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The development of non-precious metal catalysts for oxygen reduction reactions (ORR) is vital for promising clean energy technologies such as fuel cells, and zinc-air batteries. Herein, we present a stepwise synthesis of N-doped and carbon encapsulated BiOCl-CNTs heterostructures. Electrocatalytic ORR studies show that the optimized catalyst has a high half-wave potential (E1/2) of 0.85 V (vs. RHE), large limiting current density (-5.34 mA cm−2@0.6 V) in alkaline medium, and nearly perfect 4e− reduction characteristics, even surpassing commercial Pt/C. Meanwhile, the catalyst has exceptional durability (above 97.5 % after 40000 s) and strong resistance towards methanol poisoning. The good ORR activity also results in high-performance zinc-air batteries with a specific capacity (724 mAh g−1@10 mA cm−2), a high open-circuit potential of 1.51 V and a peak power density of 170.7 mW cm−2, as well as an ultra-long charge–discharge cycle stability (155 h), comparable with the Pt/C catalyst. The catalytic mechanism reveals that the excellent electrocatalytic performance originates from the synergistic effect of N doping, oxygen vacancies, and BiOCl sites.

Considerable toxic tellurium-containing wastewater has been discharged into water environment and constantly accumulates, due to the widespread applications but low utilization of tellurium, causing irreversible harm to the environment and human health, thus it is crucial to find an efficient strategy for tellurium separation. Herein, hierarchical porous magnesium oxide modified cellulose acetate membranes (MgO@CAM) were prepared via a facile physical blending and phase inversion method for tellurium separation. Diverse characterization methods and batch separation experiments were conducted to investigate the morphological structure of MgO@CAM, tellurium separation mechanism, and the separation behavior under different influencing factors. The results exhibit that MgO@CAM has a hierarchical porous structure and a hydroxyl-rich surface, which facilitates the separation of tellurium. Besides, MgO@CAM reveals eligible regeneration performance, good stability and thermal stability due to the hydrogen bonding and skeletal structure of cellulose acetate. The study on the effect of pH suggests that an acidic environment is more conducive to the separation of tellurium by MgO@CAM, and the prepared membranes show outstanding separation efficiency of tellurium, with a maximum of 97.6%. Furthermore, the membranes also achieve satisfactory separation efficiency of tellurium in the presence of multiple coexisting ions. Thomas dynamics indicate the practical application of MgO@CAM in tellurium separation. More importantly, prominent hydrophilic enables MgO@CAM to demonstrate excellent antifouling performance. Therefore, the preparation of hierarchical porous MgO@CAM provides an efficient and economic strategy for tellurium separation in wastewater and has promising applications in water treatment.

Background: Data regarding the additional effect on the recurrence of hepatic encephalopathy (HE) after oral L-carnitine administration are scarce. Objective: This study aimed to assess the additional effects of L-carnitine in patients who were receiving rifaximin for HE. Methods: This randomized study comprised a screening visit and a 12-week treatment period. Patients who fulfilled the eligibility criteria were randomized to either group A (additional rifaximin) or group B (additional L-carnitine and rifaximin). Group A received 1,200 mg/day of rifaximin. Group B received 1,500 mg/day of L-carnitine and rifaximin at 1,200 mg/day. The endpoints were the changes in the portal systemic encephalopathy (PSE) index and the admission rate from the baseline for the duration of the study in both groups. Results: Eighty-three patients were randomized to either group A (n = 42) or group B (n = 41). In group A, the PSE index decreased from 0.35 ± 0.09 at baseline to 0.27 ± 0.11 on the final evaluation day (p = 0.001). In group B, the PSE index decreased from 0.37 ± 0.09 at baseline to 0.24 ± 0.11 on the final evaluation day (p = 0.001). Although there was not a significant reduction in the PSE index in group A compared to that in group B (p = 0.202), the admission rates were 30.9% and 9.8% in groups A and B, respectively. Additional L-carnitine significantly reduced the admission rate (p = 0.028). Conclusion: L-Carnitine addition reduced the risk of hospitalization for patients who received rifaximin for HE.

The rational design of non-precious-metal bifunctional catalysts of oxygen and hydrogen evolution reactions that generate a high current density and stability at low over potentials is of great significance in the field of water electrolysis. Herein, we report a facile and controllable method for the in-situ growth of urchin-like FeOOH–NiOOH catalyst on Ni foam (FeOOH–NiOOH/NF). X-ray photoelectron spectroscopy confirms that the proportion of Ni and Fe species with high valence state gradually increase with the extension of growth time. Electrochemical studies have shown that the optimized FeOOH–NiOOH/NF-24 h and −12 h catalysts demonstrate excellent electrochemical activity and stability in oxygen/hydrogen evolution reactions. Moreover, the cell voltage is reduced around 0.15 V at high current density (0.5–1.0 A cm−2) as compared to the state-of the art RuO2/NF(+)||Pt–C/NF(−) system, far better than most of the previously reported catalysts. The cost analyst revealed that using FeOOH–NiOOH/NF catalyst as both electrodes could potentially reduce the price of H2 around 7% compared with traditional industrial electrolyzers. These excellent electrocatalytic properties can be attributed to the unique urchin-like structure and the synergy between Ni and Fe species, which can not only provide more active sites and accelerate electron transfer, but also promote electrolyte transport and gas emission.

