Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses.

Major depressive disorder, a prevalent and severe psychiatric condition, necessitates development of new and fast-acting antidepressants. Genetic suppression of astrocytic inwardly rectifying potassium channel 4.1 (Kir4.1) in the lateral habenula ameliorates depression-like phenotypes in mice. However, Kir4.1 remains an elusive drug target for depression. Here, we discovered a series of Kir4.1 inhibitors through high-throughput screening. Lys05, the most potent one thus far, effectively suppressed native Kir4.1 channels while displaying high selectivity against established targets for rapid-onset antidepressants. Cryogenic-electron microscopy structures combined with electrophysiological characterizations revealed Lys05 directly binds in the central cavity of Kir4.1. Notably, a single dose of Lys05 reversed the Kir4.1-driven depression-like phenotype and exerted rapid-onset (as early as 1 hour) antidepressant actions in multiple canonical depression rodent models with efficacy comparable to that of (S)-ketamine. Overall, we provided a proof of concept that Kir4.1 is a promising target for rapid-onset antidepressant effects.

The collaborative monitored natural attenuation (CMNA) of soil and groundwater pollution in large petrochemical enterprises: A case study.

A large in-service petrochemical enterprises in Northeast China was taken as the research object, and the Collaborative Monitored Natural Attenuation (CMNA) for soil and groundwater pollution was carried out to remedy combined pollution and reduce environmental risks. The pollutants distributions were obtained based on detailed regional investigation (Mar. 2019), and feature pollutants in soil and groundwater were then screened. The spatiotemporal variations of feature pollutants and relative microbial responses were explored during the CMNA process. Furthermore, the CMNA efficiency of the contaminated site at initial stage was evaluated by calculation of natural attenuation rate constant. The results showed that the feature pollutants in soil were 2,2',5,5'-tetrachlorobiphenyl (2,2',5,5'-TCB) and petroleum hydrocarbons (C10∼C40), and the feature pollutant in groundwater was 1,2-dichloroethane (1,2-DCA). The concentrations of all feature pollutants decreased continuously during four years of monitoring. Feature pollutants played a dominant role in the variability of microbial species both in soil and groundwater, increasing the relative abundance of petroleum tolerant/biodegradation bacteria, such as Actinobacteria, Proteobacteria and Acidobacteriota. The average natural attenuation rate constant of 2,2',5,5'-TCB and C10∼C40 in soil was 0.0012 d-1 and 0.0010 d-1, respectively, meeting the screening value after four years' attenuation. The average natural attenuation rate constant of 1,2-DCA was 0.0004 d-1, which need strengthening measures to improve the attenuation efficiency.

Diet Control and Swimming Exercise Ameliorate HFD-Induced Cognitive Impairment Related to the SIRT1-NF-κB/PGC-1α Pathways in ApoE-/- Mice.

High-fat diet- (HFD-) induced neuroinflammation may ultimately lead to an increased risk of cognitive impairment. Here, we evaluate the effects of diet control and swimming or both on the prevention of cognitive impairment by enhancing SIRT1 activity. Twenty-week-old ApoE-/- mice were fed a HFD for 8 weeks and then were treated with diet control and/or swimming for 8 weeks. Cognitive function was assessed using the novel object recognition test (NORT) and Y-maze test. The expression of sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), brain-derived neurotrophic factor (BDNF), nuclear factor kappa B p65 (NF-κB p65), interleukin-1ß (IL-1ß), and tumour necrosis factor-α (TNF-α) in the hippocampus was measured by western blotting. The levels of fractional anisotropy (FA), N-acetylaspartate (NAA)/creatine (Cr) ratio, choline (Cho)/Cr ratio, and myo-inositol (MI)/Cr ratio in the hippocampus were evaluated by diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) using 7.0-T magnetic resonance imaging (MRI). Our results showed that cognitive dysfunction and hippocampal neuroinflammation appeared to be remarkably observed in apolipoprotein E (ApoE)-/- mice fed with HFD. Diet control plus swimming significantly reversed HFD-induced cognitive decline, reduced the time spent exploring the novel object, and ameliorated spontaneous alternation in the Y-maze test. Compared with the HFD group, ApoE-/- mice fed diet control and/or subjected to swimming had an increase in FA, NAA/Cr, and Cho/Cr; a drop in MI/Cr; elevated expression levels of SIRT1, PGC-1α, and BDNF; and inhibited production of proinflammatory cytokines, including NF-κB p65, IL-1ß, and TNF-α. SIRT1, an NAD+-dependent class III histone enzyme, deacetylases and regulates the activity of PGC-1α and NF-κB. These data indicated that diet control and/or swimming ameliorate cognitive deficits through the inhibitory effect of neuroinflammation via SIRT1-mediated pathways, strongly suggesting that swimming and/or diet control could be potentially effective nonpharmacological treatments for cognitive impairment.

