Title: A Multifunctional (-)-Meptazinol-Serotonin Hybrid Ameliorates Oxidative Stress-Associated Apoptotic Neuronal Death and Memory Deficits via Activating the Nrf2/Antioxidant Enzyme Pathway Zhao F, Zhao L, Zhou Y, Tan X, Yang Y, Ni W, Zheng W, Chen H, Qiu Y, Li J Ref: Oxid Med Cell Longev, 2023:6935947, 2023 : PubMed
The pathogenesis of Alzheimer's disease (AD) involves multiple pathophysiological processes. Oxidative stress is a major cause of AD-associated neuronal injury. The current research was designed to examine whether a novel (-)-meptazinol-serotonin hybrid (Mep-S) with potent antioxidant activity and additional inhibitory properties for acetylcholinesterase (AChE) activity could attenuate oxidative neuronal damage and cognitive deficits. In human SH-SY5Y cells, Mep-S suppressed H(2)O(2)-induced apoptosis by restoring mitochondrial membrane potential and inhibiting caspase-3 activation. Meanwhile, it attenuated oxidative stress elicited by H(2)O(2) through lessening generation of reactive oxygen species as well as enhancing production of glutathione (GSH) and activity of superoxide dismutase (SOD). Mechanistically, Mep-S promoted nuclear translocation of a transcription factor nuclear factor E2-related factor-2 (Nrf2) in H(2)O(2)-challenged cells. This effect was accompanied by reduction in Kelch-like ECH-associated protein-1 (Keap1) levels as well as augmentation of Akt phosphorylation and expression of heme oxygenase-1 (HO-1) and NAD(P)H quinine oxidoreductase-1 (NQO-1). Molecular docking analysis revealed that Mep-S may disrupt the protein-protein interactions between Keap1 and Nrf2. In an in vivo mouse model, Mep-S attenuated scopolamine-caused cognitive deficits with inhibition of apoptotic neuronal death and brain AChE activity. Furthermore, the scopolamine-induced impairment of total antioxidant capacity and reduction in SOD1, SOD2, and gamma-glutamate-cysteine ligase expression in the brain were counteracted by Mep-S, accompanied by decreased Keap1 levels, increased Akt catalytic subunit and Nrf2 phosphorylation, and decreased Nrf2, HO-1, and NQO-1 expression. Collectively, our results suggest that Mep-S ameliorates apoptotic neuronal death and memory dysfunction associated with oxidative stress by regulating the Nrf2/antioxidant enzyme pathway through inactivating Keap1 and phosphorylating Nrf2 via Akt activation. Therefore, Mep-S may be a potential lead for multitarget neuroprotective agents to treat AD-like symptoms.
        
Title: DPP3: From biomarker to therapeutic target of cardiovascular diseases Ye P, Duan W, Leng YQ, Wang YK, Tan X, Wang WZ Ref: Front Cardiovasc Med, 9:974035, 2022 : PubMed
Cardiovascular disease is the leading cause of death globally among non-communicable diseases, which imposes a serious socioeconomic burden on patients and the healthcare system. Therefore, finding new strategies for preventing and treating cardiovascular diseases is of great significance in reducing the number of deaths and disabilities worldwide. Dipeptidyl peptidase 3 (DPP3) is the first zinc-dependent peptidase found among DPPs, mainly distributes within the cytoplasm. With the unique HEXXGH catalytic sequence, it is associated with the degradation of oligopeptides with 4 to 10 amino acids residues. Accumulating evidences have demonstrated that DPP3 plays a significant role in almost all cellular activities and pathophysiological mechanisms. Regarding the role of DPP3 in cardiovascular diseases, it is currently mainly used as a biomarker for poor prognosis in patients with cardiovascular diseases, suggesting that the level of DPP3 concentration in plasma is closely linked to the mortality of diseases such as cardiogenic shock and heart failure. Interestingly, it has been reported recently that DPP3 regulates blood pressure by interacting with the renin-angiotensin system. In addition, DPP3 also participates in the processes of pain signaling, inflammation, and oxidative stress. But the exact mechanism by which DPP3 affects cardiovascular function is not clear. Hence, this review summarizes the recent advances in the structure and catalytic activity of DPP3 and its extensive biological functions, especially its role as a therapeutic target in cardiovascular diseases. It will provide a theoretical basis for exploring the potential value of DPP3 as a therapeutic target for cardiovascular diseases.
