Taste traces: Capsaicin and sweeteners as anthropogenic markers in municipal wastewater.

Dietary-derived substances possess significant potential as anthropogenic markers owing to the large consumption and different intake habit. To investigate and evaluate such markers, wastewater samples from 35 wastewater treatment plants across 29 Chinese cities were collected to analyze artificial sweeteners (acesulfame and cyclamate) and natural spicy compounds (capsaicin and dihydrocapsaicin). Acesulfame (mean: 14.6 µg/L), cyclamate (mean: 24.3 µg/L), and capsaicin (mean: 101 ng/L) can be further investigated as anthropogenic markers due to their high detection frequency at high concentrations. Spatial use patterns revealed that acesulfame (5.31 g/d/1000 inhabitants (inh)) and cyclamate (8.16 g/d/1000 inh) use in northern China notably surpassed that in southern China (1.79 g/d/1000 inh and 3.23 g/d/1000 inh, p < 0.05). Conversely, chili pepper use was significantly higher (p < 0.05) in southern China (6702 g/d/1000 inh) than in northern China (2751 g/d/1000 inh), signifying a preference for sweetness in the northern regions and a predilection for spiciness in the southern regions. The total annual use of acesulfame (1842 t), cyclamate (3110 t), and chili (18.4 million tonnes) in China was estimated by this study, which was close to the national statistical production. In addition, sweetener use was negatively associated with the elderly population ratio, suggesting that the elderly population might not consume sweet foods. This study reveals the dietary sources of anthropogenic markers, highlighting the need for further research on the environmental implications of such markers.

Surveillance of COVID-19 and influenza A(H1N1) prevalence in China via medicine-based wastewater biomarkers.

The simultaneous monitoring of individual or multiple diseases can be achieved by selecting therapeutic medicines used to treat the primary symptoms of the condition as biomarkers in wastewater. This study proposes a novel approach to monitor the prevalence of COVID-19 and influenza A (H1N1) by selecting nine medicines to serve as biomarkers, including three antipyretics, three antivirals, and three cough suppressants. To verify our approach, wastewater samples were collected from seventeen urban and five rural wastewater treatment plants (WWTPs) in a Chinese city over a period of one year. The use of antipyretics increased notably during the COVID-19 pandemic, while the consumption of antivirals for influenza A (H1N1) rose in the post-COVID-19 pandemic period, indicating a minor spike in the occurrence of influenza A (H1N1) after the COVID-19 pandemic. Fever is a significant symptom of COVID-19 and can serve as a reliable indicator of disease prevalence. Our research found that the prevalence of COVID-19 in urban areas was significantly higher (at 78.5 %, 95 % CI: 73.4 % - 83.9 %) than in rural areas (with a prevalence of 48.1 %, 95 % CI: 42.4 % - 53.8 %). The prevalence of COVID-19 in urban areas in this study was consistent with the data reported by the Chinese center for Disease Control and Prevention (82.4 %). Continuous monitoring of WWTPs in urban areas with fluctuating populations and complex demographics can provide early disease warning. Our results demonstrate the feasibility of evaluating community disease prevalence by selecting major therapeutic medicines as biomarkers in wastewater.

M4IDP stimulates ROS elevation through inhibition of mevalonate pathway and pentose phosphate pathway to inhibit colon cancer cells.

Maintaining redox homeostasis is an essential feature of cancer cells, and disrupting this homeostasis to cause oxidative stress and induce cell death is an important strategy in cancer therapy. M4IDP, a zoledronic acid derivative, can cause the death of human colorectal cancer cells by increasing the level of intracellular reactive oxygen species (ROS). However, its potential molecular mechanism is unclear. Our in vitro studies showed that treatment with M4IDP promoted oxidative stress in HCT116 cells, as measured by the decreased ratios of GSH/GSSG and NADPH/NADP+ and increased level of MDA. M4IDP could cause the decrease of GSH content, the increase of GSSG content, the decrease of NADPH content and pentose phosphate pathway flux, the downregulation of G6PD expression, the upregulation of unprenylated Rap1A and total expression of RhoA and CDC42. The increase of ROS and cytotoxicity induced by M4IDP could be reversed by the supplementation of NADPH, the overexpression of G6PD and the supplementation of GGOH. In vivo studies showed that M4IDP inhibited tumor growth in the human colorectal cancer xenograft mouse model, which was accompanied with a decreased [18F]FDG uptake. Collectively, these results provide evidence that M4IDP can promote oxidation in colon cancer cells by inhibiting mevalonate pathway and pentose phosphate pathway and produce therapeutic effect. This study revealed for the first time a possible mechanism of bisphosphonate-induced increase of ROS in malignant tumor cells. This is helpful for the development of new molecular therapeutic targets and can provide new ideas for the combined therapy of bisphosphonates in tumors.