Calcium and magnesium in China's public drinking water and their daily estimated average requirements.

Calcium (Ca) and magnesium (Mg) in drinking water and the relevant health effects have been ignored for too long. This study aims to reveal the concentrations, spatial distributions, origins and contributions to the daily estimated average requirements of Ca and Mg in public drinking water. Using hydrochemical data of collected samples of public drinking water in 314 cities across China, the contributions of Ca and Mg intakes from public drinking water to their daily estimated average requirements (EARs) were assessed. And the significance of Ca/Mg ratio and total hardness (TH) was evaluated as well. The Ca and Mg concentrations of the samples were in the range of 2.5-155.1 mg/L and 0.2-81.9 mg/L, with an average of 40.4 mg/L and 12.4 mg/L, respectively. There exist obvious differences in Ca and Mg concentrations in different regions, under the impact of climate conditions and water-rock interactions. The intake of Ca via the consumption of public drinking water for adults may be twice as much as that for other age groups. In cities with high Ca levels in public drinking water, the Ca contributions to EAR could reach up to 51.59% for adults. By contrast, Mg in drinking water is an important and even the main pathway to ingest Mg for infants and children. Therefore, public drinking water is critical for Ca and Mg intake among urban residents of China. Besides, attention should be paid to the health effects of high Ca/Mg ratio and low TH in public drinking water, especially in southern China. This research is the first systematic and comprehensive national scale study of Ca and Mg in public drinking water and can provide an important reference to improve healthy public drinking water standards around the world.

Neuroprotective effects of alisol A 24-acetate on cerebral ischaemia-reperfusion injury are mediated by regulating the PI3K/AKT pathway.

BACKGROUND: Neuroinflammation and apoptosis are involved in the pathogenesis of ischaemic stroke. Alisol A 24-acetate (24A) exerts a strong inhibitory effect on inflammation and cell apoptosis. The neuroprotective effect of 24A on global cerebral ischaemia/reperfusion (GCI/R) injury remains unclear. METHODS: GCI/R mice were used to investigate the neuroprotective effect of 24A. Modified neurological deficit scores, Morris water maze and object recognition tests were used to evaluate behaviours. Metabolism in brain regions was detected using magnetic resonance spectroscopy (MRS), and changes in microglia, astrocytes and neurons were detected. Inflammation and apoptosis were measured. RESULTS: The results showed that 24A suppressed neurological deficits scores and improved GCI/R induced cognitive dysfunction. It was also observed that 24A could alleviate neuroinflammation, which manifested as 24A inhibited microglia and astrocytes proliferation, downregulated the expression of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and inducible nitric oxide synthase (iNOS) in the GCI/R mice brain. The apoptosis of neurons reduced, and dendritic spines of hippocampal neurons increased in the presence of 24A. In addition, 24A could up-regulate the expression of phosphorylated phosphoinositide 3-kinases (p-PI3K) and phosphorylated protein kinase B (p-AKT) in GCI/R mice brain, and all the morphological, neurological, and biochemical changes of 24A treatment were abolished by the application of PI3K/AKT pathway inhibitor LY294002. CONCLUSIONS: Taken together, our study indicated that 24A alleviated GCI/R injury by inhibiting neuroinflammation and apoptosis through the regulation of the PI3K/AKT pathway.

Rapid Repurposing of Novel Combination Drugs for the Treatment of Heart Failure via a Computationally Guided Network Screening Approach.

