Stable nanoscale sea-island structure of biobased polyamide 56/poly (butylene adipate-co-terephthalate) blends compatibilized by interfacial hyperbranched structure: Toward biobased polymer blends with ultrahigh toughness.

Developing biobased materials is a considerably effective approach to save fossil resources and reduce emissions. Biobased polyamide 56 (PA56) is an excellent engineering material, but it has low toughness. Herein, to enhance the toughness of PA56, an ultra-tough biodegradable material, i.e., poly (butylene adipate-co-terephthalate) (PBAT) was introduced into PA56. Moreover, a self-synthesized epoxy-terminated hyperbranched polyester (EHBP) was used to improve the compatibility of the blended materials. The results of differential scanning calorimetry and Fourier-transform infrared spectroscopy indicated that the epoxide group of EHBP could react with PA56 and PBAT to form a block-like polymer structure and limit the crystallization behavior of the blends. The scanning electron microscopy results show that the addition of EHBP considerably reduced the dispersed-phase size in the blends, forming a nanoscale island structure. Moreover, the hydrogen bonds formed between EHBP and PA56/PBAT enhanced the intermolecular interaction between the two materials. Thus, PA56 blends with ultrahigh toughness were successfully prepared. The prepared PA56/PBAT/EHBP blend exhibited a notch impact strength of 20.71 kJ/m2 and a breaking elongation of 38.3 %, which represent increases of 427.3 % and 252.8 %, respectively, compared with those of pure PA56. Thus, the proposed method is suitable for toughening PA56 and broadening its applications.

The role of mammalian Sirtuin 6 in cardiovascular diseases and diabetes mellitus.

Cardiovascular diseases are severe diseases posing threat to human health because of their high morbidity and mortality worldwide. The incidence of diabetes mellitus is also increasing rapidly. Various signaling molecules are involved in the pathogenesis of cardiovascular diseases and diabetes. Sirtuin 6 (Sirt6), which is a class III histone deacetylase, has attracted numerous attentions since its discovery. Sirt6 enjoys a unique structure, important biological functions, and is involved in multiple cellular processes such as stress response, mitochondrial biogenesis, transcription, insulin resistance, inflammatory response, chromatin silencing, and apoptosis. Sirt6 also plays significant roles in regulating several cardiovascular diseases including atherosclerosis, coronary heart disease, as well as cardiac remodeling, bringing Sirt6 into the focus of clinical interests. In this review, we examine the recent advances in understanding the mechanistic working through which Sirt6 alters the course of lethal cardiovascular diseases and diabetes mellitus.

Stress granule activation attenuates lipopolysaccharide-induced cardiomyocyte dysfunction.

BACKGROUND: Sepsis is the leading cause of death in intensive care units. Sepsis-induced myocardial dysfunction, one of the most serious complications of sepsis, is associated with higher mortality rates. As the pathogenesis of sepsis-induced cardiomyopathy has not been fully elucidated, there is no specific therapeutic approach. Stress granules (SG) are cytoplasmic membrane-less compartments that form in response to cellular stress and play important roles in various cell signaling pathways. The role of SG in sepsis-induced myocardial dysfunction has not been determined. Therefore, this study aimed to determine the effects of SG activation in septic cardiomyocytes (CMs). METHODS: Neonatal CMs were treated with lipopolysaccharide (LPS). SG activation was visualized by immunofluorescence staining to detect the co-localization of GTPase-activating protein SH3 domain binding protein 1 (G3BP1) and T cell-restricted intracellular antigen 1 (TIA-1). Eukaryotic translation initiation factor alpha (eIF2α) phosphorylation, an indicator of SG formation, was assessed by western blotting. Tumor necrosis factor alpha (TNF-α) production was assessed by PCR and enzyme-linked immunosorbent assays. CMs function was evaluated by intracellular cyclic adenosine monophosphate (cAMP) levels in response to dobutamine. Pharmacological inhibition (ISRIB), a G3BP1 CRISPR activation plasmid, and a G3BP1 KO plasmid were employed to modulate SG activation. The fluorescence intensity of JC-1 was used to evaluate mitochondrial membrane potential. RESULTS: LPS challenge in CMs induced SG activation and resulted in eIF2α phosphorylation, increased TNF-α production, and decreased intracellular cAMP in response to dobutamine. The pharmacological inhibition of SG (ISRIB) increased TNF-α expression and decreased intracellular cAMP levels in CMs treated with LPS. The overexpression of G3BP1 increased SG activation, attenuated the LPS-induced increase in TNF-α expression, and improved CMs contractility (as evidenced by increased intracellular cAMP). Furthermore, SG prevented LPS-induced mitochondrial membrane potential dissipation in CMs. CONCLUSION: SG formation plays a protective role in CMs function in sepsis and is a candidate therapeutic target.