AIM Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor, which suppress tumor angiogenesis and tumor progression. It was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma (HCC). Sorafenib had a beneficial effect on portocollateral circulation with portal hypertension in translating and clinical studies. However, the hemodynamic effects of lenvatinib appear to be different from those of sorafenib because the efficacy of lenvatinib for vascular endothelial growth factor receptors and fibroblast growth factor receptors is different from that of sorafenib. This study was prospectively performed to evaluate the portal hemodynamic effect of lenvatinib in patients with advanced HCC using duplex Doppler ultrasonography. METHODS In total, 28 Child-Pugh class A or B patients with advanced HCC received lenvatinib depending on body weight daily for 2 weeks. Primary outcomes were changes in the hemodynamics of the portal venous system using duplex Doppler ultrasonography before and after the 2-week administration of lenvatinib. RESULTS The portal venous flow velocity (cm/s) significantly reduced (27 ± 12.1 vs. 22.6 ± 8.0, P = 0.019), while portal venous area (cm2 ) did not change after the 2-week administration (0.80 ± 0.36 vs. 0.82 ± 0.27, P = 0.665). Therefore, the congestion index (portal venous area/portal venous flow velocity), which reflects the pathophysiological hemodynamics of the portal venous system significantly worsened (0.037 ± 0.025 vs. 0.043 ± 0.024, P = 0.045). CONCLUSIONS Considering that this was a short-term study, because lenvatinib could be an agent that aggravates portal hypertension, it will be necessary to verify its clinical effects for portal hypertension in future studies.

Tellurium is massively used as the main light-absorbing layer component in the manufacturing of CdTe thin-film solar cells, a critical component in the photovoltaic industry. However, the process of manufacturing and renewing components has produced large amounts of tellurium-containing wastewater that is difficult to degrade and poses a serious threat to the aquatic ecosystem and human health. Hence, to achieve the recovery of tellurium resources for reducing their damages, a win-win approach was employed to utilize waste lignin to construct functional copper-doped activated lignin (CAL) adsorbents for selective separation and recovery of tellurium from wastewater. CAL exhibited superior adsorption properties towards tellurium (248.45 mg/g), mainly attributed to the adsorption mechanism of coordination interactions. Kinetic and isotherm results elucidated that monolayer chemisorption dominated CAL adsorption process. Besides, CAL had a satisfactory regeneration capability with minimal loss adsorption capacity after six consecutive cycles, which also exhibited high antifouling properties. Meanwhile, CAL achieved high selectivity for tellurium adsorption under the simulated wastewater, revealing the potential of CAL for practical application in wastewater. Therefore, this work provides a promising environmental strategy for exploring the application of lignin-based materials for tellurium recovery from wastewater.

The role of mitochondrial dysfunction and its molecular mechanism in inflammation-induced acute liver failure (ALF) remain unknown. Despite the numerous studies performed to date, very few therapies are available for inflammation-induced ALF. Therefore, our study is aimed to explore the regulatory effects of mitochondrial stress and the Akt-Sirt3 pathway on the development of TNF-α-induced hepatocyte death and assess the therapeutic effects of melatonin on the damaged liver. Our results exhibited that TNF-α treatment induced hepatocyte damage in vitro; the effect of which was dose-dependently inhibited by melatonin. At the molecular level, TNF-α-treated hepatocytes expressed lower levels of Sirt3 and subsequently exhibited mitochondrial stress. Interestingly, melatonin treatment improved mitochondrial bioenergetics, reduced mitochondrial oxidative stress, reversed mitochondrial dynamics, and repressed mitochondrial apoptosis by reversing the decrease in Sirt3 expression after TNF-α challenge. In addition, we found that melatonin-regulated Sirt3 expression in a manner dependent on the Akt pathway. Blockade of the Akt pathway abolished the protective exerted by melatonin on mitochondria and hepatocyte under TNF-α treatment. In conclusion, TNF-α promotes hepatocyte apoptosis by inducing mitochondrial stress. However, melatonin significantly increases the activity of the Akt/Sirt3 axis and consequently maintains mitochondrial homeostasis, restoring hepatocyte viability in an inflammatory environment. Thus, the information compiled here might provide important perspectives for the use of melatonin in the clinic for preventive and therapeutic applications in patients with ALF based on its anti-inflammatory and mitochondria-protective effects.

Recovery of the tellurium from wastewater is significance for both industrial applications and sustainable development due to the adverse impacts emanating from environmental pollution and strategic values in the photovoltaic industry. Herein, this study presents the recovery of tellurium from wastewater by flower-like structure ZnO-Ag@cellulose (ZAC) composites. For adsorbent preparation, lignocellulose was first extracted from waste wood debris by an alkaline extraction process. Then, the flower-like structure of ZAC composites were synthesized by a facile one-step hydrothermal method. The obtained materials are conducted under different parameters to investigate tellurium adsorption properties. The results indicate that the tellurium adsorption process is an exothermic reaction and fits well to the Freundlich model. Kinetic data are well described by pseudo-second-order model, indicating ZAC adsorption of tellurium is a chemical process. Besides, as-prepared ZAC exhibited excellent performance for tellurium elimination from wastewater with a maximum removal efficiency of 98.86%. The ZAC also shows outstanding antifouling performance in polluted environment and can still achieve the rate of 94.23% for tellurium. Moreover, the ZAC composite reveals high reusability and stability after six desorption-regeneration cycles. Importantly, the ZAC composite exhibits disinfection performance against E. coli and S. aureus with high killing efficiency. Therefore, this work not only demonstrates ZAC composite is efficient adsorbent with antifouling and antibacterial capability for tellurium recovery, but also provides an effective channel for promising candidates to decontaminate similar pollutants and practical applications of wastewater.

