Title: Combined-methods elucidate the multi-organ toxicity of cylindrospermopsin (CYN) on Daphnia magna He Z, Chen Y, Huo D, Gao J, Xu Y, Yang R, Yang Y, Yu G Ref: Environ Pollut, :121250, 2023 : PubMed
Global water bodies are now at risk from inevitable cyanobacterial blooms and their production of multiple cyanotoxins, in particular cylindrospermopsin (CYN). However, research on the CYN toxicity and its molecular mechanisms is still limited, whilst the responses of aquatic species against CYN are uncovered. By integrating behavioral observations, chemical detections and transcriptome analysis, this study demonstrated that CYN exerted multi-organ toxicity to model species, Daphnia magna. The present study confirmed that CYN could cause protein inhibition by undermining total protein contents, and altered the gene expression related to proteolysis. Meantime, CYN induced oxidative stress by increasing reactive oxidative species (ROS) level, decreasing the glutathione (GSH) concentration, and interfered with protoheme formation process molecularly. Neurotoxicity led by CYN was solidly determined by abnormal swimming patterns, reduced acetylcholinesterase (AChE), and downward expression of muscarinic acetylcholine receptor (CHRM). Importantly, for the first time, this research determined CYN directly interfered with energy metabolism in cladocerans. CYN distinctively reduced filtration and ingestion rate by targeting on heart and thoracic limbs, which declined the energy intake, and could be further displayed by the reduction of motional strength and the trypsin concentration. These phenotypic alterations were supported by transcriptomic profile, including the down-regulation of oxidative phosphorylation and ATP synthesis. Moreover, CYN was speculated to trigger the self-defense responses of D. magna, known as "abandon-ship" by moderating lipid metabolism and distribution. This study, overall, comprehensively demonstrated the CYN toxicity and the responses of D. magna against it, which is of great significance to the advancements of CYN toxicity knowledge.
        
Title: Comprehensive Enantioselectivity Evaluation of Insecticidal Activity and Mammalian Toxicity of Fenobucarb He Z, Li C, Xia W, Wang Z, Li R, Zhang Y, Wang M Ref: Journal of Agricultural and Food Chemistry, :, 2022 : PubMed
To comprehensively evaluate the efficiency and risk of the chiral pesticide fenobucarb, the bioactivity, toxicity, and environmental behavior of fenobucarb (FNC) enantiomers were investigated. The results showed that R-FNC possesses 1.8-2.7 times more bioactivity than S-FNC but 1.3-3.0 times lower toxicity than S-FNC against four nontarget organisms: Chlorella pyrenoidosa, HepG2, and Danio rerio and its embryos. The corresponding enzyme inhibitory activity showed consistent results; the acetylcholinesterase inhibitory activity of target organisms was ordered as R-FNC > rac-FNC > S-FNC, while the reduction in catalase activity after exposure to R-FNC was 2.5 times that after exposure to S-FNC in zebrafish. The enantioselective bioactivity mechanism of FNC enantiomers was further explored in silico. No significant enantioselective degradation was found in soils or rat liver microsomes. In sum, R-FNC possesses higher insecticidal activity and lower toxicity. The development of R-FNC as a commercial agrochemical is beneficial for reducing pesticide inputs.
        
Title: New fluorescent probe with recognition moiety of bipiperidinyl reveals the rise of hepatocellular carboxylesterase activity during heat shock Liu Y, He Z, Yang Y, Li X, Li Z, Ma H Ref: Biosensors & Bioelectronics, 211:114392, 2022 : PubMed
Heat shock is a heat-related pathology characterized by a high body temperature and an obvious change of many enzymatic activities. Carboxylesterase (CE), as the major hydrolase in liver, is responsible for the hydrolysis of many drugs or the detoxification of various toxins from all organs. However, the correlation between heat shock and the CE activity in cells remains unknown, mainly due to the lack of a suitable research approach. Herein, a new water-soluble fluorescence probe, MYO-CE, with a specific bipiperidinyl recognition moiety has been developed for detecting the CE activity. MYO-CE reacted selectively with CE instead of other esterase, causing a large fluorescence off-on response at 560 nm with a detection limit of 0.39 U/mL. The applicability of MYO-CE for cell imaging was demonstrated by monitoring the alteration of the hepatocellular CE activity under inflammation. More importantly, we investigated the change of the CE activity during heat shock, uncovering a significant increase for the first time. This finding was further validated by a commercial colorimetric kit assay. The proposed probe shows a promising prospect for the CE study in cells under different pathological conditions.
