Lin S

References (63)

Title : Frontostriatal circuit dysfunction leads to cognitive inflexibility in neuroligin-3 R451C knockin mice - Lin_2024_Mol.Psychiatry__
Author(s) : Lin S , Fan CY , Wang HR , Li XF , Zeng JL , Lan PX , Li HX , Zhang B , Hu C , Xu J , Luo JH
Ref : Mol Psychiatry , : , 2024
Abstract : Cognitive and behavioral rigidity are observed in various psychiatric diseases, including in autism spectrum disorder (ASD). However, the underlying mechanism remains to be elucidated. In this study, we found that neuroligin-3 (NL3) R451C knockin mouse model of autism (KI mice) exhibited deficits in behavioral flexibility in choice selection tasks. Single-unit recording of medium spiny neuron (MSN) activity in the nucleus accumbens (NAc) revealed altered encoding of decision-related cue and impaired updating of choice anticipation in KI mice. Additionally, fiber photometry demonstrated significant disruption in dynamic mesolimbic dopamine (DA) signaling for reward prediction errors (RPEs), along with reduced activity in medial prefrontal cortex (mPFC) neurons projecting to the NAc in KI mice. Interestingly, NL3 re-expression in the mPFC, but not in the NAc, rescued the deficit of flexible behaviors and simultaneously restored NAc-MSN encoding, DA dynamics, and mPFC-NAc output in KI mice. Taken together, this study reveals the frontostriatal circuit dysfunction underlying cognitive inflexibility and establishes a critical role of the mPFC NL3 deficiency in this deficit in KI mice. Therefore, these findings provide new insights into the mechanisms of cognitive and behavioral inflexibility and potential intervention strategies.
ESTHER : Lin_2024_Mol.Psychiatry__
PubMedSearch : Lin_2024_Mol.Psychiatry__
PubMedID: 38459194

Title : Fungal feruloyl esterases can catalyze release of diferulic acids from complex arabinoxylan - Lin_2023_Int.J.Biol.Macromol__123365
Author(s) : Lin S , Hunt CJ , Holck J , Brask J , Krogh K , Meyer AS , Wilkens C , Agger JW
Ref : Int J Biol Macromol , :123365 , 2023
Abstract : Feruloyl esterases (FAEs, EC catalyze the hydrolytic cleavage of ester bonds between feruloyl and arabinosyl moieties in arabinoxylans. Recently, we discovered that two bacterial FAEs could catalyze release of diferulic acid moieties (diFAs) from highly substituted, cross-linked corn bran arabinoxylan. Here, we show that several fungal FAEs, notably AnFae1 (Aspergillus niger), AoFae1 (A. oryzae), and MgFae1 (Magnaporthe oryzae (also known as M. grisae)) also catalyze liberation of diFAs from complex arabinoxylan. By comparing the enzyme kinetics of diFA release to feruloyl esterase activity of the enzymes on methyl- and arabinosyl-ferulate substrates we demonstrate that the diFA release activity cannot be predicted from the activity of the enzymes on these synthetic substrates. A detailed structure-function analysis, based on AlphaFold2 modeled enzyme structures and docking with the relevant di-feruloyl ligands, reveal how distinct differences in the active site topology and surroundings may explain the diFA releasing action of the enzymes. Interestingly, the analysis also unveils that the carbohydrate binding module of the MgFae1 may play a key role in the diFA releasing ability of this enzyme. The findings contribute further understanding of the function of FAEs in the deconstruction of complex arabinoxylans and provide new opportunities for enzyme assisted upgrading of complex bran arabinoxylans.
ESTHER : Lin_2023_Int.J.Biol.Macromol__123365
PubMedSearch : Lin_2023_Int.J.Biol.Macromol__123365
PubMedID: 36690236
Gene_locus related to this paper: humin-HiFae1 , malci-McFae1 , 9zzzz-CE1.6RZN , 9zzzz-DAC80243 , 9pezi-a0a481sy08 , aspni-FAEA , aspor-q2uh24 , aspor-q2umx6 , aspor-q2unw5 , aspor-q2up89 , neucr-faeb , magoy-l7ic25

Title : (+\/-)-Yanhusuomide A, a pair of ornithine-fused benzylisoquinoline enantiomers from Corydalis yanhusuo - Wang_2023_Bioorg.Chem_133_106407
Author(s) : Wang LY , Xia GY , Xia H , Wei XH , Lin S
Ref : Bioorg Chem , 133 :106407 , 2023
Abstract : (+/-)-Yanhusuomide A (1), a novel enantiomeric pair of ornithine-fused benzylisoquinoline, were characterized from the dried tubers of Corydalis yanhusuo, along with a biogenetically related intermediate oblongine (2). Yanhusuomide A features an unprecedented skeleton based on a benzylisoquinoline coupled with an ornithine derivative to form a rare 5,6-dihydro-4H-pyrido[3,4,5-de]quinazoline motif. Plausible biosynthetic pathway of 1 was proposed, and (+/-)-yanhusuomide A (1) presented potential inhibitory bioactivity against acetylcholinesterase (AChE) with IC(50) = 14.07 +/- 2.38 microM. The simulation of molecular docking displayed that 1 generated strong interaction with Asp-74 and Trp-86 residues of AChE through attractive charge of the quaternary nitrogen.
ESTHER : Wang_2023_Bioorg.Chem_133_106407
PubMedSearch : Wang_2023_Bioorg.Chem_133_106407
PubMedID: 36758275

Title : Novel miR-108 and miR-234 target juvenile hormone esterase to regulate the response of Plutella xylostella to Cry1Ac protoxin - Yang_2023_Ecotoxicol.Environ.Saf_254_114761
Author(s) : Yang J , Chen S , Xu X , Lin S , Wu J , Lin G , Bai J , Song Q , You M , Xie M
Ref : Ecotoxicology & Environmental Safety , 254 :114761 , 2023
Abstract : Insect hormones, such as juvenile hormone (JH), precisely regulate insect life-history traits. The regulation of JH is tightly associated with the tolerance or resistance to Bacillus thuringiensis (Bt). JH esterase (JHE) is a primary JH-specific metabolic enzyme which plays a key role in regulating JH titer. Here, we characterized a JHE gene from Plutella xylostella (PxJHE), and found it was differentially expressed in the Bt Cry1Ac resistant and susceptible strains. Suppression of PxJHE expression with RNAi increased the tolerance of P. xylostella to Cry1Ac protoxin. To investigate the regulatory mechanism of PxJHE, two target site prediction algorithms were applied to predict the putative miRNAs targeting PxJHE, and the resulting putative miRNAs were subsequently verified for their function targeting PxJHE using luciferase reporter assay and RNA immunoprecipitation. MiR-108 or miR-234 agomir delivery dramatically reduced PxJHE expression in vivo, whilst only miR-108 overexpression consequently increased the tolerance of P. xylostella larvae to Cry1Ac protoxin. By contrast, reduction of miR-108 or miR-234 dramatically increased PxJHE expression, accompanied by the decreased tolerance to Cry1Ac protoxin. Furthermore, injection of miR-108 or miR-234 led to developmental defects in P. xylostella, whilst injection of antagomir did not cause any obvious abnormal phenotypes. Our results indicated that miR-108 or miR-234 can be applied as potential molecular targets to combat P. xylostella and perhaps other lepidopteran pests, providing novel insights into miRNA-based integrated pest management.
ESTHER : Yang_2023_Ecotoxicol.Environ.Saf_254_114761
PubMedSearch : Yang_2023_Ecotoxicol.Environ.Saf_254_114761
PubMedID: 36907089

Title : New bysspectin A derivatives as potent inhibitors of human carboxylesterase 2A - Li_2023_Eur.J.Med.Chem_259_115708
Author(s) : Li W , Zhang Y , Wu Y , Zhu G , Liu X , Song Y , Ma B , Lin S , Ge G , Jiao X , Xie P
Ref : Eur Journal of Medicinal Chemistry , 259 :115708 , 2023
Abstract : Human carboxylesterase 2A (hCES2A), the most abundant carboxylesterase in the human gut, plays a crucial role in the metabolic clearance and activation of various ester-bearing drugs, environmental toxins and carcinogens. Inhibition of intestinal hCES2A can alleviate irinotecan-induced gut toxicity and modulate the oral bioavailability of hCES2A-substrate drugs. Bysspectin A, a natural product isolated from the endophytic fungus Byssochlamys spectabilis, has been identified as a highly selective hCES2A inhibitor. Herein, two sets of bysspectin A derivatives have been designed and synthesized, utilizing a Cu-catalyzed domino Sonogashira-cyclization as the key step. Following two rounds of structure activity relationship (SAR) studies and structural optimizations, compound 20w was identified as the most potent hCES2A inhibitor, with an IC(50) value of 1.6 nM, an approximately 1000-fold improvement over bysspectin A. Further investigation showed that 20w potently inhibited hCES2A in a mixed inhibition manner, while this agent could also potently inhibit intracellular hCES2A in living cells and exhibited suitable metabolic stability. In summary, our findings demonstrate that a new bysspectin A derivative (20w) is a promising candidate for the development of clinically used hCES2A inhibitor.
ESTHER : Li_2023_Eur.J.Med.Chem_259_115708
PubMedSearch : Li_2023_Eur.J.Med.Chem_259_115708
PubMedID: 37544184

Title : Transesterification of phosphatidylcholine with DHA-rich algal oil using immobilized Candida antarctica lipase B to produce DHA-phosphatidylcholine - Shu_2023_Enzyme.Microb.Technol_169_110266
Author(s) : Shu L , Zheng X , Qi S , Lin S , Lu Y , Yao C , Ling X
Ref : Enzyme Microb Technol , 169 :110266 , 2023
Abstract : Docosahexaenoic acid (DHA) enriched with phospholipids (PLs) (DHA-PLs) is a type of structured PL with good physicochemical and nutritional properties. Compared to PLs and DHA, DHA-PLs has higher bioavailability and structural stability and many nutritional benefits. To improve the enzymatic synthesis of DHA-PLs, this study investigated the preparation of phosphatidylcholine (PC) enriched with DHA (DHA-PC) via enzymatic transesterification of algal oil, which is rich in DHA-triglycerides, using immobilized Candida antarctica lipase B (CALB). The optimized reaction system incorporated 31.2% DHA into the acyl chain of PC and converted 43.6% PC to DHA-PC within 72 h at 50 degreesC, 1:8 PC: algal oil mass ratio, 25% enzyme load (based on total substrate mass), and 0.02 g/mL molecular sieve concentration. Consequently, the side reactions of PC hydrolysis were effectively suppressed and products with high PC content (74.8%) were produced. Molecular structure analysis showed that exogenous DHA was specifically incorporated into the sn-1 site of the PC by immobilized CALB. Furthermore, the evaluation of reusability with eight cycles showed that the immobilized CALB had good operational stability in the present reaction system. Collectively, this study demonstrated the applicability of immobilized CALB as a biocatalyst for synthesizing DHA-PC and provided an improved enzyme-catalyzed method for future DHA-PL synthesis.
ESTHER : Shu_2023_Enzyme.Microb.Technol_169_110266
PubMedSearch : Shu_2023_Enzyme.Microb.Technol_169_110266
PubMedID: 37311283

Title : Synthesis and Characterization of Epoxidized Silkworm Pupae Oil and Its Application as Polyvinyl Chloride - Ji_2022_Appl.Biochem.Biotechnol_194_1290
Author(s) : Ji Y , Xu L , Xu Q , Liu X , Lin S , Liao S , Wang W , Lan D
Ref : Appl Biochem Biotechnol , 194 :1290 , 2022
Abstract : More and more industries demand environmental friendliness. Silkworm pupae oil (SPO), extracted from the desilked silkworm pupae, can serve as a promising substrate alternative to use in plasticization. This study aimed to prepare epoxidized silkworm pupae oil (ESPO) and investigate their effects on the thermal stability and plasticization of polyvinyl chloride (PVC) films. A chemo-enzymatic method of ESPO was developed in the presence of Lipase SMG1-F278N and H(2)O(2) in natural deep eutectic solvents (DESs). Lipase SMG1-F278N could initiate the epoxidation reaction effectively at room temperature with a negligible loss of activities 10 batches. A maximum oxirane value of 6.94% was obtained. The formation of oxirane ring in ESPO was confirmed by FTIR and (13)C NMR spectra. Moreover, ESPO showed a better thermal stability and lower freezing point than epoxidized soybean oil (ESO). It was demonstrated that ESPO had a good frost resistance. In addition, ESPO showed a significantly improved plasticizing effect on flexible polyvinyl chloride (PVC). Compared with ESO, ESPO could increase the tensile elongation at break effectively. A significantly lower migration rate of plasticizer was observed in PVC plasticized with ESPO.
ESTHER : Ji_2022_Appl.Biochem.Biotechnol_194_1290
PubMedSearch : Ji_2022_Appl.Biochem.Biotechnol_194_1290
PubMedID: 34677760
Gene_locus related to this paper: malgo-a8puy1

Title : Screening Potential Diagnostic Biomarkers for Age-Related Sarcopenia in the Elderly Population by WGCNA and LASSO - Lin_2022_Biomed.Res.Int_2022_7483911
Author(s) : Lin S , Ling M , Chen C , Cai X , Yang F , Fan Y
Ref : Biomed Res Int , 2022 :7483911 , 2022
Abstract : BACKGROUND: Sarcopenia is a common chronic disease characterized by age-related decline in skeletal muscle mass and function, and the lack of diagnostic biomarkers makes community-based screening problematic. METHODS: Three gene expression profiles related with sarcopenia were downloaded and merged by searching the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and eigengenes of a module in the merged dataset were identified by differential expression analysis and weighted gene coexpression network analysis (WGCNA), and common genes (CGs) were defined as the intersection of DEGs and eigengenes of a module. CGs were subjected to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Subsequently, the least absolute shrinkage and selection operator (LASSO) analysis was performed to screen the CGs for identifying the diagnostic biomarkers of sarcopenia. Based on the diagnostic biomarkers, we established a novel nomogram model of sarcopenia. At last, we validated the diagnostic biomarkers and evaluated the diagnostic performance of the nomogram model by the area under curve (AUC) value. RESULTS: We screened out 107 DEGs and 788 eigengenes in the turquoise module, and 72 genes were selected as CGs of sarcopenia by intersection. GO analysis showed that CGs were mainly involved in metal ion detoxification and mitochondrial structure, and KEGG analysis revealed that CGs were mainly enriched in the mineral absorption, glucagon signaling pathway, FoxO signaling pathway, insulin signaling pathway, AMPK signaling pathway, and estrogen signaling pathway. Then, six diagnostic biomarkers (ARHGAP36, FAM171A1, GPCPD1, MT1X, ZNF415, and RXRG) were identified by LASSO analysis. Finally, the validation AUC values indicated that the six diagnostic biomarkers had high diagnostic accuracy for sarcopenia. CONCLUSION: We identified six diagnostic biomarkers with high diagnostic performance, providing new insights into the incidence and progression of sarcopenia in future research.
ESTHER : Lin_2022_Biomed.Res.Int_2022_7483911
PubMedSearch : Lin_2022_Biomed.Res.Int_2022_7483911
PubMedID: 36147639

