In Situ and in Vivo Study of Nasal Absorption of Paeonol in Rats

The objective of this work was to study the in situ and in vivo nasal absorption of paeonol. A novel single pass in situ nasal perfusion technique was applied to examine the rate and extent of nasal absorption of paeonol by rats. Various experimental conditions, such as perfusion rate, pH, osmotic pressure and drug concentration, were investigated. The in situ experiments showed that the nasal absorption of paeonol was not dependent on drug concentration, and fitted a first order process. The absorption rate constant, Ka, increased with an increase in perfusion speed. Paeonol was better absorbed in acidic solutions than in neutral or alkaline solutions. The value of Ka was higher in a hypertonic environment than under isotonic or hypotonic conditions. In vivo studies of paeonol absorption were carried out in rats and the pharmacokinetics parameters of intranasal (i.n.) and intragastric (i.g.) administration were compared with intravenous (i.v.) administration. The bioavailabilities of paeonol were 52.37% and 15.81% for i.n. and i.g, respectively, while Tmax values were 3.05 ± 1.46 min and 6.30 ± 0.70 min. MRT (Mean Residence Time) were 23.19 ± 6.46 min, 41.49 ± 2.96 min and 23.09 ± 5.88 min for i.n., i.g. and i.v. methods, respectively. The results demonstrate that paeonol could be absorbed promptly and thoroughly by i.n. administration in rats

Epigenetic Dysregulation in Mesenchymal Stem Cell Aging and Spontaneous Differentiation

BACKGROUND: Mesenchymal stem cells (MSCs) hold great promise for the treatment of difficult diseases. As MSCs represent a rare cell population, ex vivo expansion of MSCs is indispensable to obtain sufficient amounts of cells for therapies and tissue engineering. However, spontaneous differentiation and aging of MSCs occur during expansion and the molecular mechanisms involved have been poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Human MSCs in early and late passages were examined for their expression of genes involved in osteogenesis to determine their spontaneous differentiation towards osteoblasts in vitro, and of genes involved in self-renewal and proliferation for multipotent differentiation potential. In parallel, promoter DNA methylation and hostone H3 acetylation levels were determined. We found that MSCs underwent aging and spontaneous osteogenic differentiation upon regular culture expansion, with progressive downregulation of TERT and upregulation of osteogenic genes such as Runx2 and ALP. Meanwhile, the expression of genes associated with stem cell self-renewal such as Oct4 and Sox2 declined markedly. Notably, the altered expression of these genes were closely associated with epigenetic dysregulation of histone H3 acetylation in K9 and K14, but not with methylation of CpG islands in the promoter regions of most of these genes. bFGF promoted MSC proliferation and suppressed its spontaneous osteogenic differentiation, with corresponding changes in histone H3 acetylation in TERT, Oct4, Sox2, Runx2 and ALP genes. CONCLUSIONS/SIGNIFICANCE: Our results indicate that histone H3 acetylation, which can be modulated by extrinsic signals, plays a key role in regulating MSC aging and differentiation

DEPOT: graph learning delineates the roles of cancers in the progression trajectories of chronic kidney disease using electronic medical records

Chronic kidney disease (CKD) is a common, complex, and heterogeneous disease impacting aging populations. Determining the landscape of disease progression trajectories from midlife to senior age in a real-world context allows us to better understand the progression of CKD, the heterogeneity of progression patterns among the risk population, and the interactions with other clinical conditions like cancers. In this study, we use electronic health records (EHRs) to outline the CKD progression trajectory roadmap for the Wake Forest Baptist Medical Center (WFBMC) patient population. We establish an EHR cohort (n = 79,434) with patients' health status identified by 18 Essential Clinical Indices across 508,732 clinical encounters. We develop the DisEase PrOgression Trajectory (DEPOT) approach to model CKD progression trajectories and individualize clinical decision support. The DEPOT is an evidence-driven, graph-based clinical informatics approach that addresses the unique challenges in longitudinal EHR data by systematically using the graph artificial intelligence (graph-AI) model for representation learning and reverse graph embedding for trajectory reconstruction. Moreover, DEPOT includes a prediction model to assign new patients along the progression trajectory. We successfully establish the EHR-based CKD progression trajectories with DEPOT in the WFUBMC cohort. We annotate the trajectories with clinical features, including kidney function, age, and other indices, including cancer. This CKD progression trajectory roadmap reveals diverse kidney failure pathways associated with different clinical conditions. Specifically, we have identified one high-risk trajectory and two low-risk trajectories. Switching pathways from low-risk trajectories to the high-risk one is associated with accelerated decline in kidney function. On this roadmap, high-risk patients are enriched in the skin and GU cancers, which differs from low-risk patients, suggesting fundamentally different disease progression mechanisms. Overall, the CKD progression trajectory roadmap reveals novel diverse renal failure pathways in type 2 diabetes mellitus and highlights disease progression patterns associated with cancer phenotypes

