Crystal structure and function analysis of 6-phosphogluconate dehydrogenase in Mycobacterium tuberculosis.

6-phosphogluconate dehydrogenase (6PGDH) is an essential enzyme in energy metabolism and redox reactions, and represents a potential drug target for the development of therapies targeting trypanosomes, plasmodium, or other pathogens. Tuberculosis, caused by Mycobacterium tuberculosis, is a contagious disease that severely affects human health, with approximately one-third of the world's population infected. However, the protein structure, exact oligomeric state, and catalytic mechanism of 6PGDH in Mycobacterium tuberculosis (Mt6PGDH) have remained largely unknown. In this study, we successfully purified and determined the structure of Mt6PGDH, revealing its function as a tetramer in both solution and crystal states. Through structural comparisons, we clarified the tetramer formation mechanism and the oligomeric organization of short-chain 6PGDHs. Additionally, we identified key residues for coenzyme recognition and catalytic activity. This work not only deepens our understanding of the enzymatic function of Mt6PGDH but also lays a foundation for the development of drugs targeting this enzyme.

Disciplining a Rubidium Atomic Clock Based on Adaptive Kalman Filter.

Rubidium atomic clocks have been used extensively in various fields, with applications such as a core component of Global Navigation Satellite Systems (GNSS). However, they exhibit inherently poor long-term stability. This paper presents the development of a control system for rubidium atomic clocks. It introduces an adaptive Kalman filtering algorithm for the disciplining of a rubidium atomic clock, utilizing autocovariance least squares (ALS) to estimate the clock's noise parameters. The experimental results demonstrate that the proposed algorithm achieves a high estimation accuracy. The standard deviation of the clock error between the steered rubidium atomic clock 1 Pulse Per Second (1PPS) and Coordinated Universal Time (UTC) provided by the National Time Service Center (NTSC) is better than 2.568 nanoseconds(ns), with peak-to-peak values improving to within 11.358 ns. Notably, its frequency stability is reduced to 3.06 × 10-13 @100,000 s. The results for the rubidium atomic clock demonstrate that the adaptive Kalman filtering algorithm proposed herein constitutes an accurate and effective control strategy for the rubidium atomic clock discipline.

Exogenous Ca2+ enhances antioxidant defense in rice to simulated acid rain by regulating ascorbate peroxidase and glutathione reductase.

MAIN CONCLUSION: Exogenous calcium enhances rice tolerance to acid rain stress by regulating isozymes composition and transcriptional expression of ascorbate peroxidase and glutathione reductase. Calcium (Ca) participates in signal transduction in plants under abiotic stress, and addition of Ca2+ is beneficial to alleviate damage of plants caused by acid rain. To clarify the effect of exogenous Ca2+ on tolerance of plants to acid rain stress, we investigated regulation of Ca2+ (5 mM) on activities, isozymes composition and transcriptional expression of ascorbate peroxidase (APX) and glutathione reductase (GR), redox state, and H2O2 concentration and growth in rice leaves and roots under simulated acid rain (SAR) stress. SAR (pH 3.5/2.5) decreased the total activities of APX and GR in rice by decreasing the concentration of APX isoforms (APXII in leaves and APXIII in roots) as well as activation degree of GR isozymes and transcription level of GR1, indicating that SAR (pH 3.5/2.5) destroyed the redox state in rice cells and induced H2O2 excessive accumulation, and inhibited growth of rice. Exogenous Ca2+ alleviated SAR-induced inhibition on activities of APX and GR by regulating the concentration, activation, and transcription of their isozymes, and then maintained the redox level of cells and protected cells from oxidative damage, being beneficial to the growth of rice. Therefore, the promotion of exogenous Ca2+ on activities of APX and GR can be important to enhance rice tolerance to acid rain by maintaining redox state and avoiding oxidative damage.

Short-chain chlorinated paraffins (SCCPs) disrupt hepatic fatty acid metabolism in liver of male rat via interacting with peroxisome proliferator-activated receptor α (PPARα).