Title : Bioactive neolignans and lignans from the roots of Paeonia lactiflora - Xia_2022_Chin.J.Nat.Med_20_210
Author(s) : Xia H , Zhang JF , Wang LY , Xia GY , Wang YN , Wu YZ , Lin PC , Xiong L , Lin S
Ref : Chin J Nat Med , 20 :210 , 2022
Abstract : Two new neolignans and one new lignan (1-3) were obtained from the roots of Paeonia lactiflora. Their structures were unambiguously elucidated based on extensive spectroscopic analysis, single-crystal X-ray crystallography, and the calculated and experimental electronic circular dichroism (ECD) spectra. Compound 1 was a racemic mixture and successfully resolved into the anticipated enantiomers via chiral-phase HPLC. Compound 3 demonstrated moderate inhibitory activity against human carboxylesterase 2A1 (hCES2A1) with an IC(50) value of 7.28 +/- 0.94 micromol.(-1).
ESTHER : Xia_2022_Chin.J.Nat.Med_20_210
PubMedSearch : Xia_2022_Chin.J.Nat.Med_20_210
PubMedID: 35369965

Title : Construction of a Novel Lipase Catalytic System Based on Hybrid Membranes with Interwoven Electrospun Polyacrylic Acid and Polyvinyl Pyrrolidone Gel Fibers - Wang_2022_Gels_8_
Author(s) : Wang Z , Lin S , Zhang Q , Li J , Yin S
Ref : Gels , 8 : , 2022
Abstract : Efficient lipase catalysis requires sufficient oil-water interface engineered through structural design. Inspired by the architectural features of fabrics, a novel lipase-membrane catalytic system with interwoven polyacrylic acid (PAA) gel fibers and polyvinyl pyrrolidone (PVP) gel fibers was developed in this study by using double-needle electrospinning and gelation. It has been demonstrated that PAA/PVP hybrid gel fiber membranes (HGFMs) have a high swelling capacity for both water and oil phases, which created numerous discontinuous oil-water contact surface units in limited space of HGFMs, consequently forming effective interfacial catalytic systems. Volume competition between the water and oil phases suggests that balancing the proportions of these phases is very important for effective construction of oil-water interfaces and conditioning catalysis. Regulation of multiple factors of PAA/PVP HGFMs resulted in a catalytic efficiency of up to 2.1 times that of a macroscopic 'oil-up/water-down' system (room temperature, pH = 7), and 2.9 times when three membranes are superimposed, as well as excellent pH and temperature stability. HGFMs were stacked to build a high-performing catalytic performance reactor. We expect that this study will be a beneficial exploration for expanding the lipase catalytic system.
ESTHER : Wang_2022_Gels_8_
PubMedSearch : Wang_2022_Gels_8_
PubMedID: 36547336

Title : Polygoni multiflori radix extracts inhibit SARS-CoV-2 pseudovirus entry in HEK293T cells and zebrafish larvae - Wang_2022_Phytomedicine_102_154154
Author(s) : Wang X , Lin S , Tang RW , Lee HC , Chan HH , Choi SSA , Leung KW , Webb SE , Miller AL , Tsim KWK
Ref : Phytomedicine , 102 :154154 , 2022
Abstract : BACKGROUND: Globally, COVID-19 has caused millions of deaths and led to unprecedented socioeconomic damage. There is therefore, in addition to vaccination, an urgent need to develop complementary effective treatments and/or protective and preventative therapies against this deadly disease. METHODS: Here, a multi-component testing platform was established to screen a library of herbal extracts from traditional Chinese medicine (TCM), to identify potent herbal extracts/phytochemicals as possible therapeutics for COVID-19. We utilized assays for spike protein (S-protein) binding to angiotensin-converting enzyme II (ACE2); the enzymatic inhibition of 3CL protease; and entry of the SARS-CoV-2 pseudovirus into cultured HEK293T cells and zebrafish larvae. RESULTS: Over a thousand herbal extracts were screened and approximately 20 positive hits were identified. Among these, we found that the water and ethanol extracts of Polygoni Multiflori Radix (PMR) significantly inhibited S-protein binding to ACE2, 3CL protease activity, and viral entry into the cell and fish models. The water extract was more effective than the ethanol extract, with IC(50) values of 25 to 500 microg/ml. In addition, the polysaccharide-depleted fraction of the former, and epigallocatechin gallate (EGCG) which was found in both extracts, displayed significant antiviral activity. CONCLUSIONS: Our results indicate that the water and ethanol extracts of PMR have an inhibitory effect on SARS-CoV-2 pseudovirus host-cell entry. Furthermore, EGCG might be an active component of PMR, which blocks SARS-CoV-2 entry to cells. Taken together, our findings suggest that PMR might be considered as a potential treatment for COVID-19.
ESTHER : Wang_2022_Phytomedicine_102_154154
PubMedSearch : Wang_2022_Phytomedicine_102_154154
PubMedID: 35576740

Title : Penicipurate A, a new polyketide derivative from the endophytic fungus Penicillium purpurogenum - Wang_2022_J.Asian.Nat.Prod.Res__1
Author(s) : Wang LY , Xia GY , Wang M , Wu YZ , Wang YN , Chai LM , Lin S
Ref : J Asian Nat Prod Res , :1 , 2022
Abstract : A new polyketide derivative containing a 3-hydroxydecanoic acid ester moiety, penicipurate A (1), was purified from the solid cultures of the fungus Penicillium purpurogenum, a fungal strain endophytic in the leaves of Edgeworthia chrysantha. The structure of 1 was established by spectroscopic methods, including UV, IR, HRESIMS, 1D, and 2D NMR and (13)C NMR chemical shifts calculations coupled with DP4+ analysis, as well as the chemical degradation method. Compound 1 showed moderate inhibitory activity against pancreatic lipase (PL) with an IC(50) value of 9.61 +/- 1.42 microM.
ESTHER : Wang_2022_J.Asian.Nat.Prod.Res__1
PubMedSearch : Wang_2022_J.Asian.Nat.Prod.Res__1
PubMedID: 35852111

Title : Role of Bmal1 in mediating the cholinergic system to regulate the behavioral rhythm of nocturnal marine molluscs - Gao_2022_Comput.Struct.Biotechnol.J_20_2815
Author(s) : Gao X , Zhang M , Lyu M , Lin S , Luo X , You W , Ke C
Ref : Comput Struct Biotechnol J , 20 :2815 , 2022
Abstract : The circadian rhythm is one of the most general and important rhythms in biological organisms. In this study, continuous 24-h video recordings showed that the cumulative movement distance and duration of the abalone, Haliotis discus hannai, reached their maximum values between 20:00-00:00, but both were significantly lower between 08:00-12:00 than at any other time of day or night (P < 0.05). To investigate the causes of these diel differences in abalone movement behavior, their cerebral ganglia were harvested at 00:00 (group D) and 12:00 (group L) to screen for differentially expressed proteins using tandem mass tagging (TMT) quantitative proteomics. Seventy-five significantly different proteins were identified in group D vs. group L. The differences in acetylcholinesterase (AchE) expression levels between day- and nighttime and the key role in the cholinergic nervous system received particular attention during the investigation. A cosine rhythm analysis found that the concentration of acetylcholine (Ach) and the expression levels of AchE tended to be low during the day and high at night, and high during the day and low at night, respectively. However, the rhythmicity of the diel expression levels of acetylcholine receptor (nAchR) appeared to be insignificant (P > 0.05). Following the injection of three different concentrations of neostigmine methylsulfate, as an AchE inhibitor, the concentration of Ach in the hemolymph, and the expression levels of nAchR in the cerebral ganglia increased significantly (P < 0.05). Four hours after drug injection, the cumulative movement distance and duration of abalones were significantly higher than those in the uninjected control group, and the group injected with saline (P < 0.05). The expression levels of the core diurnal clock Bmal1 over a 24-h period also tended to be high during the day and low at night. First, a co-immunoprecipitation assay demonstrated the binding between Bmal1 and AchE or nAchR. A dual-luciferase gene test and electrophoretic mobility shift assay showed that Bmal1 bound to the promoter regions of AchE and nAchR. Twenty-four hours after silencing the Bmal1 gene, the expression levels of AchE and nAchR decreased significantly compared to those of the dsEGFP and PBS control groups, further showing that Bmal1 mediates the cholinergic system to regulate the behavioral rhythm of abalone. These findings shed light on the endocrine mechanism regulating the rhythmic behavior of abalone, and provide a reference for understanding the life history adaptation strategies of nocturnal organisms and the proliferation and protection of bottom dwelling economically important organisms.
ESTHER : Gao_2022_Comput.Struct.Biotechnol.J_20_2815
PubMedSearch : Gao_2022_Comput.Struct.Biotechnol.J_20_2815
PubMedID: 35765646

Title : NMDA receptor hypofunction underlies deficits in parvalbumin interneurons and social behavior in neuroligin 3 R451C knockin mice - Cao_2022_Cell.Rep_41_111771
Author(s) : Cao W , Li JH , Lin S , Xia QQ , Du YL , Yang Q , Ye YZ , Zeng LH , Li XY , Xu J , Luo JH
Ref : Cell Rep , 41 :111771 , 2022
Abstract : Neuroligins (NLs), a family of postsynaptic cell-adhesion molecules, have been associated with autism spectrum disorder. We have reported that dysfunction of the medial prefrontal cortex (mPFC) leads to social deficits in an NL3 R451C knockin (KI) mouse model of autism. However, the underlying molecular mechanism remains unclear. Here, we find that N-methyl-D-aspartate receptor (NMDAR) function and parvalbumin-positive (PV+) interneuron number and expression are reduced in the mPFC of the KI mice. Selective knockdown of NMDAR subunit GluN1 in the mPFC PV+ interneuron decreases its intrinsic excitability. Restoring NMDAR function by its partial agonist D-cycloserine rescues the PV+ interneuron dysfunction and social deficits in the KI mice. Interestingly, early D-cycloserine administration at adolescence prevents adult KI mice from social deficits. Together, our results suggest that NMDAR hypofunction and the resultant PV+ interneuron dysfunction in the mPFC may constitute a central node in the pathogenesis of social deficits in the KI mice.
ESTHER : Cao_2022_Cell.Rep_41_111771
PubMedSearch : Cao_2022_Cell.Rep_41_111771
PubMedID: 36476879

Title : Improved Aitongxiao prescription (I-ATXP) induces apoptosis, cell cycle arrest and blocks exosomes release in hepatocellular carcinoma (HCC) cells - Huang_2022_Int.J.Physiol.Pathophysiol.Pharmacol_14_90
Author(s) : Huang MB , Gao Z , Xia M , Zhao X , Fan X , Lin S , Zhang L , Huang L , Wei A , Zhou H , Wu JY , Roth WW , Bond VC , Leng J
Ref : Int Journal de Physiologie Pathophysiol Pharmacol , 14 :90 , 2022
Abstract : BACKGROUND: Hepatocellular carcinoma (HCC) is the second most common malignancy globally, after lung cancer, accounting for 85-90% of primary liver cancer. Hepatitis B virus (HBV) infection is considered the leading risk factor for HCC development in China. HCC is a highly malignant cancer whose metastasis is primarily influenced by the tumor microenvironment. The role of exosomes in cancer development has become the focus of much research due to the many newly described contents of exosomes, which may contribute to tumorigenesis. However, the possible role exosomes play in the interactions between HCC cells and their surrounding hepatic milieu is mainly unknown. We discovered an Improved Aitongxiao Prescription (I-ATXP): an 80% alcohol extract from a mix of 15 specific plant and animal compounds, which had been shown to have an anticancer effect through inducing apoptosis and cell cycle arrest and blocking exosomes release in HCC cells. However, the anticancer mechanism of I-ATXP on human liver carcinoma is still unclear. OBJECTIVE: Due to its inhibitory effects on chemical carcinogenesis and inflammation, I-ATXP has been proposed as an effective agent for preventing or treating human liver carcinoma. In this study, we aimed to explore the effect of I-ATXP on proliferation, apoptosis, and cell cycles of different HCC cell lines. We investigated the impact of I-ATXP on exosomes' secretion derived from these HCC cells. METHODS: The inhibitory effect of I-ATXP on proliferation and cytotoxicity of HepG2, SMMC7721, HKCL-C3 HCC cell lines, and MIHA immortalized hepatocyte cell line was assessed by CCK-8 assay. The cell cycle distribution and cell apoptosis were determined by flow cytometry using Annexin V-FITC/PI staining. The expression of Alix and CD63 of exosome marker proteins was detected by western blotting. The exosome protein concentration was measured by a fluorescent plate reader. The exosome-specific enzyme activity was measured by acetylcholinesterase (AchE) assay, and exosome morphological characteristics were identified by transmission electron microscopy (TEM). RESULTS: I-ATXP inhibited the growth of HCC cells in a dose and time-dependent manner. Flow cytometry analysis showed that I-ATXP induced G0/G1 phase arrest and cell apoptosis. The I-ATX reduced HepG2, SMMC7721, and HKCI-C HCC cell lines exosomes release and low-dose I-ATXP significantly enhanced the growth inhibition induced by 5-Fu. Western blot analysis shows that after HCC cell lines were treated with various concentrations of I-ATXP (0.125-1 mg/ml) for 24 h, exosomes derived from three different HCC cells expressed exosome-specific proteins Alix and CD63. Compared with the untreated group, with the increment of the concentration of I-ATXP, the expression of exosome-specific proteins Alix and CD63 were reduced. These results suggest that I-ATXP can inhibit the release of exosomes with Alix and CD63 protein from HCC cells. CONCLUSIONS: I-ATXP is a traditional Chinese medicine that acts as an effective agent for preventing or treating human liver carcinoma. (i) I-ATXP can effectively inhibit cell proliferation of different HCC cells in a time and dose-dependent manner. Compared with 5-Fu, I-ATXP exhibited more selective proliferation inhibition in HCC cells, displaying traditional Chinese medicine advantages on tumor therapy and providing the experimental basis for I-ATXP clinical application. (ii) I-ATXP can induce apoptosis and cell cycle arrest in HCC cells. The CCK-8 assay results indicated that I-ATXP could inhibit HCC cell proliferation mediated by apoptosis and cell cycle arrest. (iii) I-ATXP can inhibit both the exosome releases and expression of CD63, and Alix derived from HCC cells, but the exosomes derived from liver cancer cells affect liver cancer cells' biological properties such as proliferation, invasion, and migration. These suggest that I-ATXP may affect HCC cells via regulation of exosomes of HCC cells, further indicating the potential clinical values of I-ATXP for the prevention or treatment of human liver carcinoma.
ESTHER : Huang_2022_Int.J.Physiol.Pathophysiol.Pharmacol_14_90
PubMedSearch : Huang_2022_Int.J.Physiol.Pathophysiol.Pharmacol_14_90
PubMedID: 35619665