Combination drugs, characterized by high efficacy and few side effects, have received extensive attention from pharmaceutical companies and researchers for the treatment of complex diseases such as heart failure (HF). Traditional combination drug discovery depends on large-scale high-throughput experimental approaches that are time-consuming and costly. Herein we developed a novel, rapid, and potentially universal computer-guided combination drug-network-screening approach based on a set of databases and web services that are easy for individuals to obtain and operate, and we discovered for the first time that the menthol-allethrin combination screened by this approach exhibited a significant synergistic cardioprotective effect in vitro. Further mechanistic studies indicated that allethrin and menthol could synergistically block calcium channels. Allethrin bound to the central cavity of the voltage-dependent L-type calcium channel subunit alpha-1S (CACNA1S) lead to a conformational change in an allosteric site of CACNA1S, thereby enhancing the binding of menthol to this allosteric site. In summary, we reported a potentially universal computational approach to combination drug screening that has been used to discover a new combination of menthol-allethrin against HF in vitro, providing a new synergistic mechanism and prospective agent for HF treatment.

Trace elements in public drinking water in Chinese cities: Insights from their health risks and mineral nutrition assessments.

The trace elements in the public drinking water have a duality: on the one hand, trace elements play an important role in maintaining human metabolism; on the other hand, high trace elements levels lead to significant health risks. To determine the impacts of trace elements in the public drinking water on physical health in China, water samples were collected from 314 Chinese cities to analyze the concentrations and spatial distributions of trace elements on a national scale. On this basis, the non-carcinogenic health risk assessments and the nutrient-based scores of trace elements (NSTEs) were applied to evaluate the public drinking water quality in terms of safety and nutrition. Most of the water samples were weakly alkaline: pH values fell in the range of 6.62-8.54, with a mean of 7.80. The results indicated that Sr and F- had the highest concentrations in public drinking water, with averages of 0.3604 mg/L and 0.2351 mg/L, respectively. Moreover, hazard index (HI) values in different regions followed the order: northwest China (NWC) > northern China (NC) > Qinghai-Tibetan Plateau (QT) > southern China (SC). The percentages of water samples with HI > 1 in SC, NC, NWC, and QT were 5.49%, 16.82%, 25.81%, and 16.67%, respectively, indicating that the public drinking water in some cities had significant non-carcinogenic health risks. In addition, the intakes of Mn, Fe, Cu, and Rb through public drinking water made negligible contributions to their recommended nutrient intakes. In contrast, trace elements like Sr, F, B, Li, Mo, etc., contributed a lot. The NSTEs in NWC and most parts of NC were relatively high with averages of 8.0300 and 11.2082, respectively; however, the NSTEs in SC and the northeast part of NC were low with averages of 3.3284 and 5.2106, respectively. The results from this study provide a reference for establishing the public drinking water standards and improving drinking water quality.

Insight into the inhibitory mechanism of inorganic ligands on the adsorption of tetracycline onto hematite.

Inorganic ligands, ubiquitous in the natural environment, can interact with iron oxide minerals. To date, our knowledge regarding the effects of inorganic ligands on the adsorption properties of antibiotics onto iron oxides is still limited. In this work, the influences of different inorganic ligands (chosen iodate, silicate, and phosphate as the model ligands) on the adsorption of tetracycline (TC) onto hematite were examined. Adsorption isotherms indicated that inorganic ligands inhibited TC adsorption. The observations were attributed to the increase of electrostatic repulsion between anionic species (i.e., TC-) and negatively charged hematite particles as well as the competition between TC- species and inorganic ligand anions for the adsorption sites on hematite surfaces. Interestingly, the inhibitory effects of the three inorganic ligands were in the order of phosphate > silicate > iodate; the trend was stemmed from their differences in the binding affinities to hematite and the molecular size. When the background solutions contained divalent cations (e.g., Ca2+), surface precipitation of Ca-inorganic ligand compounds on hematite was another important mechanism for the inhibitory effects. Furthermore, adsorption of TC onto hematite with or without inorganic ligands was strongly affected by solution pH, which was due to the combination of the amphoteric behavior of TC and highly pH-dependent surface charges of the hematite mineral. Current results highlight the critical roles of ubiquitous inorganic ligands in revealing the fate of tetracycline antibiotics in natural systems.

Elements in potable groundwater in Rugao longevity area, China: Hydrogeochemical characteristics, enrichment patterns and health assessments.