We investigated whether or not nitric oxide synthase 3 (NOS3) rs2070744 genotypes can affect the response for lenvatinib treatment in patients with hepatocellular carcinoma (HCC). We evaluated the relation of the NOS3 rs2070744 genotypes to the tumor response, progression-free survival (PFS), and overall survival (OS) as the response for lenvatinib. We also examined the association between fibroblast growth factor receptor (FGFR) gene polymorphisms, a potential feature of lenvatinib, and the response. There were no significant differences between the studies for either PFS or OS, even though patients with the TT genotype had a longer mean PFS (hazard ratio [HR] 0.60; p = 0.069) and mean OS (HR 0.46; p = 0.075) than those with the TC/CC genotypes. However, patients with a single-nucleotide polymorphism (SNP) combination pattern of the NOS3 rs2070744 TC/CC and FGFR4 rs351855 CT/TT genotypes had a significantly shorter mean PFS (HR 2.56; p = 0.006) and mean OS (HR 3.36; p = 0.013) than those with the other genotypes. The NOS3 rs2070744 genotypes did not influence the clinical response. However, the SNP combination pattern of the NOS3 rs2070744 and FGFR4 rs351855 genotypes may be helpful as treatment effect predictors and prognostic factors for HCC patients treated with lenvatinib.

Previous studies have found that the primary pathogenesis of liver cancer progression is linked to excessive cancer cell proliferation and rapid metastasis. Although therapeutic advances have been made for the treatment of liver cancer, the mechanism underlying the liver cancer progression has not been fully addressed. In the present study, we explored the role of spliced X-box binding protein 1 (XBP1) in regulating the viability and death of liver cancer cells in vitro. Our study demonstrated that XBP1 was upregulated in liver cancer cells when compared to the primary hepatocytes. Interestingly, the deletion of XBP1 could reduce the viability of liver cancer cells in vitro via inducing apoptotic response. Further, we found that XBP1 downregulation was also linked to proliferation arrest and migration inhibition. At the molecular levels, XBP1 inhibition is followed by activation of the Mst1 pathway which promoted the phosphorylation of c-Jun N-terminal kinase (JNK). Then, the active Mst1-JNK pathway mediated mitochondrial reactive oxygen species (mROS) overproduction and then excessive ROS induced cancer cell death. Therefore, our study demonstrated a novel role played by XBP1 in modulating the viability of liver cancer cells via the Mst1-JNK-mROS pathways.

Background The nucleus accumbens in the midbrain dopamine limbic system plays a key role in cocaine addiction. Toll-like receptors (TLRs) are important pattern-recognition receptors (PPRs) in the innate immune system that are also involved in drug dependence; however, the detailed mechanism is largely unknown. Methods The present study was designed to investigate the potential role of TLR3 in cocaine addiction. Cocaine-induced conditioned place preference (CPP), locomotor activity, and self-administration were used to determine the effects of TLR3 in the rewarding properties of cocaine. Lentivirus-mediated re-expression of Tlr3 (LV-TLR3) was applied to determine if restoration of TLR3 expression in the NAc is sufficient to restore the cocaine effect in TLR3−/− mice. The protein levels of phospho-NF-κB p65, IKKβ, and p-IκBα both in the cytoplasm and nucleus of cocaine-induced CPP mice were detected by Western blot. Results We showed that both TLR3 deficiency and intra-NAc injection of TLR3 inhibitors significantly attenuated cocaine-induced CPP, locomotor activity, and self-administration in mice. Importantly, the TLR3−/− mice that received intra-NAc injection of LV-TLR3 displayed significant increases in cocaine-induced CPP and locomotor activity. Finally, we found that TLR3 inhibitor reverted cocaine-induced upregulation of phospho-NF-κB p65, IKKβ, and p-IκBα. Conclusions Taken together, our results describe that TLR3 modulates cocaine-induced behaviors and provide further evidence supporting a role for central pro-inflammatory immune signaling in drug reward. We propose that TLR3 blockade could be a novel approach to treat cocaine addiction. Electronic supplementary material The online version of this article (10.1186/s12974-018-1130-8) contains supplementary material, which is available to authorized users.