Title : Predictive Value of Perioperative Cytokine Levels on the Risk for In-Stent Restenosis in Acute Myocardial Infarction Patients - Chen_2022_Contrast.Media.Mol.Imaging_2022_7832564
Author(s) : Chen D , Xie X , Lu Y , Chen S , Lin S
Ref : Contrast Media Mol Imaging , 2022 :7832564 , 2022
Abstract : To investigate the value of perioperative cytokine levels in predicting the risk for in-stent restenosis in patients with acute myocardial infarction. 452 patients with acute myocardial infarction admitted to our hospital between June 2018 and June 2020 were prospectively selected as subjects. All patients underwent percutaneous coronary intervention. The baseline data of the patients were collected. Venous blood was taken before, 24 hours, and 3 days after the operation to detect the levels of related cytokines. Follow-up was performed for 1 year. The patients were assigned to restenosis and nonrestenosis groups according to the presence and absence of restenosis. Multivariate logistic analysis was used to explore the influencing factors of the risk for in-stent restenosis in patients with acute myocardial infarction. By July 1, 2021, 449 cases had been followed up. Of them, 44 cases suffered from in-stent restenosis and 405 cases did not affect in-stent restenosis. The incidence of in-stent restenosis was 9.80%. Before, 24 hours, and 3 days after the operation, the lipoprotein-associated phospholipase A2 (Lp-PLA2) level was significantly higher in the restenosis group than that in the nonrestenosis group. At 3 days after the operation, the interleukin 6 (IL-6) level was significantly higher in the restenosis group than that in the nonrestenosis group (P < 0.05). Multivariate logistic analysis displayed that Lp-PLA2 level preoperatively (OR = 1.048, 95% CI 1.029-1.068), Lp-PLA2 level 24 hours postoperatively (OR = 1.013, 95% CI 1.007-1.019), Lp-PLA2 level 3 days postoperatively (OR = 1.032, 95% CI 1.015-1.048), and IL-6 level 3 days postoperatively (OR = 1.020, 95% CI 1.000-1.040) were risk factors for in-stent restenosis (all P < 0.05). IL-6 and Lp-PLA2 levels can predict the risk for in-stent restenosis in patients with acute myocardial infarction in the perioperative period.
ESTHER : Chen_2022_Contrast.Media.Mol.Imaging_2022_7832564
PubMedSearch : Chen_2022_Contrast.Media.Mol.Imaging_2022_7832564
PubMedID: 35542755

Title : Enzymatic Cleavage of Diferuloyl Cross-Links in Corn Bran Arabinoxylan by Two Bacterial Feruloyl Esterases - Lin_2022_J.Agric.Food.Chem_70_13349
Author(s) : Lin S , Brask J , Munk L , Holck J , KBRM , Meyer AS , Agger JW , Wilkens C
Ref : Journal of Agricultural and Food Chemistry , 70 :133349 , 2022
Abstract : Corn bran is an abundant coprocessing stream of corn-starch processing, rich in highly substituted, diferuloyl-cross-linked glucurono-arabinoxylan. The diferuloyl cross-links make the glucurono-arabinoxylan recalcitrant to enzymatic conversion and constitute a hindrance for designing selective enzymatic upgrading of corn glucurono-arabinoxylan. Here, we show that two bacterial feruloyl esterases, wtsFae1A and wtsFae1B, each having a carbohydrate-binding module of family 48, are capable of cleaving the ester bonds of the cross-linkages and releasing 5-5', 8-5', 8-5' benzofuran, and 8-O-4' diferulate from soluble and insoluble corn bran glucurono-arabinoxylan. All four diferulic acids were released at similar efficiency, indicating nondiscriminatory enzymatic selectivity for the esterified dimer linkages, the only exception being that wtsFae1B had a surprisingly high propensity for releasing the dimers, especially 8-5' benzofuran diferulate, indicating a potential, unique catalytic selectivity. The data provide evidence of direct enzymatic release of diferulic acids from corn bran by newly discovered feruloyl esterases, i.e., a new enzyme activity. The findings yield new insight and create new opportunities for enzymatic opening of diferuloyl cross-linkages to pave the way for upgrading of recalcitrant arabinoxylans.
ESTHER : Lin_2022_J.Agric.Food.Chem_70_13349
PubMedSearch : Lin_2022_J.Agric.Food.Chem_70_13349
PubMedID: 36205442
Gene_locus related to this paper: 9zzzz-CE1.6RZN , 9zzzz-DAC80243

Title : [Construction and application of pharmacophore model of human carboxylesterase 2 inhibitors] - Zhang_2021_Zhongguo.Zhong.Yao.Za.Zhi_46_638
Author(s) : Zhang JF , Li YC , Xia GY , Song YQ , Wang LY , Lin PC , Ge GB , Lin S
Ref : Zhongguo Zhong Yao Za Zhi , 46 :638 , 2021
Abstract : According to human carboxylesterase 2(hCE2) inhibitors reported in the literature, the pharmacophore model of hCE2 inhibitors was developed using HipHop module in Discovery Studio 2016. The optimized pharmacophore model, which was validated by test set, contained two hydrophobic, one hydrogen bond acceptor, and one aromatic ring features. Using the pharmacophore model established, 5 potential hCE2 inhibitors(CS-1,CS-2,CS-3,CS-6 and CS-8) were screened from 20 compounds isolated from the roots of Paeonia lactiflora, which were further confirmed in vitro, with the IC_(50) values of 5.04, 5.21, 5.95, 6.64 and 7.94 micromol.L~(-1), respectively. The results demonstrated that the pharmacophore model exerted excellent forecasting ability with high precision, which could be applied to screen novel hCE2 inhibitors from Chinese medicinal materials.
ESTHER : Zhang_2021_Zhongguo.Zhong.Yao.Za.Zhi_46_638
PubMedSearch : Zhang_2021_Zhongguo.Zhong.Yao.Za.Zhi_46_638
PubMedID: 33645031

Title : Inducing new bioactive metabolites production from coculture of Pestalotiopsis sp. and Penicillium bialowiezense - Li_2021_Bioorg.Chem_110_104826
Author(s) : Li F , Yan S , Huang Z , Gao W , Zhang S , Mo S , Lin S , Wang J , Hu Z , Zhang Y
Ref : Bioorg Chem , 110 :104826 , 2021
Abstract : Coculturing two or more fungi is a useful strategy to awaken the silent genes to produce structurally diverse and bioactive natural products. Through the coculture of Pestalotiopsis sp. and Penicillium bialowiezense, six new isoprenylated chromane derivatives, including two pairs of enantiomeric ones (1a/1b-2a/2b) and two optical pure ones (3-4), two new isoprenylated phenol glucoside derivatives (6-7), as well as eight known structural analogues (5 and 8-14), were obtained. The structures of these new compounds were characterized by NMR spectroscopy, single-crystal X-ray crystallography, and ECD calculation. The delta(10,11) double bond of pestaloficin D (5) was revised to E-configurated based on the extensive spectroscopic analyses. Compounds 1a/1b and 2a/2b were the first examples of enantiomeric isoprenylated chromane derivatives, which were successfully separated by chiral HPLC. Additionally, all the isolated compounds were evaluated for the in vitro beta-glucuronidase (GUS) and butyrylcholinesterase (BChE) inhibitory activities. Compounds 1a and 1b showed significant beta-glucuronidase inhibitory potency with IC(50) values of 7.6 and 10.3 microM, respectively. Compound 14 exhibited moderate BChE inhibitory activity with an IC(50) value of 21.3 microM. In addition, the structure-enzyme inhibitory activity relationship of compounds 1-14 is discussed.
ESTHER : Li_2021_Bioorg.Chem_110_104826
PubMedSearch : Li_2021_Bioorg.Chem_110_104826
PubMedID: 33780746

Title : Paeonone A, a novel nonanortriterpenoid from the roots of Paeonia lactiflora - Zhang_2021_Bioorg.Chem_110_104783
Author(s) : Zhang JF , Li YC , Song YQ , Xia GY , Xia H , Wang YN , Tian GH , Ge GB , Lin S
Ref : Bioorg Chem , 110 :104783 , 2021
Abstract : Paeonone A (1), a unique nonanortriterpenoid, and a new octanortriterpenoid, paeonone B (2), were isolated from the roots of Paeonia lactiflora, together with a known analogue, palbinone (3). Paeonone A (1) is the first example of naturally occurring nonanortriterpenoid with a diketo acid group. Extensive NMR and HRESIMS experiments were applied to identify the structures of 1 and 2, and their absolute configurations were solved by single-crystal X-ray diffraction and ECD data. Biological properties of 1-3 were explored against pancreatic lipase and cancer cell lines.
ESTHER : Zhang_2021_Bioorg.Chem_110_104783
PubMedSearch : Zhang_2021_Bioorg.Chem_110_104783
PubMedID: 33714021

Title : Neuroprotective effects of NDEELNK from sea cucumber ovum against scopolamine-induced PC12 cell damage through enhancing energy metabolism and upregulation of the PKA\/BDNF\/NGF signaling pathway - Zhao_2021_Food.Funct__
Author(s) : Zhao Y , Dong Y , Ge Q , Cui P , Sun N , Lin S
Ref : Food Funct , : , 2021
Abstract : The aim of the study was to evaluate the neuroprotective function of sea cucumber ovum peptide-derived NDEELNK and explore the underlying molecular mechanisms. NDEELNK exerted the neuroprotective effect by improving the acetylcholine (ACh) level and reducing the acetylcholinesterase (AChE) activity in PC12 cells. By molecular docking, we confirmed that the NDEELNK backbone and AChE interacted through hydrophobic and hydrogen bonds in contact with the amino acid residues of the cavity wall. NDEELNK increased superoxide dismutase (SOD) activity and decreased reactive oxygen species (ROS) production, thereby reducing mitochondrial dysfunction and enhancing energy metabolism. Our results demonstrated that NDEELNK supplementation alleviated scopolamine-induced PC12 cell damage by improving the cholinergic system, increasing energy metabolism and upregulating the expression of phosphorylated protein kinase A (p-PKA), brain-derived neurotrophic factor (BNDF) and nerve growth factor (NGF) signaling proteins in in vitro experiments. These results demonstrated that the sea cucumber ovum peptide-derived NDEELNK might play a protective role in PC12 cells.
ESTHER : Zhao_2021_Food.Funct__
PubMedSearch : Zhao_2021_Food.Funct__
PubMedID: 34259275

Title : Secoyanhusamine A, an Oxidatively Ring-Opened Isoquinoline Inner Salt From Corydalis yanhusuo - Wang_2021_Front.Chem_9_831173
Author(s) : Wang L , Xia H , Wu Y , Wang Y , Lin P , Lin S
Ref : Front Chem , 9 :831173 , 2021
Abstract : Secoyanhusamine A (1), a rare rearranged seco-isoquinoline alkaloid derived from ring oxidative cleavage, was isolated from an aqueous extract of Corydalis yanhusuo tubers, together with its biosynthetic precursor dehydrocorybulbine (2). Secoyanhusamine A (1) was the first example of a highly oxidized isoquinoline inner salt resulting in a 5-(2-azanylethyl)-2-carboxylate-4-oxo-4H-pyran ring system. The biosynthetic pathway of 1 was also postulated. Secoyanhusamine A (1) exhibited potent inhibition against acetylcholinesterase (AChE) with an IC(50) value of 0.81 +/- 0.13 microM. Molecular simulation docking demonstrated that 1 created a strong interaction with the Asp-74 residue of AChE via attractive charge of the quaternary nitrogen.
ESTHER : Wang_2021_Front.Chem_9_831173
PubMedSearch : Wang_2021_Front.Chem_9_831173
PubMedID: 35178381

Title : Yanhusanines A-F, Isoquinoline-Derived Alkaloid Enantiomers from Corydalis yanhusuo and Their Biological Activity - Wang_2020_J.Nat.Prod__
Author(s) : Wang LY , Qiu BL , Xia H , Xia GY , Xiao BB , Zhang JF , Zhong WC , Lin S
Ref : Journal of Natural Products , : , 2020
Abstract : Six new pairs of isoquinoline alkaloid enantiomers, designated as yanhusanines A-F (1-6), were isolated from an aqueous extract of Corydalis yanhusuo tubers. The structures of these enantiomers were elucidated via physicochemical analysis and a variety of spectroscopic methods. All compounds were resolved into their enantiomers via chiral-phase HPLC, and their configurations were determined by DP4+ NMR calculation methods, specific rotations, and comparison of experimental and calculated ECD spectra. Compounds 1-6 bear a rare 9-methyl moiety, and compound 1 possesses a rare 1-oxa-6-azaspiro[4.5]decane core containing an N-CHO group. Compounds (+)-2, (-)-2, (+)-4, (-)-4, (+)-5, (-)-5, (+)-6, and (-)-6 exhibited selective inhibitory activities against human carboxylesterase (hCE2), in the IC50 value range of 2.0-13.2 muM.
ESTHER : Wang_2020_J.Nat.Prod__
PubMedSearch : Wang_2020_J.Nat.Prod__
PubMedID: 32058719

Title : A novel streptonigrin type alkaloid from the Streptomyces flocculus CGMCC 4.1223 mutant stnA\/Q2 - Wang_2020_Nat.Prod.Res__3
Author(s) : Wang X , Xu F , Huang T , Deng Z , Lin S
Ref : Nat Prod Res , :1 , 2020
Abstract : Streptonigrin (STN) is a highly functionalized aminoquinone alkaloid with broad and potent antitumor activities. Previously, the biosynthetic gene cluster of STN was identified in Streptomyces flocculus CGMCC 4.1223, revealing an alpha/beta-hydrolase (StnA) and a methyltransferase (StnQ2). In this work, a double mutant delta stnA/Q2 was constructed by genetic manipulation and produced a novel derivative of STN, named as streptonigramide. Structure of streptonigramide was established by spectroscopic analyses. Its biosynthetic pathway has been proposed as well.
ESTHER : Wang_2020_Nat.Prod.Res__3
PubMedSearch : Wang_2020_Nat.Prod.Res__3
PubMedID: 33280413
Gene_locus related to this paper: 9actn-l7pij2

Title : Neuroprotective function of a novel hexapeptide QMDDQ from shrimp via activation of PKA\/CREB\/BNDF signaling pathway and its structure-activity relationship - Wu_2020_J.Agric.Food.Chem__
Author(s) : Wu D , Zhang S , Sun N , Zhu B , Lin S
Ref : Journal of Agricultural and Food Chemistry , : , 2020
Abstract : This study aimed to evaluate the neuroprotective function of shrimp-derived peptides QMDDQ and KMDDQ. Biochemical results revealed that both peptides exerted neuroprotective effects by increasing acetylcholine (ACh) content and inhibiting acetylcholinesterase (AChE) activity in PC12 cells; QMDDQ was more active than KMDDQ. COSY-NOESY spectroscopic data showed that the superior neuroprotective function of QMDDQ might be attributed to its N-terminal glutamine as it exhibited an extended spatial conformation, facilitating its interactions with AChE. QMDDQ can promote the basic energy metabolism of cells more than KMDDQ. The peptides showed neuroprotective ability due to activating the anti-apoptosis and PKA/CREB/BNDF signaling pathway. QMDDQ was selected to investigate its memory-enhancing activity in scopolamine-induced amnesic mice, revealing memory protection in mice, as it improved their performance in the Morris water maze experiment. In addition, QMDDQ increased ACh content (4.98+/-0.51 mug/mg prot) and decreased AChE activity (4.72+/-0.11 U/mg prot) in the mouse hippocampus. These data indicate the systemic mechanism through which naturally derived QMDDQ improved neuroprotection and memory ability.
ESTHER : Wu_2020_J.Agric.Food.Chem__
PubMedSearch : Wu_2020_J.Agric.Food.Chem__
PubMedID: 32452680