miR­141 impairs mitochondrial function in cardiomyocytes subjected to hypoxia/reoxygenation by targeting Sirt1 and MFN2.

Mitochondrial oxidative stress and dysfunction are major pathogenic features of cardiac injury induced by ischemia/reperfusion (I/R). MicroRNA-141 (miR-141) has been implicated in the mitochondrial dysfunction in cell-based models of oxidant stress. Thus, the main aim of the present study was to systematically assess the role of miR-141 in cardiomyocyte injury induced by simulated I/R. The challenge of HL-1 cardiomyocytes with hypoxia/reoxygenation (H/R) decreased cell viability, which was also associated with an increase in miR-141 expression. The H/R-induced cell injury was mitigated by a miR-141 inhibitor and exacerbated by a miR-141 mimic. Furthermore, H/R induced mitochondrial superoxide production, dysfunction (decreased oxygen utilization and membrane depolarization), as well as ultrastructural damage. These mitochondrial effects were mitigated by a miR-141 inhibitor and intensified by a miR-141 mimic. Luciferase reporter assay, reverse transcription-quantitative PCR, and western blot analyses identified sirtuin-1 (Sirt1) and mitofusin-2 (MFN2) as targets of miR-141. The silencing of Sirt1 reduced the MFN2 cardiomyocyte levels and reversed the alleviating effects of miR-141 inhibitor on mitochondrial function during H/R. Collectively, these findings suggest that miR-141 functions as a causative agent in cardiomyocyte injury induced by I/R, primarily by interfering with two mitochondrial regulatory proteins, Sirt1 and MFN2.

Synthesis of Ag/BiOBr/CeO2 composites with enhanced photocatalytic degradation for sulfisoxazole.

A novel Ag/BiOBr/CeO2 composite was successfully prepared for the first time, which had excellent performance in degrading sulfisoxazole (SSX) under visible light irradiation. The as-prepared samples were characterized by SEM, XRD, UV-vis DRS and BET et al. The composite of 10% Ag/BiOBr/CeO2 showed the best photocatalytic activity and more than 99.5% SSX can be removed within 20 min. It exhibited the highest k value of 0.2428 min-1, which was about 39.7 times higher than pure BiOBr (6.11 × 10-3 min-1) and 22.1 times higher than BiOBr/CeO2 (1.09 × 10-2 min-1), respectively. The addition of Ag significantly improved the absorption rate of visible light and the separation rate of photogenerated electron-hole pairs. The initial pH and dosage of samples could have an influence on the photocatalytic activity. The radical trapping experiments proved that ·O2- and h+ were the main active species involved in photocatalytic degradation. Finally, the synthesized catalyst maintained excellent photocatalytic activity after 5 repeated cycles, which indicated the extraordinary stability and recyclability of Ag/BiOBr/CeO2.

Biomimetic Copper Forest Wick Enables High Thermal Conductivity Ultrathin Heat Pipe.