Fabrication of an acid-resistant, biodegradable and recoverable highly efficient adsorbent to selectively recover tellurium resources from acidic wastewater for minimizing their threat still presents a significant challenge. Herein, a sheet-like magnetic FeS@Lignin-derived carbon (FeS@LC) nanocomposite with acid-resistant was obtained as an efficient adsorbent for tellurium separation through a simple two-step hydrothermal reaction. The results indicated that this FeS@LC fabricated with biodegradable lignin-derived carbon (LC) and highly reactive FeS revealed a superior adsorption capacity (148.36 mg/g) for tellurium. Isotherm and kinetic results suggested that the tellurium adsorption process was dominated by a monolayer chemisorption process. The thermodynamic parameters for tellurium adsorption on FeS@LC confirmed that the tellurium adsorption was exothermic and spontaneous. Precipitation, reduction, ion exchange, and surface complexation are regarded as the main adsorption mechanisms for tellurium purification. Besides, FeS@LC composites can selectively adsorb tellurium from a multitude of coexisting ions. Meanwhile, the FeS@LC maintained quick magnetic recyclable capability (10S) and excellent adsorption performance (108.87 mg/g) after five consecutive adsorption-desorption. Importantly, FeS@LC exhibited a superior stability and antifouling properties, facilitating its practical application in complex environments. Therefore, this work expands the application field of lignin-derived carbon-based materials, presenting a bright application for similar pollutants purification in wastewater.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Interleukin (IL)-35 is a newly identified IL-12 cytokine family member, which has been demonstrated to induce immunotolerance by suppression of CD8+ T cells function in chronic viral hepatitis. However, the role of IL-35 in modulating CD8+ T cells activity in non-viral hepatitis-related hepatocellular carcinoma (HCC) was not fully elucidated. Forty-four patients with non-viral hepatitis-related HCC and 20 healthy individuals were enrolled. Serum IL-35 concentration was measured by ELISA. CD8+ T cells were purified from peripheral bloods and liver tissues. mRNA expression of cytotoxic/inhibitory molecules in CD8+ T cells with IL-35 stimulation was semi-quantified by real-time PCR. Direct and indirect contact co-culture systems of CD8+ T cells and HCC cell lines were set up. The modulatory function of IL-35 on peripheral and liver-resident CD8+ T cells was assessed by measurement of lactate dehydrogenase release and cytokine production in the co-culture supernatants. Serum IL-35 was notably elevated in HCC patients, while effective anti-tumor therapies down-regulated IL-35 concentration. Recombinant IL-35 stimulation suppressed cytotoxicity and proinflammatory cytokine secretion of peripheral and liver-resident CD8+ T cells in direct and indirect contact co-culture systems. This process was accompanied by reduction of perforin expression and interferon-γ production, as well as programmed death-1 and cytotoxic T-lymphocyte-associated protein 4 elevation in CD8+ T cells. The current data suggested that IL-35 inhibited both cytolytic and non-cytolytic function of CD8+ T cells to non-viral hepatitis-related HCC probably via repression of perforin expression. IL-35 might be considered to be one of the therapeutic targets for patients with HCC.

Theaflavins (TFs) have attracted much attention due to their various bioactivities in black tea. This paper describes the first trial for enzymatic production of TFs by recombinant polyphenol oxidases (PPOs). PPO genes were cloned from nine species and expressed in E. coli. Crude enzyme assays by LC-MS revealed that eight recombinant PPOs were active for TFs production from tea polyphenols as substrates. Much higher activities were observed for crude enzymes of Md2 from Malus domestica (apple), Pp4 from Pyrus pashia (pear), and Ej2 from Eriobotrya japonica (loquat). When immobilized on mesoporous silica, crude Md2 was most active. The purified Md2 was immobilized and showed almost twice activity as high as its free enzyme. While the maximum activity of free enzyme was found at pH 5 and 10–30 °C, the immobilized enzyme had broader range of pH 4–6 and 10–40 °C. The activity of immobilized enzyme was relatively constant during the pH and thermal stability test. When used at 0.2 mg/ml in the beginning, the immobilized enzyme retained approximately 40% of its initial activity after 8 cycles of operation.

Electro-optic (EO) property of titanium-diffused LiNbO3 optical waveguide was studied using prism coupling technique. The EO-effect-induced increment ΔN of effective refractive index (at the wavelength 1311 nm) was measured as a function of externally applied electric field E for TM0 and TM1 modes guided in the titanium-diffused LiNbO3 planar waveguide. By using the linearity between ΔN and E, the EO coefficient r33 is determined. For reference, the measurement was also performed on a bulk material of congruent LiNbO3, yielding r33 = 24.9 ± 0.8 p.m./V, which is in qualitative agreement with that obtained by extrapolating previously reported result to the 1311 nm wavelength, ~24 p.m./V, confirming the feasibility of the measurement method. Measurements on the titanium-diffused planar waveguide give r33 = 25.7 ± 0.6 p.m./V for the TM0 mode and 25.7 ± 0.4 p.m./V for the TM1 mode. Both values can be considered as identical within the error, and are the same as that of the bulk material, indicating that the EO property is well preserved in the titanium-diffused LiNbO3 waveguide. The main reason is that the LiNbO3 crystalline phase is well preserved in the titanium-diffused waveguide layer.

Background/aims Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) worldwide, and the importance of tubular injury has been highlighted in recent years. However, the underlying mechanisms and effective therapeutic targets are still unclear. In this study, we investigated mtDNA, mitochondrial dynamics, function and metabolic pathways to determine if mitochondrial damage plays a critical role in the development of tubular injury in DKD patients. Methods A cross-sectional study was carried out among healthy controls (HCs, n = 65), diabetes patients without kidney disease (DCs, n = 48) and DKD patients (n = 60). Serum, peripheral blood mononuclear cells (PBMCs) and kidney biopsy specimens were obtained from participants. Metabolomics was employed to investigate cellular metabolism. Results DKD patients had decreased mtDNA copy numbers and increased mtDNA damage compared to DCs. Mitochondrial fragmentation was specifically presented in tubules, but not in podocytes of DKD patients. The accumulation of damaged mtDNA and fragmented mitochondria resulted in increased reactive oxygen species (ROS) generation, activation of apoptosis and loss of mitochondrial membrane potential (ΔΨm) in tubules and PBMCs. Furthermore, glycolysis and tricarboxylic acid (TCA) cycle was perturbed, and increased dihydroxyacetone phosphate (DHAP) and decreased succinyl-CoA synthetase (SCS) respectively in these two metabolic pathways were identified as potential biomarkers for tubular injury in DKD. Conclusion Our study indicates that mitochondrial damage could be the hallmark of tubular injury in DKD patients, and this would provide a novel and attractive therapeutic target to improve this disease.