Title : AGLPM and QMDDQ peptides exert a synergistic action on memory improvement against scopolamine-induced amnesiac mice - Wu_2020_Food.Funct_11_10925
Author(s) : Wu D , Xu X , Sun N , Li D , Zhu B , Lin S
Ref : Food Funct , 11 :10925 , 2020
Abstract : This study aimed to explore the synergistic action of pentapeptides Gln-Met-Asp-Asp-Gln (QMDDQ) and Ala-Gly-Leu-Pro-Met (AGLPM) on memory improvement against scopolamine-induced impairment in mice compared to those of either peptide alone. In behavioral tests, the codelivery of QMDDQ and AGLPM was superior to the individual supplements of either peptide alone not only in enhancing the memory ability at training trials but also in recovering the memory impairment in scopolamine-induced amnesiac mice in test trials. Furthermore, combination treatment with QMDDQ and AGLPM could significantly reduce the acetylcholinesterase (AChE) level and increase the acetylcholine (ACh) level in the hippocampus, and noticeably improve the pathological morphology of the neuron cells in hippocampal regions CA1 and CA2 and dentate gyrus (DG). The findings indicated that the combination treatment with QMDDQ and AGLPM could improve the memory function by regulating the cholinergic system.
ESTHER : Wu_2020_Food.Funct_11_10925
PubMedSearch : Wu_2020_Food.Funct_11_10925
PubMedID: 33242042

Title : Bioactivity-Guided Discovery of Human Carboxylesterase Inhibitors from the Roots of Paeonia lactiflora - Zhang_2020_J.Nat.Prod_83_2940
Author(s) : Zhang JF , Zhong WC , Li YC , Song YQ , Xia GY , Tian GH , Ge GB , Lin S
Ref : Journal of Natural Products , 83 :2940 , 2020
Abstract : In a continuing search for potential inhibitors against human carboxylesterases 1A1 and 2A1 (hCES1A1 and hCES2A1), an EtOAc extract of the roots of Paeonia lactiflora showed strong hCES inhibition activity. Bioassay-guided fractionation led to the isolation of 26 terpenoids including 12 new ones (1-5, 7-12, and 26). Among these, sesquiterpenoids 1 and 6, monoterpenoids 10, 11, and 13-15, and triterpenoids 18-20, 22, and 24-26 contributed to the hCES2A1 inhibition, in the IC(50) range of 1.9-14.5 microM, while the pentacyclic triterpenoids 18-26 were responsible for the potent inhibitory activity against hCES1A1, with IC(50) values less than 5.0 microM. The structures of all the compounds were elucidated using MS and 1D and 2D NMR data, and the absolute configurations of the new compounds were resolved via specific rotation, experimental and calculated ECD spectra, and single-crystal X-ray diffraction analysis. The structure-activity relationship analysis highlighted that the free HO-3 group in the pentacyclic triterpenoids is crucial for their potent inhibitory activity against hCES1A1.
ESTHER : Zhang_2020_J.Nat.Prod_83_2940
PubMedSearch : Zhang_2020_J.Nat.Prod_83_2940
PubMedID: 32951423

Title : Western diet induces severe nonalcoholic steatohepatitis, ductular reaction, and hepatic fibrosis in liver CGI-58 knockout mice - Yang_2020_Sci.Rep_10_4701
Author(s) : Yang P , Wang Y , Tang W , Sun W , Ma Y , Lin S , Jing J , Jiang L , Shi H , Song Z , Yu L
Ref : Sci Rep , 10 :4701 , 2020
Abstract : Humans and rodents with Comparative Gene Identification-58 (CGI-58) mutations manifest nonalcoholic fatty liver disease (NAFLD). Here we show that liver CGI-58 knockout (LivKO) mice fed a Western diet rapidly develop advanced NAFLD, including nonalcoholic steatohepatitis (NASH) and hepatic fibrosis. After 14 weeks of diet challenge, starting at 6 weeks of age, LivKO mice showed increased inflammatory cell infiltration and proinflammatory gene expression in the liver, which was associated with elevated plasma levels of aminotransferases. Hepatic ductular reactions, pericellular fibrosis, and bridging fibrosis were observed only in the LivKO mice. Consistently, the KO mice had a significant increase in hepatic mRNAs for fibrogenic genes. In addition, LivKO mice displayed massive accumulation of lipid droplets (LDs) in hepatocytes. LDs were also observed in the cholangiocytes of the LivKO mice, but not the floxed controls. Four of the five LD coat proteins, including perilipins 2, 3, 4, and 5, were increased in the CGI-58 KO liver. CRISPR/Cas9-mediated knockout of CGI-58 in Huh7 human hepatoma cells induced LD deposition and perilipin expression, suggesting a cell autonomous effect. Our findings establish the Western diet-fed LivKO mice as an animal model of NASH and hepatic fibrosis. These animals may facilitate preclinical screening of therapeutic agents that counter against NAFLD progression.
ESTHER : Yang_2020_Sci.Rep_10_4701
PubMedSearch : Yang_2020_Sci.Rep_10_4701
PubMedID: 32170127
Gene_locus related to this paper: human-ABHD5 , mouse-abhd5

Title : Enantioselective Hydrolysis of Styrene Oxide and Benzyl Glycidyl Ether by a Variant of Epoxide Hydrolase from Agromyces mediolanus - Jin_2019_Mar.Drugs_17_
Author(s) : Jin H , Li Y , Zhang Q , Lin S , Yang Z , Ding G
Ref : Mar Drugs , 17 : , 2019
Abstract : Enantiopure epoxides are versatile synthetic intermediates for producing optically active pharmaceuticals. In an effort to provide more options for the preparation of enantiopure epoxides, a variant of the epoxide hydrolase (vEH-Am) gene from a marine microorganism Agromyces mediolanus was synthesized and expressed in Escherichia coli. Recombiant vEH-Am displayed a molecular weight of 43 kDa and showed high stability with a half-life of 51.1 h at 30 degrees C. The purified vEH-Am exhibited high enantioselectivity towards styrene oxide (SO) and benzyl glycidyl ether (BGE). The vEH-Am preferentially converted (S)-SO, leaving (R)-SO with the enantiomeric excess (ee) >99%. However, (R)-BGE was preferentially hydrolyzed by vEH-Am, resulting in (S)-BGE with >99% ee. To investigate the origin of regioselectivity, the interactions between vEH-Am and enantiomers of SO and BGE were analyzed by molecular docking simulation. In addition, it was observed that the yields of (R)-SO and (S)-BGE decreased with the increase of substrate concentrations. The yield of (R)-SO was significantly increased by adding 2% (v/v) Tween-20 or intermittent supplementation of the substrate. To our knowledge, vEH-Am displayed the highest enantioselectivity for the kinetic resolution of racemic BGE among the known EHs, suggesting promising applications of vEH-Am in the preparation of optically active BGE.
ESTHER : Jin_2019_Mar.Drugs_17_
PubMedSearch : Jin_2019_Mar.Drugs_17_
PubMedID: 31226863
Gene_locus related to this paper: agrme-a0a088b180

Title : Effects of Bread Yeast Cell Wall Beta-Glucans on Mice with Loperamide-Induced Constipation - Chen_2019_J.Med.Food_22_1009
Author(s) : Chen Z , Lin S , Jiang Y , Liu L , Jiang J , Chen S , Tong Y , Wang P
Ref : J Med Food , 22 :1009 , 2019
Abstract : Constipation is a common gastrointestinal disorder characterized by changes in intestinal habits. Increasing evidence indicates that long-term use of irritant laxatives causes serious side effects. Meanwhile, more than 50% of patients are dissatisfied with sense of use of non-prescriptional laxatives. beta-glucans are natural polysaccharides widely found in yeast, fungus, and plants, which have been reported to exhibit various pharmacological effects. The aim of this study was to characterize the effect of beta-glucans extracted from the bread yeast cell wall on loperamide-induced constipation mice. Forty mice were fed with loperamide (10 mg/kg) to make the constipation model and a diet supplemented with 2.5, 5, and 10 mg/kg beta-glucan. We assessed the defecation frequency, intestinal transit function of mice, as well as used high-throughput sequencing to analyze the intestinal microbiota composition and functional biological profiles data. Meanwhile, we detected expression of neurotransmitters including acetylcholinesterase, substance P, and serotonin (5-HT) and expression of tight junction protein (TJP) including zonula occludens-1 and mucin-2 in distal colon to characterize the possible molecular mechanisms. beta-glucans significantly enhanced intestinal motility and provided a possibility to regulate the expression of neurotransmitters and TJP in mice. The intestinal microecological portion of the treatment group partially recovered and was closer to the normal group. This study showed that beta-glucans can influence the intestinal microbiota and restore microecological balance to regulate the express of neurotransmitters and TJP to recover intestinal epithelial mechanical barrier. We suggested that beta-glucans could be used as an active nutritional supplement to protect the damaged intestinal barrier and help patients who have constipation complications and dysbiosis.
ESTHER : Chen_2019_J.Med.Food_22_1009
PubMedSearch : Chen_2019_J.Med.Food_22_1009
PubMedID: 31536448

Title : Theoretical Studies on Catalysis Mechanisms of Serum Paraoxonase 1 and Phosphotriesterase Diisopropyl Fluorophosphatase Suggest the Alteration of Substrate Preference from Paraoxonase to DFP - Zhang_2018_Molecules_23_
Author(s) : Zhang H , Yang L , Ma YY , Zhu C , Lin S , Liao RZ
Ref : Molecules , 23 : , 2018
Abstract : The calcium-dependent β-propeller proteins mammalian serum paraoxonase 1 (PON1) and phosphotriesterase diisopropyl fluorophosphatase (DFPase) catalyze the hydrolysis of organophosphorus compounds and enhance hydrolysis of various nerve agents. In the present work, the phosphotriesterase activity development between PON1 and DFPase was investigated by using the hybrid density functional theory method B3LYP. Based on the active-site difference between PON1 and DFPase, both the wild type and the mutant (a water molecule replacing Asn270 in PON1) models were designed. The results indicated that the substitution of a water molecule for Asn270 in PON1 had little effect on the enzyme activity in kinetics, while being more efficient in thermodynamics, which is essential for DFP hydrolysis. Structure comparisons of evolutionarily related enzymes show that the mutation of Asn270 leads to the catalytic Ca(2+) ion indirectly connecting the buried structural Ca(2+) ion via hydrogen bonds in DFPase. It can reduce the plasticity of enzymatic structure, and possibly change the substrate preference from paraoxon to DFP, which implies an evolutionary transition from mono- to dinuclear catalytic centers. Our studies shed light on the investigation of enzyme catalysis mechanism from an evolutionary perspective.
ESTHER : Zhang_2018_Molecules_23_
PubMedSearch : Zhang_2018_Molecules_23_
PubMedID: 29986514

Title : Gamma Oscillation Dysfunction in mPFC Leads to Social Deficits in Neuroligin 3 R451C Knockin Mice - Cao_2018_Neuron_97_1253
Author(s) : Cao W , Lin S , Xia QQ , Du YL , Yang Q , Zhang MY , Lu YQ , Xu J , Duan SM , Xia J , Feng G , Luo JH
Ref : Neuron , 97 :1253 , 2018
Abstract : Neuroligins (NLs) are critical for synapse formation and function. NL3 R451C is an autism-associated mutation. NL3 R451C knockin (KI) mice exhibit autistic behavioral abnormalities, including social novelty deficits. However, neither the brain regions involved in social novelty nor the underlying mechanisms are clearly understood. Here, we found decreased excitability of fast-spiking interneurons and dysfunction of gamma oscillation in the medial prefrontal cortex (mPFC), which contributed to the social novelty deficit in the KI mice. Neuronal firing rates and phase-coding abnormalities were also detected in the KI mice during social interactions. Interestingly, optogenetic stimulation of parvalbumin interneurons in the mPFC at 40 Hz nested at 8 Hz positively modulated the social behaviors of mice and rescued the social novelty deficit in the KI mice. Our findings suggest that gamma oscillation dysfunction in the mPFC leads to social deficits in autism, and manipulating mPFC PV interneurons may reverse the deficits in adulthood.
ESTHER : Cao_2018_Neuron_97_1253
PubMedSearch : Cao_2018_Neuron_97_1253
PubMedID: 29503190
Gene_locus related to this paper: mouse-3neur

Title : Characterization, in vitro binding properties, and inhibitory activity on pancreatic lipase of beta-glucans from different Qingke (Tibetan hulless barley) cultivars - Guo_2018_Int.J.Biol.Macromol_120_2517
Author(s) : Guo H , Lin S , Lu M , Gong JDB , Wang L , Zhang Q , Lin DR , Qin W , Wu DT
Ref : Int J Biol Macromol , 120 :2517 , 2018
Abstract : In order to explore Qingke beta-glucans as functional food ingredients for prevention of obesity, the physicochemical structures, in vitro binding properties, and inhibitory activities on pancreatic lipase of beta-glucans from three different Qingke cultivars, including Ganyucang (black), Dingqing (blue), and Zangqing 320 (white), were investigated and compared. Results showed that molecular weights, particle sizes, and intrinsic viscosities of beta-glucans from colored (black and blue) Qingke cultivars were much higher than those of white Qingke beta-glucans, respectively. In addition, the constituent monosaccharides of beta-glucans from colored Qingke cultivars were determined as arabinose, xylose, glucose, and galactose, and glucose was the dominant monosaccharide. Furthermore, colored Qingke beta-glucans exerted strong fat binding, cholesterol binding, and bile-acid binding capacities, as well as inhibitory activities on pancreatic lipase, which were much higher than those of white Qingke beta-glucans. Indeed, the fat binding, cholesterol binding, and bile-acid binding capacities, as well as the inhibitory activities on pancreatic lipase of Qingke beta-glucans were positively associated with their molecular weights and intrinsic viscosities. Results are beneficial for better understanding of the structure-function relationship of Qingke beta-glucans, and beta-glucans from colored Qingke cultivars (Ganyucang and Dingqing) could be further explored as functional food ingredients for prevention of obesity.
ESTHER : Guo_2018_Int.J.Biol.Macromol_120_2517
PubMedSearch : Guo_2018_Int.J.Biol.Macromol_120_2517
PubMedID: 30195000

Title : Bysspectin A, an unusual octaketide dimer and the precursor derivatives from the endophytic fungus Byssochlamys spectabilis IMM0002 and their biological activities - Wu_2018_Eur.J.Med.Chem_145_717
Author(s) : Wu YZ , Zhang HW , Sun ZH , Dai JG , Hu YC , Li R , Lin PC , Xia GY , Wang LY , Qiu BL , Zhang JF , Ge GB , Lin S
Ref : Eur Journal of Medicinal Chemistry , 145 :717 , 2018
Abstract : Bysspectin A (1), a polyketide-derived octaketide dimer with a novel carbon skeleton, and two new precursor derivatives, bysspectins B and C (2 and 3), were obtained from an organic extract of the endophytic fungus Byssochlamys spectabilis that had been isolated from a leaf tissue of the traditional Chinese medicinal plant Edgeworthia chrysantha, together with a known octaketide, paecilocin A (4). Their structures were determined by HRMS, 1D and 2D NMR spectroscopic analysis. A plausible route for their biosynthetic pathway is proposed. Compounds 1-3 were tested for their antimicrobial activities. Only compound 3 was weakly active against Escherichia coli and Staphyloccocus aureus with MIC values of 32 and 64mug/mL, respectively. Further, the inhibitory effects on human carboxylesterases (hCE1, hCE2) of compounds 1 and 4 were evaluated. The results demonstrated that bysspectin A (1) was a novel and highly selective inhibitor against hCE2 with the IC50 value of 2.01muM. Docking simulation also demonstrated that active compound 1 created interaction with the Ser-288 (the catalytic amino-acid in the catalytic cavity) of hCE2 via hydrogen bonding, revealing its highly selective inhibition toward hCE2.
ESTHER : Wu_2018_Eur.J.Med.Chem_145_717
PubMedSearch : Wu_2018_Eur.J.Med.Chem_145_717
PubMedID: 29353723