Rugao city is a typical longevity area taking shallow groundwater as the primary drinking water source. To determine the relationship between longevity and groundwater conditions, the hydrogeochemical characteristics and related causes of potable groundwater were investigated. On this basis, the water quality index (WQI) and hazard index (HI) of groundwater were evaluated. Meanwhile, the nutrient indicators beneficial to human health, like Ca and Mg concentrations, were also considered to explore the relationship. The results were as following: (1) 91.3% of water samples fell under the Ca/Mg-HCO3 water type, which resulted from the dissolution of silicate rock. Na, Cl-, Br, B in groundwater emanated from seawater intrusion. The abnormal concentrations of NO3- and As also indicated that anthropogenic activities had exerted significant influences on groundwater quality. (2) The average WQI value was 30.19, which meant that the overall groundwater quality in Rugao city was pretty good. However, 8 water samples were found to have HI values above 1, which might be attributed to the high concentration of As (maximum value 0.0407 mg/L; mean value 0.0076 mg/L). In general, low WQI and HI values corresponded to towns with a high longevity population; what's more, WQI and HI values of Rugao city were lower than those of non-longevity areas. (3) Comparing with adjacent non-longevity areas, the potable groundwater in Rugao city had the characteristics of high Ca (mean value 123.57 mg/L), high Mg (mean value 50.33 mg/L) and high SO42- (mean value 525.19 mg/L). The daily intake of Ca and Mg from drinking water could meet 12.4% and 22.4% of daily Ca and Mg requirements, respectively. Also, the areas where the Sr and B concentrations were higher usually had higher life expectancy. The high concentrations of Ca, Mg, SO42-, Sr and B in drinking water, as well as low WQI and HI values, probably contribute to physical health and longevity. This research helps provide an insight into the relationship between groundwater quality and health and can serve as a reference for drinking water quality management.

Colloid-mediated transport of tetracycline in saturated porous media: Comparison between ferrihydrite and montmorillonite.

Given the ubiquitous mineral (e.g., clays and iron oxides) playing critical roles in impacting the fate of antibiotics in the subsurface environment, the effects of two mineral colloids (i.e., ferrihydrite and montmorillonite) on tetracycline (TC, a representative of antibiotic) transport in sand columns were investigated in this study. Interestingly, the results clearly showed that ferrihydrite colloids inhibited TC transport, while montmorillonite colloids enhanced TC mobility under neutral conditions (pH 7.0). This phenomenon resulted from the positively charged ferrihydrite colloids with weak mobility, which assisted TC deposition; besides, providing additional deposition sites for TC by the deposited ferrihydrite colloids was another important mechanism. In contrast, the transport-enhancement effect of montmorillonite on TC was attributed to the strong binding affinity of TC to clay particles as well as the competition between colloids and TC for deposition sites on sand surfaces. Moreover, the transport-inhibition effect of ferrihydrite at pH 7.0 was greater than that at pH 5.0, mainly due to more colloid-associated TC under neutral conditions. Surprisingly, ferrihydrite colloids could act as carriers of antibiotics and enhanced TC transport at pH 9.0. Because the surface charge of colloids was altered to negative and could break through the column. Meanwhile, the transport-enhancement effect of montmorillonite decreased with increasing pH from 5.0 to 9.0, resulting from the decrease of colloid-adsorbed TC. Furthermore, colloid-mediated transport of TC was influenced by ionic strength, which affected the aggregation characteristics of colloids and the binding affinities of TC to minerals. These findings provide critical information for assessing the risks of antibiotics in aquatic ecosystems where abundant natural minerals are present.

Alisol A 24-acetate protects oxygen-glucose deprivation-induced brain microvascular endothelial cells against apoptosis through miR-92a-3p inhibition by targeting the B-cell lymphoma-2 gene.