        
Title: Reduced insecticide sensitivity of the wheat aphid Sitobion miscanthi after infection by the secondary bacterial symbiont Hamiltonella defensa Li Q, Sun J, Qin Y, Fan J, Zhang Y, Tan X, Hou M, Chen J Ref: Pest Manag Sci, 77:1936, 2020 : PubMed
BACKGROUND: Bacterial symbionts in insects, especially aphids, have a major influence on host adaptation. The authors previously showed that infection with the secondary symbiont Hamiltonella defensa increases the fitness of the wheat aphid Sitobion miscanthi, yielding increases in fitness parameters such as adult weight and offspring number. However, whether H. defensa affects the sensitivity of host aphids to insecticides remains unknown. RESULTS: We tested the effects of H. defensa on host aphid susceptibility to the insecticides chlorpyrifos methyl, imidacloprid, cyantraniliprole and acetamiprid. Our results showed that compared with Hamiltonella-free aphid clones, Hamiltonella-infected aphid clones exhibited lower sensitivity to most of the tested insecticides at low concentrations. Quantitative PCR showed that the density of H. defensa in the infected clones was slightly decreased at 24 h but then sharply increased until the late stage after treatment with the different insecticides. H. defensa in the host aphids was detected by fluorescence in situ hybridization and was localized to the aphid hindgut. The levels of the detoxification enzymes acetylcholinesterase (AChE), glutathione transferase (GST) and carboxylesterase (CarE) were significantly higher in the Hamiltonella-infected clones than in the Hamiltonella-free clones. CONCLUSIONS: The findings indicated that infection with H. defensa reduced aphid sensitivity to the investigated insecticides at low concentrations, potentially by increasing detoxification enzyme activity in the host. Therefore, symbiont-mediated insecticide resistance should be taken into account when performing resistance-monitoring studies. Studies of symbiont-mediated insecticide resistance may enhance our understanding of the emergence of insecticide resistance in agricultural systems. This article is protected by copyright. All rights reserved.
        
Title: A multifunctional bis-(-)-nor-meptazinol-oxalamide hybrid with metal-chelating property ameliorates Cu(II)-induced spatial learning and memory deficits via preventing neuroinflammation and oxido-nitrosative stress in mice Tan X, Zhou Y, Gong P, Guan H, Wu B, Hou L, Feng X, Zheng W, Li J Ref: J Trace Elem Med Biol, 52:199, 2019 : PubMed
Excess copper exposure is a risk factor of neurodegeneration related to Alzheimer's disease (AD). Evidence indicates that, besides promoting amyloid beta aggregation, activation of neuroinflammation and oxido-nitrosative stress (two key pathophysiological processes of AD) may also play important roles in Cu(II)-induced neuronal injury. Therefore, the copper-chelating strategy has gained attention in search for new anti-AD drugs. We previously reported a novel multifunctional compound N(1),N(2)-bis(3-(S)-meptazinol-propyl) oxalamide (ZLA), a bis-(-)-nor-meptazinol-oxalamide hybrid with properties of dual binding site acetylcholinesterase (AChE) inhibition and Cu(II)/Zn(II) chelation. The present study was aimed to explore its effect on cognitive deficits caused by intrahippocampal injection of Cu(II) in mice. Results showed that ZLA (2, 5 mg/kg; i.p.) treatment significantly ameliorated the Cu(II)-induced impairment of hippocampus-dependent learning and memory, whereas rivastigmine, an AChE inhibitor showing a similar potency of enzyme inhibition to ZLA, had no obvious effect. Immunohistochemical and Western blot analyses revealed that ZLA attenuated the decrease in hippocampal expression of microtubule-associated protein 2 (MAP2, a dendritic marker) in Cu(II)-challenged mice. Further analysis showed that ZLA suppressed the Cu(II)-evoked microglial activation. Moreover, it inhibited the Cu(II)-evoked production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-1beta and expression of inducible nitric oxide synthase in the hippocampus. The Cu(II)-induced oxidative and nitrosative stress in the hippocampus was also attenuated after ZLA treatment. Collectively, these results suggest that ZLA ameliorates the Cu(II)-caused cognitive deficits. Inhibition of neuroinflammation and oxido-nitrosative stress, and thus ameliorating neuronal injury, may be the potential mechanism for the anti-amnesic effect of ZLA.