Title : Crystal Structure of StnA for the Biosynthesis of Antitumor Drug Streptonigrin Reveals a Unique Substrate Binding Mode - Qian_2017_Sci.Rep_7_40254
Author(s) : Qian T , Wo J , Zhang Y , Song Q , Feng G , Luo R , Lin S , Wu G , Chen HF
Ref : Sci Rep , 7 :40254 , 2017
Abstract : Streptonigrin methylesterase A (StnA) is one of the tailoring enzymes that modify the aminoquinone skeleton in the biosynthesis pathway of Streptomyces species. Although StnA has no significant sequence homology with the reported alpha/beta-fold hydrolases, it shows typical hydrolytic activity in vivo and in vitro. In order to reveal its functional characteristics, the crystal structures of the selenomethionine substituted StnA (SeMet-StnA) and the complex (S185A mutant) with its substrate were resolved to the resolution of 2.71 A and 2.90 A, respectively. The overall structure of StnA can be described as an alpha-helix cap domain on top of a common alpha/beta hydrolase domain. The substrate methyl ester of 10'-demethoxystreptonigrin binds in a hydrophobic pocket that mainly consists of cap domain residues and is close to the catalytic triad Ser185-His349-Asp308. The transition state is stabilized by an oxyanion hole formed by the backbone amides of Ala102 and Leu186. The substrate binding appears to be dominated by interactions with several specific hydrophobic contacts and hydrogen bonds in the cap domain. The molecular dynamics simulation and site-directed mutagenesis confirmed the important roles of the key interacting residues in the cap domain. Structural alignment and phylogenetic tree analysis indicate that StnA represents a new subfamily of lipolytic enzymes with the specific binding pocket located at the cap domain instead of the interface between the two domains.
ESTHER : Qian_2017_Sci.Rep_7_40254
PubMedSearch : Qian_2017_Sci.Rep_7_40254
PubMedID: 28074848
Gene_locus related to this paper: 9actn-l7pij2

Title : Operon for biosynthesis of lipstatin, the Beta-lactone inhibitor of human pancreatic lipase - Bai_2014_Appl.Environ.Microbiol_80_7473
Author(s) : Bai T , Zhang D , Lin S , Long Q , Wang Y , Ou H , Kang Q , Deng Z , Liu W , Tao M
Ref : Applied Environmental Microbiology , 80 :7473 , 2014
Abstract : Lipstatin, isolated from Streptomyces toxytricini as a potent and selective inhibitor of human pancreatic lipase, is a precursor for tetrahydrolipstatin (also known as orlistat, Xenical, and Alli), the only FDA-approved antiobesity medication for long-term use. Lipstatin features a 2-hexyl-3,5-dihydroxy-7,10-hexadecadienoic-beta-lactone structure with an N-formyl-l-leucine group attached as an ester to the 5-hydroxy group. It has been suggested that the alpha-branched 3,5-dihydroxy fatty acid beta-lactone moiety of lipstatin in S. toxytricini is derived from Claisen condensation between two fatty acid substrates, which are derived from incomplete oxidative degradation of linoleic acid based on feeding experiments. In this study, we identified a six-gene operon (lst) that was essential for the biosynthesis of lipstatin by large-deletion, complementation, and single-gene knockout experiments. lstA, lstB, and lstC, which encode two beta-ketoacyl-acyl carrier protein synthase III homologues and an acyl coenzyme A (acyl-CoA) synthetase homologue, were indicated to be responsible for the generation of the alpha-branched 3,5-dihydroxy fatty acid backbone. Subsequently, the nonribosomal peptide synthetase (NRPS) gene lstE and the putative formyltransferase gene lstF were involved in decoration of the alpha-branched 3,5-dihydroxy fatty acid chain with an N-formylated leucine residue. Finally, the 3beta-hydroxysteroid dehydrogenase-homologous gene lstD might be responsible for the reduction of the beta-keto group of the biosynthetic intermediate, thereby facilitating the formation of the unique beta-lactone ring.
ESTHER : Bai_2014_Appl.Environ.Microbiol_80_7473
PubMedSearch : Bai_2014_Appl.Environ.Microbiol_80_7473
PubMedID: 25239907

Title : Characterization of streptonigrin biosynthesis reveals a cryptic carboxyl methylation and an unusual oxidative cleavage of a N-C bond - Xu_2013_J.Am.Chem.Soc_135_1739
Author(s) : Xu F , Kong D , He X , Zhang Z , Han M , Xie X , Wang P , Cheng H , Tao M , Zhang L , Deng Z , Lin S
Ref : Journal of the American Chemical Society , 135 :1739 , 2013
Abstract : Streptonigrin (STN, 1) is a highly functionalized aminoquinone alkaloid with broad and potent antitumor activity. Here, we reported the biosynthetic gene cluster of STN identified by genome scanning of a STN producer Streptomyces flocculus CGMCC4.1223. This cluster consists of 48 genes determined by a series of gene inactivations. On the basis of the structures of intermediates and shunt products accumulated from five specific gene inactivation mutants and feeding experiments, the biosynthetic pathway was proposed, and the sequence of tailoring steps was preliminarily determined. In this pathway, a cryptic methylation of lavendamycin was genetically and biochemically characterized to be catalyzed by a leucine carboxyl methyltransferase StnF2. A [2Fe-2S](2+) cluster-containing aromatic ring dioxygenase StnB1/B2 system was biochemically characterized to catalyze a regiospecific cleavage of the N-C8' bond of the indole ring of the methyl ester of lavendamycin. This work provides opportunities to illuminate the enzymology of novel reactions involved in this pathway and to create, using genetic and chemo-enzymatic methods, new streptonigrinoid analogues as potential therapeutic agents.
ESTHER : Xu_2013_J.Am.Chem.Soc_135_1739
PubMedSearch : Xu_2013_J.Am.Chem.Soc_135_1739
PubMedID: 23301954
Gene_locus related to this paper: 9actn-l7pij2

Title : Structure of the enzyme-acyl carrier protein (ACP) substrate gatekeeper complex required for biotin synthesis - Agarwal_2012_Proc.Natl.Acad.Sci.U.S.A_109_17406
Author(s) : Agarwal V , Lin S , Lukk T , Nair SK , Cronan JE
Ref : Proc Natl Acad Sci U S A , 109 :17406 , 2012
Abstract : Although the pimeloyl moiety was long known to be a biotin precursor, the mechanism of assembly of this C7 alpha,omega-dicarboxylic acid was only recently elucidated. In Escherichia coli, pimelate is made by bypassing the strict specificity of the fatty acid synthetic pathway. BioC methylates the free carboxyl of a malonyl thioester, which replaces the usual acetyl thioester primer. This atypical primer is transformed to pimeloyl-acyl carrier protein (ACP) methyl ester by two cycles of fatty acid synthesis. The question is, what stops this product from undergoing further elongation? Although BioH readily cleaves this product in vitro, the enzyme is nonspecific, which made assignment of its physiological substrate problematical, especially because another enzyme, BioF, could also perform this gatekeeping function. We report the 2.05-A resolution cocrystal structure of a complex of BioH with pimeloyl-ACP methyl ester and use the structure to demonstrate that BioH is the gatekeeper and its physiological substrate is pimeloyl-ACP methyl ester.
ESTHER : Agarwal_2012_Proc.Natl.Acad.Sci.U.S.A_109_17406
PubMedSearch : Agarwal_2012_Proc.Natl.Acad.Sci.U.S.A_109_17406
PubMedID: 23045647
Gene_locus related to this paper: ecoli-bioh

Title : Evolution of a new function in an esterase: simple amino acid substitutions enable the activity present in the larger paralog, BioH - Flores_2012_Protein.Eng.Des.Sel_25_387
Author(s) : Flores H , Lin S , Contreras-Ferrat G , Cronan JE , Morett E
Ref : Protein Engineering Des Sel , 25 :387 , 2012
Abstract : Gene duplication and divergence are essential processes for the evolution of new activities. Divergence may be gradual involving simple amino acid residue substitutions or drastic such that larger structural elements are inserted deleted or rearranged. Vast protein sequence comparisons supported by some experimental evidence argue that large structural modifications have been necessary for certain catalytic activities to evolve. However it is not clear whether these activities could not have been attained by gradual changes. Interestingly catalytic promiscuity could play a fundamental evolutionary role a preexistent secondary activity could be increased by simple amino acid residue substitutions that do not affect the enzyme's primary activity. The promiscuous profile of the enzyme may be modified gradually by genetic drift making a pool of potentially useful activities that can be selected before duplication In this work we used random mutagenesis and in vivo selection to evolve the Pseudomonas aeruginosa PAO1 carboxylesterase PA3859 a small protein to attain the function of BioH a much larger paralog involved in biotin biosynthesis. BioH was chosen as a target activity because it provides a highly sensitive selection for evolved enzymatic activities by auxotrophy complementation. After only two cycles of directed evolution mutants with the ability to efficiently complement biotin auxotrophy were selected. The in vivo and in vitro characterization showed that the activity of one of our mutant proteins was similar to that of the wild-type BioH enzyme. Our results demonstrate that it is possible to evolve enzymatic activities present in larger proteins by discrete amino acid substitutions.
ESTHER : Flores_2012_Protein.Eng.Des.Sel_25_387
PubMedSearch : Flores_2012_Protein.Eng.Des.Sel_25_387
PubMedID: 22691705
Gene_locus related to this paper: pseae-PA3859

Title : Fatigue and muscle atrophy in a mouse model of myasthenia gravis is paralleled by loss of sarcolemmal nNOS - Meinen_2012_PLoS.One_7_e44148
Author(s) : Meinen S , Lin S , Ruegg MA , Punga AR
Ref : PLoS ONE , 7 :e44148 , 2012
Abstract : Myasthenia Gravis (MG) patients suffer from chronic fatigue of skeletal muscles, even after initiation of proper immunosuppressive medication. Since the localization of neuronal nitric oxide synthase (nNOS) at the muscle membrane is important for sustained muscle contraction, we here study the localization of nNOS in muscles from mice with acetylcholine receptor antibody seropositive (AChR+) experimental autoimmune MG (EAMG). EAMG was induced in 8 week-old male mice by immunization with AChRs purified from torpedo californica. Sham-injected wild type mice and mdx mice, a model for Duchenne muscular dystrophy, were used for comparison. At EAMG disease grade 3 (severe myasthenic weakness), the triceps, sternomastoid and masseter muscles were collected for analysis. Unlike in mdx muscles, total nNOS expression as well as the presence of its binding partner syntrophin alpha-1, were not altered in EAMG. Immunohistological and biochemical analysis showed that nNOS was lost from the muscle membrane and accumulated in the cytosol, which is likely the consequence of blocked neuromuscular transmission. Atrophy of all examined EAMG muscles were supported by up-regulated transcript levels of the atrogenes atrogin-1 and MuRF1, as well as MuRF1 protein, in combination with reduced muscle fiber diameters. We propose that loss of sarcolemmal nNOS provides an additional mechanism for the chronic muscle fatigue and secondary muscle atrophy in EAMG and MG.
ESTHER : Meinen_2012_PLoS.One_7_e44148
PubMedSearch : Meinen_2012_PLoS.One_7_e44148
PubMedID: 22952904

Title : Muscle-selective synaptic disassembly and reorganization in MuSK antibody positive MG mice - Punga_2011_Exp.Neurol_230_207
Author(s) : Punga AR , Lin S , Oliveri F , Meinen S , Ruegg MA
Ref : Experimental Neurology , 230 :207 , 2011
Abstract : MuSK antibody seropositive (MuSK+) Myasthenia Gravis (MG) patients present a distinct selective fatigue, and sometimes atrophy, of bulbar, facial and neck muscles. Here, we study the mechanism underlying the focal muscle involvement in mice with MuSK+ experimental autoimmune MG (EAMG). 8 week-old female wildtype C57BL6 mice and transgenic mice, which express yellow fluorescence protein (YFP) in their motor neurons, were immunized with the extracellular domain of rat MuSK and compared with control mice. The soleus, EDL, sternomastoid, omohyoid, thoracic paraspinal and masseter muscles were examined for pre- and postsynaptic changes with whole mount immunostaining and confocal microscopy. Neuromuscular junction derangement was quantified and compared between muscles and correlated with transcript levels of MuSK and other postsynaptic genes. Correlating with the EAMG disease grade, the postsynaptic acetylcholine receptor (AChR) clusters were severely fragmented with a subsequent reduction also of the presynaptic nerve terminal area. Among the muscles analyzed, the thoracic paraspinal, sternomastoid and masseter muscles were more affected than the leg muscles. The masseter muscle was the most affected, leading to denervation and atrophy and this severity correlated with the lowest levels of MuSK mRNA. On the contrary, the soleus with high MuSK mRNA levels had less postsynaptic perturbation and more terminal nerve sprouting. We propose that low muscle-intrinsic MuSK levels render some muscles, such as the masseter, more vulnerable to the postsynaptic perturbation of MuSK antibodies with subsequent denervation and atrophy. These findings augment our understanding of the sometimes severe, facio-bulbar phenotype of MuSK+ MG.
ESTHER : Punga_2011_Exp.Neurol_230_207
PubMedSearch : Punga_2011_Exp.Neurol_230_207
PubMedID: 21565192

Title : MuSK levels differ between adult skeletal muscles and influence postsynaptic plasticity - Punga_2011_Eur.J.Neurosci_33_890
Author(s) : Punga AR , Maj M , Lin S , Meinen S , Ruegg MA
Ref : European Journal of Neuroscience , 33 :890 , 2011
Abstract : Muscle-specific tyrosine kinase (MuSK) is involved in the formation and maintenance of the neuromuscular junction (NMJ), and is necessary for NMJ integrity. As muscle involvement is strikingly selective in pathological conditions in which MuSK is targeted, including congenital myasthenic syndrome with MuSK mutation and MuSK antibody-seropositive myasthenia gravis, we hypothesized that the postsynaptic response to MuSK-agrin signalling differs between adult muscles. Transcript levels of postsynaptic proteins were compared between different muscles in wild-type adult mice. MuSK expression was high in the soleus and sternomastoid muscles and low in the extensor digitorum longus (EDL) and omohyoid muscles. The acetylcholine receptor (AChR) alpha subunit followed a similar expression pattern, whereas expression of Dok-7, Lrp4 and rapsyn was comparable between the muscles. We subsequently examined muscles in mice that overexpressed a miniaturized form of neural agrin or MuSK. In these transgenic mice, the soleus and sternomastoid muscles responded with formation of ectopic AChR clusters, whereas such clusters were almost absent in the EDL and omohyoid muscles. Electroporation of Dok-7 revealed its important role as an activator of MuSK in AChR cluster formation in adult muscles. Together, our findings indicate for the first time that adult skeletal muscles harbour different endogenous levels of MuSK and that these levels determine the ability to form ectopic AChR clusters upon overexpression of agrin or MuSK. We believe that these findings are important for our understanding of adult muscle plasticity and the selective muscle involvement in neuromuscular disorders in which MuSK is diminished.
ESTHER : Punga_2011_Eur.J.Neurosci_33_890
PubMedSearch : Punga_2011_Eur.J.Neurosci_33_890
PubMedID: 21255125

