mathematical right angle bracket-oriented Ag NPs can enhance the peak intensity of Si(100) and Si(111) by 45.3% and 32.5%, respectively. The orientation-controlled Ag NPs with anisotropic optical properties are promising materials for Si-based optoelectronics.