Effects of Panax Notoginseng Saponins on Esterases Responsible for Aspirin Hydrolysis In Vitro

Herb–drug interactions strongly challenge the clinical combined application of herbs and drugs. Herbal products consist of complex pharmacological-active ingredients and perturb the activity of drug-metabolizing enzymes. Panax notoginseng saponins (PNS)-based drugs are often combined with aspirin in vascular disease treatment in China. PNS was found to exhibit inhibitory effects on aspirin hydrolysis using Caco-2 cell monolayers. In the present study, a total of 22 components of PNS were separated and identified by UPLC-MS/MS. Using highly selective probe substrate analysis, PNS exerted robust inhibitory potency on human carboxylesterase 2 (hCE2), while had a minor influence on hCE1, butyrylcholinesterase (BChE) and paraoxonase (PON). These effects were also verified through molecular docking analysis. PNS showed a concentration-dependent inhibitory effect on hydrolytic activity of aspirin in HepaRG cells. The protein level of hCE2 in HepaRG cells was suppressed after PNS treatment, while the level of BChE or PON1 in the extracellular matrix were elevated after PNS treatment. Insignificant effect was observed on the mRNA expression of the esterases. These findings are important to understand the underlying efficacy and safety of co-administration of PNS and aspirin in clinical practice

The Effects of Adjuvants on the Wetting and Deposition of Insecticide Solutions on Hydrophobic Wheat Leaves

Pesticide droplet deposition determines the efficacy of pesticide solution and is a critical process in pesticide application. Adding spray adjuvants can improve droplet deposition to a certain extent, but there are currently many types of adjuvants with different properties. The improper selection or unreasonable use of adjuvants may be counterproductive, increasing the loss of pesticides or causing crop damage. In this study, the adjuvants methylated plant oil (Beidatong), alkoxy modified polytrisiloxane (Silwet408), hyperbranched fatty alcohol ether modified polymer (ND500), and polymers adjuvants (G2801) were selected through surface tension, contact angle, the determination of the maximum retention (Rm) and point of run-off (POR), and field deposition to explore the effect of adjuvants on the wetting and deposition performance of pesticides on wheat leaves. Compared with Beidatong and G2801, Silwet408 and ND500 could significantly reduce the surface tension of pesticides and greatly promote the wetting properties on wheat leaves, but Rm and POR value on wheat leaves were reduced. The field test results also showed that the deposition amount of the adjuvant Silwet408 and ND500 on wheat was slightly lower than that of the adjuvant Beidatong and G2801. Studying the effects of adjuvants on the wetting and deposition properties of insecticide solutions can provide practical guidance for the use of adjuvants

The Effects of Adjuvants on the Wetting and Deposition of Insecticide Solutions on Hydrophobic Wheat Leaves

Pesticide droplet deposition determines the efficacy of pesticide solution and is a critical process in pesticide application. Adding spray adjuvants can improve droplet deposition to a certain extent, but there are currently many types of adjuvants with different properties. The improper selection or unreasonable use of adjuvants may be counterproductive, increasing the loss of pesticides or causing crop damage. In this study, the adjuvants methylated plant oil (Beidatong), alkoxy modified polytrisiloxane (Silwet408), hyperbranched fatty alcohol ether modified polymer (ND500), and polymers adjuvants (G2801) were selected through surface tension, contact angle, the determination of the maximum retention (Rm) and point of run-off (POR), and field deposition to explore the effect of adjuvants on the wetting and deposition performance of pesticides on wheat leaves. Compared with Beidatong and G2801, Silwet408 and ND500 could significantly reduce the surface tension of pesticides and greatly promote the wetting properties on wheat leaves, but Rm and POR value on wheat leaves were reduced. The field test results also showed that the deposition amount of the adjuvant Silwet408 and ND500 on wheat was slightly lower than that of the adjuvant Beidatong and G2801. Studying the effects of adjuvants on the wetting and deposition properties of insecticide solutions can provide practical guidance for the use of adjuvants