CONTEXT: Alisol A 24-acetate has been used to treat vascular diseases. However, the underlying mechanisms still remain unclear. OBJECTIVE: The present study evaluated the antiapoptotic effect of alisol A 24-acetate on brain microvascular endothelial cells (BMECs) and explored the underlying mechanisms. MATERIALS AND METHODS: BMECs were injured through oxygen -glucose deprivation (OGD) after alisol A 24-acetate treatment. Cell viability and half-maximal inhibitory concentration (IC50) were measured using CCK-8, whereas inflammatory factors and oxidative stress indicators were measured using enzyme linked immunosorbent assay. Cell invasion and wound healing assays were detected. Cell apoptosis was assessed using flow cytometry. B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X (Bax) expression were analyzed using Western blotting. Dual-luciferase assay was applied to detect target genes of miR-92a-3p. RESULT: Alisol A 24-acetate had an IC50 of 98.53 mg/L and inhibited cell viability at concentrations over 50mg/L. OGD induced apoptosis and promoted miR-92a-3p overexpression in BMECs. However, alisol A 24-acetate treatment suppressed inflammation, improved migration and invasion abilities, increased Bcl-2 expression, inhibited Bax expression, and repressed apoptosis and miR92a-3p overexpression in OGD-induced BMECs. MiR-92a-3p overexpression promoted cell apoptosis and suppressed Bcl-2 expression, whereas its inhibitor reversed the tendency. Alisol A 24-acetate treatment relieved the effects of miR-92a-3p overexpression. Dual-luciferase assay confirmed that miR-92a-3p negatively regulated the Bcl-2 expression. CONCLUSIONS: These findings suggest that alisol A 24-acetate exerts antiapoptotic effects on OGD-induced BMECs through miR-92a-3p inhibition by targeting the Bcl-2 gene, indicating its potential for BMECs protection and as a novel therapeutic agent for the treatment of cerebrovascular disease.

Effects of phosphate on the transport of graphene oxide nanoparticles in saturated clean and iron oxide-coated sand columns.

In this study, transport behaviors of graphene oxide (GO) in saturated uncoated (i.e., clean sand) and goethite-coated sand porous media were examined as a function of the phosphate. We found that phosphate enhanced the transport of GO over a wide range of solution chemistry (i.e., pH 5.0-9.0 and the presence of 10 mmol/L Na+ or 0.5 mmol/L Ca2+). The results were mainly ascribed to the increase of electrostatic repulsion between nanoparticles and porous media. Meanwhile, deposition site competition induced by the retained phosphate was another important mechanism leading to promote GO transport. Interestingly, when the phosphate concentration increased from 0.1 to 1.0 mmol/L, the transport-enhancement effect of phosphate in goethite-coated sand was to a much larger extent than that in clean sand. The observations were primarily related to the difference in the total mass of retained phosphate between the iron oxide-coated sand and clean sand columns, which resulted in different degrees of the electrostatic repulsion and competitive effect of phosphate. When the background solution contained 0.5 mmol/L Ca2+, phosphate could be bind to sand/ goethite-coated sand surface by cation bridging; and consequently, promoted competition between phosphate and nanoparticles for deposition sites, which was an important mechanism for the enhanced effect of phosphate. Moreover, the DLVO theory was applicable to describe GO transport behaviors in porous media in the absence or presence of phosphate. Taken together, these findings highlight the important status and role of phosphate on the transport and fate of colloidal graphene oxide in the subsurface environment.

Effect of phosphate on the adsorption of antibiotics onto iron oxide minerals: Comparison between tetracycline and ciprofloxacin.

With the broadly application of antibiotics to treat infectious diseases in humans and animals, antibiotic contaminants such as tetracycline (TC) and ciprofloxacin (CIP) have been detected in soil environments, where iron oxide minerals and phosphate are ubiquitous. To date, the influence of phosphate on the adsorption behaviors of TC/CIP onto iron oxides is still poorly understood. In this study, the effects of phosphate on the adsorptions of TC and CIP onto iron oxide minerals were investigated. Adsorption isotherms showed that the adsorption affinities of TC and CIP onto the three iron oxide minerals were in the order of goethite > hematite > magnetite with or without phosphate, the trend was dominated by different surface area and amount of surface hydroxyl groups of iron oxide minerals. Meanwhile, TC contains more functional groups than CIP for bonding, which resulted in greater adsorption affinity of three iron oxides to TC than that to CIP. Interestingly, phosphate weakened TC adsorption, while enhanced CIP adsorption, on the three iron oxides. This observation was ascribed to that phosphate anion enhanced the surface negative charge of iron oxides, which reinforced the electrostatic repulsion between iron oxides and negatively charged TC, also reinforced the electrostatic attraction between iron oxides and positively charged CIP. Furthermore, the inhibitory effect of phosphate on TC adsorption was dramatically enhanced at high pH, while the promoting effect of phosphate on CIP adsorption was slightly changed with various pH. Our results highlight the importance of phosphate in exploring the environmental fate of antibiotics in natural environment.

Effects of clay colloids on ciprofloxacin transport in saturated quartz sand porous media under different solution chemistry conditions.