As a forceful nematicide, fosthiazate has been largely applied in the management of root-knot nematodes and other herbivorous nematodes. However, the toxicity of fosthiazate to nontarget nematodes is unclear. To explore the toxicity and the mechanisms of fosthiazate in nontarget nematodes, Caenorhabditis elegans was exposed to 0.01-10 mg/L fosthiazate. The results implied that treatment with fosthiazate at doses above 0.01 mg/L could cause injury to the growth, locomotion behavior, and reproduction of the nematodes. Moreover, L1 larvae were more vulnerable to fosthiazate exposure than L4 larvae. Reactive oxygen species (ROS) production and lipofuscin accumulation were fairly increased in 1 mg/L fosthiazate-exposed nematodes. Treatment with 0.1 mg/L fosthiazate significantly inhibited the activity of acetylcholinesterase (p < 0.01). Furthermore, subacute exposure to 10 mg/L fosthiazate strongly influenced the expression of genes related to oxidative stress, reproduction, and nerve function (e.g., gst-1, sod-1, puf-8, wee-1.3, and ace-1 genes). These findings suggested that oxidative stress, reproduction and nerve disorders could serve as key endpoints of toxicity induced by fosthiazate. The cyp-35a family gene was the main metabolic fosthiazate in C. elegans, and the cyp-35a5 subtype was the most sensitive, with a change in expression level of 2.11-fold compared with the control. These results indicate that oxidative stress and neurological and reproductive disorders played fundamental roles in the toxicity of fosthiazate in C. elegans and may affect the abundance and function of soil nematodes.
Currently, no suitable clinical drugs are available for patients with neurodegenerative diseases complicated by depression. Based on a fusion technique to create effective multi-target-directed ligands (MTDLs), we synthesized a series of (R)-N-(benzo[d]thiazol-2-yl)-2-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl) acetamides with substituted benzothiazoles and (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline. All compounds were tested for their inhibitory potency against monoamine oxidase (MAO) and cholinesterase (ChE) by in vitro enzyme activity assays, and further tested for their specific inhibitory potency against monoamine oxidase B (MAO-B) and butyrylcholinesterase (BuChE). Among them, six compounds (4b-4d, 4f, 4g and 4i) displayed excellent activity. The classical antidepressant forced swim test (FST) was used to verify the in vitro results, revealing that six compounds reduced the immobility time significantly, especially compound 4g. The cytotoxicity of the compounds was assessed by the MTT method and Acridine Orange (AO) staining, with cell viability found to be above 90% at effective compound concentrations, and not toxic to L929 cells reversibility, kinetics and molecular docking studies were also performed using compound 4g, which showed the highest MAO-B and BuChE inhibitory activities. The results of these studies showed that compound 4g binds to the primary interaction sites of both enzymes and has good blood-brain barrier (BBB) penetration. This study provides new strategies for future research on neurodegenerative diseases complicated by depression.
        
Title: Improving Effect of the Policosanol from Ericerus pela Wax on Learning and Memory Impairment Caused by Scopolamine in Mice Sun L, Li X, Ma C, He Z, Zhang X, Wang C, Zhao M, Gan J, Feng Y Ref: Foods, 11:, 2022 : PubMed
Policosanol (PC) is a mixture of long-chain fatty alcohols that exhibits multiple biological activities, such as reducing blood lipid and cholesterol levels, lowering blood pressure, and extenuating liver inflammation. To assess PC's impact on cognitive behavior and function, PC was prepared from Ericerus pela wax using a reduction method and analyzed using gas chromatography (GC). A total of 60 mice were randomly divided into six groups of 10 animals each: control (0.5% CMC-Na solution, i.g.), model (0.5% CMC-Na solution, i.g.), donepezil (3 mg/kg, i.g.), PC low- (2 g/kg, i.g.), medium (4 g/kg, i.g.), and high- (6 g/kg, i.g.) dose groups. All the groups were administered daily for 28 consecutive days. There were four parameters-escape latency, crossings of platform, swimming distance, and time spent in the target quadrant-that were recorded to evaluate the cognitive performance of mice in the Morris Water Maze (MWM). After MWM testing, the levels of acetylcholine (ACh), acetylcholinesterase (AChE), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) that were present in brain tissue were determined using assay kits. The GC data showed that PC consisted of four major components: tetracosanol (14.40%), hexacosanol (48.97%), octacosanol (25.40%), and triacontanol (4.80%). In the MWM test, PC significantly decreased the escape latency (p < 0.05) and increased the crossings of the platform (p < 0.05) and swimming distance (p < 0.05) and time in the target quadrant (p < 0.05) in rodents compared to that in the model group. Moreover, PC increased the levels of ACh, SOD, and GSH; inhibited AChE; and reduced MDA in the brain tissue of the tested animals. This is the first report to evaluate the efficacy of PC for cognitive behavior and function in animals. Our findings demonstrate that PC from E. pela wax is likely to exert an enhancing effect on learning and memory by promoting the cholinergic system and attenuating oxidative stress, which will provide a new insight into the efficacy of PC and expand its application in the food, nutraceutical, and beverage industries.