Short-chain chlorinated paraffins (SCCPs) are frequently detected in environmental matrices and human tissues. It was hypothesized that SCCPs might interact with the peroxisome proliferator-activated receptor α (PPARα). In the present study, an in vitro, dual-luciferase reporter gene assay and in silico molecular docking analysis were employed together to study the interactions between SCCPs congeners and PPARα. Expressions of genes downstream in pathways activated by PPARα in liver of rats exposed to 1, 10, or 100 mg/kg bm/d of C10-13-CPs (56.5% Cl) for 28 days were examined to confirm activation potencies of SCCPs toward PPARα signaling. Effects of exposure to C10-13-CPs (56.5% Cl) on fatty acid metabolism in rat liver were also explored via a pseudo-targeted metabolomics strategy. Our results showed that C10-13-CPs (56.5% Cl) caused a dose-dependent greater expression of luciferase activity of rat PPARα. Molecular docking modeling revealed that SCCPs had a strong capacity to bind with PPARα only through hydrophobic interactions and the binding affinity was dependent on the degree of chlorination in SCCPs congeners. In livers of male rats, exposure to 100 mg/kg bm/d of C10-13-CPs (56.5% Cl) resulted in up-regulated expressions of 11 genes that are downstream in the PPARα-activated pathway and regulate catabolism of fatty acid. Consistently, accelerated fatty acid oxidation was observed mainly characterized by lesser concentrations of ∑fatty acids in livers of rats. Overall, these results demonstrated, for the first time, that SCCPs could activate rat PPARα signaling and thereby disrupt metabolism of fatty acid in livers of male rats.

Effect of exogenous abscisic acid on morphology, growth and nutrient uptake of rice (Oryza sativa) roots under simulated acid rain stress.

MAIN CONCLUSION: Application of proper ABA can improve acid tolerance of rice roots by balancing endogenous hormones and promoting nutrient uptake. Abscisic acid (ABA) has an important signaling role in enhancing plant tolerance to environmental stress. To alleviate the inhibition on plant growth and productivity caused by acid rain, it is crucial to clarify the regulating mechanism of ABA on adaptation of plants to acid rain. Here, we studied the effects of exogenously applied ABA on nutrients uptake of rice roots under simulated acid rain (SAR) stress from physiological, biochemical and molecular aspects. Compared to the single SAR treatment (pH 4.5 or 3.5), exogenous 10 µM ABA alleviated the SAR-induced inhibition of root growth by balancing endogenous hormones (abscisic acid, indole-3-acetic acid, gibberellic acid and zeatin), promoting nutrient uptake (nitrate, P, K and Mg) in rice roots, and increasing the activity of the plasma membrane H+-ATPase by up-regulating expression levels of genes (OSA2, OSA4, OSA9 and OSA10). However, exogenous 100 µM ABA exacerbated the SAR-caused inhibition of root growth by disrupting the balance of endogenous hormones, and inhibiting nutrient uptake (nitrate, P, K, Ca and Mg) through decreasing the activity of the plasma membrane H+-ATPase. These results indicate that proper concentration of exogenous ABA could enhance tolerance of rice roots to SAR stress by promoting nutrients uptake and balancing endogenous hormones.

New Insights into the Cytotoxic Mechanism of Hexabromocyclododecane from a Metabolomic Approach.