H2O2, is an attractive oxidant for synthetic chemistry, especially if activated as percarboxylic acid. H2O2, however, is also a potent inactivator of enzymes. Protein engineering efforts to improve enzyme resistance against H2O2 in the past have mostly focused on tedious probabilistic directed evolution approaches. Here we demonstrate that a rational approach combining multiscale MD simulations and Born-Oppenheimer ab initio QM/MM MD simulations is an efficient approach to rapidly identify improved enzyme variants. Thus, the lipase from Penicillium camembertii was redesigned with a single mutation (I260R), leading to drastic improvements in H2O2 resistance while maintaining the catalytic activity. Also the extension of this methodology to other enzymes is demonstrated.
        
Title: Huperzine A alleviates neuroinflammation, oxidative stress and improves cognitive function after repetitive traumatic brain injury Mei Z, Zheng P, Tan X, Wang Y, Situ B Ref: Metabolic Brain Disease, 32:1861, 2017 : PubMed
Traumatic brain injury (TBI) may trigger secondary injury cascades including endoplasmic reticulum stress, oxidative stress, and neuroinflammation. Unfortunately, there are no effective treatments targeting either primary or secondary injuries that result in long-term detrimental consequences. Huperzine A (HupA) is a potent acetylcholinesterase inhibitor (AChEI) that has been used treatment of Alzheimer's disease (AD). This study aimed to explore the neuroprotective effects of HupA in TBI and its possible mechanisms. Repetitive mild closed head injury (CHI) model was used to mimic concussive TBI. Mice were randomly assigned into three groups including sham, vehicle-treated and HupA-treated injured mice. The HupA was given at dose of 1.0 mg/kg/day and was initiated 30 min after the first injury, then administered daily for a total of 30 days. The neuronal functions including motor functions, emotion-like behaviors, learning and memory were tested. Axonal injury, reactive oxygen species (ROS), and neuroinflammation were examined as well. The results showed that injured mice treated with HupA had significant improvement in Morris water maze performance compared with vehicle-treated injured mice. HupA treatment significantly attenuated markers of neuroinflammation and oxidative stress in the injured mice. Taken together, HupA was effective in reducing neuroinflammation, oxidative stress and behavioral recovery after TBI. HupA is a promising candidate for treatment of TBI.
        
Title: Deltamethrin affects the expression of voltage-gated calcium channel alpha1 subunits and the locomotion, egg-laying, foraging behavior of Caenorhabditis elegans Zeng R, Yu X, Tan X, Ye S, Ding Z Ref: Pestic Biochem Physiol, 138:84, 2017 : PubMed
Deltamethrin belongs to the class of synthetic pyrethroids, which are being widely used as insecticides in agricultural practices. Voltage-gated sodium channels (VGSCs) are the primary targets of these chemicals for toxicity to insects. Caenorhabditis elegans (C. elegans) does not have VGSCs but is susceptible to deltamethrin. Recent findings have suggested that pyrethroids can affect voltage-gated calcium channels (VGCCs). However, it remains elusive whether deltamethrin induces toxicity to C. elegans via modulating the activity of VGCCs. To identify the potential target of deltamethrin, we exposed C. elegans to different concentrations of deltamethrin and Ca2+ channel blockers for different times, characterized the behavioral toxicity of deltamethrin on C. elegans, and determined the expression of egl-19, unc-2, and cca-1, which encode the alpha1-subunit of the L-, R/N/P/Q-, and T-type VGCC, respectively. We found that deltamethrin inhibited the locomotion, egg-laying and foraging ability of C. elegans in a concentration dependent manner. We also showed that body length of worms on agar plates containing 200mgL-1 deltamethrin for 12h was not significantly different from controls, whereas the cholinesterase inhibitor carbofuran caused hypercontraction which is a characteristic of organophosphates and carbamates, suggesting that deltamethrin's mode of action is distinct from those nematicides. In addition, unc-2 was significantly up-regulated following 0.05mgL-1 deltamethrin exposure for 24h; while egl-19 and cca-1 were significantly up-regulated following 5 and 50mgL-1 deltamethrin exposure for 24h. Further tests of worms' sensitivity and expression of three alpha1-subunits of VGCC to Ca2+ channel blockers indicate that deltamethrin may induce toxic behavior C. elegans via modulation of the expression of the alpha1-subunits of VGCC. This study provides insights into the linkage between deltamethrin-induced toxic behavior and the regulation of alpha1-subunits of VGCC in C. elegans.
