Metabolomics of Clinical Poisoning by Aconitum Alkaloids Using Derivatization LC-MS

The root of Aconitum kusnezoffii (Caowu in Chinese, CW) is not only commonly used as a traditional Chinese medicine (TCM), but also served as a tonic in China. Due to its high toxicity, clinical poisoning cases induced by CW have frequently been reported. However, the mechanism is still unclear. In this study, Aconitum alkaloids and altered endogenous metabolites in CW poisoning patients were investigated to elucidate the possible intoxication mechanism. Eighteen alkaloids, including 6 toxic diester diterpenoid alkaloids (DDAs), were determined from the sera of patients. At the same time, 5-(diisopropylamino)amylamine (DIAAA) derivatization-ultrahigh performance liquid chromatography- quadrupole-time of flight mass spectrometry (UHPLC-Q-TOF/MS) approach was applied in the metabolomics analysis to find much more carboxyl-containing metabolites (CCMs), which are the essential components for life and critical to elucidate the mechanism of toxicity. As a result, 32 altered metabolites after poisoning were identified. Among them, hydroxyeicosatetraenoic acids (HETEs) and some dicarboxylic acids were first found to be related to Aconitum alkaloids toxicity. Finally, biological pathway analysis indicated that the significantly changed metabolites were primarily involved in amino acid metabolism, TCA cycle, fatty acid metabolism, pyruvate metabolism, arachidonic acid metabolism, sphingolipid metabolism and so on. These results can not only provide more information on the mechanism of CW intoxication but also help the clinical diagnosis of CW poisoning

Identification of polyunsaturated fatty acids as potential biomarkers of osteoarthritis after sodium hyaluronate and mesenchymal stem cell treatment through metabolomics

Introduction: Osteoarthritis (OA) is a prevalent joint disorder worldwide. Sodium hyaluronate (SH) and mesenchymal stem cells (MSCs) are promising therapeutic strategies for OA. Previous studies showed they could improve knee function and clinical symptoms of OA. However, the mechanism of the therapeutic effects on the improvement of OA has not been clearly explained.Methods: In our study, we used a technique called 5-(diisopropylamino)amylamine derivatization liquid chromatography coupled with mass spectrometry to find the metabolites in OA synovial fluid under different treatments.Results and Discussion: After looking into the metabolomics, we discovered that SH and MSC treatment led to the downregulation of ω-6 polyunsaturated fatty acids (PUFAs) and the upregulation of ω-3 PUFAs. Significantly, the contents of 5(S)-HETE, PGA2, PGB2, and PGJ2 were lower in the MSC group than in the SH group after quantification using 5-(diisopropylamino)amylamine derivatization–UHPLC–QQQ-MS. This is the first report on the relationship of 11(S)-HETE, PGA2, PGB2, PGF2β, 11β-PGF2α, and DK-PGE2 with OA. Moreover, the correlation analysis of metabolites and inflammation factors showed the positive association of ω-6 PUFAs with pro-inflammation cytokines, and of ω-3 PUFAs with anti-inflammation cytokines. Our results indicated the therapeutic effect of SH and MSCs in patients with OA. In addition, this reliable metabolic approach could uncover novel biomarkers to treat OA

Shengui Sansheng San Ameliorates Cerebral Energy Deficiency via Citrate Cycle After Ischemic Stroke