        
Title: Microplastics exposure as an emerging threat to ancient lineage: A contaminant of concern for abnormal bending of amphioxus via neurotoxicity Xiang K, He Z, Fu J, Wang G, Li H, Zhang Y, Zhang S, Chen L Ref: J Hazard Mater, 438:129454, 2022 : PubMed
Growing inputs of microplastics into marine sediment have increased significantly the needs for assessment of their potential risks to the marine benthos. A knowledge gap remains with regard to the effect of microplastics on benthos, such as cephalochordates. By employing amphioxus as a model benthic chordate, here we show that exposure to microplastics for 96 h at doses of 1 mg/L and 100 mg/L results in evident accumulation of the polyethylene microplastics. The accumulated microplastics are as much as 0.027% of body weight upon high-dose exposure, causing an abnormal body-bending phenotype that limits the locomotion capability of amphioxus. Mechanistic insight reveals that microplastics can bring about histological damages in gill, intestine and hepatic cecum; In-depth assay of relevant biomarkers including superoxide dismutase, catalase, glutathione, pyruvic acid and total cholesterol indicates the occurrence of oxidative damage and metabolic disorder; Further, microplastics exposure depresses the activity of acetylcholinesterase while allowing the level of acetylcholine to rise in muscle, suggesting the emergence of neurotoxicity. These consequences eventually contribute to the muscle dysfunction of amphioxus. This study rationalizes the abnormal response of the vulnerable notochord to microplastics, signifying the dilemma suffered by the ancient lineage under the emerging threat. Given the enrichment of microplastics through marine food chains, this study also raises significant concerns on the impact of microplastics to other marine organisms, and eventually human beings.
Off-target drug release and insufficient drug delivery are the main obstacles for effective anticancer chemotherapy. Prodrug-based self-assembled nanoparticles bioactivated under tumor-specific conditions are one of the effective strategies to achieve on-demand drug release and effective tumor accumulation. Herein, stimuli-activable prodrugs are designed yielding smart tumor delivery by combination of the triglyceride-mimic (TG-mimetic) prodrug structure and disulfide bond. Surprisingly, these prodrugs can self-assemble into uniform nanoparticles (NPs) with a high drug loading (over 40%) and accumulate in tumor sites specifically. The super hydrophobic TG structure can act as a gate that senses lipase to selectively control over NP dissociation and affect the glutathione-triggered prodrug activation. In addition, the impacts of the double bonds in the prodrug NPs on parent drug release and the following cytotoxicity, pharmacokinetics, and antitumor efficiency are further demonstrated. Our findings highlight the promising potential of TG-mimetic structure-gated prodrug nanoparticles for tumor-specific drug delivery.
        
Title: Enantioselective disposition and metabolic products of isofenphos-methyl in rats and the hepatotoxic effects Gao B, Zhao S, Shi H, Zhang Z, Li L, He Z, Wen Y, Covaci A, Wang M Ref: Environ Int, 143:105940, 2020 : PubMed
Isofenphos-methyl (IFP), a chiral organophosphorus pesticide, is one of the main chemicals used to control underground insects and nematodes. Recently, the use of IFP on vegetables and fruits has been prohibited due to its high toxicity. In this study, we investigated the enantioselective distribution and metabolism of IFP and its metabolites, namely, isofenphos-methyl oxon (IFPO) and isocarbophos oxon (ICPO), in male Sprague Dawley (SD) rats. Forty eight hours (48 h) after exposure, ICPO was the main detectable compound in blood (up to 75%) and urine (up to 77%), and we found that (S)-ICPO was significantly more stable than (R)-ICPO (p < 0.05). Therefore, (S)-ICPO was proposed as a suitable candidate biomarker for the biomonitoring of IFP in human urine and blood. After 48 h exposure, 21.2-41.0%, 4.1-15.1%, and 8.6-18.7% of dosed IFP was detected in the liver of racemic, R and S enantiomer-exposed rats, respectively, and R-IFP and R-IFPO showed a faster degradation (p < 0.05). Our results showed that after one week of consecutive exposure to IFP, ICPO was accumulated in the liver of rats in both racemic and enantiopure groups (no difference between the groups, p > 0.05). We found that cytochrome P450 (CYP) (i.e. CYP2C11, CYP2D2 and CYP3A2 enzymes and carboxylesterases) is responsible for the enantioselective metabolism of IFP in liver. In addition, rats exposed to (S)-IFP exhibited hepatic lipid peroxidation, liver inflammation and hepatic fibrosis. This study provides useful information and a reference for the biomonitoring and risk assessment of IFP and organophosphorus pesticide exposure.