        
Title: Evogliptin: a new dipeptidyl peptidase inhibitor for the treatment of type 2 diabetes Tan X, Hu J Ref: Expert Opin Pharmacother, 17:1285, 2016 : PubMed
INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel, potent oral antihyperglycemic agents that reduce degradation of endogenous glucagon-like peptide 1 (GLP-1) to increase insulin secretion and satiety and decrease glucagon. DPP-4 inhibitors enhance insulin secretion in a glucose-dependent manner, which potentially reduces hypoglycemia risks during monotherapy or combination therapy with other antidiabetic agents. Evogliptin (Suganon(TM)) is a new oral DPP-4 inhibitor developed for the treatment of patients with type 2 diabetes inadequately controlled by diet and exercise. AREAS COVERED: This review summarizes the collected data concerning mechanism of action, clinical efficacy, and safety of evogliptin in improving glycemic control in patients with type 2 diabetes. Additional non-glycemic benefits and safety profiles of evogliptin are also discussed. EXPERT OPINION: Evogliptin is effective in improving glycosylated hemoglobin (HbA1c) and fasting plasma glucose without inducing hypoglycemia events, which potentially can improve adherence and prevent complications. It is also found that evogliptin has benefits on insulin secretory and beta-cell functions. Based on the current clinical data, evogliptin has a neutral effect on body weight. These attributes contribute to the clinical practice in monotherapy or in combination with other antidiabetic agents.
        
Title: Characterization of a Desiccation Stress Induced Lipase Gene from Brassica napus L. Zhang H, Zhou J, Zheng X, Zhang Z, Wang Z, Tan X Ref: J Agr Sci Tech, 18:1129, 2016 : PubMed
Lipases are known to have important functions in many physiological processes in plants. Here, we cloned a lipase gene via Rapid Amplification of cDNA Ends (RACE) technique from Brassica napus L., designated as BnDIL1 (B. napus Desiccation-Induced Lipase 1). The lipase enzyme activity was confirmed by estimating the lipase activity and reduced lipids content in Saccharomyces cerevisiae (pep4) transformant. Two B. napus lines with different oil contents were employed to examine the transcription profiles of BnDIL1 during the processes of seed morphogenesis, maturation, dormancy, pregermination and germination. The transcription level of lipid degradation pathway was enhanced during the processes of seed maturation, dormancy, pregermination and germination, and was higher in seeds of low oil-contents line than that of high oil-contents line. However, BnDIL1 was significantly activated when seed desiccation started. Both slow desiccation and -fast desiccation- treatments on seedlings dramatically activated the transcription of BnDIL1, while only -slow desiccation- stress, which would induce the cell apoptosis, significantly activated the transcription of lipid degradation gene. This result demonstrated that BnDIL1 in B. napus was desiccation stress dependent gene rather than fatty acids degradation gene.
