Sub-Acute Oral Toxicity of a Novel Derivative of Agomelatine in Rats in a Sex-Dependent Manner

Agomelatine (AGO) is a new type of antidepressant with demonstrated antidepressant effects and a unique modulating circadian rhythm action. However, AGO has hepatotoxicity, which limits its clinical application. In order to develop new drugs that cause less liver injury than AGO, a series of derivatives were synthesized; compound GW117 was screened from derivatives due to its high receptor affinity. This study will investigate its sub-acute oral toxicity profile in rats in a sex-dependent manner. GW117 and AGO was administrated by gavage (200, 400, or 800 mg/kg/day) for 28 days. Hematological, biochemical tests, organ weights, histopathological examinations were carried out, the results showed that AGO and GW117 had adverse effects on platelet, liver and kidney, and had sex-differences in some indicators. Hematological tests showed that AGO and GW117 reduced the platelet count in male animals but had no effect in females. AGO increased plasma alanine aminotransferase (ALT) and total bilirubin in male animals, and GW117 had no effect on these two indicators. For females, AGO moderately elevated ALT, alkaline phosphatase (ALP), and total bilirubin, while GW117 only elevated ALP slightly. Two drugs could increase liver weight and coefficient, and cause liver pathological injury, including hepatic sinusoidal dilatation, hepatocyte fatty deposition and dotted cell necrosis in two genders. AGO caused mild to moderate hepatocyte and hepatobiliary injury in both genders, while only a mild hepatobiliary injury was caused by GW117 in females. Renal function tests showed that both drugs can increase blood urea nitrogen levels in males, while AGO, but not GW117, can slightly increase blood creatinine and urea nitrogen in females. The kidney weight and coefficient could be significantly increased by two drugs in males, and by AGO medium and GW117 high and low doses in females. The kidney pathological damage was mainly characterized by tubule dilatation, a thinning of the renal cortex. Kidney damage caused by GW117 was less than that of AGO, and there was no sex-difference. In summary, GW117 can cause mild liver and kidney damage in both genders, as well as mild platelets reduction in males, while degree of damage is less severe than AGO. Therefore, as an excellent derivative, GW117 deserves further development as an antidepressant

Regulatory Effect of Connexin 43 on Basal Ca2+ Signaling in Rat Ventricular Myocytes

Background: It has been found that gap junction-associated intracellular Ca 2+ [Ca 2+]i disturbance contributes to the arrhythmogenesis and hyperconstriction in diseased heart. However, whether functional gaps are also involved in the regulation of normal Ca 2+ signaling, in particular the basal [Ca 2+] i activities, is unclear. Methods and Results: Global and local Ca 2+ signaling and gap permeability were monitored in cultured neonatal rat ventricular myocytes (NRVMs) and freshly isolated mouse ventricular myocytes by Fluo4/AM and Lucifer yellow (LY), respectively. The results showed that inhibition of gap communication by heptanol, Gap 27 and flufenamic acid or interference of connexin 43 (Cx43) with siRNA led to a significant suppression of LY uptake and, importantly, attenuations of global Ca 2+ transients and local Ca 2+ sparks in monolayer NRVMs and Ca 2+ sparks in adult ventricular myocytes. In contrast, overexpression of rat-Cx43 in NRVMs induced enhancements in the above measurements, and so did in HEK293 cells expressing rat Cx43. Additionally, membrane-permeable inositol 1,4,5-trisphosphate (IP3 butyryloxymethyl ester) and phenylephrine, an agonist of adrenergic receptor, could relieve the inhibited Ca 2+ signal and LY uptake by gap uncouplers, whereas blockade of IP 3 receptor with xestospongin C or 2-aminoethoxydiphenylborate mimicked the effects of gap inhibitors. More importantly, all these gap-associated effects on Ca 2+ signaling were also found in single NRVMs that only have hemichannels instead of gap junctions. Further immunostaining/immunoblotting single myocytes with antibod