In this paper, the acute toxicity of monobutyl phthalate (MBP), the main hydrolysis product of dibutyl phthalate, on adult zebrafish liver antioxidant system was studied. Compared the toxicity effect of MBP and DBP by histopathology and apoptosis experiments, we speculated that the toxic effects of DBP on animals may be caused by its metabolite MBP. The results indicated that the antioxidant Nrf2-Keap1 pathway was insufficient to resist MBP-induced hepatotoxicity and led to an imbalance of membrane ion homeostasis and liver damage. Decreased cell viability, significant tissue lesions and early hepatocyte apoptosis were observed in the zebrafish liver in MBP exposure at high concentration (10 mg/L). The activities of antioxidant enzymes and ATPases in zebrafish liver were inhibited with increased malondialdehyde (MDA) content and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Integrated biomarker response (IBR) calculation results indicated that MBP mainly inhibited catalase (CAT) activity. Simultaneously, the expression of antioxidant-related genes (SOD, CAT, GPx, Nrf2, HO-1) was down-regulated, while apoptosis-related genes (p53, bax, cas3) were significantly up-regulated.
        
Title: Cognitive-enhancing effects of fibrauretine on Abeta1-42-induced Alzheimer's disease by compatibilization with ginsenosides Zhang M, Chen W, Zong Y, Shi K, Li J, Zeng F, He Z, Du R Ref: Neuropeptides, :102020, 2020 : PubMed
Fibrauretine is the main active ingredient in rattan stems of Fibraurea recisa Pierre. The aim of this study was to evaluate the cognitive-enhancing effects and underlying molecular mechanisms of fibrauretine compatibilized with ginsenosides on Alzheimer's disease (AD) induced in mice with amyloid beta-protein (Abeta1-42). The results showed that the spatial learning and memory abilities of AD mice were significantly enhanced after combined treatment with fibrauretine and ginsenosides using the Morris water maze test. The levels of acetylcholinesterase (AChE) and phosphorylated Tau protein (p-Tau) in brain tissue and the levels of nitric oxide (NO), malondialdehyde (MDA), and N-terminal pro-brain natriuretic peptide (NT-proBNP) in plasma were significantly increased in Abeta1-42-induced AD mice, and these effects were reversed after combined treatment with fibrauretine and ginsenosides. By contrast, a significant increase in the levels of catalase (CAT), superoxide dismutase (SOD), choline acetyltransferase (ChAT) and glutathione peroxidase (GSH-Px) was observed in the combined treatment group. The results of haematoxylin and eosin (H&E) staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) analysis, immunohistochemistry (IHC) and Western blot analysis showed that the apoptosis rate, Bax, nuclear factor kappa-B p65 (NF-kappaBp65), cleaved caspase-3 and cleaved caspase-9 expression levels were obviously decreased and that the Bcl-2 expression levels were significantly increased in the hippocampi of mice treated with fibrauretine and ginsenosides. The results of this study show that the ameliorative effect of fibrauretine against AD can be significantly enhanced by compatibilization with ginsenosides. The underlying molecular mechanisms of fibrauretine may be related to antioxidation and anti-apoptosis.
Isofenphos-methyl (IFP) is a very active and persistent chiral insecticide. However, IFP has lower activity against acetylcholinesterases (AChEs). Previously, it was confirmed that phosphorothioate organophosphorus pesticides with N-alkyl (POPN) require activation by oxidative desulfuration and N-dealkylation. In this work, we demonstrated that IFP could be metabolized in human liver microsomes to isofenphos-methyl oxon (IFPO, 52.7%), isocarbophos (ICP, 14.2%) and isocarbophos oxon (ICPO, 11.2%). It was found that (R)-IFP was preferentially degraded compared to the (S)-enantiomer, and the enantiomeric fraction (EF) value reached 0.61 at 60min. However, (S)-enantiomers of the three metabolites, were degraded preferentially, and the EF values ranged from 0.34 to 0.45. Cytochrome P450 (CYP) isoforms CYP3A4, CYP2E1, and CYP1A2 and carboxylesterase enzyme have an essential role in the enantioselective metabolism of IFP; but, the enzymes that participate in the degradation of IFP metabolites are different. The AChE inhibition bioassay indicated that ICPO is the only effective inhibitor of AChE. The covalent molecular docking has proposed that the metabolites of IFP and its analogs after N-dealkylation and oxidative desulfuration will possess the highest inhibitory activity against AChE. This study is the first to demonstrate that ICPO can be regarded as a potential biomarker for the biomonitoring of IFP and ICP exposure in humans.