BACKGROUND Hepatic fibrosis is a reversible pathological process. Inflammatory responses are the prevailing reactions during hepatic fibrosis. Decoy receptor 3 (DcR3) has been reported to have an anti-inflammatory effect. OBJECTIVES The aim of the study was to investigate the preventive effects of DcR3 on hepatic fibrosis. MATERIAL AND METHODS Hepatic fibrosis was induced in rats by administering intraperitoneally (ip.) 1% dimethylnitrosamine (DMN). DcR3 plasmid was delivered into rats by intravenous injection. After 4 weeks, the expression of DcR3, TNF-like molecule 1A (TL1A) and α-SMA of the liver tissue were checked. The levels of inflammatory cytokines such as TNF-α, IL-6 and IL-1β were detected using western blotting and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Masson's trichrome staining for histopathological changes of the liver tissue was observed. Finally, the activity of NF-κB in the liver was examined by enzyme-linked immunosorbent assay (ELISA). RESULTS A higher expression of DcR3 was observed in rats treated with DcR3 (p < 0.05). Histological results showed that DcR3 significantly attenuated pathology in hepatic fibrosis rats. Consistently, mRNA and protein levels of α-SMA, TL1A, TNF-α, IL-6, and IL-1β were repressed in the liver tissue after treatment with DcR3 (p < 0.05). Moreover, DcR3 also inhibited the activation of NF-κB in the liver tissue (p < 0.05). CONCLUSIONS This study demonstrated that DcR3 attenuated liver injury and inflammatory responses in rats with hepatic fibrosis. We suggest DcR3 may be a prophylactic and promising therapeutic agent in the treatment of hepatic fibrosis.

Methamphetamine (METH) abuse has become a major public health concern worldwide without approved pharmacotherapies. The brain renin–angiotensin system (RAS) is involved in the regulation of neuronal function as well as neurological disorders. Angiotensin II (Ang II), which interacts with Ang II type 1 receptor (AT(1)-R) in the brain, plays an important role as a neuromodulator in dopaminergic transmission. However, the role of brain RAS in METH-induced behavior is largely unknown. Here, we revealed that repeated METH administration significantly upregulated the expression of AT(1)-R in the striatum of mice, but downregulated dopamine D3 receptor (D3R) expression. A specific AT(1)-R blocker telmisartan, which can penetrate the brain–blood barrier (BBB), or genetic deletion of AT(1)-R was sufficient to attenuate METH-triggered hyperlocomotion in mice. However, intraperitoneal injection of AT(1)-R blocker losartan, which cannot penetrate BBB, failed to attenuate METH-induced behavior. Moreover, intra-striatum re-expression of AT(1) with lentiviral virus expressing AT(1) reversed the weakened locomotor activity of AT(1)(−/−) mice treated with METH. Losartan alleviated METH-induced cytotoxicity in SH-SY5Y cells in vitro, which was accompanied by upregulated expressions of D3R and dopamine transporter. In addition, intraperitoneal injection of perindopril, which is a specific ACE inhibitor and can penetrate BBB, significantly attenuated METH-induced hyperlocomotor activity. Collectively, our results show that blockade of brain RAS attenuates METH-induced hyperlocomotion and neurotoxicity possibly through modulation of D3R expression. Our findings reveal a novel role of Ang II–AT(1)-R in METH-induced hyperlocomotion. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-018-0613-8) contains supplementary material, which is available to authorized users.

Nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis in mammals, converts nicotinamide into nicotinamide mononucleotide (NMN). NMN is subsequently converted to NAD, a component that is critical for cell energy metabolism and survival. Sirtuin 1 (SIRT1), an NAD-dependent histone deacetylase, plays an important role in mediating memory and synaptic plasticity. Here, we found that NAMPT was significantly upregulated in the ventral tegmental area (VTA) of cocaine-conditioned mice. Intraperitoneal or intra-VTA injection of FK866, a specific inhibitor of NAMPT, significantly attenuated cocaine reward. However, such effects were clearly repressed by intra-VTA expression of NAMPT or supplementation with NMN. Using 1H-nuclear magnetic resonance metabolomic analysis, we found that the content of NAD and NMN were increased in the VTA of cocaine-conditioned mice; moreover, the expression of SIRT1 was also upregulated. Interestingly, the inhibitory effect of FK866 on cocaine reward was significantly weakened in Sirt1 midbrain conditional knockout mice. Our results suggest that NAMPT-mediated NAD biosynthesis may modify cocaine behavioral effects through SIRT1. Moreover, our findings reveal that the interplay between NAD biosynthesis and SIRT1 regulation may comprise a novel regulatory pathway that responds to chronic cocaine stimuli.

When the reactor is added with ectoine of concentrations of 0, 0.1, 1 and 10 mmol/L, the impacts on brine waste treatment efficiency are investigated. The results show that the outflow COD and ammonia nitrogen removal rates are the highest, when the ectoine concentration is 0.1 mmol/L. The brine waste treatment efficiency under addition of ectoine of 1 and 10 mmol/L is even worse than that without ectoine addition. It can be preliminarily determined that the best ectoine dosage is in between 0.1-1.0 mmol/L. When ectoine concentrations added in reactors are 0.2, 0.5, 0.8 and 1.0 mmol/L, the results show that the average reactor outflow COD and ammonia nitrogen removal rates are increased compared with those of reactor without adding ectoine. But when ectoine of 1.0 mmol/L is added, the outflow COD and ammonia nitrogen removal rates decrease. When ectoine dosage is 0.5 mmol/L, the reactor outflow COD and ammonia nitrogen values are the lowest, the removal rates are the highest, the average COD removal rate is 74.46%, and the average ammonium nitrogen removal rate is 54.97%. Compared with reactor without adding ectoine, COD and ammonium nitrogen removal rates are increased by 13.16% and 26.81%. Therefore, the best dosage of ectoine is 0.5 mmol/L.

