NMR-based metabolomics approach to study the effect and related molecular mechanisms of Saffron essential oil against depression.

Depression currently ranks as the fourth leading cause of disability globally, affecting approximately 20% of the world's population. we established a chronic restraint stress (CRS) induced depression model in mice and employed fluoxetine as a reference drug. We assessed the therapeutic potential of saffron essential oil (SEO) and elucidated its underlying mechanisms through behavioral indices and NMR-based metabolomic analysis. The findings indicate that SEO ameliorates behavioral symptoms of depression, such as the number of entries into the central area, fecal count, latency to immobility, and duration of immobility in both the Tail Suspension Test (TST) and the Forced Swim Test (FST), along with correcting the dysregulation of 5-serotonin. Metabolomic investigations identified sixteen potential biomarkers across the liver, spleen, and kidneys. SEO notably modulated nine of these biomarkers: dimethylglycine, glycerol, adenosine, ß-glucose, α-glucose, uridine, mannose, sarcosine, and aspartate, with glycerol emerging as a common biomarker in both the liver and spleen. Pathway analysis suggests that these biomarkers participate in glycolysis, glycine serine threonine metabolism, and energy metabolism, potentially implicating a role in neural regulation. In summary, SEO effectively mitigates depressive-like behaviors in CRS mice, predominantly via modulation of glycolysis, amino acid metabolism, and energy metabolism, and potentially exerts antidepressant effects through neural regulation. Our study offers insights into small molecule metabolite alterations in CRS mice through a metabolomics lens, providing evidence for the antidepressant potential of plant essential oils and contributing to our understanding of the mechanisms of traditional Chinese medicine in treating depression.

Clinicopathological characteristics and prognosis in patients with monoclonal gammopathy and renal damage in central China: a multicenter retrospective cohort study.

Renal involvement is common in monoclonal gammopathy (MG); however, the same patient may have both MG and non-paraprotein-associated renal damage. Accordingly, distinguishing the cause of renal damage is necessary because of the different clinical characteristics and associated treatments. In this multicenter retrospective cohort study, we described the clinicopathological characteristics and prognosis of 703 patients with MG and renal damage in central China. Patients were classified as having MG of renal significance (MGRS), MG of undetermined significance (MGUS), or hematological malignancy. 260 (36.98%), 259 (36.84%), and 184 (26.17%) had MGRS, MGUS, and hematological malignancies, respectively. Amyloidosis was the leading pattern of MGRS (74.23%), followed by thrombotic microangiopathy (8.85%) and monoclonal immunoglobulin deposition disease (8.46%). Membranous nephropathy was the leading diagnosis of MGUS (39.38%). Renal pathological findings of patients with hematological malignancies included paraprotein-associated lesions (84.78%) and non-paraprotein-associated lesions (15.22%). The presence of nephrotic syndrome and an abnormal free light chain (FLC) ratio were independently associated with MGRS. The overall survival was better in patients with MGUS than in those with MGRS or hematological malignancies.

Simultaneous quantification of donafenib, sorafenib, and their N-oxide metabolites in rat plasma using a HPLC-MS/MS method.

Donafenib and sorafenib are small molecule chemotherapy drugs for the management of hepatocellular carcinoma, with donafenib being a deuterated derivative of sorafenib. To date, a high liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method that quantify donafenib, sorafenib, and their main metabolites has not yet been developed. The objective of this study was to establish a HPLC-MS/MS method for the simultaneous detection of donafenib, donafenib-N-oxide, sorafenib, and sorafenib-N-oxide and for the pharmacokinetic studies in rat. The extraction of all analytes was achieved by simple protein precipitation utilizing acetonitrile. The Waters XBridge C18 column (2.1 × 100 mm, 3.5 µm) was selected, and the analytes could be efficiently separated and quantitated during a 2.8 min gradient elution procedure. The method was linear within the predefined quantification ranges and provided acceptable precision (%CV < 9.4%), reproducible extraction recovery (99.4%-111.5%), and low matrix effect (88.1%-98.6%). The hemolysis effect did not interfere with the quantification of all analytes, and similar results were obtained by changing the anticoagulant K2-EDTA to heparin or sodium citrate. Plasma pharmacokinetics revealed that the values of t1/2, Cmax, and AUC0-t of donafenib were 1.4-, 6.2-, and 3.1-fold higher than those of sorafenib, respectively. In conclusion, the proposed bioassay was successfully applied to pharmacokinetic studies in rat after administration of donafenib and sorafenib. Our work not only improves the bioanalytical method for determining the plasma concentrations of donafenib, sorafenib, and their N-oxide metabolites, but also provides a scientific reference for clinical pharmacokinetic studies.