The toxic effects of hexabromocyclododecane (HBCD) are complex, and the underlying toxicological mechanisms are still not completely understood. In this study, a pseudotargeted metabolomic approach based on the UHPLC/Q-Trap MS system was developed to assess the HBCD-intervention-related metabolic alteration in HepG2 cells. In addition, some physiologic indicators and relevant enzyme activities were measured. HBCD exposure obviously impaired metabolic homeostasis and induced oxidative stress, even at an environmentally relevant dose (0.05 mg/L). Metabolic profiling and multivariate analysis indicated that the main metabolic pathways perturbed by HBCD included amino acid metabolism, protein biosynthesis, fatty acid metabolism, and phospholipid metabolism. HBCD suppressed the cell uptake of amino acids, mainly through inhibition of the activity of membrane transport protein Na(+)/K(+)-ATPase. HBCD down-regulated glycolysis and ß-oxidation of long-chain fatty acids, causing a large decrease of ATP production. As a result, the across-membrane transport of amino acids was further inhibited. Meanwhile, HBCD induced a significant increase of total phospholipids, mainly through the remodeling of phospholipids from the increased free fatty acids. The obtained metabolomic results also provided some new evidence and clues regarding the toxicological mechanisms of HBCD that contribute to obesity, diabetes, nervous system damage, and developmental disorders.

Whole Body Control of Mobile Manipulators With Series Elastic Actuators for Cart Pushing Tasks.

Human-centered environments provide affordance for the use of two-handed mobile manipulators. Yet robots designed to function in and physically interact with such environments are not yet capable of meeting human users' requirements. This work proposes a whole body control framework of a two-handed mobile manipulator driven by series elastic actuators (SEAs) for cart pushing tasks. A whole body dynamic model for an integrated mobile platform and on-board arms is revealed, which takes into account the interaction forces with the cart. Then, the explicit force/position control of the mobile manipulator is performed. It enables the robot to interact dynamically with the environment while providing motion, i.e., the manipulators provide both output force control and motion control for pushing a cart. To cope with the highly nonlinear system dynamics and parameter variation of a SEA-driven mobile manipulator, this work proposes an adaptive robust controller based on a novel integral barrier Lyapunov function for cart pushing tasks by considering model uncertainty. The proposed controller enables the mobile manipulator to complete cart pushing tasks by regulating the position and output force of the mobile base and arms. The experimental results show the effectiveness of this approach in cart pushing tasks.

Metabolic disturbance of short- and medium-chain chlorinated paraffins to zebrafish larva.

Chlorinated paraffins (CPs) are widely produced chemicals. Short-chain CPs (SCCPs) and medium-chain CPs (MCCPs) were listed as Persistent Organic Pollutants (POPs) and candidate POPs under the Stockholm Convention, respectively. The present study explored the developmental toxicity and metabolic disruption caused by SCCPs and MCCPs in zebrafish (Danio rerio) larvae. CPs exposure at environmentally relevant levels caused no obvious phenotypic changes with zebrafish larvae except that the body length shortening was observed after exposure to CPs at 1-200 µg/L for 7 day post fertilization. A further metabolomic approach was conducted to explore the early biological responses of developmental toxicity induced by CPs at low dose (1, 5, and 10 µg/L). The results of metabolic disorder, pathway analysis and chronic values indicated that, compared with SCCPs, MCCPs exhibited more risks to zebrafish larvae at low doses. Lipid metabolism was markedly affected in SCCPs exposure group, whereas MCCPs primarily disturbed lipid metabolism, amino acid, and nucleotide metabolisms. Compare with SCCPs, the relatively higher lipid solubility, protein affinity and metabolic rate of MCCPs can probably explain why MCCP-mediated metabolic disruption was significantly higher than that of SCCP. Notably, SCCPs and MCCPs have the same potential to cause cancer, but no evidence indicates the mutagenicity. In summary, our study provides insight into the potential adverse outcome for SCCP and MCCP at low doses.

Noble Metal Phosphides Supported on CoNi Metaphosphate for Efficient Overall Water Splitting.