Biological and catalytically functional two-dimensional organic–inorganic hybrid materials with regular peptides were developed through the grafting of glutathione (GSH) and L -Proline ( L -Pro), Pro-Pro-Asp-NH 2 (PPA) in layered carboxyl propanamide phenylsilica (CPAPhS), which was developed in our previous research. The two-dimensional organic–inorganic hybrid material, p -glutathione-amide propanamide phenylsilica (GSH-APAPhS) showed favorable antioxidant capacity. The two-dimensional organic–inorganic hybrid materials, p - L -proline-amide propanamide phenylsilica ( L -Pro-APAPhS) and p -Pro-Pro-Asp-amide propanamide phenylsilica (PPA-APAPhs) showed effective asymmetric catalytic ability in aldol reaction. This research exhibited the application potential of two-dimensional organic–inorganic hybrid materials with peptides in biological functions and catalytic reaction processes, and will facilitate the application of bioactive peptides in a broader range of fields.

Methamphetamine (METH), a commonly abused psychostimulant, has been shown to induce neuronal damage by causing reactive oxygen species (ROS) formation, apoptosis and autophagy. Taurine (2-aminoethanesulfonic acid) is involved in several physiological actions in the brain, including neuroprotection, osmoregulation and neurotransmission. In this study, we investigate the protective effect of taurine against METH-induced neurotoxicity in PC12 cells and the underlying mechanism. The results showed that taurine significantly increased the cell viability inhibited by METH. LC3-II expression was elevated by METH treatment, whereas such increase was obviously attenuated by taurine. Co-treatment of taurine strongly reversed the decline of antioxidase activities induced by METH. Moreover, phosphorylated mammalian target of rapamycin (p-mTOR) was significantly inhibited by METH, whereas complementation of taurine markedly increased the expression of p-mTOR in PC12 cells, rather than phosphorylated Erk. Interestingly, taurine-induced decreasing expression of LC3-II was partially blocked by pretreatment of RAD001, an mTOR inhibitor. These results indicated that taurine inhibits METH-induced autophagic process through activating mTOR rather than Erk signaling. Collectively, our study shows that taurine protects METH-induced PC12 cells damage by attenuating ROS production, apoptosis and autophagy, at least in part, via mTOR signaling pathway.

Metabolic consequences of morphine dependence and withdrawal intervention have not been well explored. In the present study, the metabolic changes in brain hippocampus, nucleus accumbens (NAc), prefrontal cortex (PFC) and striatum of rats with morphine dependence and withdrawal intervention were explored by using 1 H nuclear magnetic resonance coupled with principal component analysis, partial least squares and orthogonal signal correction analysis. We found that the concentrations of neurotransmitters including glutamate, glutamine and gamma-aminobutyric acid changed differentially in hippocampus, NAc, PFC and striatum after repeated morphine treatment. Significant changes were also found in a number of cerebral metabolites including N-acetyl aspartate (NAA), lactic acid, creatine, myo-inositol and taurine. These findings indicate the profound disturbances of energy metabolism, amino acid metabolism and neurotransmitters caused by chronic morphine treatment. Interestingly, morphine-induced changes in lactic acid, creatine and NAA were clearly reversed by intervention of methadone or clonidine. Our study provides a comprehensive understanding of the metabolic alteration associated with morphine addiction and withdrawal therapy, which may help to develop new pharmacotherapies.

BACKGROUND: Plant expression system for mass production of recombinant proteins has several advantages over other existing expression systems with economical and safety issues. Breast cancer is a cancer originating from breast tissue and comprises almost 25% of all cancers in women world widely. Lewis-Y antigen is difucosylated oligosaccharide and is carried by glycoconjugates at cancer cell surface. In this study, the anti-breast cancer mAb BR55, which recognizes the epitope Lewis-Y, was expressed in the plant expression system. METHODS AND RESULTS: We have developed plant system for production of mAb BR55 with or without KDEL (the ER retention signal). This ER retention signal was attached to C-terminus of protein to help retain the recombinant glycoprotein carrying oligomannose glycans and enhance glycoprotein accumulation. PCR analysis was performed and confirmed the presence of recombinant genes. Western blot validated that the recombinant proteins mAb BR55 with or without KDEL were expressed in transgenic plants, moreover, the expression level of the mAb BR55 with KDEL was higher compared to the mAb BR55 without KDEL. CONCLUSION: These results indicate that KDEL fusion is a good way to produce proteins and plant can be an ideal expression system to obtain proteins and enhance accumulation of proteins.

A dual functional three-dimensional porous NbO-type metal–organic framework with inserted acylamide units was solvothermally synthesized, which exhibits large CO2-uptake capacity (160 cm3 g− 1 at 1 bar), high selectivity toward CO2/N2 (41.6 at 273 K) and satisfied catalytic activity in Knoevenagel condensation reaction.