Electronic devices with high heat flux are currently facing heat dissipation problems. Heat pipes can be used as efficient heat spreaders to address this critical problem. However, as electronic devices become smaller, the space for heat dissipation is becoming ever so limited; hence, ultrathin heat pipes are desired. This study proposes a biomimetic copper forest wick for an ultrathin heat pipe (UTHP). It is made by a simple one-step electrodeposition process and appears as a natural forest structure with abundant Ω-like grooves. Capillary rise tests with ethanol were performed to characterize the capillary force of the wick structure. Compared to traditional sintered particles, this wick structure has a much higher capillary performance parameter, K/Reff. The biomimetic copper forest wick was used to fabricate a 0.6 mm thick UTHP. The UTHP was tested at different filling ratios; the optimum filling ratio was found to be about 71%. At a heating power of 6 W, the temperature difference between the condenser and evaporator was only 1.2 °C, with an effective thermal conductivity, λeff, up to 1.26 × 104 W m-1 K-1.

CPF impedes cell cycle re-entry of quiescent lung cancer cells through transcriptional suppression of FACT and c-MYC.

Blockade of cell cycle re-entry in quiescent cancer cells is a strategy to prevent cancer progression and recurrence. We investigated the action and mode of action of CPF mixture (Coptis chinensis, Pinellia ternata and Fructus trichosanthis) in impeding a proliferative switch in quiescent lung cancer cells. The results indicated that CPF impeded cell cycle re-entry in quiescent lung cancer cells by reduction of FACT and c-MYC mRNA and protein levels, with concomitant decrease in H3K4 tri-methylation and RNA polymerase II occupancy at FACT and c-MYC promoter regions. Animals implanted with quiescent cancer cells that had been exposed to CPF had reduced tumour volume/weight. Thus, CPF suppresses proliferative switching through transcriptional suppression of FACT and the c-MYC, providing a new insight into therapeutic target and intervention method in impeding cancer recurrence.

Interspecies variation of clopidogrel hydrolysis in liver microsomes from various mammals.

Clopidogrel, a clinically used antiplatelet agent, can be readily hydrolyzed by human carboxylesterase 1A (CES1A) to release an inactive metabolite clopidogrel carboxylic acid (CCA). In this study, clopidogrel was used as a tool substrate to investigate the interspecies variation of clopidogrel hydrolysis in hepatic microsomes from various mammals including human and six laboratory animals (such as mouse, rat, rabbit, beagle dog, minipig and cynomolgus monkey). The results demonstrated that clopidogrel could be hydrolyzed into CCA by all tested hepatic microsomes from human or other mammals, but the hydrolytic rates greatly varied among species. Inhibition assays demonstrated that BNPP (an inactivator of mammalian CES) strongly inactivated clopidogrel hydrolytic activity in all tested hepatic microsomes, suggested that mammalian CES were major contributor(s) responsible for clopidogrel hydrolysis in hepatic preparations from all above-mentioned species. By contrast, the response of a reversible inhibitor of human CES1A on clopidogrel hydrolysis in these liver preparations varied significantly among different species. Moreover, the enzymatic kinetics and the apparent kinetic parameters of clopidogrel hydrolysis in hepatic microsomes from various animal species were evaluated and compared to each other. These findings provide crucial information for deeply understanding the differences in catalytic behaviors of mammalian CES, which will be very helpful for choosing suitable laboratory animal(s) for whole tests of CES1A substrate-drugs.

Discovery of a highly specific and efficacious inhibitor of human carboxylesterase 2 by large-scale screening.

Human carboxylesterase 2 (CES2A), one of the most abundant hydrolases distributed in human small intestine and colon, play key roles in the hydrolysis of a wide range of prodrugs and other esters. Recent studies have demonstrated that CES2A inhibitors may ameliorate irinotecan-induced severe diarrhea, but the specific and efficacious inhibitors targeting intracellular CES2A are rarely reported. Herein, a large-scale screening campaign was conducted for discovery of potent and specific CES2A inhibitor(s). Following screening of more than one hundred of natural products, glabridin (a bioactive compound of Glycyrrhiza glabra L.) was found displaying potent inhibition on CES2A and high specificity over CES1A (>500-fold) and other serine hydrolases. Further investigation showed that glabridin was cell permeable and low cytotoxic, as well as capable of inhibiting intracellular CES2A in living cells, with the IC50 value of 0.52 µM. Molecular dynamics simulations showed that glabridin formed strong and stable interactions with both the catalytic cavity and Z site of CES2A via hydrophobic interactions. In summary, glabridin was a potent and specific inhibitor targeting intracellular CES2A, which could be used as an ideal lead compound to develop more efficacious CES2A inhibitors for modulating the pharmacokinetic behaviors of CES2A-substrate drugs and alleviating irinotecan-induced diarrhea.