Transition metal metaphosphates and noble metal phosphides prepared under similar conditions are potential hybrid catalysts for electrocatalytic water splitting, which is of great significance for H2 production. Herein, the structure and electrocatalytic activity of different noble metal species (i.e., Rh, Pd, Ir) on CoNiP4O12 nanoarrays have been systematically studied. Due to the different formation energies of noble metal phosphides, the phosphides of Rh (RhPx) and Pd (PdPx) as well as the noble metal Ir are obtained under the same phosphorylation conditions perspectively. RhPx/CoNiP4O12 and PdPx/CoNiP4O12 exhibit much better HER activity than Ir/CoNiP4O12 due to the advantages of phosphides. Density functional theory (DFT) calculations reveal that the extraordinary activity of RhPx/CoNiP4O12 originated from the strong affinity to H2O and optimal adsorption for H*. The best RhPx/CoNiP4O12 only requires a low overpotential of 30 and 234 mV to deliver 10 mA cm-2 for HER and OER, respectively, and therefore is effective for overall water splitting (requiring 1.57 V to achieve a current density of 10 mA cm-2). This work not only develops a novel RhPx/CoNiP4O12 electrocatalyst for overall water splitting but also provides deep insight into the formation mechanism of noble metal phosphides.

Observing reduction of 4-nitrobenzenthiol on gold nanoparticles in situ using surface-enhanced Raman spectroscopy.

In this article, reduction of 4-nitrobenzenthiol (4-NBT) on Au nanoparticles (NPs) was characterized using surface-enhanced Raman scattering (SERS). Plasmon-driven chemical transformation from 4-NBT dimering into p,p'-dimercaptoazobenzene (DMAB) has been investigated on the surface of Au NPs. The laser power-dependent SERS spectra of 4-NBT on the surface of Au substrates were studied, and show that the laser power has an influence on the SERS signals of 4-NBT on Au NPs and production of DMAB by a plasmon-driven surface-catalyzed chemical reaction tends to be much easier under relative high laser power. Furthermore, we have used simple and efficient Au substrates (gold NPs with a size around 45 nm) exhibiting both catalytic properties and SERS activities to monitor the catalytic reaction of surface catalytic reaction process with borohydride solution. The experiments prove that the nitro-to-amino group conversion could be completed by borohydride at ambient conditions on Au substrates. Illuminated with high laser power, 4-NBT molecules and already formed DMAB molecules are further reduced into 4-aminobenzenthiol (4-ABT) by the addition of borohydride, While with low laser power 4-NBT molecules are transformed into 4-ABT with DMAB as the intermediate, which proves Au NPs are a mild and promising catalyst. Our studies might be helpful in extending the understanding of chemical reactions of 4-NBT and related research as well as providing a new strategy synthesis of azo dyes and anilines.

Recent Advances of Transition Metal Basic Salts for Electrocatalytic Oxygen Evolution Reaction and Overall Water Electrolysis.

Electrocatalytic oxygen evolution reaction (OER) has been recognized as the bottleneck of overall water splitting, which is a promising approach for sustainable production of H2. Transition metal (TM) hydroxides are the most conventional and classical non-noble metal-based electrocatalysts for OER, while TM basic salts [M2+(OH)2-x(Am-)x/m, A = CO32-, NO3-, F-, Cl-] consisting of OH- and another anion have drawn extensive research interest due to its higher catalytic activity in the past decade. In this review, we summarize the recent advances of TM basic salts and their application in OER and further overall water splitting. We categorize TM basic salt-based OER pre-catalysts into four types (CO32-, NO3-, F-, Cl-) according to the anion, which is a key factor for their outstanding performance towards OER. We highlight experimental and theoretical methods for understanding the structure evolution during OER and the effect of anion on catalytic performance. To develop bifunctional TM basic salts as catalyst for the practical electrolysis application, we also review the present strategies for enhancing its hydrogen evolution reaction activity and thereby improving its overall water splitting performance. Finally, we conclude this review with a summary and perspective about the remaining challenges and future opportunities of TM basic salts as catalysts for water electrolysis.

Neuroprotective effects of novel compound FMDB on cognition, neurogenesis and apoptosis in APP/PS1 transgenic mouse model of Alzheimer's disease.