Title : The Medicago genome provides insight into the evolution of rhizobial symbioses - Young_2011_Nature_480_520
Author(s) : Young ND , Debelle F , Oldroyd GE , Geurts R , Cannon SB , Udvardi MK , Benedito VA , Mayer KF , Gouzy J , Schoof H , Van de Peer Y , Proost S , Cook DR , Meyers BC , Spannagl M , Cheung F , De Mita S , Krishnakumar V , Gundlach H , Zhou S , Mudge J , Bharti AK , Murray JD , Naoumkina MA , Rosen B , Silverstein KA , Tang H , Rombauts S , Zhao PX , Zhou P , Barbe V , Bardou P , Bechner M , Bellec A , Berger A , Berges H , Bidwell S , Bisseling T , Choisne N , Couloux A , Denny R , Deshpande S , Dai X , Doyle JJ , Dudez AM , Farmer AD , Fouteau S , Franken C , Gibelin C , Gish J , Goldstein S , Gonzalez AJ , Green PJ , Hallab A , Hartog M , Hua A , Humphray SJ , Jeong DH , Jing Y , Jocker A , Kenton SM , Kim DJ , Klee K , Lai H , Lang C , Lin S , Macmil SL , Magdelenat G , Matthews L , McCorrison J , Monaghan EL , Mun JH , Najar FZ , Nicholson C , Noirot C , O'Bleness M , Paule CR , Poulain J , Prion F , Qin B , Qu C , Retzel EF , Riddle C , Sallet E , Samain S , Samson N , Sanders I , Saurat O , Scarpelli C , Schiex T , Segurens B , Severin AJ , Sherrier DJ , Shi R , Sims S , Singer SR , Sinharoy S , Sterck L , Viollet A , Wang BB , Wang K , Wang M , Wang X , Warfsmann J , Weissenbach J , White DD , White JD , Wiley GB , Wincker P , Xing Y , Yang L , Yao Z , Ying F , Zhai J , Zhou L , Zuber A , Denarie J , Dixon RA , May GD , Schwartz DC , Rogers J , Quetier F , Town CD , Roe BA
Ref : Nature , 480 :520 , 2011
Abstract : Legumes (Fabaceae or Leguminosae) are unique among cultivated plants for their ability to carry out endosymbiotic nitrogen fixation with rhizobial bacteria, a process that takes place in a specialized structure known as the nodule. Legumes belong to one of the two main groups of eurosids, the Fabidae, which includes most species capable of endosymbiotic nitrogen fixation. Legumes comprise several evolutionary lineages derived from a common ancestor 60 million years ago (Myr ago). Papilionoids are the largest clade, dating nearly to the origin of legumes and containing most cultivated species. Medicago truncatula is a long-established model for the study of legume biology. Here we describe the draft sequence of the M. truncatula euchromatin based on a recently completed BAC assembly supplemented with Illumina shotgun sequence, together capturing approximately 94% of all M. truncatula genes. A whole-genome duplication (WGD) approximately 58 Myr ago had a major role in shaping the M. truncatula genome and thereby contributed to the evolution of endosymbiotic nitrogen fixation. Subsequent to the WGD, the M. truncatula genome experienced higher levels of rearrangement than two other sequenced legumes, Glycine max and Lotus japonicus. M. truncatula is a close relative of alfalfa (Medicago sativa), a widely cultivated crop with limited genomics tools and complex autotetraploid genetics. As such, the M. truncatula genome sequence provides significant opportunities to expand alfalfa's genomic toolbox.
ESTHER : Young_2011_Nature_480_520
PubMedSearch : Young_2011_Nature_480_520
PubMedID: 22089132
Gene_locus related to this paper: medtr-b7fki4 , medtr-b7fmi1 , medtr-g7itl1 , medtr-g7iu67 , medtr-g7izm0 , medtr-g7j641 , medtr-g7jtf8 , medtr-g7jtg2 , medtr-g7jtg4 , medtr-g7kem3 , medtr-g7kml3 , medtr-g7ksx5 , medtr-g7leb3 , medtr-q1s5d8 , medtr-q1s9m3 , medtr-q1t171 , medtr-g7k9e1 , medtr-g7k9e3 , medtr-g7k9e5 , medtr-g7k9e8 , medtr-g7k9e9 , medtr-g7lbp2 , medtr-g7lch3 , medtr-g7ib94 , medtr-g7ljk8 , medtr-g7i6w5 , medtr-g7kvg4 , medtr-g7iam1 , medtr-g7iam3 , medtr-g7l754 , medtr-g7jr41 , medtr-g7l4f5 , medtr-g7l755 , medtr-a0a072vyl4 , medtr-g7jwk8 , medtr-a0a072vhg0 , medtr-a0a072vrv9 , medtr-g7kmk5 , medtr-a0a072uuf6 , medtr-a0a072urp3 , medtr-g7zzc3 , medtr-g7ie19 , medtr-g7kst7 , medtr-a0a072u5k5 , medtr-a0a072v056 , medtr-scp1 , medtr-g7kyn0 , medtr-g7inw6 , medtr-g7j3q3

Title : Biotin synthesis begins by hijacking the fatty acid synthetic pathway. - Lin_2010_Nat.Chem.Biol_6_682
Author(s) : Lin S , Hanson RE , Cronan JE
Ref : Nat Chemical Biology , 6 :682 , 2010
Abstract : Although biotin is an essential enzyme cofactor found in all three domains of life, our knowledge of its biosynthesis remains fragmentary. Most of the carbon atoms of biotin are derived from pimelic acid, a seven-carbon dicarboxylic acid, but the mechanism whereby this intermediate is assembled remains unknown. Genetic analysis in Escherichia coli identified only two genes of unknown function required for pimelate synthesis, bioC and bioH. We report in vivo and in vitro evidence that the pimeloyl moiety is synthesized by a modified fatty acid synthetic pathway in which the omega-carboxyl group of a malonyl-thioester is methylated by BioC, which allows recognition of this atypical substrate by the fatty acid synthetic enzymes. The malonyl-thioester methyl ester enters fatty acid synthesis as the primer and undergoes two reiterations of the fatty acid elongation cycle to give pimeloyl-acyl carrier protein (ACP) methyl ester, which is hydrolyzed to pimeloyl-ACP and methanol by BioH.
ESTHER : Lin_2010_Nat.Chem.Biol_6_682
PubMedSearch : Lin_2010_Nat.Chem.Biol_6_682
PubMedID: 20693992
Gene_locus related to this paper: 9gamm-BioJ , ecoli-bioh

Title : Characterization of the epoxide hydrolase NcsF2 from the neocarzinostatin biosynthetic gene cluster - Lin_2010_Org.Lett_12_3816
Author(s) : Lin S , Horsman GP , Shen B
Ref : Org Lett , 12 :3816 , 2010
Abstract : Neocarzinostatin (1) biosynthesis is proposed to involve a vicinal diol intermediate. It is reported that NcsF2, one of two epoxide hydrolases encoded by the NCS gene cluster, catalyzes regiospecific addition of H(2)O to C-2 of both (R)- and (S)-styrene oxides to afford (R)- and (S)-1-phenyl-1,2-ethanediols, respectively, supporting its proposed role in 1 biosynthesis. (R)-1-Phenyl-1,2-ethanediol (87% yield and 99% ee) was obtained from (+/-)-styrene oxide hydrolysis by cocatalysis using NcsF2 and SgcF, the complementary epoxide hydrolase from the C-1027 biosynthetic pathway.
ESTHER : Lin_2010_Org.Lett_12_3816
PubMedSearch : Lin_2010_Org.Lett_12_3816
PubMedID: 20704329
Gene_locus related to this paper: strcz-Q84HB8

Title : The sequence and de novo assembly of the giant panda genome - Li_2010_Nature_463_311
Author(s) : Li R , Fan W , Tian G , Zhu H , He L , Cai J , Huang Q , Cai Q , Li B , Bai Y , Zhang Z , Zhang Y , Wang W , Li J , Wei F , Li H , Jian M , Nielsen R , Li D , Gu W , Yang Z , Xuan Z , Ryder OA , Leung FC , Zhou Y , Cao J , Sun X , Fu Y , Fang X , Guo X , Wang B , Hou R , Shen F , Mu B , Ni P , Lin R , Qian W , Wang G , Yu C , Nie W , Wang J , Wu Z , Liang H , Min J , Wu Q , Cheng S , Ruan J , Wang M , Shi Z , Wen M , Liu B , Ren X , Zheng H , Dong D , Cook K , Shan G , Zhang H , Kosiol C , Xie X , Lu Z , Li Y , Steiner CC , Lam TT , Lin S , Zhang Q , Li G , Tian J , Gong T , Liu H , Zhang D , Fang L , Ye C , Zhang J , Hu W , Xu A , Ren Y , Zhang G , Bruford MW , Li Q , Ma L , Guo Y , An N , Hu Y , Zheng Y , Shi Y , Li Z , Liu Q , Chen Y , Zhao J , Qu N , Zhao S , Tian F , Wang X , Wang H , Xu L , Liu X , Vinar T , Wang Y , Lam TW , Yiu SM , Liu S , Huang Y , Yang G , Jiang Z , Qin N , Li L , Bolund L , Kristiansen K , Wong GK , Olson M , Zhang X , Li S , Yang H
Ref : Nature , 463 :311 , 2010
Abstract : Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes.
ESTHER : Li_2010_Nature_463_311
PubMedSearch : Li_2010_Nature_463_311
PubMedID: 20010809
Gene_locus related to this paper: ailme-ABH15 , ailme-ACHE , ailme-BCHE , ailme-d2gtv3 , ailme-d2gty9 , ailme-d2gu87 , ailme-d2gu97 , ailme-d2gve7 , ailme-d2gwu1 , ailme-d2gx08 , ailme-d2gyt0 , ailme-d2gz36 , ailme-d2gz37 , ailme-d2gz38 , ailme-d2gz39 , ailme-d2gz40 , ailme-d2h5r9 , ailme-d2h7b7 , ailme-d2h9c9 , ailme-d2h794 , ailme-d2hau7 , ailme-d2hau8 , ailme-d2hcd9 , ailme-d2hdi6 , ailme-d2heu6 , ailme-d2hga4 , ailme-d2hqw5 , ailme-d2hs98 , ailme-d2hsx4 , ailme-d2hti6 , ailme-d2htv3 , ailme-d2htz6 , ailme-d2huc7 , ailme-d2hwj8 , ailme-d2hwy7 , ailme-d2hxm1 , ailme-d2hyc8 , ailme-d2hyv2 , ailme-d2hz11 , ailme-d2hza3 , ailme-d2hzr4 , ailme-d2i1l4 , ailme-d2i2g8 , ailme-g1l7m3 , ailme-g1lu36 , ailme-g1m769 , ailme-g1mc29 , ailme-g1mdj8 , ailme-g1mdr5 , ailme-g1mfp4 , ailme-g1mfx5 , ailme-g1lj41 , ailme-g1lm28 , ailme-g1l3u1 , ailme-g1l7l1 , ailme-g1m5i3 , ailme-g1l2f6 , ailme-g1lji5 , ailme-g1lqk3 , ailme-g1l8s9 , ailme-d2h717 , ailme-d2h718 , ailme-d2h719 , ailme-d2h720 , ailme-g1m5v0 , ailme-g1m5y7 , ailme-g1lkt7 , ailme-g1l2a1 , ailme-g1lsc8 , ailme-g1lrp4 , ailme-d2gv02 , ailme-g1mik5 , ailme-g1ljr1 , ailme-g1lxw7 , ailme-d2h8b5 , ailme-d2h2r2 , ailme-d2h9w7 , ailme-g1meh3 , ailme-g1m719

Title : PME-1 protects extracellular signal-regulated kinase pathway activity from protein phosphatase 2A-mediated inactivation in human malignant glioma - Puustinen_2009_Cancer.Res_69_2870
Author(s) : Puustinen P , Junttila MR , Vanhatupa S , Sablina AA , Hector ME , Teittinen K , Raheem O , Ketola K , Lin S , Kast J , Haapasalo H , Hahn WC , Westermarck J
Ref : Cancer Research , 69 :2870 , 2009
Abstract : Extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway activity is regulated by the antagonist function of activating kinases and inactivating protein phosphatases. Sustained ERK pathway activity is commonly observed in human malignancies; however, the mechanisms by which the pathway is protected from phosphatase-mediated inactivation in the tumor tissue remain obscure. Here, we show that methylesterase PME-1-mediated inhibition of the protein phosphatase 2A promotes basal ERK pathway activity and is required for efficient growth factor response. Mechanistically, PME-1 is shown to support ERK pathway signaling upstream of Raf, but downstream of growth factor receptors and protein kinase C. In malignant gliomas, PME-1 expression levels correlate with both ERK activity and cell proliferation in vivo. Moreover, PME-1 expression significantly correlates with disease progression in human astrocytic gliomas (n=222). Together, these observations identify PME-1 expression as one mechanism by which ERK pathway activity is maintained in cancer cells and suggest an important functional role for PME-1 in the disease progression of human astrocytic gliomas.
ESTHER : Puustinen_2009_Cancer.Res_69_2870
PubMedSearch : Puustinen_2009_Cancer.Res_69_2870
PubMedID: 19293187
Gene_locus related to this paper: human-PPME1

Title : The role of nerve- versus muscle-derived factors in mammalian neuromuscular junction formation - Lin_2008_J.Neurosci_28_3333
Author(s) : Lin S , Landmann L , Ruegg MA , Brenner HR
Ref : Journal of Neuroscience , 28 :3333 , 2008
Abstract : Neuromuscular junctions (NMJs) normally form in the central region of developing muscle. In this process, agrin released from motor neurons has been considered to initiate the formation of synaptic acetylcholine receptor (AChR) clusters (neurocentric model). However, in muscle developing in the absence of nerves and thus of agrin, AChR clusters still form in the muscle center. This raises the possibility that the region of NMJ formation is determined by muscle-derived cues that spatially restrict the nerve to form synapses from aneural AChR clusters, e.g., by patterned expression of the agrin receptor MuSK (muscle-specific kinase) (myocentric model). Here we examine at initial stages of synaptogenesis whether the responsiveness of myotubes to agrin is spatially restricted, whether the regions of NMJ formation in wild-type muscle and of aneural AChR cluster formation in agrin-deficient animals correlate, and whether AChR cluster growth depends on the presence of agrin. We show that primary myotubes form AChR clusters in response to exogenous agrin in their central region only, a pattern that can spatially restrict NMJ formation. However, the nerve also makes synapses in regions in which aneural AChR clusters do not form, and agrin promotes synaptic cluster growth from the first stages of neuromuscular contact formation. These data indicate that aneural AChR clusters per se are not required for NMJ formation. A model is proposed that explains either the neurocentric or the myocentric mode of NMJ formation depending on a balance between the levels of MuSK expression and the availability of nerve-released agrin.
ESTHER : Lin_2008_J.Neurosci_28_3333
PubMedSearch : Lin_2008_J.Neurosci_28_3333
PubMedID: 18367600