Effects of the CYP3A inhibitors, voriconazole, itraconazole, and fluconazole on the pharmacokinetics of osimertinib in rats.

Background: Osimertinib, as third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line treatment approved to treat advanced T790M mutation-positive tumors. Triazole antifungals are therapeutic drugs for cancer patients to reduce the risk of opportunistic fungal infections. Our objective was to investigate whether three triazole antifungals (voriconazole, itraconazole, and fluconazole) could change the pharmacokinetics of osimertinib in rats. Methods: The adult male Sprague-Dawley rats were randomly divided into four groups (n = 6): control (0.3% CMC-Na), and voriconazole (20 mg/kg), itraconazole (20 mg/kg), or fluconazole (20 mg/kg) combined with osimertinib (10 mg/kg) group. Tail vein blood samples were collected into heparin tubes at various time points within 0-48 h after osimertinib administration. Osimrtinib's plasma concentration was detected using HPLC-MS/MS system equipped with a Waters XBridge C18 column, with the mobile phase consisting of acetonitrile and 0.2% formic acid water at a flow rate of 0.5 mL/min. Results: Co-administration with voriconazole or fluconazole increased the Cmax of osimertinib by 58.04% and 53.45%, respectively; the AUC0-t increased by 62.56% and 100.98%, respectively. However, when co-administered with itraconazole, the Cmax and AUC0-t of osimertinib only increased by 13.91% and 34.80%, respectively. Conclusions: Our results revealed that the pharmacokinetics of osimertinib were significantly changed by voriconazole and fluconazole in rats, whereas it was slightly affected by itraconazole. This work will contribute to a more comprehensive understanding of the pharmacokinetic properties of osimertinib when co-administered with triazole antifungals.

Ramulus Cinnamomi essential oil exerts an anti-inflammatory effect on RAW264.7 cells through N-acylethanolamine acid amidase inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: Ramulus Cinnamomi, the dried twig of Cinnamomum cassia (L.) J.Presl., is a traditional Chinese medicine (TCM) with anti-inflammatory effects. The medicinal functions of Ramulus Cinnamomi essential oil (RCEO) have been confirmed, although the potential mechanisms by which RCEO exerts its anti-inflammatory effects have not been fully elucidated. AIM OF THE STUDY: To investigate whether N-acylethanolamine acid amidase (NAAA) mediates the anti-inflammatory effects of RCEO. MATERIALS AND METHODS: RCEO was extracted by steam distillation of Ramulus Cinnamomi, and NAAA activity was detected using HEK293 cells overexpressing NAAA. N-Palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), both of which are NAAA endogenous substrates, were detected by liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). The anti-inflammatory effects of RCEO were analyzed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and the cell viability was measured with a Cell Counting Kit-8 (CCK-8) kit. The nitric oxide (NO) in the cell supernatant was measured using the Griess method. The level of tumor necrosis factor-α (TNF-α) in the RAW264.7 cell supernatant was determined using an enzyme-linked immunosorbent assay (ELISA) kit. The chemical composition of RCEO was assessed by gas chromatography-mass spectroscopy (GC-MS). The molecular docking study for (E)-cinnamaldehyde and NAAA was performed by using Discovery Studio 2019 software (DS2019). RESULTS: We established a cell model for evaluating NAAA activity, and we found that RCEO inhibited the NAAA activity with an IC50 of 5.64 ± 0.62 µg/mL. RCEO significantly elevated PEA and OEA levels in NAAA-overexpressing HEK293 cells, suggesting that RCEO might prevent the degradation of cellular PEA and OEA by inhibiting the NAAA activity in NAAA-overexpressing HEK293 cells. In addition, RCEO also decreased NO and TNF-α cytokines in lipopolysaccharide (LPS)-stimulated macrophages. Interestingly, the GC-MS assay revealed that more than 93 components were identified in RCEO, of which (E)-cinnamaldehyde accounted for 64.88%. Further experiments showed that (E)-cinnamaldehyde and O-methoxycinnamaldehyde inhibited NAAA activity with an IC50 of 3.21 ± 0.03 and 9.62 ± 0.30 µg/mL, respectively, which may represent key components of RCEO that inhibit NAAA activity. Meanwhile, docking assays revealed that (E)-cinnamaldehyde occupies the catalytic cavity of NAAA and engages in a hydrogen bond interaction with the TRP181 and hydrophobic-related interactions with LEU152 of human NAAA. CONCLUSIONS: RCEO showed anti-inflammatory effects by inhibiting NAAA activity and elevating cellular PEA and OEA levels in NAAA-overexpressing HEK293 cells. (E)-cinnamaldehyde and O-methoxycinnamaldehyde, two components in RCEO, were identified as the main contributors of the anti-inflammatory effects of RCEO by modulating cellular PEA levels through NAAA inhibition.