Clinical and experimental studies have shown that the sharp reduction of estrogen is one of the important reasons for the high incidence of Alzheimer's disease (AD) in elderly women, but there is currently no such drug for treatment of AD. Our group first designed and synthesized a novel compound R-9-(4fluorophenyl)-3-methyl-10,10,-Hydrogen-6-hydrogen-benzopyran named FMDB. In this study, our aim is to investigate the neuroprotective effects and mechanism of FMDB in APP/PS1 transgenic mice. 6 months old APP/PS1 transgenic mice were intragastrical administered with FMDB (1.25, 2.5 and 5 mg/kg) every other day for 8 weeks. LV-ERß-shRNA was injected bilaterally into the hippocampus of APP/PS1 mice to knockdown estrogen receptor ß (ERß). We found that FMDB ameliorated cognitive impairment in the Morris water maze and novel object recognition tests, increased hippocampal neurogenesis and prevented hippocampal apoptotic responses in APP/PS1 mice. Importantly, FMDB activated nuclear ERß mediated CBP/p300, CREB and brain-derived neurotrophic factor (BDNF) signaling, and membrane ERß mediated PI3K/Akt, CREB and BDNF signaling in the hippocampus. Our study demonstrated the contributions and mechanism of FMDB to cognition, neurogenesis and apoptosis in APP/PS1 mice. These lay the experimental foundation for the development of new anti-AD drugs.

Noble Metal Phosphides: Robust Electrocatalysts toward Hydrogen Evolution Reaction.

Facing with serious carbon emission issues, the production of green H2 from electrocatalytic hydrogen evolution reaction (HER) has received extensive research interest. Almost all kinds of noble metal phosphides (NMPs) consisting of Pt-group elements (i.e., Ru, Rh, Pd, Os, Ir and Pt) are all highly active and pH-universal electrocatalysts toward HER. In this review, the recent progress of NMP-based HER electrocatalysts is summarized. It is further take typical examples for discussing important impact factors on the HER performance of NMPs, including crystalline phase, morphology, noble metal element and doping. Moreover, the synthesis and HER application of hybrid catalysts consisting of NMPs and other materials such as transition metal phosphides, oxides, sulfides and phosphates, carbon materials and noble metals is also reviewed. Reducing the use of noble metal is the key idea for NMP-based hybrid electrocatalysts, while the expanded functionality and structure-performance relationship are also noticed in this part. At last, the potential opportunities and challenges for this kind of highly active catalyst is discussed.

Correction: Adsorption of polycyclic aromatic hydrocarbons over CuZnFeAl-LDH modified by sodium dodecyl sulfate.

[This corrects the article DOI: 10.1039/D2RA03968K.].

Adsorption of polycyclic aromatic hydrocarbons over CuZnFeAl-LDH modified by sodium dodecyl sulfate.

Polycyclic aromatic hydrocarbons (PAHs) have received extensive attention due to being highly toxic, mutagenic, and carcinogenic organic pollutants. As a result, a series of adsorbents have been designed and developed to solve the problem. In this paper, CuZnFeAl-S has been explored as a highly efficient adsorbent for PAHs. First, CuZnFeAl-LDH was prepared using a coprecipitation method and then calcined at 500 °C to obtain CuZnFeAlO. Finally, CuZnFeAl-S was prepared by modifying CuZnFeAlO with sodium dodecyl sulfate (SDS). The physical and chemical properties of the adsorbents were characterized by XRD, N2 adsorption-desorption, SEM, ICP, FT-IR, TG-DSC, and IGC; subsequently their adsorption performance was investigated. The results show that the surface properties of CuZnFeAl-S changed from hydrophilic to hydrophobic after SDS modification, which enhanced the adsorption of PAHs obviously. The removal of naphthalene and phenanthrene on CuZnFeAl-S reached 97.3% and 90.3%, respectively. And the adsorption process of naphthalene and phenanthrene conforms to Langmuir adsorption and Freundlich adsorption, respectively. Besides, the adsorption thermodynamics indicate that the adsorption of PAHs was a spontaneous exothermic reaction. The highly efficient PAH adsorption performance of CuZnFeAl-S is the synergistic result of various molecule interactions, such as hydrogen bonding, π-π interactions, and electrostatic attraction.