Cerebral energy deficiency is a key pathophysiologic cascade that results in neuronal injury and necrosis after ischemic stroke. Shengui Sansheng San (SSS) has been used to treat stroke for more than 300 years. In present study, we investigated the therapeutic efficacy and mechanism of SSS extraction on cerebral energy deficiency post-stroke. In permanent middle cerebral artery occlusion (pMCAo) model of rats, it suggested that SSS extraction in dose-dependent manner improved neurological function, cerebral blood flow (CBF), 18F-2-deoxy-glucose uptake and the density and diameter of alpha smooth muscle actin (α-SMA) positive vasculature in ipsilateral area, as well as decreased infarcted volume. Meanwhile, the metabolomics study in cerebrospinal fluid (CSF) was performed by using 5-(diisopropylamino)amylamine (DIAAA) derivatization-UHPLC-Q-TOF/MS approach. Eighty-eight endogenous metabolites were identified, and mainly involved in citrate cycle, fatty acid biosynthesis, aminoacyl-tRNA biosynthesis, amino acids metabolism and biosynthesis, etc. The remarkable increase of citrate in CSF after treatment with three dosages indicated that the therapeutic mechanism of SSS extraction might be related with citrate cycle. Simultaneously, it showed that high dosage group significantly increased peripheral blood glucose level, the expressions of glucose transporter (GLUT) 1, GLUT3, and monocarboxylic acid transporter 1 (MCT1), which contributed to the transportation of glucose and lactate. By the regulations of phosphorylated pyruvate dehydrogenase E1-alpha (p-PDHA1), acetyl CoA synthetase and citrate synthetase (CS), the levels of citrate and its upstream molecules (pyruvate and acetyl CoA) in peri-infarction zone further enhanced, which ultimately caused the massive yield of adenosine triphosphate (ATP). Our study first demonstrated that SSS extraction could ameliorate cerebral energy deficiency after ischemia by citrate cycle, which is characterized by the enhancements of glucose supply, transportation, utilization, and metabolism

Online Retailer’s Contingent Free-Shipping Decisions under Large-Scale Promotions Considering Delayed Delivery

Large-scale promotions lead to a huge number of orders, and the quantity of deliveries grows sharply, which puts considerable strain on cities’ logistics and imposes high related shipping costs. To alleviate these consequences, in this paper we provide a new contingent free shipping policy with delayed delivery (DD-CFS) for an online retailer during large-scale promotions and study its CFS threshold decisions, considering consumers’ different sensitivities to delivery time delays.We start by analyzing a consumer’s purchasing decision based on consumer utility theory. Next, we establish a mathematical model to help the online retailer find the optimal CFS threshold to maximize its expected profit. Finally, we analyze the benefit of delayed delivery to the online retailer and conduct a sensitivity analysis to examine the impacts of important parameters on the online retailer’s CFS threshold decisions, profit, and the value of the delayed delivery. We find that the DD-CFS policy can lead to more profits during the large-scale promotions period compared with the traditional CFS policy. As the delayed delivery time and the consumer’s negative attitude towards delayed delivery time increase, the online retailer should reduce the low CFS threshold value. On the other hand, as the shipping fee and the consumer’s negative attitude towards the shipping fee increase, the online retailer should raise the high and low CFS threshold values

Online Retailer’s Contingent Free-Shipping Decisions under Large-Scale Promotions Considering Delayed Delivery

Large-scale promotions lead to a huge number of orders, and the quantity of deliveries grows sharply, which puts considerable strain on cities’ logistics and imposes high related shipping costs. To alleviate these consequences, in this paper we provide a new contingent free shipping policy with delayed delivery (DD-CFS) for an online retailer during large-scale promotions and study its CFS threshold decisions, considering consumers’ different sensitivities to delivery time delays.We start by analyzing a consumer’s purchasing decision based on consumer utility theory. Next, we establish a mathematical model to help the online retailer find the optimal CFS threshold to maximize its expected profit. Finally, we analyze the benefit of delayed delivery to the online retailer and conduct a sensitivity analysis to examine the impacts of important parameters on the online retailer’s CFS threshold decisions, profit, and the value of the delayed delivery. We find that the DD-CFS policy can lead to more profits during the large-scale promotions period compared with the traditional CFS policy. As the delayed delivery time and the consumer’s negative attitude towards delayed delivery time increase, the online retailer should reduce the low CFS threshold value. On the other hand, as the shipping fee and the consumer’s negative attitude towards the shipping fee increase, the online retailer should raise the high and low CFS threshold values

Polarity-regulated derivatization-assisted LC-MS method for amino-containing metabolites profiling in gastric cancer