        
Title: Study on the interaction of catalase with pesticides by flow injection chemiluminescence and molecular docking Tan X, Wang Z, Chen D, Luo K, Xiong X, Song Z Ref: Chemosphere, 108:26, 2014 : PubMed
The interaction mechanisms of catalase (CAT) with pesticides (including organophosphates: disulfoton, isofenphos-methyl, malathion, isocarbophos, dimethoate, dipterex, methamidophos and acephate; carbamates: carbaryl and methomyl; pyrethroids: fenvalerate and deltamethrin) were first investigated by flow injection (FI) chemiluminescence (CL) analysis and molecular docking. By homemade FI-CL model of lg[(I0-I)/I]=lgK+nlg[D], it was found that the binding processes of pesticides to CAT were spontaneous with the apparent binding constants K of 10(3)-10(5) L mol(-1) and the numbers of binding sites about 1.0. The binding abilities of pesticides to CAT followed the order: fenvalerate>deltamethrin>disulfoton>isofenphos-methyl>carbaryl>malathion>isocarbo phos>dimethoate>dipterex>acephate>methomyl>methamidophos, which was generally similar to the order of determination sensitivity of pesticides. The thermodynamic parameters revealed that CAT bound with hydrophobic pesticides by hydrophobic interaction force, and with hydrophilic pesticides by hydrogen bond and van der Waals force. The pesticides to CAT molecular docking study showed that pesticides could enter into the cavity locating among the four subdomains of CAT, giving the specific amino acid residues and hydrogen bonds involved in CAT-pesticides interaction. It was also found that the lgK values of pesticides to CAT increased regularly with increasing lgP, Mr, MR and MV, suggesting that the hydrophobicity and steric property of pesticide played essential roles in its binding to CAT.
        
Title: EPHX1 Tyr113His and His139Arg polymorphisms in esophageal cancer risk: a meta-analysis Tan X, He WW, Wang YY, Shi LJ, Chen MW Ref: Genet Mol Res, 13:649, 2014 : PubMed
Microsomal epoxide hydrolase 1 (EPHX1) is an important biological phase II metabolic enzyme that is extensively involved in the metabolism of diverse environmental carcinogens such as polycyclic aromatic hydrocarbons and heterocyclic amines. Many articles have reported the association between EPHX1 (Tyr113His and His139Arg) polymorphisms and esophageal cancer risk, but the results are controversial. This study aimed to identify the association between EPHX1 (Tyr113His and His139Arg) polymorphisms and esophageal cancer risk by meta-analysis. The odds ratio (OR) with 95% confidence interval (95%CI) was used to evaluate the strength of the associations. Heterogeneity was estimated by the chi-square-based Q-statistic test and the P value. Meanwhile, the random-effect or fixed-effect model was used according to the between-study heterogeneity. Begg's funnel plot and the Egger test were performed to assess the publication bias of articles. Finally, 8 case-control studies involving 1158 cases and 1868 controls for the Tyr113His polymorphism and 7 case-control studies involving 901 cases and 1615 controls for the His139Arg polymorphism were included in this meta-analysis. Meta-analysis showed that the Tyr113His polymorphism was a stronger power trend towards risk for esophageal cancer using a recessive model (CC versus CT+TT, OR = 1.204, 95%CI = 1.001-1.450, P = 0.049). However, no significant associated risk was found between the His139Arg polymorphism and esophageal cancer. These findings suggest that the Tyr113His polymorphism might be a stronger power trend towards risk for esophageal cancer. However, no evidence was found for the association between the EPHX1 His139Arg polymorphism and esophageal cancer risk.
        
Title: Quantitative assessment of the effects of the EPHX1 Tyr113His polymorphism on lung and breast cancer Tan X, Wang YY, Chen XY, Xian L, Guo JJ, Liang GB, Chen MW Ref: Genet Mol Res, 13:7437, 2014 : PubMed
The association between the microsomal epoxide hydrolase 1 gene (EPHX1) Tyr113His polymorphism and lung cancer and breast cancer risk has been reported in many recent studies, but there is no consensus among the results. Thus, we examined the association between the EPHX1 Tyr113His polymorphism and lung cancer through a meta-analysis. A comprehensive literature search was performed using the Pubmed and Embase databases. Odds ratios with 95% confidence intervals were used to assess the strength of associations. Our meta-analysis suggested that the Tyr113His polymorphism was associated with lung cancer risk in Asians under 3 genetic models, including a C vs T, CC vs TT, and recessive model. However, the risk was decreased in Caucasians under the genetic models, including a C vs T, CC vs TT, or CT vs TT, dominant, and recessive model. In contrast, there was no association with breast cancer risk for any of the genetic models. Our meta-analysis suggested that the EPHX1 Tyr113His polymorphism may be a risk factor for lung cancer in Asians, whereas it may be a decreased risk factor among Caucasians. However, this polymorphism was not found to be associated with breast cancer.