Inhibition of human carboxylesterases by magnolol: Kinetic analyses and mechanism.

Magnolol, the most abundant bioactive constituent of the Chinese herb Magnolia officinalis, has been found with multiple biological activities, including anti-oxidative, anti-inflammatory and enzyme-regulatory activities. In this study, the inhibitory effects and inhibition mechanism of magnolol on human carboxylesterases (hCEs), the key enzymes responsible for the hydrolytic metabolism of a variety of endogenous esters as well as ester-bearing drugs, have been well-investigated. The results demonstrate that magnolol strongly inhibits hCE1-mediated hydrolysis of various substrates, whereas the inhibition of hCE2 by magnolol is substrate-dependent, ranging from strong to moderate. Inhibition of intracellular hCE1 and hCE2 by magnolol was also investigated in living HepG2 cells, and the results showed that magnolol could strongly inhibit intracellular hCE1, while the inhibition of intracellular hCE2 was weak. Inhibition kinetic analyses and docking simulations revealed that magnolol inhibited both hCE1 and hCE2 in a mixed manner, which could be partially attributed to its binding at two distinct ligand-binding sites in each carboxylesterase, including the catalytic cavity and the regulatory domain. In addition, the potential risk of the metabolic interactions of magnolol via hCE1 inhibition was predicted on the basis of a series of available pharmacokinetic data and the inhibition constants. All these findings are very helpful in deciphering the metabolic interactions between magnolol and hCEs, and also very useful for avoiding deleterious interactions via inhibition of hCEs.

[Inhibitory effect of flavonoids from Scutellariae Radix on human cytochrome P450 1A].

This study investigated the inhibitory effect of eight natural flavonoids in Chinese herb Scutellariae Radix on huamn cytochrome P450 1 A(CYP1 A), a key cancer chemo-preventive target. In this study, phenacetin was used as a probe substrate for CYP1 A, while human liver microsomes and recombinant human CYP1 A enzymes were used as enzyme sources. Liquid chromatography-tandem mass spectrometry was used to monitor the formation rates of acetaminophen, the O-deethylated metabolite of phenacetin. The dose-dependent inhibition curves were depicted based on the changes of the formation rates of acetaminophen, while the IC_(50) were determined. Inhibition kinetic analyses and docking simulations were used to investigate the inhibition modes and mechanism of wogonin(the most potent CYP1 A inhibitor in this herb), while the inhibition constants(K_i) of wogonin against both CYP1 A1 and CYP1 A2 were determined. Among all tested flavonoids, wogonin, 7-methoxyflavanone and oroxylin A displayed a strong inhibitory effect on CYP1 A(IC_(50)<1 µmol·L~(-1)), baicalein exhibited a moderate inhibitory effect on CYP1 A(IC_(50) between 1-10 µmol·L~(-1)), and baicalin, scutellarein and wogonoside displayed a very weak inhibitory effect on CYP1 A(IC_(50) between 10-25 µmol·L~(-1)), but scutellarin displayed a negligible inhibitory effect on CYP1 A(IC_(50)>100 µmol·L~(-1)). Further investigations demonstrated that wogonin had a weak inhibitory effect on other human CYP enzymes, suggesting that it could be used as a lead compound for the development of specific inhibitors of CYP1 A. Furthermore, the inhibition kinetic analyses clearly demonstrated that wogonin could strongly inhibit phenacetin O-deethylation in both CYP1 A1 and CYP1 A2 in a competitive manner, with K_i values at 0.118 and 0.262 µmol·L~(-1), respectively. Molecular docking demonstrated that wogonin could strongly interact with CYP1 A1 and CYP1 A2 via hydrophobic and π-π interactions, as well as Ser120 and Ser116 in CYP1 A1 via hydrogen-bonding. In conclusion, this study found that some flavonoids in Scutellariae Radix displayed a strong inhibitory effect on CYP1 A, while wogonin is the most potent CYP1 A inhibitor with a relatively high selectivity towards CYP1 A over other human CYPs.