Title : Muscle-wide secretion of a miniaturized form of neural agrin rescues focal neuromuscular innervation in agrin mutant mice - Lin_2008_Proc.Natl.Acad.Sci.U.S.A_105_11406
Author(s) : Lin S , Maj M , Bezakova G , Magyar JP , Brenner HR , Ruegg MA
Ref : Proc Natl Acad Sci U S A , 105 :11406 , 2008
Abstract : Agrin and its receptor MuSK are required for the formation of the postsynaptic apparatus at the neuromuscular junction (NMJ). In the current model the local deposition of agrin by the nerve and the resulting local activation of MuSK are responsible for creating and maintaining the postsynaptic apparatus including clusters of acetylcholine receptors (AChRs). Concomitantly, the release of acetylcholine (ACh) and the resulting depolarization disperses those postsynaptic structures that are not apposed by the nerve and thus not stabilized by agrin-MuSK signaling. Here we show that a miniaturized form of agrin, consisting of the laminin-binding and MuSK-activating domains, is sufficient to fully restore NMJs in agrin mutant mice when expressed by developing muscle. Although miniagrin is expressed uniformly throughout muscle fibers and induces ectopic AChR clusters, the size and the number of those AChR clusters contacted by the motor nerve increase during development. We provide experimental evidence that this is due to ACh, because the AChR agonist carbachol stabilizes AChR clusters in organotypic cultures of embryonic diaphragms. In summary, our results show that agrin function in NMJ development requires only two small domains, and that this function does not depend on the local deposition of agrin at synapses. Finally, they suggest a novel local function of ACh in stabilizing postsynaptic structures.
ESTHER : Lin_2008_Proc.Natl.Acad.Sci.U.S.A_105_11406
PubMedSearch : Lin_2008_Proc.Natl.Acad.Sci.U.S.A_105_11406
PubMedID: 18685098

Title : Genome sequence of a nephritogenic and highly transformable M49 strain of Streptococcus pyogenes - McShan_2008_J.Bacteriol_190_7773
Author(s) : McShan WM , Ferretti JJ , Karasawa T , Suvorov AN , Lin S , Qin B , Jia H , Kenton S , Najar F , Wu H , Scott J , Roe BA , Savic DJ
Ref : Journal of Bacteriology , 190 :7773 , 2008
Abstract : The 1,815,783-bp genome of a serotype M49 strain of Streptococcus pyogenes (group A streptococcus [GAS]), strain NZ131, has been determined. This GAS strain (FCT type 3; emm pattern E), originally isolated from a case of acute post-streptococcal glomerulonephritis, is unusually competent for electrotransformation and has been used extensively as a model organism for both basic genetic and pathogenesis investigations. As with the previously sequenced S. pyogenes genomes, three unique prophages are a major source of genetic diversity. Two clustered regularly interspaced short palindromic repeat (CRISPR) regions were present in the genome, providing genetic information on previous prophage encounters. A unique cluster of genes was found in the pathogenicity island-like emm region that included a novel Nudix hydrolase, and, further, this cluster appears to be specific for serotype M49 and M82 strains. Nudix hydrolases eliminate potentially hazardous materials or prevent the unbalanced accumulation of normal metabolites; in bacteria, these enzymes may play a role in host cell invasion. Since M49 S. pyogenes strains have been known to be associated with skin infections, the Nudix hydrolase and its associated genes may have a role in facilitating survival in an environment that is more variable and unpredictable than the uniform warmth and moisture of the throat. The genome of NZ131 continues to shed light upon the evolutionary history of this human pathogen. Apparent horizontal transfer of genetic material has led to the existence of highly variable virulence-associated regions that are marked by multiple rearrangements and genetic diversification while other regions, even those associated with virulence, vary little between genomes. The genome regions that encode surface gene products that will interact with host targets or aid in immune avoidance are the ones that display the most sequence diversity. Thus, while natural selection favors stability in much of the genome, it favors diversity in these regions.
ESTHER : McShan_2008_J.Bacteriol_190_7773
PubMedSearch : McShan_2008_J.Bacteriol_190_7773
PubMedID: 18820018
Gene_locus related to this paper: strpy-ESTA , strpy-PEPXP , strpy-SPY1308

Title : Tyrosine phosphatases such as SHP-2 act in a balance with Src-family kinases in stabilization of postsynaptic clusters of acetylcholine receptors - Camilleri_2007_BMC.Neurosci_8_46
Author(s) : Camilleri AA , Willmann R , Sadasivam G , Lin S , Ruegg MA , Gesemann M , Fuhrer C
Ref : BMC Neurosci , 8 :46 , 2007
Abstract : BACKGROUND: Development of neural networks requires that synapses are formed, eliminated and stabilized. At the neuromuscular junction (NMJ), agrin/MuSK signaling, by triggering downstream pathways, causes clustering and phosphorylation of postsynaptic acetylcholine receptors (AChRs). Postnatally, AChR aggregates are stabilized by molecular pathways that are poorly characterized. Gain or loss of function of Src-family kinases (SFKs) disassembles AChR clusters at adult NMJs in vivo, whereas AChR aggregates disperse rapidly upon withdrawal of agrin from cultured src-/-;fyn-/- myotubes. This suggests that a balance between protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs) such as those of the Src-family may be essential in stabilizing clusters of AChRs.
RESULTS: We have analyzed the role of PTPs in maintenance of AChR aggregates, by adding and then withdrawing agrin from cultured myotubes in the presence of PTP or PTK inhibitors and quantitating remaining AChR clusters. In wild-type myotubes, blocking PTPs with pervanadate caused enhanced disassembly of AChR clusters after agrin withdrawal. When added at the time of agrin withdrawal, SFK inhibitors destabilized AChR aggregates but concomitant addition of pervanadate rescued cluster stability. Likewise in src-/-;fyn-/- myotubes, in which agrin-induced AChR clusters form normally but rapidly disintegrate after agrin withdrawal, pervanadate addition stabilized AChR clusters. The PTP SHP-2, known to be enriched at the NMJ, associated and colocalized with MuSK, and agrin increased this interaction. Specific SHP-2 knockdown by RNA interference reduced the stability of AChR clusters in wild-type myotubes. Similarly, knockdown of SHP-2 in adult mouse soleus muscle by electroporation of RNA interference constructs caused disassembly of pretzel-shaped AChR-rich areas in vivo. Finally, we found that src-/-;fyn-/- myotubes contained elevated levels of SHP-2 protein. CONCLUSION: Our data are the first to show that the fine balance between PTPs and SFKs is a key aspect in stabilization of postsynaptic AChR clusters. One phosphatase that acts in this equilibrium is SHP-2. Thus, PTPs such as SHP-2 stabilize AChR clusters under normal circumstances, but when these PTPs are not balanced by SFKs, they render clusters unstable.
ESTHER : Camilleri_2007_BMC.Neurosci_8_46
PubMedSearch : Camilleri_2007_BMC.Neurosci_8_46
PubMedID: 17605785

Title : Spliced leader RNA trans-splicing in dinoflagellates - Zhang_2007_Proc.Natl.Acad.Sci.U.S.A_104_4618
Author(s) : Zhang H , Hou Y , Miranda L , Campbell DA , Sturm NR , Gaasterland T , Lin S
Ref : Proc Natl Acad Sci U S A , 104 :4618 , 2007
Abstract : Through the analysis of hundreds of full-length cDNAs from fifteen species representing all major orders of dinoflagellates, we demonstrate that nuclear-encoded mRNAs in all species, from ancestral to derived lineages, are trans-spliced with the addition of the 22-nt conserved spliced leader (SL), DCCGUAGCCAUUUUGGCUCAAG (D = U, A, or G), to the 5' end. SL trans-splicing has been documented in a limited but diverse number of eukaryotes, in which this process makes it possible to translate polycistronically transcribed nuclear genes. In SL trans-splicing, SL-donor transcripts (SL RNAs) contain two functional domains: an exon that provides the SL for mRNA and an intron that contains a spliceosomal (Sm) binding site. In dinoflagellates, SL RNAs are unusually short at 50-60 nt, with a conserved Sm binding motif (AUUUUGG) located in the SL (exon) rather than the intron. The initiation nucleotide is predominantly U or A, an unusual feature that may affect capping, and hence the translation and stability of the recipient mRNA. The core SL element was found in mRNAs coding for a diverse array of proteins. Among the transcripts characterized were three homologs of Sm-complex subunits, indicating that the role of the Sm binding site is conserved, even if the location on the SL is not. Because association with an Sm-complex often signals nuclear import for U-rich small nuclear RNAs, it is unclear how this Sm binding site remains on mature mRNAs without impeding cytosolic localization or translation of the latter. The sequences reported in this paper have been deposited in the GenBank database (accession nos. AF 512889, DQ 864761-DQ 864971, DQ 867053-DQ 867070, DQ 884413-DQ 884451, EF 133854-EF 133905, EF 133961-EF 134003, EF 134083-EF 134402, EF 141835, and EF 143070-EF 143105).
ESTHER : Zhang_2007_Proc.Natl.Acad.Sci.U.S.A_104_4618
PubMedSearch : Zhang_2007_Proc.Natl.Acad.Sci.U.S.A_104_4618
PubMedID: 17360573
Gene_locus related to this paper: karmi-a7yxv6

Title : Cloning, expression, and characterization of a cold-adapted lipase gene from an antarctic deep-sea psychrotrophic bacterium, Psychrobacter sp 7195 - Zhang_2007_J.Microbiol.Biotechnol_17_604
Author(s) : Zhang J , Lin S , Zeng R
Ref : J Microbiol Biotechnol , 17 :604 , 2007
Abstract : A psychrotrophic strain 7195 showing extracellular lipolytic activity towards tributyrin was isolated from deep-sea sediment of Prydz Bay and identified as a Psychrobacter species. By screening a genomic DNA library of Psychrobacter sp. 7195, an open reading frame of 954 bp coding for a lipase gene, lipA1, was identified, cloned, and sequenced. The deduced LipA1 consisted of 317 amino acids with a molecular mass of 35,210 kDa. It had one consensus motif, G-N-S-M-G (GXSXG), containing the putative active-site serine, which was conserved in other cold-adapted lipolytic enzymes. The recombinant LipA1 was purified by column chromatography with DEAE Sepharose CL-4B, and Sephadex G-75, and preparative polyacrylamide gel electrophoresis, in sequence. The purified enzyme showed highest activity at 30 degrees C, and was unstable at temperatures higher than 30 degrees C, indicating that it was a typical cold-adapted enzyme. The optimal pH for activity was 9.0, and the enzyme was stable between pH 7.0-10.0 after 24 h incubation at 4 degrees C. The addition of Ca2+ and Mg2+ enhanced the enzyme activity of LipA1, whereas the Cd2, Zn2+, Co2+, Fe3+, Hg2+, Fe2+, Rb2+, and EDTA strongly inhibited the activity. The LipA1 was activated by various detergents, such as Triton X-100, Tween 80, Tween 40, Span 60, Span 40, CHAPS, and SDS, and showed better resistance towards them. Substrate specificity analysis showed that there was a preference for trimyristin and p-nitrophenyl myristate (C14 acyl groups).
ESTHER : Zhang_2007_J.Microbiol.Biotechnol_17_604
PubMedSearch : Zhang_2007_J.Microbiol.Biotechnol_17_604
PubMedID: 18051271
Gene_locus related to this paper: 9gamm-q2ktb4

Title : Src-family kinases stabilize the neuromuscular synapse in vivo via protein interactions, phosphorylation, and cytoskeletal linkage of acetylcholine receptors - Sadasivam_2005_J.Neurosci_25_10479
Author(s) : Sadasivam G , Willmann R , Lin S , Erb-Vogtli S , Kong XC , Ruegg MA , Fuhrer C
Ref : Journal of Neuroscience , 25 :10479 , 2005
Abstract : Postnatal stabilization and maturation of the postsynaptic membrane are important for development and function of the neuromuscular junction (NMJ), but the underlying mechanisms remain poorly characterized. We examined the role of Src-family kinases (SFKs) in vivo. Electroporation of kinase-inactive Src constructs into soleus muscles of adult mice caused NMJ disassembly: acetylcholine receptor (AChR)-rich areas became fragmented; the topology of nerve terminal, AChRs, and synaptic nuclei was disturbed; and occasionally nerves started to sprout. Electroporation of kinase-overactive Src produced similar but milder effects. We studied the mechanism of SFK action using cultured src(-/-);fyn(-/-) myotubes, focusing on clustering of postsynaptic proteins, their interaction with AChRs, and AChR phosphorylation. Rapsyn and the utrophin-glycoprotein complex were recruited normally into AChR-containing clusters by agrin in src(-/-);fyn(-/-) myotubes. But after agrin withdrawal, clusters of these proteins disappeared rapidly in parallel with AChRs, revealing that SFKs are of general importance in postsynaptic stability. At the same time, AChR interaction with rapsyn and dystrobrevin and AChR phosphorylation decreased after agrin withdrawal from mutant myotubes. Unexpectedly, levels of rapsyn protein were increased in src(-/-);fyn(-/-) myotubes, whereas rapsyn-cytoskeleton interactions were unaffected. The overall cytoskeletal link of AChRs was weak but still strengthened by agrin in mutant cells, consistent with the normal formation but decreased stability of AChR clusters. These data show that correctly balanced activity of SFKs is critical in maintaining adult NMJs in vivo. SFKs hold the postsynaptic apparatus together through stabilization of AChR-rapsyn interaction and AChR phosphorylation. In addition, SFKs control rapsyn levels and AChR-cytoskeletal linkage.
ESTHER : Sadasivam_2005_J.Neurosci_25_10479
PubMedSearch : Sadasivam_2005_J.Neurosci_25_10479
PubMedID: 16280586