Identification of potential serum biomarkers for congenital heart disease children with pulmonary arterial hypertension by metabonomics.

BACKGROUND: Pulmonary arterial hypertension is a common complication in patients with congenital heart disease. In the absence of early diagnosis and treatment, pediatric patients with PAH has a poor survival rate. Here, we explore serum biomarkers for distinguishing children with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) from CHD. METHODS: Samples were analyzed by nuclear magnetic resonance spectroscopy-based metabolomics and 22 metabolites were further quantified by ultra-high-performance liquid chromatography-tandem mass spectroscopy. RESULTS: Serum levels of betaine, choline, S-Adenosyl methionine (SAM), acetylcholine, xanthosine, guanosine, inosine and guanine were significantly altered between CHD and PAH-CHD. Logistic regression analysis showed that combination of serum SAM, guanine and N-terminal pro-brain natriuretic peptide (NT-proBNP), yielded the predictive accuracy of 157 cases was 92.70% with area under the curve of the receiver operating characteristic curve value of 0.9455. CONCLUSION: We demonstrated that a panel of serum SAM, guanine and NT-proBNP is potential serum biomarkers for screening PAH-CHD from CHD.

Saffron essential oil ameliorates CUMS-induced depression-like behavior in mice via the MAPK-CREB1-BDNF signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Saffron, the dried stigma of Crocus sativus L., has a long history of use in the treatment of depression in traditional Chinese medicine and Islamic medicine. The unique aroma of saffron, primarily derived from its volatile oil, has been widely used by folk to mitigate anxiety and depression via sniffing because the aroma of saffron has a pleasant and invigorating effect. AIM OF THE STUDY: This study aimed to investigate the antidepressant effect and the underlying mechanism of saffron essential oil (SEO) in mice exposed to chronic unpredictable mild stress (CUMS). MATERIALS AND METHODS: In this study, compounds of SEO were identified using gas chromatography-mass spectrometry analysis, while network pharmacology was used to predict potential active compounds, antidepressant targets, and related signaling pathways of SEO. The CUMS depression model was further used to explore the therapeutic effect and possible mechanism of SEO. During the modeling period, mice were regularly administered fluoxetine (3.6 mg/kg, i.g.) or diluted SEO (2%, 4%, and 6% SEO, inhalation). The antidepressant and neuroprotective effects of SEO were evaluated by behavior tests (the open field test, the sucrose preference test, the tail suspension test, and the forced swimming test), hematoxylin-eosin staining, and Nissl staining. The enzyme-linked immunosorbent assay kits were used to measure dopamine (DA), 5-serotonin (5-HT), brain-derived neurotrophic factor (BDNF), and γ-aminobutyric