Transaldolase inhibits CD36 expression by modulating glutathione-p38 signaling, exerting protective effects against macrophage foam cell formation

In atherosclerosis, macrophage-derived foam cell formation is considered to be a hallmark of the pathological process; this occurs via the uptake of modified lipoproteins. In the present study, we aim to determine the role of transaldolase in foam cell formation and atherogenesis and reveal the mechanisms underlying its role. Bone marrow-derived macrophages (BMDMs) isolated from mice successfully form foam cells after treatment with oxidized low-density lipoprotein (80 μg/mL). Elevated transaldolase levels in the foam cell model are assessed by quantitative polymerase chain reaction and western blot analysis. Transaldolase overexpression and knockdown in BMDMs are achieved via plasmid transfection and small interfering RNA technology, respectively. We find that transaldolase overexpression effectively attenuates, whereas transaldolase knockdown accelerates, macrophage-derived foam cell formation through the inhibition or activation of cholesterol uptake mediated by the scavenger receptor cluster of differentiation 36 (CD36) in a p38 mitogen-activated protein kinase (MAPK) signaling-dependent manner. Transaldolase-mediated glutathione (GSH) homeostasis is identified as the upstream regulator of p38 MAPK-mediated CD36-dependent cholesterol uptake in BMDMs. Transaldolase upregulates GSH production, thereby suppressing p38 activity and reducing the CD36 level, ultimately preventing foam cell formation and atherosclerosis. Thus, our findings indicate that the transaldolase-GSH-p38-CD36 axis may represent a promising therapeutic target for atherosclerosis

Insights into effect of first-step austempering temperature on the microstructure and properties of austempered ductile iron

Austempered ductile iron (ADI) is a revolutionary material with high strength and hardness combined with excellent ductility and toughness. The discovery of a two-step austempering process has resulted in superior combination of all the mechanical properties. Therefore, ADI has many different applications in varying fields. One notable application of ADI is in transmission components for new energy vehicles. As the automotive continues to develop, ADI transmission components with higher damping properties are required, because the damping properties of ADI affect the vibration and noise of the transmission system. However, the mechanism behind the damping of ADI, as well as a full characterisation of the damping properties, has not been thoroughly investigated in the literature. Therefore, it is necessary to reveal the influencing factors and mechanism of the damping properties of ADI. In this paper, the effect of first-step austempering temperature on the microstructure, mechanical properties, and damping properties of ADI was investigated. The results revealed that the tensile strength, yield strength, and elongation of ADI all initially increased, until reaching a global maximum value (1320 MPa, 1230 MPa, and 13.2%, respectively) when the first-step austempering temperature was 280 °C, followed by a decrease in value. Interestingly, the impact energy of ADI initially decreased before reaching a global minimum and then increasing to a maximum value of 93.5 J, when the first-step austempering temperature reached 320 °C. With increasing strain amplitude, the internal friction values (Q ^−1 ) of ADI treated with different first-step austempering temperatures all increased gradually, and the Q ^−1 values of ADI with first-step austempering temperatures of 240 and 260 °C were higher than those of other samples. Moreover, the damping properties of ADI varied with frequency with obvious S-K peaks and Ge peaks

Polymer additives regulate the deposition behavior of pesticide droplets on target plants

Pesticide formulation is usually combined with spraying additives to enhance the spraying effect in the actual field spraying. Polymer additives are new polymer materials developed in recent years and widely used in agriculture field. In this article, four different degrees of polymerization polymer additives (G101, G103, G100A and G200A) regulate the spray droplets of glyphosate herbicide on the target crop foliar deposition performance was studied. Through the study of equilibrium and dynamic surface tension, the dynamic contact angle of the droplet on the hydrophilic and hydrophobic leaves and the droplet impacting the target leaf surface at a high speed in a simulated field spraying process, the results showed that although glyphosate isopropylamine salt (Gly-IPA) with polymer additives can wet the target leaf surface, but only Gly-IPA adding G200A can deposited on the leaf surface during dynamic impact. This work opens up new prospects and provides a series of good evaluation methods for the study of polymer additives in regulating the deposition behavior of pesticide droplets on the target interface