Calcium regulates antioxidative isozyme activity for enhancing rice adaption to acid rain stress.

Acid rain, as a typical abiotic stress, damages plant growth and production. Calcium (Ca) mediates plant growth and links the signal transduction in plants for adapting to abiotic stresses. To understand the effect of Ca2+ on plant adaptable response to acid rain, we investigated changes in activities and gene expression of antioxidative enzymes and fatty acid composition of membrane lipid in rice seedlings treated with exogenous Ca2+ (5 mM) or/and simulated acid rain (SAR, pH 3.5 / 2.5). Exogenous Ca2+ enhanced activities of superoxide dismutase, catalase and peroxidase isozymes in rice leaves under SAR stress by promoting activation of existing isoforms and up-regulation of Cu/Zn-SOD1, Cu/Zn-SOD2, Cu/Zn-SOD3, CAT1, CAT2 and POD1. Compared to SAR treatment alone, exogenous Ca2+ alleviated SAR-induced oxidative damage to cell membrane by enhancing antioxidative capacity, as shown by the decrease in concentrations of H2O2, O2- and malondialdehyde in rice leaves. Meanwhile, Ca2+ alleviated SAR-induced decrease in unsaturation of membrane lipid for maintaining membrane fluidity. Finally, exogenous Ca2+ alleviated SAR-induced inhibition on relative growth rate of rice. Therefore, Ca2+ could play a role in regulating activities of antioxidative enzymes as well as maintaining unsaturation of membrane lipid for enhancing tolerance in rice seedlings to acid rain stress.

Neuroprotective effects of novel compound Tozan on cognition, neurogenesis and apoptosis in diabetes.

BACKGROUND: Cognitive impairment is a serious complication of diabetes that manifests as an impairment of spatial memory and learning ability. Its pathogenesis is unclear, and effective therapeutic drugs are very limited. Our group designed and synthesized a novel compound named 3-p-tolyl-9H-xanthen-9-one (Tozan). In this study, we sought to investigate the effects and mechanism of Tozan on diabetic cognitive impairment. METHODS: Methylglyoxal (MG)-induced SH-SY5Y cells and streptozotocin (STZ)-induced type 1 diabetic mice were treated with Tozan. Methyl thiazolul tetrazolium (MTT) and lactate dehydrogenase (LDH) were used to test cytotoxicity. Morris water maze (MWM) and Y-maze tests were used to evaluate cognitive function. Immunofluorescence and western blot analyses were used to evaluate neurogenesis, apoptosis, and signal transduction pathway-related proteins. In addition, Lentivirus (LV)-estrogen receptor beta (ERß)-ribonucleic acid interference (RNAi) was used to knockdown the ERß gene in SH-SY5Y cells. RESULTS: We found that Tozan ameliorated MG-induced cytotoxicity in SH-SY5Y cells, improved cognitive dysfunction in STZ-induced type 1 diabetic mice, increased neurogenesis, and prevented apoptotic responses in vitro and in vivo. Importantly, Tozan (2, 4, and 8 mg/kg) mediated phosphatidylinositol-3-kinase and protein kinase B cAMP-response element binding protein (PI3K/Akt-CREB) signaling by activating membrane ERß, and a high dose of Tozan (8 mg/kg) mediated CREB signaling by activating nuclear ERß in the hippocampus. Notably, Tozan did not have an anti-apoptosis and regeneration protective role in ERß gene knockdown cells. CONCLUSIONS: Our study demonstrates Tozan's contributions to and role in cognition, neurogenesis, and apoptosis in diabetes, and lays an experimental foundation for the development of new anti-diabetic cognitive impairment drugs.

Comparing the disrupting effects of short-, medium- and long-chain chlorinated Paraffins on cell viability and metabolism.