acid (GABA) levels in serum. The relative abundance of Raf1, MEK1, P-ERK1/2/ERK1/2, P-CREB1/CREB1, BDNF, and P-Trk B/Trk B in the hippocampus was determined using western blot (WB). RESULTS: According to the network pharmacology analysis, seven active SEO compounds mediated 113 targets related to depression treatment, most of which were enriched in the 5-HT synapse, calcium signaling pathway, and cAMP signaling pathway. In vivo experiments indicated that fluoxetine and SEO improved depression-like behaviors in depressed mice. The levels of 5-HT, DA, BDNF, and GABA in serum increased significantly. Histopathological examinations revealed that fluoxetine and SEO ameliorated neuronal damage in the hippocampus. WB analysis showed that the relative expressions of Raf1, MEK1, P-ERK1/2/ERK1/2, P-CREB1/CREB1, BDNF, and P-Trk B/Trk B were significantly higher in the fluoxetine and SEO groups than in the CUMS group. CONCLUSION: Overall, these findings suggest that SEO significantly alleviates the depressive symptoms in CUMS exposed mice and partially restores hippocampal neuronal damage. Meanwhile, the best efficacy was observed in 4% SEO. Furthermore, the antidepressant mechanism of SEO is primarily dependent on the regulation of the MAPK-CREB1-BDNF signaling pathway.

Development and validation of a novel LC-MS/MS method for simultaneous quantitative determination of tyrosine kinase inhibitors in human plasma.

The objective of this study was to develop and validate a simple, rapid, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of three tyrosine kinase inhibitors (ceritinib, osimertinib, and crizotinib) in human plasma using a single-step protein precipitation extraction. Chromatographic separation was achieved using a Waters X Bridge C18 (2.1 mm × 100 mm, 3.5 µm) and gradient elution with 0.2 % formic acid in water and acetonitrile. The total run time was 4.0 min, and the injection volume was 5 µL. The analytes were detected in the multiple reaction monitoring mode using electrospray ionization with positive ion mode. The m/z transitions of ceritinib, osimertinib, crizotinib and nilotinib were 558.0 â†’ 433.2, 500.0 â†’ 72.1, 450.0 â†’ 259.3, and 530.0 â†’ 289.1, respectively. The method was linear in the range of 2-500 ng/mL with lower limit of quantification of 2 ng/mL. Based on the guidelines on bioanalytical methods by the FDA, the validation studies demonstrated that the three analytes were both precise and accurate at four concentration levels, and the coefficient of variation was < 10.59 % and accuracy was > 88.26 %. We present a simple, rapid, and sensitive method for the simultaneous quantification of ceritinib, osimertinib, and crizotinib in human plasma by LC-MS/MS, which could be used in routine therapeutic drug monitoring.

How to boost an obstetrician's confidence in vaginal delivery after high-intensity focused ultrasound: a comparison study on delivery outcomes.