        
Title: Ultrasonic-pretreated lipase-catalyzed synthesis of medium-long-medium lipids using different fatty acids as sn-2 acyl-site donors Wang Q, Xie Y, Johnson DR, Li Y, He Z, Li H Ref: Food Sci Nutr, 7:2361, 2019 : PubMed
The current work aimed to evaluate the effect of ultrasonic treatment on the enzymatic transesterification of medium-long-medium (MLM) lipids using 2-monoacylglycerol, bearing distinct fatty acids at the sn-2 position with palmitic acid, octadecanoic acid, oleic acid, eicosapentaenoic acid, and docosahexaenoic acids as sn-2 acyl donors. The effects of ultrasonic treatment conditions, including substrate concentration, reaction temperature and time, and enzyme loading, on the insertion of fatty acids into the sn-2 acyl position of MLM lipids were investigated. The data showed that low-frequency ultrasonic treatment could remarkably improve the insertion rate of polyunsaturated fatty acid (PUFA) into the sn-2 position of MLM lipids, compared with the conventional treatment method. By increasing the ultrasonic frequency from 20 to 30 KHz, while maintaining power at 150 W, the rate of synthesis of monounsaturated fatty acid and PUFA increased from 23.7% and 26.8% to 26.6% and 32.4% (p < 0.05), respectively. Moreover, ultrasonic treatment reduced the optimum reaction temperature from 45 to 35 degC. However, the activity of Lipozyme RM-IM treated with ultrasound considerably declined from 31.10% to 26.90% (p < 0.05) after its fourth cycle, which was lower than that without ultrasonic treatment. This work provokes new routes for the utilization of ultrasonic technology in the synthesis of MLM lipids using different fatty acids as sn-2 acyl donors.
        
Title: Hydroxy-alpha-sanshool isolated from Zanthoxylum bungeanum attenuates learning and memory impairments in scopolamine-treated mice Zhang M, Xie M, Wei D, Wang L, Hu M, Zhang Q, He Z, Peng W, Wu C Ref: Food Funct, 10:7315, 2019 : PubMed
Learning and memory impairments are common symptoms of dementia in neurodegenerative disorders. Occasionally, we found that Zanthoxylum bungeanum pericarps (ZBP) significantly activated the spontaneous activity of the hippocampus (HIPP) and paraHIPP (P < 0.001, uncorrected), implying the potential ability of ZBP to improve cognitive impairments. Thus, this study aimed to investigate the improving effect of hydroxy-alpha-sanshool (HAS), a characteristic ingredient of ZBP, against scopolamine (1 mg kg(-1), i.p.)-induced learning and memory deficits. HAS (5 mg kg(-1), p.o.) markedly reversed scopolamine-induced cognitive impairments, as indicated by its performance in the passive avoidance test and Morris water maze test (P < 0.01). Furthermore, HAS (2.5 and 5.0 mg kg(-1), p.o.) also dose-dependently prevented changes in hippocampal neuronal morphology and apoptosis, inhibited acetylcholinesterase (AChE) activity, increased the acetylcholine (ACh) content, and increased the protein and mRNA expression of brain-derived neurotrophic factor (BDNF) and phospho-cAMP response element-binding (p-CREB) compared with those in the model group (P < 0.05 & P < 0.01). These findings demonstrated that HAS attenuated scopolamine-induced cognitive impairments mainly by enhancing the activity of the cholinergic system and increasing the CREB/BDNF signalling pathway.
This work developed a bioaugmentation strategy that simultaneously reduced soil di(2-ethylhexyl) phthalate (DEHP) pollution and its bioaccumulation in Brassica parachinensis by inoculating the isolated strain Rhodococcus sp. 2G. This strain could efficiently degrade DEHP at a wide concentration range from 50 to 1600 mg/L and transformed DEHP through a unique biochemical degradation pathway that distinguished it from other Rhodococcus species. Besides, strain 2G colonized well in the rhizosphere soil of the inoculated vegetable without competition with indigenous microbes, resulting in increased removal of DEHP from soil (95%) and reduced DEHP bioaccumulation in vegetables (75% in the edible part) synchronously. Improved enzyme activities and DOC content in the rhizosphere of the planting vegetable and inoculating strain 2G were responsible for the high efficiency in mitigating DEHP contamination to vegetable cultivation. This work demonstrated a great potential application to grow vegetables in contaminated soil for safe food production.
The accumulation of neutral lipids in intracellular lipid droplets has been associated with the formation and progression of many cancers, including prostate cancer (PCa). Alpha-beta Hydrolase Domain Containing 5 (ABHD5) is a key regulator of intracellular neutral lipids that has been recently identified as a tumor suppressor in colorectal cancer, yet its potential role in PCa has not been investigated. Through mining publicly accessible PCa gene expression datasets, we found that ABHD5 gene expression is markedly decreased in metastatic castration-resistant PCa (mCRPC) samples. We further demonstrated that RNAi-mediated ABHD5 silencing promotes, whereas ectopic ABHD5 overexpression inhibits, the invasion and proliferation of PCa cells. Mechanistically, we found that ABHD5 knockdown induces epithelial to mesenchymal transition, increasing aerobic glycolysis by upregulating the glycolytic enzymes hexokinase 2 and phosphofrucokinase, while decreasing mitochondrial respiration by downregulating respiratory chain complexes I and III. Interestingly, knockdown of ATGL, the best-known molecular target of ABHD5, impeded the proliferation and invasion, suggesting an ATGL-independent role of ABHD5 in modulating PCa aggressiveness. Collectively, these results provide evidence that ABHD5 acts as a metabolic tumor suppressor in PCa that prevents EMT and the Warburg effect, and indicates that ABHD5 is a potential therapeutic target against mCRPC, the deadly aggressive PCa.