Antibiotics, a highly prevalent class of environmental organic pollutants, are becoming a matter of global concern. Clay minerals that are ubiquitous in subsurface environments may play an important role in the fate and transport of antibiotics. Taking ciprofloxacin (CIP) as a model antibiotic, this work explored the role of clay colloids (kaolinite and montmorillonite) on the adsorption and transport of CIP under different chemical solution conditions. The adsorption isotherms showed that montmorillonite colloids had a larger CIP sorption capacity than kaolinite colloids. The results of transport experiments indicated that montmorillonite colloids could promote CIP transport in saturated sand columns, but the addition of kaolinite colloids affected CIP mobility to a much smaller extent. The much stronger transport-enhancement effect of montmorillonite colloids was due to CIP adsorbed strongly to the colloids and desorption hysteresis of colloid-adsorbed CIP, likely stemming from the intercalation of this antibiotic in the interlayer of montmorillonite. Interestingly, transport of clay colloids increased with the increasing pH from 5.0 to 9.0; however, CIP transport decreased with the increasing pH in the presence of clay colloids. The observations were likely attributable to pH-dependent ciprofloxacin adsorption/desorption to clay minerals. Increasing the concentrations of NaCl and CaCl2 generally decreased the contaminant-mobilizing ability of montmorillonite colloids, mainly by increasing the aggregation of colloids and thus, decreasing the transport of colloid-adsorbed CIP. Moreover, under the test conditions (1 mM NaCl and pH 7.0), the presence of CIP inhibited the transport of clay colloids due to the increase in aggregate size of clay colloids with the addition of CIP. Overall, these findings suggest that clay colloids with high adsorption abilities for antibiotics in the subsurface environment may act as a carrier for certain antibiotic compounds.

Luminescent Mechanochromic Dinuclear Cu(I) Complexes with Macrocyclic Diamine-Tetracarbene Ligands.

Dinuclear Cu(I) complexes bearing hexadentate, macrocyclic N-heterocyclic carbene (NHC) ligands, [Cu2(L1)(CH3CN)][PF6]2 (1) and [Cu2(L2)(CH3CN)]2[Cu2(L2)(CH3CN)2][PF6]6 (2), have been synthesized by the reactions of [H4L][PF6]4 (L = L1, L2) with excess Cu2O in acetonitrile. Crystallizations of the heat-treated samples of 1 and 2 from acetone/methanol/ether or CH3NO2/ether result in [Cu2(L1)][PF6]2 (3) and [Cu2(L2)][PF6]2 (4). Complexes 1-4 are emissive with luminescent maxima at 464, 472, 540, and 488 nm in the solid state, respectively. The origin of the red shift of the emission maximum of 3 relative to the other three complexes has been studied by theoretical calculations, showing the cuprophilic interactions in the excited state of 3. The mechanochromic luminescent properties of 1-4 have been studied. After grinding in a mortar, a significant emission color change is found with a red shift of 98 nm for 1, 82 nm for 2, 20 nm for 3, and 64 nm for 4, respectively. These mechanochromic transformations are found to be a crystalline-to-amorphous conversion, which can be reverted by adding drops of the organic solvent or recrystallization. The possible correlations between the luminescent properties and structural modifications such as Cu···Cu distances are discussed.

Metal Complexes with a Hexadentate Macrocyclic Diamine-Tetracarbene Ligand.

A hexadentate macrocyclic N-heterocyclic carbene (NHC) ligand precursor (H4L)(PF6)4 containing four benzimidazolium and two secondary amine groups, has been synthesized and characterized. Coordination chemistry of this new macrocyclic diamine-tetracarbene ligand has been studied by the synthesis of its Ag(I), Au(I), Ni(II), and Pd(II) complexes. Reactions of (H4L)(PF6)4 with different equiv of Ag2O result in Ag(I) complexes [Ag(H2L)](PF6)3 (1) and [Ag2(H2L)](PF6)4 (2). A mononuclear Au(I) complex [Au(H2L)](PF6)3 (3) and a trinuclear Au(I) complex [Au3(H2L)(Cl)2](PF6) (4) are obtained by transmetalation of 1 and 2 with AuCl(SMe2), respectively. Reactions of (H4L)(PF6)4 with Ni(OAc)2 and Pd(OAc)2 in the presence of NaOAc yield [Ni(L)](PF6)2 (5) and [Pd(L)](PF6)2 (6), respectively, containing one Ni(II) and Pd(II) ion with distorted square-planar geometry. Using more NaOAc results in the formation of unusual dinuclear complexes [Ni2(L-2H)](PF6)2 (7) and [Pd2(L-2H)](PF6)2 (8) (L-2H = deprotonated ligand after removing two H+ ions from two secondary amine groups in L), respectively, featuring a rare M2N2 core formed by two bridging amides. 7 is also formed by the reaction of 5 with 1.0 equiv of Ni(OAc)2·4H2O in the presence of NaOAc. Transmetalation of 2 with 2.0 equiv of Ni(PPh3)2Cl2 gives [Ni2(L)(µ-O)](PF6)2 (9), the first example of a dinuclear Ni(II) complex with a singly bridging oxo group. 9 is converted to 7 in good yield through the treatment with NaOAc.