OBJECTIVE: To assess the feasibility of vaginal delivery after HIFU. METHODS: A total of 37 women who met the trial of labor after HIFU (TOLAH) inclusion criteria and 368 women who met the trial of labor after cesarean delivery (TOLAC) inclusion criteria gave birth at Shanghai First Maternity and Infant Hospital between 14th June 2018 and 24th September 2021. The delivery outcomes of the two groups were compared. Multivariable logistic regression analysis was used to estimate the adjusted risk of postpartum hemorrhage (PPH). RESULTS: In the Qualified Candidates for TOLAH group, vaginal delivery is substantially less common (p = 0.000). The prevalence of PPH in the Qualified Candidates for TOLAH group is lower than in the Candidates for TOLAC group (8.82% vs 10.51%, p = 0.534; 0% vs 2.51%, p = 0.418). Hemoglobin drop in the Qualified Candidates for TOLAH group is also lower (7.03 ± 7.39vs 12.11 ± 12.62, p = 0.001). The rate of using more than two types of uterotonic medications to promote contraction is significantly lower in the Qualified Candidates for TOLAH group (54.05% vs 69.84%, p = 0.04), and the percentage of abnormal uterine contraction is lower in the Qualified Candidates for TOLAH group (35.14% vs 49.18%, p = 0.072). PPH is strongly predicted by abnormal uterine contraction (aOR: 17.177, 95% CI:5.046 ∼ 58.472, p = 0.000), but not by HIFU (aOR:1.105; 95% CI:0.240 ∼ 5.087, p = 0.898). No uterine rupture occurred in the cases after HIFU. CONCLUSIONS: No uterine rupture occurred in our study group after HIFU. HIFU is not a risk for PPH. It is promising for those after HIFU to choose vaginal delivery.

Study of Chemical Compositions and Anticancer Effects of Paris polyphylla var. Chinensis Leaves.

Paris polyphylla var. chinensis (Franch.) Hara is a perennial herb belonging to the Trilliaceae family. Ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) was used to detect the composition of different fractions of Paris polyphylla var. chinensis leaves. Meanwhile, the extracts of different fractions were evaluated for their cytotoxic activities against four selected human cancer cell lines and one human normal epithelial cell line based on the MTT assay method. Multivariate statistical analysis was performed to screen differential compounds and to analyze the distributions between different fractions. Finally, more than 60 compounds were obtained and identified from the different fractions of Paris polyphylla var. chinensis leaves, and the chloroform and n-butanol extracts showed significant cytotoxic effects on these four cancer cells. Several compounds were preliminarily identified from different fractions, including 36 steroidal saponins, 11 flavonoids, 10 ceramides, 8 lipids, 6 organic acids, and 8 other compounds. Various compounds were screened out as different chemical components of different fractions, which were considered as a potential substance basis for the cytotoxicity of Paris polyphylla var. chinensis leaves.

NMR-Based Metabolomics Analysis Predicts Response to Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most fatal type of breast cancer (BC). Due to the lack of relevant targeted drug therapy, in addition to surgery, chemotherapy is still the most common treatment option for TNBC. TNBC is heterogeneous, and different patients have an unusual sensitivity to chemotherapy. Only part of the patients will benefit from chemotherapy, so neoadjuvant chemotherapy (NAC) is controversial in the treatment of TNBC. Here, we performed an NMR spectroscopy-based metabolomics study to analyze the relationship between the patients' metabolic phenotypes and chemotherapy sensitivity in the serum samples. Metabolic phenotypes from patients with pathological partial response, pathological complete response, and pathological stable disease (pPR, pCR, and pSD) could be distinguished. Furthermore, we conducted metabolic pathway analysis based on identified significant metabolites and revealed significantly disturbed metabolic pathways closely associated with three groups of TNBC patients. We evaluated the discriminative ability of metabolites related to significantly disturbed metabolic pathways by using the multi-receiver-operating characteristic (ROC) curve analysis. Three significantly disturbed metabolic pathways of glycine, serine, and threonine metabolism, valine, leucine, and isoleucine biosynthesis, and alanine, aspartate, and glutamate metabolism could be used as potential predictive models to distinguish three types of TNBC patients. These results indicate that a metabolic phenotype could be used to predict whether a patient is suitable for NAC. Metabolomics research could provide data in support of metabolic phenotypes for personalized treatment of TNBC.

Effect of Drying Methods on Volatile Compounds of Burdock (Arctium lappa L.) Root Tea as Revealed by Gas Chromatography Mass Spectrometry-Based Metabolomics.