With the phasing out of short-chain chlorinated paraffins (SCCPs), the production and emissions of medium- and long-chain chlorinated paraffins (MCCPs and LCCPs) are expected to increase. In this study, cell viability assay and pseudotargeted metabolomics approach were adopted to define and compare the toxic effects induced by SCCPs, MCCPs and LCCPs. The dose response curves indicated that three CP mixtures with comparable chlorine contents produced similar inhibitory effects on cell viability. At exposure concentration of 100 µg/L, three CP mixtures all induced significant increases in levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and a significant reduction in level of adenosine triphosphate production (ATP), and produced similar impact intensities on overall metabolism. A stronger perturbation in phospholipid and fatty acid metabolism was observed in all CP exposure groups. In comparison with SCCPs and MCCPs, LCCPs produced a stronger suppressive effect on amino acid transport across cell membrane and induced an opposite effect on purine metabolism. Furthermore, the toxicity mechanism and possible health risks of the three types of CPs were discussed. MCCPs shared the most similar cytotoxicity and metabolic perturbation with SCCPs, suggesting that there should be concern about using MCCPs as alternatives to SCCPs.

ERα and/or ERß activation ameliorates cognitive impairment, neurogenesis and apoptosis in type 2 diabetes mellitus mice.

Estrogen receptors (ERs) are thought to be associated with the onset and progression of neurodegenerative injuries and diseases, but the relationship and mechanisms underlying between ERs and cognition in type 2 diabetes remain elusive. In the current study, we investigated the effects of ERα and ERß on the cognition, neurogenesis and apoptosis in high-fat diet and streptozocin-induced diabetic mice. We found that ERα and/or ERß activation using their agonists (0.5 mg/kg E2, PPT or DPN) ameliorate memory impairment in the Morris water maze and Y-maze tests, increase hippocampal neurogenesis and prevent hippocampal apoptotic responses. Importantly, treatment with the pharmacologic ERs agonists caused significant increases in the membrane ERα and ERß expression and subsequent PI3K/Akt, CREB and BDNF activation in the hippocampus of type 2 diabetes mellitus mice. Our data indicate that ERα and ERß are involved in the cognitive impairment in type 2 diabetes, and that activated ERs, such as application of ERs agonists, could be a novel and promising strategy for the treatment of diabetic cognitive impairment.

Integration of metabolomics and transcriptomics reveals short-chain chlorinated paraffin-induced hepatotoxicity in male Sprague-Dawley rat.

BACKGROUND: Short-chain chlorinated paraffins (SCCPs) used in various industrial applications have been listed as new POPs. Previous studies based on high-dose exposures indicate their hepatotoxicity. However, their mechanisms of toxicity or adverse outcome pathways and health risks remain largely unknown. OBJECTIVES: This study aimed to evaluate metabolic consequences of chronic dietary exposure to SCCPs at low doses and reveal the molecular mechanisms underlying hepatotoxicity of SCCPs. METHODS: A combination of transcriptomics and metabolomics, together with general pathophysiological tests were performed to assess the hepatic response of male rats exposed to SCCPs. RESULTS: Our results highlight two major modes of action: Inhibition of energy metabolism and activation of the peroxisome proliferator-activated receptor α (PPARα). Exposure to SCCPs suppressed oxidative phosphorylation, glycolysis, gluconeogenesis and turnover of ATP-ADP-AMP and thus results in deficiencies of amino acids and nucleotides in liver of the rat. Exposure to SCCPs affected expression levels of 13 genes downstream of PPARα that encode proteins associated with metabolism of fatty acids. As a result, peroxisomal and mitochondrial fatty acid ß-oxidation, microsomal fatty acid ω-oxidation, and lipogenesis were accelerated. CONCLUSIONS: Results of this work strongly support the conclusion that low-dose exposure to SCCPs can result in adverse outcomes in the rat model. Significant SCCP-induced inhibition of energy metabolism occurs at environmentally relevant dosages, which suggests that SCCPs exhibit metabolic toxicity. Interactions of SCCPs with PPARα signaling pathway can explain the disruption of lipids and amino acids metabolism.