Kernel Sparse Subspace Clustering with a Spatial Max Pooling Operation for Hyperspectral Remote Sensing Data Interpretation

Hyperspectral image (HSI) clustering is generally a challenging task because of the complex spectral-spatial structure. Based on the assumption that all the pixels are sampled from the union of subspaces, recent works have introduced a robust technique—the sparse subspace clustering (SSC) algorithm and its enhanced versions (SSC models incorporating spatial information)—to cluster HSIs, achieving excellent performances. However, these methods are all based on the linear representation model, which conflicts with the well-known nonlinear structure of HSIs and limits their performance to a large degree. In this paper, to overcome these obstacles, we present a new kernel sparse subspace clustering algorithm with a spatial max pooling operation (KSSC-SMP) for hyperspectral remote sensing data interpretation. The proposed approach maps the feature points into a much higher dimensional kernel space to extend the linear sparse subspace clustering model to nonlinear manifolds, which can better fit the complex nonlinear structure of HSIs. With the help of the kernel sparse representation, a more accurate representation coefficient matrix can be obtained. A spatial max pooling operation is utilized for the representation coefficients to generate more discriminant features by integrating the spatial-contextual information, which is essential for the accurate modeling of HSIs. This paper is an extension of our previous conference paper, and a number of enhancements are put forward. The proposed algorithm was evaluated on two well-known hyperspectral data sets—the Salinas image and the University of Pavia image—and the experimental results clearly indicate that the newly developed KSSC-SMP algorithm can obtain very competitive clustering results for HSIs, outperforming the current state-of-the-art clustering methods

Predicting of cutting force during gypsum fiber composite milling process using response surface methodology

Gypsum fiber composite (GFC) is a kind of building material widely used in interior decoration. Milling is the most commonly used machining process for GFC. Cutting force as an important cutting characteristic parameter has significant influence on the quality of machined surface, power consumption, and tools wear. The tangential force (Fx) and normal force (Fy) were measured and analyzed to find out the effects of milling parameters on these cutting forces. Milling parameters considered were spindle speed, feed rate, and depth of cut. The response surface methodology (RSM) was selected to develop mathematical models and optimize milling parameters. The results showed that with the increase of feed rate and depth of cut, the Fx and Fy increased. But the cutting forces decreased with the increase of spindle speed. The optimization results indicated that high spindle speed, low feed rate, and small depth of cut are preferable for milling of GFC to obtain the best result.

Bis(2,3-dibromo-4,5-dihydroxybenzyl) Ether, a Marine Algae Derived Bromophenol, Inhibits the Growth of Botrytis cinerea and Interacts with DNA Molecules

Bis(2,3-dibromo-4,5-dihydroxybenzyl) ether (BDDE) is a bromophenol isolated from marine algae. Previous reports have shown that BDDE possesses cytotoxic and antibacterial activity. In the present study, we demonstrate that BDDE displays broad-spectrum antifungal activities, especially on Botrytis cinerea. BDDE inhibits the growth of B. cinerea cultured on a solid medium of potato dextrose agar (PDA) as well as on the potato dextrose broth (PDB) medium. Moreover, BDDE decreases the incidence of fruit decay and severity of strawberries infected with B. cinerea. Further studies have revealed that BDDE decreases the germination rate and inhibits the mycelial growth of B. cinerea. The inhibition mechanisms are related to the disruption of the cell membrane integrity in B. cinerea spores and newly formed germ tubes. This study also suggests that BDDE possibly interacts with DNA via intercalation and minor groove binding. The studies provide evidence that BDDE has potential application in the control of gray mold after fruit harvest and the compound could serve as a candidate or lead template for rational drug design and for the development of antifungal agents

Simultaneous Quantification of Diazepam and Dexamethasone in Plasma by High-Performance Liquid Chromatography with Tandem Mass Spectrometry and Its Application to a Pharmacokinetic Comparison between Normoxic and Hypoxic Rats