Burdock (Arctium lappa L.) is one of the nutritional foods widely planted in many countries. Dried burdock root (BR) is available as a herbal tincture and tea in many Asian countries with good flavor and taste. In this study, the volatile components in dried BR were identified and the effects of different drying methods on the volatile components were investigated by HS-GC-MS method. A total of 49 compounds were identified. Different drying methods including hot-air drying (HD, at 50, 60, 70, and 80 °C), vacuum drying (VD, at 50, 60, 70, and 80 °C), sunlight drying (SD), natural drying (ND), and vacuum freeze drying (VFD) were evaluated by HS-GC-MS-based metabolomics method. Results showed that different drying methods produced different effects on the volatile compounds. It was observed that 2,3-pentanedione, 1-(1H-pyrrol-2-yl)-ethanone, furfural, and heptanal were detected at higher concentrations in HD 80 and VD 70. The traditional HD and SD methods produced more flavor substances than VFD. The BR treated by the VFD method could maintain the shape of the fresh BR pieces while HD50 and VD80 methods could maintain the color of fresh BR pieces. These findings could help better understand the flavor of the corresponding processed BR and provide a guide for the drying and processing of BR tea.

Design, synthesis and biological evaluation of potential anti-AD hybrids with monoamine oxidase B inhibitory and iron-chelating effects.

A series of active hybrids combining 3-hydroxypyridin-4(1H)-one and coumarin pharmacophores were designed and synthesized as potential agents for the treatment of Alzheimer's disease (AD). All the compounds exhibited excellent iron-chelating activities (pFe3+ = 14.8-19.2) and showed favorable monoamine oxidase B (MAO-B) inhibitory effects compared to the reference drug Pargyline (IC50 = 86.9 nM). Among them, compound 11 g displayed the best MAO-B inhibitory activity with an IC50 value of 99.3 nM. Molecular docking analysis showed that compound 11 g could enter the entrance cavity and substrate cavity of MAO-B. Furthermore, the compound 11 g had an excellent antioxidant effect and was capable of protecting from the amyloid-ß1-42 (Aß1-42) induced PC12 cell damage. In silico tools were applied for predicting the blood-brain barrier (BBB) penetration and compound 11 g was proved to overcome the brain exposure challenge. In the mice behavioral study, compound 11 g significantly ameliorated cognitive impairment induced by Scopolamine. More importantly, compound 11 g displayed favorable pharmacokinetic profiles in a rat model. In summary, compound 11 g, with both anti-MAO-B and iron-chelating ability, was proved to be a promising potential anti-AD agent for further optimization.

Rational design, synthesis and biological evaluation of novel multitargeting anti-AD iron chelators with potent MAO-B inhibitory and antioxidant activity.

A series of (3-hydroxypyridin-4-one)-coumarin hybrids were developed and investigated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through the incorporation of iron-chelating and monoamine oxidase B (MAO-B) inhibition. This combination endowed the hybrids with good capacity to inhibit MAO-B as well as excellent iron-chelating effects. The pFe3+ values of the compounds were ranging from 16.91 to 20.16, comparable to more potent than the reference drug deferiprone (DFP). Among them, compound 18d exhibited the most promising activity against MAO-B, with an IC50 value of 87.9 nM. Moreover, compound 18d exerted favorable antioxidant activity, significantly reversed the amyloid-ß1-42 (Aß1-42) induced PC12 cell damage. More importantly, 18d remarkably ameliorated the cognitive dysfunction in a scopolamine-induced mice AD model. In brief, a series of hybrids with potential anti-AD effect were successfully obtained, indicating that the design of iron chelators with MAO-B inhibitory and antioxidant activities is an attractive strategy against AD progression.

Four cypermethrin isomers induced stereoselective metabolism in H295R cells.