Evaluation of eight psychoactive drugs used in Chinese cities by wastewater-based epidemiology.

With rapid economic development, an increasing number of people suffer from mental health diseases, which are gradually receiving the attention of society. However, basic data from surveys of mental disorders are limited. Composite influent samples were collected from 26 wastewater treatment plants in 23 major cities in China. The concentrations of the psychoactive drugs diphenhydramine, fluoxetine, doxepin, imipramine, sulpiride, zolpidem, carbamazepine, and flunitrazepam in the wastewater were determined. The detection frequency of diphenhydramine, sulpiride, and carbamazepine was close to 100 %, whereas that of the compounds was lower than 35 %. Carbamazepine had the highest mean consumption (31.1 mg/d/1000 people), followed by diphenhydramine (10.4 mg/d/1000 people) and sulpiride (11.3 mg/d/1000 people). Wastewater-based epidemiology (WBE) estimates of the average use of the three drugs were lower than those from the drug statistics data. Consumption of diphenhydramine in northern China was higher than that in southern China. A correlation analysis of psychotropic and illicit drugs revealed a correlation between sulpiride and heroin use, which may be related to the adverse effects of sulpiride treatment after heroin withdrawal. Psychotropic drug use is associated with both economic and social factors. We found associations between the use of the three drugs and age, occupation, and obesity, which are risk factors for mental disorders. The results showed that the monitoring of psychotropic drug using WBE has a certain reference value for public health care and for improving the understanding of mental disorders.

Assessment of correlations between sildenafil use and comorbidities and lifestyle factors using wastewater-based epidemiology.

Sildenafil (SIL) is widely used to treat erectile dysfunction. Information on its consumption and the factors influencing its use is limited in China. In this study, we sampled composite influent wastewater samples from 33 Chinese cities and analyzed SIL using liquid chromatography-tandem mass spectrometry. SIL consumption was estimated using wastewater-based epidemiology (WBE) and ranged from 10.6 mg/d/1000 people to 132 mg/d/1000 people, with a mean of 53 mg/d/1000 people. Prescription sales (3570 kg) accounted for 13.3% of the estimated SIL use (26842 kg) in 2018, thereby implying that SIL illicit use was greater than prescription use in China. Some regional differences were observed in SIL use, which was significantly higher in North China than South China (p < 0.05), thereby reflecting that the prevalence of SIL was affected by differences in lifestyle and socioeconomic factors. We found significant positive correlations between SIL use and consumption of allopurinol, hydrochlorothiazide, nicotine, and alcohol, thereby suggesting that the prevalence of SIL was associated with the prevalence of gout, hypertension, smoking, and drinking. Moreover, age structures, internet use, and marriage rates were positively correlated with SIL use, whereas the unemployment rate was negatively correlated with SIL use. Our study demonstrates that WBE is valuable for medical research to investigate licit and illicit drug use and to assess the underlying associations of different chemical uses.

Presence of the ketamine analog of 2-fluorodeschloroketamine residues in wastewater.

Ketamine (KET) analogs are increasingly emerging as new psychoactive substances (NPS). The present report describes the first detection of the KET analog, 2-fluorodeschloroketamine (2F-DCK), in influent samples collected from nine wastewater treatment plants in seven major Chinese cities from 2018 to 2020 by wastewater-based epidemiology (WBE). An analytical method based on solid-phase extraction and subsequent gas chromatography-mass spectrometry was developed for the detection of 2F-DCK and KET. The stability experiments showed that 2F-DCK and KET remained stable in wastewater for 15 days at room and frozen temperatures, and at two pH values (pH = 7 and pH = 2), with residue amounts between 90% and 110%. KET was detected in all samples, whereas 2F-DCK was detected in only four samples: from Guangzhou in 2018, Shenzhen in 2019, and Quanzhou and Nanning in 2020, indicating that 2F-DCK has been used as early as 2018 in China. The renal clearance of 2F-DCK was predicted based on the quantitative structure-pharmacokinetic relationship model, which was used to calculate an excretion factor of 3.7. The 2F-DCK consumption in four cities ranged from 3.71 ± 0.05 to 55 ± 0.09 mg/day/1000 inh, and KET ranged from 1.3 ± 0.04 to 76.5 ± 4.63 mg/day/1000 inh. This is the first study to investigate 2F-DCK by WBE, which provides relevant real-time data on the growth of NPS use, as well as useful information for the government to develop new policies.