Nevadensin is a naturally occurring selective inhibitor of human carboxylesterase 1.

Human carboxylesterase 1 (hCE1) is a key enzyme responsible for the hydrolysis of a wide range of endogenous and xenobiotic esters, but the highly selective inhibitors against hCE1 are rarely reported. This study aimed to assess the inhibitory effects of natural flavonoids against hCE1 and to find potential specific hCE1 inhibitors. To this end, fifty-eight natural flavonoids were collected and their inhibitory effects against both hCE1 and hCE2 were assayed. Among all tested compounds, nevadensin, an abundant natural constitute from Lysionotus pauciflorus Maxim., displayed the best combination of inhibition potency and selectivity towards hCE1. The inhibition mechanism of nevadensin on hCE1 was further investigated using two site-specific hCE1 substrates including D-luciferin methyl ester (DME) and 2­(2­benzoyloxy­3­methoxyphenyl)benzothiazole (BMBT). Furthermore, docking simulations demonstrated that the binding area of nevadensin on hCE1 was highly overlapped with that of DME but was far away from that of BMBT, which was highly consistent with the inhibition modes of nevadensin. These findings found a natural occurring specific inhibitor of hCE1, which could be served as a lead compound for the development of novel hCE1 inhibitor with improved properties, and also hold great promise for investigating hCE1-ligand interactions.

Study on the effect of PolyFR and its FR system on the flame retardancy and foaming behavior of polystyrene.

A new class of brominated polymeric flame retardant (PolyFR) which is a kind of environmental FR was researched. Hydrotalcite (HT), applied as an environmentally-friendly heat stabilizer for PolyFR, was investigated by thermogravimetric analysis (TGA). It presented the result that no more than 0.15% HT significantly improved the thermal stability during processing but excessive HT would weaken the flame retardancy of PolyFR because of the ability to absorb hydrogen bromide (HBr). Flame-retardant polystyrene (PS) was prepared via mixing PolyFR/BDDP/HT and then introducing inorganic particles such as antimonous oxide (Sb2O3), organo montmorillonite (OMMT) and graphite to study their effect on the PolyFR/BDDP/HT system. The PS foams were prepared by batch foaming of the PS composites. Meanwhile, the combustion properties of PS composites and PS composite foams were characterized by limiting oxygen index (LOI) and vertical flame test (UL-94). The results indicated that the 2.5%PolyFR/2.5%BDDP/0.15%HT/PS composite possessed 25.7% LOI and pass UL-94 V-2 rating, while its foam possessed 30.7% LOI and pass UL-94 V-2 rating. And the addition of Sb2O3, OMMT and graphite reduced the oxygen index and vertical burning performance of PS composites and PS composite foams to different degrees. Otherwise, the flame-retardant (FR) mechanism of each FR system was studied by TGA and cone calorimetry. This revealed that PolyFR/BDDP promoted decomposition and dripping of PS early to remove heat through droplets and released HBr to quench free radicals and dilute combustible gas and oxygen during combustion. These properties of PolyFR/BDDP helped reduce the burning intensity and extinguish the flame through droplets, thereby endowing PS and its foam with better fire-resistant properties. When the addition of Sb2O3, OMMT or graphite improved the thermal stability of PS, they weakened the droplet effect as well. Besides, PS foams were characterized by scanning electron microscopy (SEM). The results indicated PolyFR played an efficient heterogeneous cell nucleation role in the foaming process to reduce average cell size (from 110.5 µm to 38.4 µm) and narrow cell distribution (from 60-160 µm to 20-60 µm).