UNLABELLED: Unraveling the drivers controlling the response and adaptation of biological communities to environmental change, especially anthropogenic activities, is a central but poorly understood issue in ecology and evolution. Comparative genomics studies suggest that lateral gene transfer (LGT) is a major force driving microbial genome evolution, but its role in the evolution of microbial communities remains elusive. To delineate the importance of LGT in mediating the response of a groundwater microbial community to heavy metal contamination, representative Rhodanobacter reference genomes were sequenced and compared to shotgun metagenome sequences. 16S rRNA gene-based amplicon sequence analysis indicated that Rhodanobacter populations were highly abundant in contaminated wells with low pHs and high levels of nitrate and heavy metals but remained rare in the uncontaminated wells. Sequence comparisons revealed that multiple geochemically important genes, including genes encoding Fe(2+)/Pb(2+) permeases, most denitrification enzymes, and cytochrome c553, were native to Rhodanobacter and not subjected to LGT. In contrast, the Rhodanobacter pangenome contained a recombinational hot spot in which numerous metal resistance genes were subjected to LGT and/or duplication. In particular, Co(2+)/Zn(2+)/Cd(2+) efflux and mercuric resistance operon genes appeared to be highly mobile within Rhodanobacter populations. Evidence of multiple duplications of a mercuric resistance operon common to most Rhodanobacter strains was also observed. Collectively, our analyses indicated the importance of LGT during the evolution of groundwater microbial communities in response to heavy metal contamination, and a conceptual model was developed to display such adaptive evolutionary processes for explaining the extreme dominance of Rhodanobacter populations in the contaminated groundwater microbiome. IMPORTANCE: Lateral gene transfer (LGT), along with positive selection and gene duplication, are the three main mechanisms that drive adaptive evolution of microbial genomes and communities, but their relative importance is unclear. Some recent studies suggested that LGT is a major adaptive mechanism for microbial populations in response to changing environments, and hence, it could also be critical in shaping microbial community structure. However, direct evidence of LGT and its rates in extant natural microbial communities in response to changing environments is still lacking. Our results presented in this study provide explicit evidence that LGT played a crucial role in driving the evolution of a groundwater microbial community in response to extreme heavy metal contamination. It appears that acquisition of genes critical for survival, growth, and reproduction via LGT is the most rapid and effective way to enable microorganisms and associated microbial communities to quickly adapt to abrupt harsh environmental stresses.
Genome-wide association studies (GWAS) have uncovered numerous variants associated with body mass index (BMI), waist circumference, and waist-to-hip ratio. Our study aims to investigate how these variants are linked to fat distribution. We genotyped 56 validated variants of BMI, waist circumference, and waist-to-hip ratio in 2958 subjects from Chinese community-based populations and performed linear regression analyses to determine the association with visceral fat area (VFA) and subcutaneous fat area (SFA) imaged by magnetic resonance imaging (MRI). We found rs671 in ALDH2 exhibited the significant associations with VFA and the VFA-SFA ratio in all subjects (P = 9.64 x 10(-5) and 6.54 x 10(-4)). rs17782313 near MC4R for VFA and rs4846567 near LYPLAL1 for SFA were found in females only (P = 2.93 x 10(-4) and 0.0015), whereas rs671 in ALDH2 for VFA and the VFA-SFA ratio was restricted to males (P = 1.75 x 10(-8) and 4.43 x 10(-8)). Given the robust association of rs671 with alcohol consumption, we next demonstrated the primary effects of rs671 on VFA and the VFA-SFA ratio were restricted to drinkers (P = 1.45 x 10(-4) and 4.65 x 10(-3)). Our data implied that variants of MC4R and LYPLAL1 modulated body fat distribution with sexual dimorphism and that alcohol consumption may mediate the impact of the ALDH2 locus on visceral fat in a Chinese population.
PURPOSE: Pretreatment serum pseudocholinesterase (PChE) has been reported to be a prognostic predictor in several cancers. However, the prognostic significance of serum PChE level in patients with upper tract urothelial carcinoma (UTUC) remains unknown. METHODS: A total of 180 patients who underwent radical nephroureterectomy (RNU) for UTUC were included in this retrospective analysis. The associations of pretreatment serum PChE levels with clinicopathological characteristics and clinical outcomes were assessed. RESULTS: The median (IQR) pretreatment serum PChE level was 6385 (5449-7260) IU/L, and an optimal cutoff value of 5336 IU/L was set according to ROC analysis. Decreased pretreatment serum PChE levels were significantly correlated with older patient age, higher preoperative chronic kidney disease (CKD) stage and pT stage (all P < 0.05). On multivariate analysis, adjusting for preoperative variables, decreased pretreatment serum PChE levels independently predicted higher pT stage (P = 0.011). Moreover, Kaplan-Meier curves suggested that patients with PChE levels <5336 IU/L were predicted to have a shorter overall survival (OS) and cancer-specific survival (CSS) than those with PChE levels >/=5336 IU/L (both P < 0.001). On multivariate analysis, decreased pretreatment serum PChE levels were significantly associated with shorter OS (HR 0.553; 95 %CI 0.322-0.951; P = 0.032) and CSS (HR 0.484; 95 %CI 0.269-0.870; P = 0.015). CONCLUSIONS: Decreased pretreatment serum PChE level is an independent predictor for higher pT stage, shorter OS and CSS in patients with UTUC. Pretreatment serum PChE levels may act as a simple and effective parameter to predict prognosis for UTUC patients after RNU.