[Mechanism of Xuefu Zhuyu Decoction in treatment of myocardial infarction based on network pharmacology and molecular docking].

To explore the action mechanism of Xuefu Zhuyu Decoction in treating myocardial infarction based on network pharmaco-logy and molecular docking. Active components and corresponding targets of Xuefu Zhuyu Decoction were obtained through Traditional Chinese Medicine Systems Pharmacology Database(TCMSP), and related targets of myocardial infarction were obtained through GeneCards, DisGeNET, and OMIM databases. Then the intersection targets were obtained by integrating the drug targets and disease targets. The "active component-target" network was constructed by Cytoscape software, and protein-protein interaction(PPI) network was drawn using STRING platform. Protein cluster analysis was carried out using MCODE. GO enrichment analysis and KEGG pathway analysis were carried out using DAVID database and ClueGO, and molecular docking was carried out using Autodock Vina and Pymol. Finally, 226 active components of Xuefu Zhuyu Decoction were obtained, 257 corresponding targets, 1 340 targets of myocardial infarction, and 109 drug and disease intersection targets were obtained. From GO enrichment analysis, 208 biological process terms, 38 molecular function terms, and 33 cellular component terms were obtained. From KEGG pathway analysis, NF-κB signaling pathway, IL-17 signaling pathway, HIF-1 signaling pathway, and other related pathways were obtained. The molecular docking results showed that the main active components(quercetin, kaempferol, ß-sitosterol, luteolin, stigmasterol and baicalein) of Xuefu Zhuyu Decoction in the treatment of myocardial infarction had good binding properties with the core proteins IL6, ALB, VEGFA, TNF, MAPK3 and CASP3. The results suggested that Xuefu Zhuyu Decoction may play a role in the treatment of myocardial infarction by reducing the inflammatory response, reducing oxidative stress, inhibiting cell apoptosis, and promoting angiogenesis.

Curcumin Recovers Intracellular Lipid Droplet Formation Through Increasing Perilipin 5 Gene Expression in Activated Hepatic Stellate Cells In Vitro.

The activation of hepatic stellate cells (HSCs) is a major event during hepatic fibrogenesis. Restoration of intracellular lipid droplet (LD) formation turns the activated HSC back to a quiescent state. Our previous studies have shown that curcumin suppresses HSC activation through increasing peroxisome proliferator-activated receptor, gamma (PPARγ) and 5' adenosine monophosphate-activated protein kinase (AMPK) activities. This study aims at evaluating the effect of curcumin on lipid accumulation in HSCs and hepatocytes, and further elucidating the underlying mechanisms. Now we showed that curcumin increased LD formation in activated HSCs and stimulated the expression of sterol regulatory element-binding protein and fatty acid synthase, and reduced the expression of adipose triglyceride lipase. Exogenous perilin5 expression in primary HSCs promoted LD formation. Perilipin 5 siRNA eliminated curcumin-induced LD formation in HSCs. These results suggest that curcumin recovers LD formation and lipid accumulation in activated HSCs by increasing perilipin 5 gene expression. Furthermore, inhibition of AMPK or PPARγ activity blocked curcumin's effect on Plin5 gene expression and LD formation. Our results provide a novel evidence in vitro for curcumin as a safe, effective candidate to treat liver fibrosis.

High transport and excellent optical property of a two-dimensional single-layered hybrid perovskite (C4H9NH3)2PbBr4: a theoretical study.

Organic-inorganic hybrid perovskites are developed to pursue high charge carrier mobility and light absorption coefficient. In this study, we present a detailed comparative research of the atomic and electronic structures of single-layered perovskites (C4H9NH3)2PbBr4 with two-dimensional/three-dimensional (2D/3D) spatial arrangement to predict the in plane charge carrier mobility along with the charge effective mass, elastic constant, and deformation potential. The calculated results reveal that the intrinsic in plane carrier mobilities of 2D single-layered hybrid perovskite (C4H9NH3)2PbBr4 along the 100 and 010 directions are superior to those of the 3D structure. Furthermore, the optical properties are calculated from the electronic structure; it is found that the light absorption spectrum of 2D single-layered perovskite (C4H9NH3)2PbBr4 with a high absorption coefficient is wider than that of the 3D phase. We speculate that the superior mobility and wider absorption spectrum of the 2D mono-layered perovskite are due to high charge density and ferroelectricity originating from structure distortion upon 3D-to-2D structure transformation. These results indicate that the 2D single-layered hybrid perovskite (C4H9NH3)2PbBr4 is a potential candidate for application in the optoelectronic and photovoltaic fields.