Cypermethrin (CP) is widely used for controlling agricultural and indoor vermin. Previous studies have reported the stereoselective difference of CP in biological activities. However, little is known about their potential mechanisms between metabolic phenotypes and endocrine-disrupting effects. Herein, nuclear magnetic resonance (NMR)-based metabolomics combining metabolite identification and pathway analysis were applied to evaluate the stereoselective metabolic cdisorders induced by CP isomers in human adrenocortical carcinoma cells (H295R) culture medium. Then, gene expression levels related to disturbed metabolic pathways were assessed to verify according to metabolic phenotypes. Metabolomics profiles showed that [(S)-cyano(3-phenoxyphenyl)methyl](1R,3R)-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate [(1R,3R,αS)-CP] induced the most significant changes in metabolic phenotypes than did the other stereoisomers. There are 10 differential metabolites (isoleucine, valine, leucine, ethanol, alanine, acetate, aspartate, arginine, lactate, and glucose) as well as two significantly disturbed pathways, including "pyruvate metabolism" and "alanine, aspartate, and glutamate metabolism," that were confirmed in H295R cells culture medium of (1R,3R,αS)-CP compared with other stereoisomers. Polymerase chain reaction (PCR) array also confirmed the results of metabolomics. Our results can help to understand the potential mechanisms between the isomer selectivity in metabolic phenotypes and endocrine-disrupting effects. Data provided here not only lend authenticity to the cautions issued by the scientists and researchers but also offer a solution for the balance between environment and political regulations.

Nuclear magnetic resonance-based tissue metabolomic analysis clarifies molecular mechanisms of gastric carcinogenesis.

Gastric cancer (GC) is one of the deadliest cancers worldwide, and the progression of gastric carcinogenesis (GCG) covers multiple complicated pathological stages. Molecular mechanisms of GCG are still unclear. Here, we undertook NMR-based metabolomic analysis of aqueous metabolites extracted from gastric tissues in an established rat model of GCG. We showed that the metabolic profiles were clearly distinguished among 5 histologically classified groups: control, gastritis, low-grade gastric dysplasia, high-grade gastric dysplasia (HGD), and GC. Furthermore, we carried out metabolic pathway analysis based on identified significant metabolites and revealed significantly disturbed metabolic pathways closely associated with the 4 pathological stages, including oxidation stress, choline phosphorylation, amino acid metabolism, Krebs cycle, and glycolysis. Three metabolic pathways were continually disturbed during the progression of GCG, including taurine and hypotaurine metabolism, glutamine and glutamate metabolism, alanine, aspartate, and glutamate metabolism. Both the Krebs cycle and glycine, serine, and threonine metabolism were profoundly impaired in both the HGD and GC stages, potentially due to abnormal energy supply for tumor cell proliferation and growth. Furthermore, valine, leucine, and isoleucine biosynthesis and glycolysis were significantly disturbed in the GC stage for higher energy requirement of the rapid growth of tumor cells. Additionally, we identified potential gastric tissue biomarkers for metabolically discriminating the 4 pathological stages, which also showed good discriminant capabilities for their serum counterparts. This work sheds light on the molecular mechanisms of GCG and is of benefit to the exploration of potential biomarkers for clinically diagnosing and monitoring the progression of GCG.

Design, synthesis and biological evaluation of hydroxypyridinone-coumarin hybrids as multimodal monoamine oxidase B inhibitors and iron chelates against Alzheimer's disease.

A series of hybrids of hydroxypyridinone and coumarin were rationally designed, synthesized and biologically evaluated for their iron ion chelating and MAO-B inhibitory activities. Most of the compounds displayed excellent iron ion chelating effects and moderate to good anti-MAO-B activities. Compound 27a exhibited the most potent activity against MAO-B, with an IC50 value of 14.7 nM. Importantly, 27a showed good U251 cell protective effect and significantly ameliorated the cognitive dysfunction of scopolamine-induced AD mice. Moreover, molecular docking was performed to elucidate the probable ligand-receptor interaction, and the structure-activity relationships were also summarized.

Analysis of metabolome changes in the HepG2 cells of apatinib treatment by using the NMR-based metabolomics.