Title : Imprinted mesodermal specific transcript (MEST) and H19 genes in renal development and diabetes - Kanwar_2003_Kidney.Int_63_1658
Author(s) : Kanwar YS , Pan X , Lin S , Kumar A , Wada J , Haas CS , Liau G , Lomasney JW
Ref : Kidney Int , 63 :1658 , 2003
Abstract : BACKGROUND: Imprinted genes, mesodermal specific cDNA or transcript (MEST) and H19, are implicated in peri-implantation embryogenesis, and their expression was assessed in embryonic kidneys undergoing glucose-induced dysmorphogenesis. METHODS: MEST and H19 mRNA expression was assessed by Northern blot analysis in embryonic kidneys of mice harvested at day 15 to day 19 of gestation and of 1-week-old mice obtained from hyperglycemic mothers. A full-length mouse MEST cDNA was isolated, subcloned into an expression vector, a recombinant protein prepared and an antibody raised; the latter was used to assess protein expression by immunoprecipitation and immunofluorescence microscopy in day 13 metanephric explants subjected to high glucose ambience. Also, MEST mRNA expression was assessed in high d glucose-treated explants by competitive reverse transcription-polymerase chain reaction (RT-PCR) analyses and by in situ tissue autoradiography. RESULTS: A high expression of MEST and H19 with respective transcript size of approximately 2.7 and approximately 2.4 kb was observed in fetal kidneys, and their expression decreased during the successive stages of gestation and was undetectable in the postnatal period. At day 13, the MEST mRNA was expressed in the mesenchyme, while H19 was expressed in the ureteric bud branches and epithelial elements of the metanephros. Their expression decreased with progression of gestation. By competitive RT-PCR and Northern blot and in situ autoradiographic analyses, both MEST and H19 expressions decreased in day 13 explants treated with high glucose and in the kidneys of fetuses obtained from diabetic mothers. The MEST protein expression was observed in the metanephric epithelial elements and ureteric bud branches instead of in the mesenchyme, and its expression decreased in glucose-treated dysmorphogenetic explants, as assessed by immunofluorescence and immunoprecipitation methods. CONCLUSION: MEST and H19 imprinted genes are strategically located in the mammalian embryonic metanephros. They are developmentally regulated and their concomitant decreased expression in high glucose ambience or diabetic state did not follow the prevailing dogma of reciprocal inactivation/activation of imprinted genes, and such a decrease may be responsible for the perturbed epithelial:mesenchymal interactions leading to dysmorphogenesis of the mammalian metanephros.
ESTHER : Kanwar_2003_Kidney.Int_63_1658
PubMedSearch : Kanwar_2003_Kidney.Int_63_1658
PubMedID: 12675841

Title : Genome sequence of Streptococcus mutans UA159, a cariogenic dental pathogen - Ajdic_2002_Proc.Natl.Acad.Sci.U.S.A_99_14434
Author(s) : Ajdic D , McShan WM , McLaughlin RE , Savic G , Chang J , Carson MB , Primeaux C , Tian R , Kenton S , Jia H , Lin S , Qian Y , Li S , Zhu H , Najar F , Lai H , White J , Roe BA , Ferretti JJ
Ref : Proceedings of the National Academy of Sciences of the United States of America , 99 :14434 , 2002
Abstract : Streptococcus mutans is the leading cause of dental caries (tooth decay) worldwide and is considered to be the most cariogenic of all of the oral streptococci. The genome of S. mutans UA159, a serotype c strain, has been completely sequenced and is composed of 2,030,936 base pairs. It contains 1,963 ORFs, 63% of which have been assigned putative functions. The genome analysis provides further insight into how S. mutans has adapted to surviving the oral environment through resource acquisition, defense against host factors, and use of gene products that maintain its niche against microbial competitors. S. mutans metabolizes a wide variety of carbohydrates via nonoxidative pathways, and all of these pathways have been identified, along with the associated transport systems whose genes account for almost 15% of the genome. Virulence genes associated with extracellular adherent glucan production, adhesins, acid tolerance, proteases, and putative hemolysins have been identified. Strain UA159 is naturally competent and contains all of the genes essential for competence and quorum sensing. Mobile genetic elements in the form of IS elements and transposons are prominent in the genome and include a previously uncharacterized conjugative transposon and a composite transposon containing genes for the synthesis of antibiotics of the gramicidin/bacitracin family; however, no bacteriophage genomes are present.
ESTHER : Ajdic_2002_Proc.Natl.Acad.Sci.U.S.A_99_14434
PubMedSearch : Ajdic_2002_Proc.Natl.Acad.Sci.U.S.A_99_14434
PubMedID: 12397186
Gene_locus related to this paper: strmu-BACT , strmu-BGLB , strmu-GBPD , strmu-pepx , strmu-SMU.118C , strmu-SMU.178 , strmu-SMU.633 , strmu-SMU.643 , strmu-SMU.737 , strmu-SMU.1028 , strmu-SMU.1071C , strmu-SMU.1280C , strmu-SMU.1314 , strmu-SMU.1319C , strmu-SMU.1337C , strmu-SMU.1393C , strmu-SMU.1443C , strmu-SMU.1482C , strmu-SMU.1678

Title : Migration of zebrafish spinal motor nerves into the periphery requires multiple myotome-derived cues - Zeller_2002_Dev.Biol_252_241
Author(s) : Zeller J , Schneider V , Malayaman S , Higashijima S , Okamoto H , Gui J , Lin S , Granato M
Ref : Developmental Biology , 252 :241 , 2002
Abstract : In vertebrate embryos, spinal motor neurons project through segmentally reiterated nerves into the somites. Here, we report that zebrafish secondary motor neurons, which are similar to motor neurons in birds and mammals, depend on myotomal cues to navigate into the periphery. We show that the absence of myotomal adaxial cells in you-too/gli2 embryos severely impairs secondary motor axonal pathfinding, including their ability to project into the somites. Moreover, in diwanka mutant embryos, in which adaxial cells are present but fail to produce cues essential for primary motor growth cones to pioneer into the somites, secondary motor axons display similar pathfinding defects. The similarities between the axonal defects in you-too/gli2 and diwanka mutant embryos strongly suggest that pathfinding of secondary motor axons depends on myotome-derived cues, and that the diwanka gene is a likely candidate to produce or encode such a cue. Our experiments also demonstrate that diwanka plays a central role in the migration of primary and secondary motor neurons, suggesting that both neural populations share mechanisms underlying axonal pathfinding. In summary, we provide compelling evidence that myotomal cells produce multiple signals to initiate and control the migration of spinal nerve axons into the somites.
ESTHER : Zeller_2002_Dev.Biol_252_241
PubMedSearch : Zeller_2002_Dev.Biol_252_241
PubMedID: 12482713

Title : Identification of developmentally regulated mesodermal-specific transcript in mouse embryonic metanephros - Kanwar_2002_Am.J.Physiol.Renal.Physiol_282_F953
Author(s) : Kanwar YS , Kumar A , Ota K , Lin S , Wada J , Chugh S , Wallner EI
Ref : American Journal of Physiology Renal Physiol , 282 :F953 , 2002
Abstract : Mesodermal-specific cDNA or transcript (MEST) was identified by suppression subtractive hybridization-PCR of cDNA isolated from embryonic day 13 vs. newborn mice kidneys. At day 13 of mouse gestation, a high expression of MEST, with a single approximately 2.7-kb transcript that was exclusively localized to the metanephric mesenchyme was observed. The MEST mRNA expression gradually decreased during the later stages and then abruptly decreased in the newborn kidneys and subsequent postnatal life, after which a very mild expression persisted in the glomerular mesangium. Regression in mRNA expression during embryonic renal development appears to be related to methylation of the MEST gene. Treatment of metanephroi, harvested at day 13 of gestation with MEST-specific antisense oligodeoxynucleotide resulted in a dose-dependent decrease in the size of the explants and the nephron population. This was associated with a selective decrease in MEST mRNA expression and accelerated apoptosis of the mesenchyme. These findings suggest that MEST, a gene with a putative mesenchymal cell-derived protein, conceivably plays a role in mammalian metanephric development.
ESTHER : Kanwar_2002_Am.J.Physiol.Renal.Physiol_282_F953
PubMedSearch : Kanwar_2002_Am.J.Physiol.Renal.Physiol_282_F953
PubMedID: 11934706

Title : Alterations of GTP-binding proteins (Gsalpha and Gq\/11alpha) in gastric smooth muscle cells from streptozotocin-induced and WBN\/Kob diabetic rats - Lin_2000_Dig.Dis.Sci_45_1517
Author(s) : Lin S , Kajimura M , Takeuchi K , Kodaira M , Hanai H , Nishimura M , Kaneko E
Ref : Digestive Diseases & Sciences , 45 :1517 , 2000
Abstract : We investigated possible impairment of the signal transduction system in gastric myocytes of streptozotocin-induced diabetic (STZ) and spontaneous diabetic WBN/Kob (WBN/Kob) rats. Gastric motility 10 weeks after the onset of diabetes mellitus was significantly reduced in both diabetic rats compared with control, and the decreased motility was not recovered by the administration of insulin to maintain normal blood glucose levels. There was no significant difference between both types of diabetic rats and control rats in total number of [3H]quinuclidinyl benzilate ([3H]QNB) binding sites (Bmmax: 545-587 fmol/mg protein) on gastric smooth muscle cell membranes or in the affinity of [3H]QNB for the binding sites (Kd: 0.06-0.07 nM). Immunoblot analysis using polyclonal anti-G-protein antibodies indicated increased expression of Gsalpha in gastric smooth muscle cell membranes, but no significant change in Gialpha or Gq/11alpha expression in STZ rats, and decreased expression of Gq/11alpha with no significant change in Gsalpha and Gialpha in WBN/Kob rats. The cAMP production in gastric smooth muscle cell membranes was augmented in the absence and presence of 100 microM isoproterenol, and 100 microM forskolin in STZ rats, whereas no significant change of cAMP production was observed in WBN/Kob rats irrespective of the presence of the stimulants. These findings suggest that long-standing diabetes may induce alterations in signal transduction at downstream receptors in gastric myocytes, resulting in the impairment of gastric motility, although the mechanism of reduced contractile activity may differ between STZ and WBN/Kob rats.
ESTHER : Lin_2000_Dig.Dis.Sci_45_1517
PubMedSearch : Lin_2000_Dig.Dis.Sci_45_1517
PubMedID: 11007099

Title : Artificial chromosome transgenesis reveals long-distance negative regulation of rag1 in zebrafish -
Author(s) : Jessen JR , Willett CE , Lin S
Ref : Nat Genet , 23 :15 , 1999
PubMedID: 10471489

Title : Functional muscarinic m3 receptor expressed in gastric cancer cells stimulates tyrosine phosphorylation and MAP kinase - Kodaira_1999_J.Gastroenterol_34_163
Author(s) : Kodaira M , Kajimura M , Takeuchi K , Lin S , Hanai H , Kaneko E
Ref : J Gastroenterol , 34 :163 , 1999
Abstract : Human gastric cancer cells were used to examine the trophic effect of the muscarinic m3 receptor subtype. Expression of the m3 receptor was detected in five of eight cell lines examined, MKN-1, 7, 28, 74, and TMK-1 cells. An increase in intracellular Ca2+ in response to carbachol was observed in more than 90% of TMK-1 cells, allowing us to use these cells in the following experiments. Western blot analysis showed that carbachol predominantly phosphorylated tyrosine in a 100-kDa protein. While mitogen-activated protein (MAP) kinase activity in the presence of 100 microM carbachol or 10 ng/ml transforming growth factor (TGF)alpha was augmented to 15- to 60-fold of the baseline level for 5min, the activation was transient. Pretreatment of the cells with 1 microM phorbol 12-myristate 13-acetate abolished carbacol-induced MAP kinase activation, whereas no suppression was observed in the presence of 500 nM Calphostin C (Kyowa Medex, Tokyo Japan), a specific protein kinase C inhibitor. No DNA synthesis or cell proliferation was observed in the presence of carbachol. These results indicate that stimulation of the m3 subtype leads to tyrosine phosphorylation and MAP kinase activation, but is unlikely to have trophic effects in gastric mucosal cells.
ESTHER : Kodaira_1999_J.Gastroenterol_34_163
PubMedSearch : Kodaira_1999_J.Gastroenterol_34_163
PubMedID: 10213113

Title : Mechanism of microsomal epoxide hydrolase. Semifunctional site-specific mutants affecting the alkylation half-reaction - Laughlin_1998_Biochemistry_37_2897
Author(s) : Laughlin LT , Tzeng HF , Lin S , Armstrong RN
Ref : Biochemistry , 37 :2897 , 1998
Abstract : Microsomal epoxide hydrolase (MEH) catalyzes the addition of water to epoxides in a two-step reaction involving initial attack of an active site carboxylate on the oxirane to give an ester intermediate followed by hydrolysis of the ester. An efficient bacterial expression system for the enzyme from rat that facilitates the production of native and mutant enzymes for mechanistic analysis is described. Pre-steady-state kinetics of the native enzyme toward glycidyl-4-nitrobenzoates, 1, indicate the rate-limiting step in the reaction is hydrolysis of the alkyl-enzyme intermediate. The enzyme is enantioselective, turning over (2R)-1 about 10-fold more efficiently than (2S)-1, and regiospecific toward both substrates with exclusive attack at the least hindered oxirane carbon. Facile isomerization of the monoglyceride product is observed and complicates the regiochemical analysis. The D226E and D226N mutants of the protein are catalytically inactive, behavior that is consistent with the role of D226 as the active-site nucleophile as suggested by sequence alignments with other alpha/beta-hydrolase fold enzymes. The D226N mutant undergoes hydrolytic autoactivation with a half-life of 9.3 days at 37 degreesC, suggesting that the mutant is still capable of catalyzing the hydrolytic half-reaction (in this instance an amidase reaction) and confirming that D226 is in the active site. The indoylyl side chain of W227, which is in or near the active site, is not required for efficient alkylation of the enzyme or for hydrolysis of the intermediate. However, the W227F mutant does exhibit altered stereoselectivity toward (2R)-1, (2S)-1, and phenanthrene-9,10-oxide, suggesting that modifications at this position might be used to manipulate the stereo- and regioselectivity of the enzyme.
ESTHER : Laughlin_1998_Biochemistry_37_2897
PubMedSearch : Laughlin_1998_Biochemistry_37_2897
PubMedID: 9485441
Gene_locus related to this paper: ratno-hyep

Title : Expression of muscarinic receptor subtypes in rat gastric smooth muscle: effect of M3 selective antagonist on gastric motility and emptying - Lin_1997_Dig.Dis.Sci_42_907
Author(s) : Lin S , Kajimura M , Takeuchi K , Kodaira M , Hanai H , Kaneko E
Ref : Digestive Diseases & Sciences , 42 :907 , 1997
Abstract : Expression of muscarinic receptor subtypes in rat gastric smooth muscle was examined with reverse transcriptase-polymerase chain reaction (RT-PCR). Under the condition for detecting the messages of m1-m4 subtypes in brain, atrium, and gastric mucosa, only the fragments of m2 and m3 subtypes were amplified with RNA prepared from rat gastric smooth muscles. Furthermore, the amplified fragments were digested by restriction enzymes, reconfirming that the predicted size products of m2 and m3 contain the partial DNA sequences of m2 and m3 subtypes, respectively. We measured gastric motility in rats with a pressure transducer system under the continuous venous infusion of the muscarinic antagonists atropine and butylscopolamine (nonselective), AF-DX 116 (M2), zamifenacine (M3), and glucagon. Heart rate was monitored simultaneously in the tail. Gastric motility was inhibited in the presence of glucagon and zamifenacine without alteration of heart rate, whereas there was no inhibition in the presence of AF-DX 116 even after the augmentation of heart rate was observed. Gastric emptying was also suppressed in the presence of zamifenacine, which had an effect comparable with that of atropine, butylscopolamine, and glucagon. These results indicate that the activation of the M3 subtype in gastric smooth muscle causes its contraction, and the M3 selective antagonist could be a potentially useful drug without an adverse effect on the heart for radiological and endoscopic examination in the upper gastrointestinal tract.
ESTHER : Lin_1997_Dig.Dis.Sci_42_907
PubMedSearch : Lin_1997_Dig.Dis.Sci_42_907
PubMedID: 9149041