In order to investigate the pharmacokinetics of a combination of diazepam and dexamethasone under hypoxic conditions, a novel, sensitive and specific liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of diazepam and dexamethasone in rat plasma was developed and validated. The chromatographic separation of analytes was successfully achieved on an XTerra® MS C18 column using a gradient elution of methanol and water containing 0.1% formic acid at a flow rate of 0.5 mL/min. This method demonstrated good linearity and no endogenous material interferences. The linear ranges were 1.0–100 ng/mL for diazepam and 2.0–200 ng/mL for dexamethasone. The intra- and inter-day precision for the two compounds in plasma were lower than 10.0%, and the accuracy was between −7.9% and 11.5%. Our method was then successfully applied in a pharmacokinetic comparison between normoxic and hypoxic rats. The results indicated that there were significant differences in the main pharmacokinetics parameters of diazepam and dexamethasone between normoxic and hypoxic rats. The results provide the important and valuable information for discovering and developing novel anti-hypoxia drug combinations, as well as a better understanding of the safety and efficacy of these drugs

Energy Efficiency Optimization for Machining of Wood Plastic Composite

Enhancing energy efficiency is the key to realizing green manufacturing. One major area of interest in this regard is the improvement of energy efficiency of machine tools during the production of building materials. This project focuses on energy efficiency during the spiral milling of wood plastic composites. To this end, a response surface method was adopted to develop a model and establish the relationship between energy efficiency and milling conditions. Analysis of variance based on individual factors as well as two-factor interactions was performed to gauge their effects on energy efficiency. It was found that milling depth was positively correlated to power efficiency, while spiral angle and feed per tooth displayed non-monotonic behavior. An attempt was made to predict milling conditions that will yield the greatest material removal rate and power efficiency. For wood plastic composites subjected to up-milling, it was determined that a feed per tooth of 0.1 mm, milling depth of 1.5 mm, and spiral angle of 70° were ideal. Considering the potential improvements in energy efficiency and surface quality that these process parameters will bring, it is strongly recommended for use in the industrial machining of wood plastic composites.Validerad;2022;Nivå 2;2022-02-16 (hanlid);Part of section: Material Processing Technology;Funder: National Natural Science Foundation of China (31971594); Jiangsu Higher Education Institutions of China (21KJB220009); Nanjing Forestry University (nlzzyq202101); Technology Innovation Alliance of Wood/BambooIndustry (TIAWBI2021-08); International Cooperation Joint Laboratory for Production, Education, Research, and Application of Ecological Health Care on Home Furnishing</p

Inhibitory effects of lapachol on rat C6 glioma in vitro and in vivo by targeting DNA topoisomerase I and topoisomerase II

Abstract Background Lapachol is a natural naphthoquinone compound that possesses extensive biological activities. The aim of this study is to investigate the inhibitory effects of lapachol on rat C6 glioma both in vitro and in vivo, as well as the potential mechanisms. Methods The antitumor effect of lapachol was firstly evaluated in the C6 glioma model in Wistar rats. The effects of lapachol on C6 cell proliferation, apoptosis and DNA damage were detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS)/ phenazinemethosulfate (PMS) assay, hoechst 33358 staining, annexin V-FITC/PI staining, and comet assay. Effects of lapachol on topoisomerase I (TOP I) and topoisomerase II (TOP II) activities were detected by TOP I and TOP II mediated supercoiled pBR322 DNA relaxation assays and molecular docking. TOP I and TOP II expression levels in C6 cells were also determined. Results High dose lapachol showed significant inhibitory effect on the C6 glioma in Wistar rats (P < 0.05). It was showed that lapachol could inhibit proliferation, induce apoptosis and DNA damage of C6 cells in dose dependent manners. Lapachol could inhibit the activities of both TOP I and II. Lapachol-TOP I showed relatively stronger interaction than that of lapachol-TOP II in molecular docking study. Also, lapachol could inhibit TOP II expression levels, but not TOP I expression levels. Conclusion These results showed that lapachol could significantly inhibit C6 glioma both in vivo and in vitro, which might be related with inhibiting TOP I and TOP II activities, as well as TOP II expression