3D-QSAR, molecular docking, and ONIOM studies on the structure-activity relationships and action mechanism of nitrogen-containing bisphosphonates.

Nitrogen-containing bisphosphonates (N-BPs) have been used widely to treat various bone diseases by inhibiting the key enzyme farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway. Understanding the structure-activity relationships and the action mechanisms of these bisphosphonates is instructive for the design and the development of novel potent inhibitors. Here, a series of N-BPs inhibitors of human FPPS (hFPPS) were investigated using a combination of three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, and three-layer ONIOM studies. The constructed 3D-QSAR model yielded a good correlation between the predicted and experimental activities. Based on the analysis of comparative molecular field analysis (CoMFA) contour maps, a series of novel N-BPs inhibitors were designed and ten novel potent N-BPs inhibitor candidates were screened out. Molecular docking and ONIOM (B3LYP/6-31 + G*:PM6:Amber) calculations revealed that the inhibitors bound to the active site of hFPPS via hydrogen-bonding interactions, hydrophobic interactions, and cation-π interactions. Six novel N-BPs inhibitors with better biological activities and higher lipophilicity were further screened out from ten candidates based on the calculated interaction energy. This study will facilitate the discovery of novel N-BPs inhibitors with higher activity and selectivity.

Estimating nicotine consumption in eight cities using sewage epidemiology based on ammonia nitrogen equivalent population.

Sewage epidemiology is a real-time tool used to monitor tobacco consumption. In this study, we investigated the tobacco consumption in eight cities in Jilin province using sewage epidemiology. We collected influent wastewater samples from ten wastewater treatment plants (WWTPs) that serve nearly four million people. Mean nicotine (NIC) loads ranged from 1.42 to 14.2mg/d/capita, whereas mean cotinine (COT) loads showed lower levels with 0.33 to 2.15mg/d/capita. Population size was estimated to provide an accurate and real-time population based on ammonia nitrogen (NH4-N) concentration in influent. To verify the NH4-N equivalent population, we compared these results with the corresponding population estimated based on the expert knowledge of the local WWTPs operators. Daily consumption of NIC was estimated to be approximately 2.39±1.47mg/d/capita. Monte Carlo simulation was used to analyze uncertainty and variability in the number of cigarettes consumed by smokers in the range of 9.8 to 31.4 per day with a median of 16.9. The data of tobacco consumption in this study coordinated strongly with a traditional survey on the consumption of tobacco in China, indicating sewage epidemiology with NH4-N equivalent population estimation may provide a suitable and useful tool for tobacco use monitoring.

Enantiomers of tetrahedral metal-organic cages: a new class of highly efficient G-quadruplex ligands with potential anticancer activities.

Four pairs of enantiomers of water-stable tetrahedral metal-organic cages [Ni4L6](8+) were facilely synthesized. They efficiently stabilized antiparallel G-quadruplex DNA with moderate enantioselectivity, and displayed promising cytotoxicity against the human cancer cell lines HCT116, HepG2 and MCF-7. These results provide a new insight into the rational design of chiral G-quadruplex-based anticancer agents.

Copper ions stimulate the proliferation of hepatic stellate cells via oxygen stress in vitro.

This study examined the effect of copper ions on the proliferation of hepatic stellate cells (HSCs) and the role of oxidative stress in this process in order to gain insight into the mechanism of hepatic fibrosis in Wilson's disease. LX-2 cells, a cell line of human HSCs, were cultured in vitro and treated with different agents including copper sulfate, N-acetyl cysteine (NAC) and buthionine sulfoximine (BSO) for different time. The proliferation of LX-2 cells was measured by non-radioactive cell proliferation assay. Real-time PCR and Western blotting were used to detect the mRNA and protein expression of platelet-derived growth factor receptor ß subunit (PDGFßR), ELISA to determine the level of glutathione (GSH) and oxidized glutathione (GSSG), dichlorofluorescein assay to measure the level of reactive oxygen species (ROS), and lipid hydroperoxide assay to quantify the level of lipid peroxide (LPO). The results showed that copper sulfate over a certain concentration range could promote the proliferation of LX-2 cells in a time- and dose-dependent manner. The effect was most manifest when LX-2 cells were treated with copper sulfate at a concentration of 100 µmol/L for 24 h. Additionally, copper sulfate could dose-dependently increase the levels of ROS and LPO, and decrease the ratio of GSH/GSSG in LX-2 cells. The copper-induced increase in mRNA and protein expression of PDGFßR was significantly inhibited in LX-2 cells pre-treated with NAC, a precursor of GSH, and this phenomenon could be reversed by the intervention of BSO, an inhibitor of NAC. It was concluded that copper ions may directly stimulate the proliferation of HSCs via oxidative stress. Anti-oxidative stress therapies may help suppress the copper-induced activation and proliferation of HSCs.