Neovascularization is required for the growth of tumors, vascular endothelial growth factor (VEGF) and related signal pathways are important in tumor angiogenesis. Apatinib is a highly selective and potent antiangiogenesis drug targeting the receptor of VEGFR2, blocking downstream signal transduction and inhibiting angiogenesis of tumor tissue. Apatinib has a wide range of antitumor activities in vitro and in vivo, but its effect on metabolic changes has not deeply research at present. Nowadays, our research first systematically studied the metabolic changes affected by apatinib in the HepG2 cells at the half-maximal inhibitory concentration value. We used the metabolomics by using 1 H nuclear magnetic resonance (1 H-NMR) to analyze the HepG2 cell culture media. Multivariable Statistics was applied to analyze the 1 H-NMR spectra of the cell media, including principal component analysis, partial least squares discriminant analysis (PLS-DA) and orthogonal PLS-DA (OPLS-DA). Compared with the uncultured and cultured media (negative/positive control), the metabolic phenotypes were changed in the apatinib treatment with a continuous effect over time. The metabolic pathway analysis is shown that the mainly disturbed metabolic pathways pyruvate metabolism, alanine, aspartate, and glutamate metabolism and amino acid metabolism associated with them in the apatinib treatment. The differential metabolites which were identified from the reconstructed OPLS-DA loading plots also reflected in these disturbed metabolic pathways. Our works could allow us to well understand the therapeutic effect of apatinib, especially in metabolism.

Metabolomics Analysis in Serum from Patients with Colorectal Polyp and Colorectal Cancer by 1H-NMR Spectrometry.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Colorectal adenomatous polyps are at high risk for the development of CRC. In this report, we described the metabolic changes in the sera from patients with colorectal polyps and CRC by using the NMR-based metabolomics. 110 serum samples were collected from patients and healthy controls, including 40 CRC patients, 32 colorectal polyp patients, and 38 healthy controls. The metabolic profiles and differential metabolites of sera were analyzed by multivariate statistical analysis (MSA), including principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA) methods. A total of 23 differential metabolites were identified from MSA. According to the pathway analysis and multivariate ROC curve-based exploratory analysis by using the relative concentrations of differential metabolites, we found abnormal metabolic pathways and potential biomarkers involved with the colorectal polyp and CRC. The results showed that the pyruvate metabolism and glycerolipid metabolism were activated in colorectal polyps. And the glycolysis and glycine, serine, and threonine metabolism were activated in CRC. The changed metabolism may promote cellular proliferation. In addition, we found that the rates of acetate/glycerol and lactate/citrate could be the potential biomarkers in colorectal polyp and CRC, respectively. The application of 1H-NMR metabolomics analysis in serum has interesting potential as a new detection and diagnostic tool for early diagnosis of CRC.

Metabolomic modulations of HepG2 cells exposed to bisphenol analogues.

Bisphenol analogues including bisphenol A (BPA), bisphenol AF (BPAF), bisphenol F (BPF), and bisphenol S (BPS) share similar chemical structures and endocrine disrupting effects. Their effects on metabolisms, however, are so far only marginally understood. In this study, NMR-based metabonomic profiles of HepG2 cell culture media and PCR array were used to assess the metabolomics disturbances and gene expression levels of HepG2 in response to four BPs (BPA, BPAF, BPF, and BPS). The results indicated that BP analogues resulted in disturbances in 7-15 metabolites that were classified as amino acid (alanine, glutamine, glutamate), intermediates and end-products in the glycolysis (pyruvate) and the tricarboxylic acid cycle (acetate, lactate). Their rank in order according to the number of metabolites and pathways was BPF > BPA > BPAF > BPS. The common disrupted pathways (pyruvate metabolism; alanine, aspartate, and glutamate metabolism) indicated enhanced glycolysis. The following glucometabolic PCR array analysis suggested that although four BPs shared the capability of disrupting glucose metabolism, they may act through different mechanisms: BPAF has increased the pyruvate kinase (PKLR) expression level, which implied enhanced glycolysis that was agreed with NMR results. The other three BP analogues, however, decreased the expression level of glucokinase (GCK) that indicated glucose sensing impairment. Our results demonstrated the potential for using metabolomic and PCR array to understand the underlying action of mechanisms and identify the potential targets for future targeted risk assessment.