        
Title: Self-assembly of amphiphilic janus particles into monolayer capsules for enhanced enzyme catalysis in organic media Cao W, Huang R, Qi W, Su R, He Z Ref: ACS Appl Mater Interfaces, 7:465, 2015 : PubMed
Encapsulation of enzymes during the creation of an emulsion is a simple and efficient route for enhancing enzyme catalysis in organic media. Herein, we report a capsule with a shell comprising a monolayer of silica Janus particles (JPs) (referred to as a monolayer capsule) and a Pickering emulsion for the encapsulation of enzyme molecules for catalysis purposes in organic media using amphiphilic silica JPs as building blocks. We demonstrate that the JP capsules had a monolayer shell consisting of closely packed silica JPs (270 nm). The capsules were on average 5-50 mum in diameter. The stability of the JP capsules (Pickering emulsion) was investigated with the use of homogeneous silica nanoparticles as a control. The results show that the emulsion stabilized via amphiphilic silica JPs presented no obvious changes in physical appearance after 15 days, indicating the high stability of the emulsions and JP capsules. Furthermore, the lipase from Candida sp. was chosen as a model enzyme for encapsulation within the JP capsules during their formation. The catalytic performance of lipase was evaluated according to the esterification of 1-hexanol with hexanoic acid. It was found that the specific activity of the encapsulated enzymes (28.7 U mL(-1)) was more than 5.6 times higher than that of free enzymes in a biphasic system (5.1 U mL(-1)). The enzyme activity was further increased by varying the volume ratio of water to oil and the JPs loadings. The enzyme-loaded capsule also exhibited high stability during the reaction process and good recyclability. In particular, the jellification of agarose in the JP capsules further enhanced their operating stability. We believe that the monolayer structure of the JP capsules, together with their high stability, rendered the capsules to be ideal enzyme carriers and microreactors for enzyme catalysis in organic media because they created a large interfacial area and had low mass transfer resistance through the monolayer shell.
        
Title: SET-mediated NDRG1 inhibition is involved in acquisition of epithelial-to-mesenchymal transition phenotype and cisplatin resistance in human lung cancer cell Liu H, Gu Y, Yin J, Zheng G, Wang C, Zhang Z, Deng M, Liu J, Jia X, He Z Ref: Cell Signal, 26:2710, 2014 : PubMed
Development of resistance to therapy continues to be a serious clinical problem in lung cancer management. Cancer cells undergoing epithelial-to-mesenchymal transition (EMT) have been shown to play roles in resistance to chemotherapy. Here, we utilized a proteomics-based method and identified a significant downregulation of the metastasis suppressor NDRG1 in drug resistant lung cancer cells. We showed that downregulation of DNRG1 constitutes a mechanism for acquisition of EMT phenotype and endows lung cancer cells with an increased resistance to cisplatin. We also identified a signal cascade, namely, SET--- PP2A---| c-myc---| NDRG1, in which upregulation of SET is critical for inhibition of NDRG1. We also found that blockade of SET (or reactivation of PP2A) by FTY720 reverted EMT, restored drug sensitivity, and inhibited invasiveness and growth of lung tumor xenografts. Together, our results indicated a functional link between SET-mediated NDRG1 regulation and acquisition of EMT phenotype and drug resistance, and provided an evidence that blockade of SET-driven EMT can overcome drug resistance and inhibit tumor progression.
        
Title: Influence of butyl benzyl phthalate (BBP) exposure on nervous system and antioxidant system in zebrafish Zhang C, Yang X, He Z, Zhong Q, Guo J, Hu XJ, Xiong L, Liu D Ref: Ecotoxicology, 23:1854, 2014 : PubMed
In order to observe the toxic effects of butyl benzyl phthalate (BBP) on zebrafish, the AChE and SOD activity of zebrafish exposed to different concentrations of BBP (0, 0.332, 0.665, 1.33 mg L(-1)) in a short-term (7d) test were determined. Semi-quantitative PCR was used to determine the mRNA transcript levels of the AChE and SOD gene in zebrafish brain and muscle. The results showed: AChE activity decreased with increased exposure concentration, and was significantly inhibited (p < 0.01) compared with the control group at 0.665 mg L(-1) concentration. Low BBP concentrations stimulated and high concentrations inhibited SOD activity with a concentration of 0.332 mg L(-1) resulting in a significant induction (p < 0.05) compared with the control, and 0.665 and 1.33 mg L(-1) concentrations resulting in significant inhibition (p < 0.05, p < 0.01) relative to the control group. The RT-PCR data showed a decrease in brain and muscle mRNA transcription of AChE gene with an increase in exposure concentration. The mRNA transcription of SOD in the brain was not different between the exposed groups and control group; in muscle, the mRNA transcription inhibition decreased and then increased: all differences from the control were statistically significant.