Poly[[diaqua-(1,10-phenanthroline-κN,N')(µ(3)-4-sulfonato-benzene-1,2-dicarboxyl-ato-κO:O,O:O)dysprosium(III)] dihydrate].

The 4-sulfophthalate trianion in the polymeric title complex, {[Dy(C(8)H(3)O(7)S)(C(12)H(8)N(2))(H(2)O)(2)]·2H(2)O}(n), bridges three water/phenanthroline-coordinated Dy(III) atoms to form a three-dimensional network architecture. The metal atom is further chelated by a carboxyl-ate group and is covalently bonded to a monodentate carboxyl-ate group and to a monodentate sulfonate group in a distorted square-anti-prismatic geometry. The coordinating and the solvent water mol-ecules are hydrogen bonded to the network. In the crystal, one solvent water mol-ecule is disordered over two positions [major component = 59 (3)%].

Poly[[diaqua-(1,10-phenanthroline-κN,N')(µ(3)-4-sulfonato-benzene-1,2-di-car-boxyl-ato-κO:O,O:O)erbium(III)] dihydrate].

The 4-sulfophthalate trianion in the polymeric complex, {[Er(C(8)H(3)O(7)S)(C(12)H(8)N(2))(H(2)O)(2)]·2H(2)O}(n), bridges three water/phenanthroline-coordinated Er(III) ions to form a three-dimensional network architecture. The metal atom is further chelated by a carboxyl-ate group and is covalently bonded to a monodentate carboxyl-ate group as well as to a monodentate sulfonate group in a distorted square anti-prismatic geometry. The coordinating water molecules and the lattice water molecules, one of which is disordered over two positions [major component 65 (3)%], are hydrogen bonded to the network.

1-Carboxy-methyl-2-ethyl-4-methyl-1H-imidazol-3-ium chloride monohydrate.

In the title compound, C(8)H(13)N(2)O(2) (+)·Cl(-)·H(2)O, the methyl C atom of the ethyl group is slightly out of the imidazole plane, with an N-C(ring)-C-C torsion angle of -15.1 (2)°. In the crystal structure, there are strong inter-molecular hydrogen-bonding inter-actions between the solvent water mol-ecule, the free chloride anion and the organic cation, resulting in a two-dimensional supra-molecular network in the ab plane.

trans,trans,trans-Diaquabis(nicotinamide-κN)bis-(2-nitro-benzoato-κO)cadmium(II) dihydrate.

The cadmium atom in the title compound, [Cd(C(7)H(4)NO(4))(2)(C(6)H(6)N(2)O)(2)(H(2)O)(2)]·2H(2)O, lies on a center of inversion in an all-trans octa-hedral environment. In the crystal, the complex inter-acts with the uncoordinated water mol-ecules through O-H⋯O and N-H⋯O hydrogen bonds, forming a layered network.

Ligand-to-metal ratio controlled assembly of nanoporous metal-organic frameworks.

Two bilayered metal-organic frameworks with nanoporous channels were synthesized at different ligand-to-metal ratios, which demonstrated an interesting crystal-to-crystal transformation property and a special fluorescent response to the different guest molecules included.

(2S,3S)-3-(4-Chloro-phen-yl)-8-methyl-tropane-2-carboxylic acid.

In the title compound, C(15)H(18)ClNO(2), the inter-nal torsion angles of the tropane ring are comparable to those of tropane rings in the crystal structures reported for cocaine and its derivatives. There is an intra-molecular hydrogen bond between the N atom in the tropane ring and the O atom of the carboxyl group. The crystal structure is further stabilized by many weak C-H⋯O inter-actions between the mol-ecules in the ab plane, forming a two-dimensional supra-molecular network.

2-(1-Methyl-ethoxy)-5-nitro-phenyl N-methyl-carbamate.

In the title compound, C(11)H(14)N(2)O(5), the nitro group is approximately coplanar with the benzene ring, making a dihedral angle of 4.26 (17)°. The dihedral angle between the methyl-carbamate group and the benzene ring is 72.47 (6)°. There is a strong inter-molecular N-H⋯O hydrogen bond between the N and O atoms from adjacent methyl-carbamate groups, forming a one-dimensional network along the a axis.