Amino-containing compounds, including amino acids, aliphatic amines, aromatic amines, small peptides and catecholamines, are involved in various biological processes and play vital roles in multiple metabolic pathways. Previous studies indicated that some amino-containing metabolites are significant diagnostic and prognostic biomarkers of gastric cancer. However, the discovery of precise biomarkers for the preoperative diagnosis of gastric cancer is still in an urgent need. Herein, we established a polarity-regulated derivatization method coupled with liquid chromatography-mass spectrometry (LC-MS) for amino-containing metabolites profiling in the serum samples of patients with gastric cancer and healthy controls, based on our newly designed and synthesized derivatization reagent (S)-3-(1-(diisopropoxyphosphoryl) pyrrolidine-2-carboxamido)-N-hydroxysuccinimidyl ester (3-DP-NHS). Enhanced separation efficiency and detection sensitivity for amino-containing metabolites were achieved after derivatization. This method exhibited good linearity, recovery, intra- and inter-day precision and accuracy. Only 5 μL serum is needed for untargeted analysis, enabling 202 amino-containing metabolites to be detected. Statistical analysis revealed altered amino acid metabolisms in patients with gastric cancer. Furthermore, ultra high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS/MS) analysis quantification revealed increased serum levels of tryptamine and decreased concentrations of arginine and tryptophan in patients with gastric cancer. Receiver operating characteristic (ROC) curves indicated that an increased tryptamine/tryptophan ratio could serve as a potential biomarker for gastric cancer diagnosis. This study demostrated the possibility of using serum amino acid biomarkers for gastric cancer diagnosis, providing new avenues for the treatment of gastric cancer

Research on Large-Scale Urban Shrinkage and Expansion in the Yellow River Affected Area Using Night Light Data

As the land use issue, caused by urban shrinkage in China, is becoming more and more prominent, research on urban shrinkage and expansion has become particularly challenging and urgent. Based on the points of interest (POI) data, this paper redefines the scope, quantity, and area of natural cities by using threshold methods, which accurately identify the shrinkage and expansion of cities in the Yellow River affected area using night light data in 2013 and 2018. The results show that: (1) there are 3130 natural cities (48,118.75 km2) in the Yellow River affected area, including 604 shrinking cities (8407.50 km2) and 2165 expanding cities (32,972.75 km2). (2) The spatial distributions of shrinking and expanding cities are quite different. The shrinking cities are mainly located in the upper Yellow River affected area, except for the administrative cities of Lanzhou and Yinchuan; the expanding cities are mainly distributed in the middle and lower Yellow River affected area, and the administrative cities of Lanzhou and Yinchuan. (3) Shrinking and expanding cities are typically smaller cities. The research results provide a quick data supported approach for regional urban planning and land use management, for when regional and central governments formulate the outlines of urban development monitoring and regional planning

Drought Monitoring over Yellow River Basin from 2003–2019 Using Reconstructed MODIS Land Surface Temperature in Google Earth Engine

Drought is one of the most complex and least-understood environmental disasters that can trigger environmental, societal, and economic problems. To accurately assess the drought conditions in the Yellow River Basin, this study reconstructed the Land Surface Temperature (LST) using the Annual Temperature Cycle (ATC) model and the Normalized Difference Vegetation Index (NDVI). The Temperature Condition Index (TCI), Vegetation Condition Index (VCI), Vegetation Health Index (VHI), and Temperature-Vegetation Drought Index (TVDI), which are four typical remote sensing drought indices, were calculated. Then, the air temperature, precipitation, and soil moisture data were used to evaluate the applicability of each drought index to different land types. Finally, this study characterized the spatial and temporal patterns of drought in the Yellow River Basin from 2003 to 2019. The results show that: (1) Using the LST reconstructed by the ATC model to calculate the drought index can effectively improve the accuracy of drought monitoring. In most areas, the reconstructed TCI, VHI, and TVDI are more reliable for monitoring drought conditions than the unreconstructed VCI. (2) The four drought indices (TCI, VCI, VH, TVDI) represent the same temporal and spatial patterns throughout the study area. However, in some small areas, the temporal and spatial patterns represented by different drought indices are different. (3) In the Yellow River Basin, the drought level is highest in the northwest and lowest in the southwest and southeast. The dry conditions in the Yellow River Basin were stable from 2003 to 2019. The results in this paper provide a basis for better understanding and evaluating the drought conditions in the Yellow River Basin and can guide water resources management, agricultural production, and ecological protection of this area