Noscapine is an antitumor alkaloid from opium poppy that binds tubulin, arrests metaphase, and induces apoptosis in dividing human cells. Elucidation of the biosynthetic pathway will enable improvement in the commercial production of noscapine and related bioactive molecules. Transcriptomic analysis revealed the exclusive expression of 10 genes encoding five distinct enzyme classes in a high noscapine-producing poppy variety, HN1. Analysis of an F(2) mapping population indicated that these genes are tightly linked in HN1, and bacterial artificial chromosome sequencing confirmed that they exist as a complex gene cluster for plant alkaloids. Virus-induced gene silencing resulted in accumulation of pathway intermediates, allowing gene function to be linked to noscapine synthesis and a novel biosynthetic pathway to be proposed.
        
Title: Identification and characterization of HTD2: a novel gene negatively regulating tiller bud outgrowth in rice Liu W, Wu C, Fu Y, Hu G, Si H, Zhu L, Luan W, He Z, Sun Z Ref: Planta, 230:649, 2009 : PubMed
Tiller number is highly regulated by controlling the formation of tiller bud and its subsequent outgrowth in response to endogenous and environmental signals. Here, we identified a rice mutant htd2 from one of the 15,000 transgenic rice lines, which is characterized by a high tillering and dwarf phenotype. Phenotypic analysis of the mutant showed that the mutation did not affect formation of tiller bud, but promoted the subsequent outgrowth of tiller bud. To isolate the htd2 gene, a map-based cloning strategy was employed and 17 new insertions-deletions (InDels) markers were developed. A high-resolution physical map of the chromosomal region around the htd2 gene was made using the F(2) and F(3) population. Finally, the gene was mapped in 12.8 kb region between marker HT41 and marker HT52 within the BAC clone OSJNBa0009J13. Cloning and sequencing of the target region from the mutant showed that the T-DNA insertion caused a 463 bp deletion between the promoter and first exon of an esterase/lipase/thioesterase family gene in the 12.8 kb region. Furthermore, transgenic rice with reduced expression level of the gene exhibited an enhanced tillering and dwarf phenotype. Accordingly, the esterase/lipase/thioesterase family gene (TIGR locus Os03g10620) was identified as the HTD2 gene. HTD2 transcripts were expressed mainly in leaf. Loss of function of HTD2 resulted in a significantly increased expression of HTD1, D10 and D3, which were involved in the strigolactone biosynthetic pathway. The results suggest that the HTD2 gene could negatively regulate tiller bud outgrowth by the strigolactone pathway.
The genome of Desulfovibrio vulgaris strain DePue, a sulfate-reducing Deltaproteobacterium isolated from heavy metal-impacted lake sediment, was completely sequenced and compared with the type strain D. vulgaris Hildenborough. The two genomes share a high degree of relatedness and synteny, but harbour distinct prophage and signatures of past phage encounters. In addition to a highly variable phage contribution, the genome of strain DePue contains a cluster of open-reading frames not found in strain Hildenborough coding for the production and export of a capsule exopolysaccharide, possibly of relevance to heavy metal resistance. Comparative whole-genome microarray analysis on four additional D. vulgaris strains established greater interstrain variation within regions associated with phage insertion and exopolysaccharide biosynthesis.
        
Title: Novel organization of catechol meta pathway genes in the nitrobenzene degrader Comamonas sp. JS765 and its evolutionary implication He Z, Parales RE, Spain JC, Johnson GR Ref: J Ind Microbiol Biotechnol, 34:99, 2007 : PubMed
The catechol meta cleavage pathway is one of the central metabolic pathways for the degradation of aromatic compounds. A novel organization of the pathway genes, different from that of classical soil microorganisms, has been observed in Sphingomonas sp HV3 and Pseudomonas sp. DJ77. In a Comamonas sp. JS765, cdoE encoding catechol 2,3-dioxygenase shares a common ancestry only with tdnC of a Pseudomonas putida strain, while codG encoding 2-hydroxymuconic semialdehyde dehydrogenase shows a higher degree of similarity to those genes in classical bacteria. Located between cdoE and cdoG are several putative genes, whose functions are unknown. These genes are not found in meta pathway operons of other microorganisms with the exception of cdoX2, which is similar to cmpX in strain HV3. Therefore, the gene cluster in JS765 reveals a third type of gene organization of the meta pathway.