Effects of extending the π-conjugation of the acetylide ligand on the photophysics and reverse saturable absorption of Pt(ii) bipyridine bisacetylide complexes.

The synthesis and photophysics of four platinum(ii) bipyridine (bpy) bisacetylide complexes with different degrees of π-conjugation and an electron-donating diphenylamino (NPh2) or electron-withdrawing benzothiazolyl (BTZ) terminal substituent on the acetylide ligands are reported. The UV-vis absorption spectra of these complexes are composed of intense ligand-localized 1π,π* transitions at 330-430 nm and broad, moderately strong ligand-to-ligand charge transfer/metal-to-ligand charge transfer (1LLCT/1MLCT) transitions at 430-530 nm. All complexes are phosphorescent in solutions at room temperature and exhibit very broad and moderately strong triplet excited-state absorption in the visible to the NIR spectral region (425-800 nm). It is found that extending the π-conjugation of the acetylide ligands via adding one or two more ethynylfluorenyl unit(s) to the acetylide ligand does not change the energies of the 1π,π* and 1LLCT/1MLCT transitions pronouncedly except for increasing the molar extinction coefficients of the 1π,π* transitions. The emitting triplet excited states of the four complexes are the 3MLCT/3LLCT states and have the same energy. However, the complex that contains the tris(ethynylfluorenyl) units and the terminal NPh2 substituent on the acetylide ligand exhibits longer triplet lifetimes than the corresponding complex that has the bis(ethynylfluorenyl) units. The transient absorption band maxima of the complexes with tris(ethynylfluorenyl) units are slightly red-shifted in comparison to those of their respective counterparts with bis(ethynylfluorenyl) units. The nature of the terminal substituent does not influence the parentage and energies of the lowest singlet and triplet excited states. However, the triplet excited-state lifetimes of the complexes with the NPh2 terminal substituent on the bis(ethynylfluorenyl) or tris(ethynylfluorenyl) ligands are much longer than that of their counterpart with monofluorenylacetylide ligands; while the triplet lifetimes of the complexes containing the BTZ terminal substituent are similar to their counterpart with monofluorenylacetylide ligands. All complexes exhibit strong reverse saturable absorption (RSA) at 532 nm for nanosecond laser pulses.

Associations of Flavonoid Intakes with Mortality among Populations with Hypertension: A Prospective Cohort Study.

BACKGROUND: The effect of flavonoid consumption on all-cause and special-cause mortality remains unclear among populations with hypertension. METHODS: A total of 6110 people with hypertension from three NHANES survey cycles (2007-2008, 2009-2010, and 2017-2018) were enrolled in this study. Cox proportional hazard models were conducted to estimate the association between the intake of total flavonoids and flavonoid subclasses and all-cause, cancer-related, and cardiovascular disease (CVD)-related mortality. Nonlinear relationships were identified using restricted cubic splines (RCS). RESULTS: During 43,977 person-years of follow-up, 1155 participants died from any cause, 282 participants died from CVD, and 265 participants died from cancer. After adjusting for relevant confounders, including demographic, lifestyle, and dietary intake, a higher intake of total flavonoids was significantly associated with lower all-cause mortality but not CVD-related and cancer-related mortality among the population with hypertension. Compared with extreme quartiles, the hazard ratio (HR) and 95% confidence interval (CI) were 0.74 (0.56-0.97) for all-cause mortality, 0.77 (0.40-1.46) for CVD-related mortality, and 0.62 (0.35-1.08) for cancer-related mortality. In terms of all-cause mortality, this inverse association was optimized at total flavonoid consumption of approximately 375 mg/day. In addition, the negative association between total flavonoid consumption and all-cause mortality was more pronounced in non-obese (BMI < 30 kg/m2) compared to obese (BMI ≥ 30 kg/m2) populations. Higher intakes of anthocyanidin, flavan-3-ol, flavonol, and isoflavone were significantly associated with lower all-cause mortality (HR (95%CI): 0.70 (0.55-0.89); 0.76 (0.59-0.96); 0.66 (0.46-0.94); 0.79 (0.67-0.93), respectively). Higher intakes of anthocyanidin, flavan-3-ol, and flavonol were significantly associated with lower cancer-related mortality (HR (95%CI): 0.55 (0.32-0.93); 0.51 (0.31-0.82); 0.52 (0.28-0.96), respectively). CONCLUSION: This study suggests that a heightened consumption of total flavonoids and some flavonoid subclasses was linked to lower mortality, which supports the proposal of increasing flavonoid intake as part of healthy diets in patients with hypertension.