Epidemiological studies have shown that an elevated uric acid (UA) level predicts the development of metabolic syndrome and diabetes; however, there is no direct evidence of this and the underlying mechanism remains unclear. Here, we showed that a high-UA diet triggered the expression of pro-inflammatory cytokines, activated the NF-κB pathway and increased gliosis in the hypothalamus. Intracerebroventricular injection of UA induced hypothalamic inflammation and reactive gliosis, whereas these effects were markedly ameliorated by the inhibition of NF-κB. Moreover, magnetic resonance imaging confirmed that hyperuricemia in rodents and humans was associated with gliosis in the mediobasal hypothalamus. Importantly, the rats administered UA exhibited dyslipidemia and glucose intolerance, which were probably mediated by hypothalamic inflammation and hypothalamic neuroendocrine alterations. These results suggest that UA can cause hypothalamic inflammation via NF-κB signaling. Our findings provide a potential therapeutic strategy for UA-induced metabolic disorders.

Background and aims: Ingestion of paraquat (PQ), a widely used herbicide, can cause severe toxicity in humans, leading to a poor survival rate and prognosis. One of the main causes of death by PQ is PQ-induced pulmonary fibrosis, for which there are no effective therapies. The aim of this study was to evaluate the effects of rapamycin (RAPA) on inhibiting PQ-induced pulmonary fibrosis in mice and to explore its possible mechanisms. Methods: Male C57BL/6J mice were exposed to either saline (control group) or PQ (10 mg/kg body weight, intraperitoneally; test group). The test group was divided into four subgroups: a PQ group (PQ-exposed, non-treated), a PQ+RAPA group (PQ-exposed, treated with RAPA at 1 mg/kg intragastrically), a PQ+MP group (PQ-exposed, treated with methylprednisolone (MP) at 30 mg/kg intraperitoneally), and a PQ+MP+RAPA group (PQ-exposed, treated with MP at 30 mg/kg intraperitoneally and with RAPA at 1 mg/kg intragastrically). The survival rate and body weight of all the mice were recorded every day. Three mice in each group were sacrificed at 14 d and the rest at 28 d after intoxication. Lung tissues were excised and stained with hematoxylin-eosin (H&E) and Masson’s trichrome stain for histopathological analysis. The hydroxyproline (HYP) content in lung tissues was detected using an enzyme-linked immunosorbent assay (ELISA) kit. The expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) in lung tissues was detected by immunohistochemical staining and Western blotting. Results: A mice model of PQ-induced pulmonary fibrosis was established. Histological examination of lung tissues showed that RAPA treatment moderated the pathological changes of pulmonary fibrosis, including alveolar collapse and interstitial collagen deposition. HYP content in lung tissues increased soon after PQ intoxication but had decreased significantly by the 28th day after RAPA treatment. Immunohistochemical staining and Western blotting showed that RAPA treatment significantly down-regulated the enhanced levels of TGF-β1 and α-SMA in lung tissues caused by PQ exposure. However, RAPA treatment alone could not significantly ameliorate the lower survival rate and weight loss of treated mice. MP treatment enhanced the survival rate, but had no significant effects on attenuating PQ-induced pulmonary fibrosis or reducing the expression of TGF-β1 and α-SMA. Conclusions: This study demonstrates that RAPA treatment effectively suppresses PQ-induced alveolar collapse and collagen deposition in lung tissues through reducing the expression of TGF-β1 and α-SMA. Thus, RAPA has potential value in the treatment of PQ-induced pulmonary fibrosis.

Background Nicotine is rapidly absorbed from cigarette smoke and therefore induces a number of chronic illnesses with the widespread use of tobacco products. Studies have shown a few cerebral metabolites modified by nicotine; however, endogenous metabolic profiling in brain has not been well explored. Results H NMR-based on metabonomics was applied to investigate the endogenous metabolic profiling of brain hippocampus, nucleus acumens (NAc), prefrontal cortex (PFC) and striatum. We found that nicotine significantly increased CPP in mice, and some specific cerebral metabolites differentially changed in nicotine-treated mice. These modified metabolites included glutamate, acetylcholine, tryptamine, glucose, lactate, creatine, 3-hydroxybutyrate and nicotinamide-adenine dinucleotide (NAD), which was closely associated with neurotransmitter and energy source. Additionally, glutathione and taurine in hippocampus and striatum, phosphocholine in PFC and glycerol in NAc were significantly modified by nicotine, implying the dysregulation of anti-oxidative stress response and membrane metabolism. Conclusions Nicotine induces significant metabonomic alterations in brain, which are involved in neurotransmitter disturbance, energy metabolism dysregulation, anti-oxidation and membrane function disruptions, as well as amino acid metabolism imbalance. These findings provide a new insight into rewarding effects of nicotine and the underlying mechanism.

Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP) models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high-dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. (1)H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc) and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism.

Fluorescence properties of Eu3+ :Y2Si05 have been investigated. Transitions between 5D and 7Fwere were studied with transmission spectra, fluorescence spectra, photoluminescence excitation (or absorption) spectra and site selective fluorescence spectra. The X-ray powder diffraction pattern of Eu3+ :Y2Si05 shows that the crystal belong to monoclinic, and lattice’s constants a, b, c and β are obtained by a simulation with the measured diffraction angles.

Natural killer (NK) cells act as innate immune cells against hepatitis C virus (HCV) infection. Interferon-α (IFN-α) and ribavirin are the standard treatments for patients with HCV infection. This study is aimed at investigating the dynamic changes in the frequency of different subsets of NK cells following treatment in xx chronic hepatitis C (CHC) patients. CHC patients were treated with peg-IFN or IFN-α, and followed up for 72 weeks. The frequency of different subsets of NK in CHC patients was determined longitudinally by flow cytometry. Treatment with the standard therapy increased the percentages of NKp30(+), NKp46(+), and CD107a(+) NK cells, which were positively correlated with the declining of serum HCV-RNA, but not IFN-γ(+) NK cells. NKG2A(+) and KIR2DL3(+) NK cells were associated with an early virological response in CHC patients. Treatment with IFN-α adjusts the balance of activated receptors and inhibitory receptors and enhances the cytotoxic activity of NK cells. Therefore, measuring NK subsets may be valuable for therapeutic responses in CHC patients.