Polyploidy often confers emergent properties, such as the higher fibre productivity and quality of tetraploid cottons than diploid cottons bred for the same environments. Here we show that an abrupt five- to sixfold ploidy increase approximately 60 million years (Myr) ago, and allopolyploidy reuniting divergent Gossypium genomes approximately 1-2 Myr ago, conferred about 30-36-fold duplication of ancestral angiosperm (flowering plant) genes in elite cottons (Gossypium hirsutum and Gossypium barbadense), genetic complexity equalled only by Brassica among sequenced angiosperms. Nascent fibre evolution, before allopolyploidy, is elucidated by comparison of spinnable-fibred Gossypium herbaceum A and non-spinnable Gossypium longicalyx F genomes to one another and the outgroup D genome of non-spinnable Gossypium raimondii. The sequence of a G. hirsutum A(t)D(t) (in which 't' indicates tetraploid) cultivar reveals many non-reciprocal DNA exchanges between subgenomes that may have contributed to phenotypic innovation and/or other emergent properties such as ecological adaptation by polyploids. Most DNA-level novelty in G. hirsutum recombines alleles from the D-genome progenitor native to its New World habitat and the Old World A-genome progenitor in which spinnable fibre evolved. Coordinated expression changes in proximal groups of functionally distinct genes, including a nuclear mitochondrial DNA block, may account for clusters of cotton-fibre quantitative trait loci affecting diverse traits. Opportunities abound for dissecting emergent properties of other polyploids, particularly angiosperms, by comparison to diploid progenitors and outgroups.
Lhx8, also named L3, is a recently identified member of the LIM homeobox gene family. Previously, we found acetylcholinesterase (AChE)-positive cells in fimbria-fornix (FF) transected rat hippocampal subgranular zone (SGZ). In the present study, we detected choline acetyltransferase (ChAT)-positive cholinergic cells in hippocampal SGZ after FF transaction, and these ChAT-positive cells were double labeled by Lhx8. Then we overexpressed Lhx8 during neural differentiation of hippocampal neural stem/progenitor cells on adherent conditions using lentivirus Lenti6.3-Lhx8. The result indicated that overexpression of Lhx8 did not affect the proportion of MAP2-positive neurons, but increased the proportion of ChAT-positive cells in vitro. These results suggested that FF-transected hippocampal niche promoted the ChAT/Lhx8-positive cholinergic neurons generation in rodent hippocampus, and Lhx8 was not associated with the MAP2-positive neurons differentiation on adherent conditions, but played a role in the specification of cholinergic neurons derived from hippocampal neural stem/progenitor cells in vitro.
We report the annotation and analysis of the draft genome sequence of Brassica rapa accession Chiifu-401-42, a Chinese cabbage. We modeled 41,174 protein coding genes in the B. rapa genome, which has undergone genome triplication. We used Arabidopsis thaliana as an outgroup for investigating the consequences of genome triplication, such as structural and functional evolution. The extent of gene loss (fractionation) among triplicated genome segments varies, with one of the three copies consistently retaining a disproportionately large fraction of the genes expected to have been present in its ancestor. Variation in the number of members of gene families present in the genome may contribute to the remarkable morphological plasticity of Brassica species. The B. rapa genome sequence provides an important resource for studying the evolution of polyploid genomes and underpins the genetic improvement of Brassica oil and vegetable crops.
Here, we report our effort in generating an ORFeome collection for the Arabidopsis transcription factor (TF) genes. In total, ORFeome clones representing 1,282 Arabidopsis TF genes have been obtained in the Gateway high throughput cloning pENTR vector, including 411 genes whose annotation lack cDNA support. All the ORFeome inserts have also been mobilized into a yeast expression destination vector, with an estimated 85% rate of expressing the respective proteins. Sequence analysis of these clones revealed that 34 of them did not match with either the reported cDNAs or current predicted open-reading-frame sequences. Among those, novel alternative splicing of TF gene transcripts is responsible for the observed differences in at least five genes. However, those alternative splicing events do not appear to be differentially regulated among distinct Arabidopsis tissues examined. Lastly, expression of those TF genes in 17 distinct Arabidopsis organ types and the cultured cells was profiled using a 70-mer oligo microarray.