Alisol A Exerts Neuroprotective Effects Against HFD-Induced Pathological Brain Aging via the SIRT3-NF-κB/MAPK Pathway.

Chronic consumption of a high-fat diet (HFD) has profound effects on brain aging, which is mainly characterized by cognitive decline, inflammatory responses, and neurovascular damage. Alisol A (AA) is a triterpenoid with therapeutic potential for metabolic diseases, but whether it has a neuroprotective effect against brain aging caused by a HFD has not been investigated. Six-month-old male C57BL6/J mice were exposed to a HFD with or without AA treatment for 12 weeks. Behavioral tasks were used to assess the cognitive abilities of the mice. Neuroinflammation and changes in neurovascular structure in the brains were examined. We further assessed the mechanism by which AA exerts neuroprotective effects against HFD-induced pathological brain aging in vitro and in vivo. Behavioral tests showed that cognitive function was improved in AA-treated animals. AA treatment reduced microglia activation and inflammatory cytokine release induced by a HFD. Furthermore, AA treatment increased the number of hippocampal neurons, the density of dendritic spines, and the expression of tight junction proteins. We also demonstrated that AA attenuated microglial activation by targeting the SIRT3-NF-κB/MAPK pathway and ameliorated microglial activation-induced tight junction degeneration in endothelial cells and apoptosis in hippocampal neurons. The results of this study show that AA may be a promising agent for the treatment of HFD-induced brain aging.

Low-molecular-weight organic acids-mediated transport of neonicotinoid pesticides through saturated soil porous media: Combined effects of the molecular structures of organic acids and the chemical properties of contaminants.

Empirical information about the transport properties of neonicotinoid pesticides through the soil as affected by the ubiquitous low molecular weight organic acids (LMWOAs) is lacking. Herein, the impacts of three LMWOAs with different molecular structures, including citric acid, acetic acid, and malic acid, on the mobility characteristics of two typical neonicotinoid pesticides (Dinotefuran (DTF) and Nitenpyram (NTP)) were explored. Interestingly, under acidic conditions, different mechanisms were involved in transporting DTF and NTP by adding exogenous LMWOAs. Concretely, acetic acid and malic acid inhibited DTF transport, ascribed to the enhanced electrostatic attraction between DTF and porous media and the additional binding sites provided by the deposited LMWOAs. However, citric acid slightly enhanced DTF mobility due to the fact that the inhibitory effect was weakened by the steric hindrance effect induced by the deposited citric acid with a large molecular size. In comparison, all three LMWOAs promoted NTP transport at pH 5.0. Because the interaction between NTP with soil organic matter (e.g., via π-π stacking interaction) was masked by the LMWOAs coating on soil surfaces. Nevertheless, LMWOAs could promote the mobility of both neonicotinoid pesticides at pH 7.0 due to the steric hindrance effect caused by the deposited organic acids and the competitive retention between LMWOAs and pesticides for effective surface deposition sites of soil particles. Furthermore, the extent of the promotion effects of LMWOAs generally followed the order of citric acid > malic acid > acetic acid. This pattern was highly related to their molecular structures (e.g., number and type of functional groups and molecular size). Additionally, when the background solutions contained Ca2+, the bridging effect of cations also contributed to the transport-enhancement effects of LMWOAs. The findings provide valuable information about the mobility behaviors of neonicotinoid pesticides co-existing with LMWOAs in soil-water systems.