Comprehensive cerebral metabolites involved in morphine dependence have not been well explored. To gain a better understanding of morphine dependence and withdrawal therapy in a model highly related to humans, metabolic changes in brain hippocampus and prefrontal cortex (PFC) of rhesus monkeys were measured by (1) H-nuclear magnetic resonance spectroscopy, coupled with partial least squares and orthogonal signal correction analysis. The results showed that concentrations of myoinositol (M-Ins) and taurine were significantly reduced, whereas lactic acid was increased in hippocampus and PFC of morphine-dependent monkeys. Phosphocholine and creatine increased in PFC but decreased in hippocampus after chronic treatment of morphine. Moreover, N-acetyl aspartate (NAA), γ-aminobutyric acid, glutamate, glutathione, methionine, and homocysteic acid also changed in these brain regions. These results suggest that chronic morphine exposure causes profound disturbances of neurotransmitters, membrane, and energy metabolism in the brain. Notably, morphine-induced dysregulations in NAA, creatine, lactic acid, taurine, M-Ins, and phosphocholine were clearly reversed after intervention with methadone or clonidine. Our study highlights the potential of metabolic profiling to enhance our understanding of metabolite alteration and neurobiological actions associated with morphine addiction and withdrawal therapy in primates.

Investigations have characterized addictive drug-induced developmental cardiovascular malformation in human, non-human primate and rodent. However, the underlying mechanism of malformation caused by drugs during pregnancy is still largely unknown, and preventive and therapeutic measures have been lacking. Using 1H NMR spectroscopy, we profiled the metabolites from human embryo endothelial cells exposed to methamphetamine (METH) and quantified a total of 226 peaks. We identified 11 metabolites modified robustly and found that taurine markedly increased. We then validated the hypothesis that this dramatic increase in taurine could attribute to its effect in inhibiting METH-induced developmental angiogenesis defect. Taurine supplement showed a more significant potential than other metabolites in protecting against METH-induced injury in endothelial cells. Taurine strongly attenuated METH-induced inhibition of proliferation and migration in endothelial cells. Furthermore, death rate and vessel abnormality of zebrafish embryos treated with METH were greatly reversed by taurine. In addition, taurine supplement caused a rapid decrease in reactive oxygen species generation and strongly attenuated the excitable arise of antioxidase activities in the beginning of METH exposure prophase. Dysregulations of NF-κB, p-ERK as well as Bax, which reflect apoptosis, cell cycle arrest and oxidative stress in vascular endothelium, were blocked by taurine. Our results provide the first evidence that taurine prevents METH-caused developmental angiogenesis defect through antioxidant mechanism. Taurine could serve as a potential therapeutic or preventive intervention of developmental vascular malformation for the pregnant women with drug use.

A novel organic-inorganic hybrid 2D molecular space with regular triphenylphosphine groups (triphenylphosphineamidephenylsilica, PPh(3)APhS) was successfully synthesized through grafting triphenylphosphine groups in the 2D structure of layered aminophenylsilica dodecyl sulfate (APhTMS-DS), which was developed in our previous research, with regular ammonium groups. The 2D structures were kept after the grafting reaction of triphenylphosphine groups in PPh(3)APhS. The catalytic potentials of 2D molecular space with regular triphenylphosphine groups were investigated. An unusual catalytic effect was found in a carbon-phosphorus ylide reaction. The PPh(3)-catalyzed reaction of modified allylic compounds, including bromides and chlorides with tropone yielded a [3 + 6] annulation product. However, an unusual [8 + 3] cycloadduct was obtained in the reaction of modified allylic compounds, including bromides and chlorides with tropone catalyzed by PPh(3)APhS. Otherwise, the stable catalytic intermediate was successfully separated, and the reaction activity of the catalytic intermediate was confirmed in the reaction of modified allylic compounds with tropone catalyzed by PPh(3)APhS. This research is the first successful example of directly influencing catalytic reaction processes and product structures by utilizing the chemical and geometrical limits of 2D molecular spaces with regular catalyst molecules and affords a novel method for controlling catalytic reaction processes and catalyst design.

This study was carried out to investigate the protective role of taurine (2-aminoethanesulphonicacid) against morphine-induced neurotoxicity in C6 cells. It was found that taurine significantly increased the viability of C6 cells treated by morphine, showing the neuroprotective role against morphine-induced neurotoxicity. However, such neuroprotective effect of taurine could not be blocked by bicuculline, an antagonist of gamma-amino butyrate (GABA) receptor. To determine the oxidative damage induced by morphine, the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were measured in C6 cells. The decreased activities of SOD, CAT, and GPx in C6 cells were observed after morphine treatment for 48 h. However, taurine administration effectively ameliorated morphine-induced oxidative insult. To estimate anti-apoptosis effect of taurine, flow cytometry analysis as well as detection for caspase-3 and Bcl-2 expressions was performed after morphine exposure for 48 h. It was found that Bcl-2 expression was down regulated by morphine, whereas taurine could reverse morphine-induced decrease in Bcl-2 expression. Taurine showed no effect on caspase-3 expression. Collectively, the results show that taurine possesses the capability to ameliorate morphine-induced oxidative insult and apoptosis in C6 cells, probably due to its antioxidant activity rather than activation of GABA receptors.