Toxoplasma gondii is a single-celled parasite that infects nearly all warm-blooded animals,including humans(Montoya and Liesenfeld,2004).It occurs worldwide and can persist for a lifetime in mammals.Humans get infecte...Toxoplasma gondii is a single-celled parasite that infects nearly all warm-blooded animals,including humans(Montoya and Liesenfeld,2004).It occurs worldwide and can persist for a lifetime in mammals.Humans get infected by eating undercooked meat of animals containing the tissue cysts of this parasite.In immune-competent individuals,T.展开更多
INTRODUCTIONOnly the liver has the great capability ofregeneration in mammal.Few hepatocytes are inthe phase of division in the normal liver of an adultmammal (including human beings),but theremaining hepatocytes can ...INTRODUCTIONOnly the liver has the great capability ofregeneration in mammal.Few hepatocytes are inthe phase of division in the normal liver of an adultmammal (including human beings),but theremaining hepatocytes can be induced to proliferatequickly by partial hepatectomy (PH),and,to somedegree,they stop dividing and re-differentiate intocells functioning as hepatocytes.This shows展开更多
Two series of tanshinone ⅡA derivatives were synthesized and evaluated for their antitumor activities as Cdc25 phosphatase inhibitors. Most of them demonstrated potent Cdc25 inhibitory activity and powerful cytotoxic...Two series of tanshinone ⅡA derivatives were synthesized and evaluated for their antitumor activities as Cdc25 phosphatase inhibitors. Most of them demonstrated potent Cdc25 inhibitory activity and powerful cytotoxicity against A549 tumor cell line, producing IC50 values in very low micromolar range. At last, the preliminary SAR was discussed.展开更多
Acute pancreatitis is an inflammation of the pancreas that may lead to systemic inflammatory response syndrome and death due to multiple organ failure. Acinar cells, together with leukocytes, trigger the inflammatory ...Acute pancreatitis is an inflammation of the pancreas that may lead to systemic inflammatory response syndrome and death due to multiple organ failure. Acinar cells, together with leukocytes, trigger the inflammatory cascade in response to local damage of the pancreas. Amplification of the inflammatory cascade requires up-regulation of proinflammatory cytokines and this process is mediated not only by nuclear factor κB but also by chromatinmodifying complexes and chromatin remodeling. Among the different families of histone acetyltransferases, the p300/CBP family seems to be particularly associated with the inflammatory process. cAMP activates gene expression via the cAMP-responsive element (CRE) and the transcription factor CRE-binding protein (CREB). CREB can be phosphorylated and activated by different kinases, such as protein kinase A and MAPK, and then it recruits the histone acetyltransferase co-activator CREB-binding protein (CBP) and its homologue p300. The recruitment of CBP/p300 and changes in the level of histone acetylation are required for transcription activation. Transcriptional repression is also a dynamic and essential mechanism of down-regulation of genes for resolution of inflammation, which seems to be mediated mainly by protein phosphatases (PP1, PP2A and MKP1) and histone deacetylases(HDACs) .Class HDACs are key transcriptional regulators whose activities are controlled via phosphorylationdependent nucleo/cytoplasmic shuttling. PP2A is responsible for dephosphorylation of class HDACs, triggeringnuclear localization and repression of target genes, whereas phosphorylation triggers cytoplasmic localization leading to activation of target genes. The potential benefit from treatment with phosphodiesterase inhibitors and histone deacetylase inhibitors is discussed.展开更多
Cementum is critical for anchoring the insertion of periodontal ligament fibers to the tooth root. Several aspects of cementogenesis remain unclear, including differences between acellular cementum and cellular cement...Cementum is critical for anchoring the insertion of periodontal ligament fibers to the tooth root. Several aspects of cementogenesis remain unclear, including differences between acellular cementum and cellular cementum, and between cementum and bone. Biomineralization is regulated by the ratio of inorganic phosphate （Pi） to mineral inhibitor pyrophosphate （PPi）, where local Pi and PPi concentrations are controlled by phosphatases including tissue-nonspecific alkaline phosphatase （TNAP） and ectonucleotide pyrophosphatase/phosphodiesterase 1 （NPP1）. The focus of this study was to define the roles of these phosphatases in cementogenesis. TNAP was associated with earliest cementoblasts near forming acellular and cellular cementum. With loss of TNAP in the Alpl null mouse, acellular cementum was inhibited, while cellular cementum production increased, albeit as hypomineralized cementoid. In contrast, NPP1 was detected in cementoblasts after acellular cementum formation, and at low levels around cellular cementum. Loss of NPP1 in the Enppl null mouse increased acellular cementum, with little effect on cellular cementum. Developmental patterns were recapitulated in a mouse model for acellular cementum regeneration, with early TNAP expression and later NPP1 expression. In vitro, cementoblasts expressed Alpl gene/protein early, whereas Enppl gene/protein expression was significantly induced only under mineralization conditions. These patterns were confirmed in human teeth, including widespread TNAP, and NPP1 restricted to cementoblasts lining acellular cementum. These studies suggest that early TNAP expression creates a low PPi environment promoting acellular cementum initiation, while later NPP1 expression increases PPi, restricting acellular cementum apposition. Alterations in PPi have little effect on cellular cementum formation, though matrix mineralization is affected.展开更多
Alkaline phosphatases(APs) are non-specifi c phosphohydrolases, and they are widely used in clinical diagnostics and biological studies. APs are widespread in nature and exhibit dif ferent structural formulations. Bas...Alkaline phosphatases(APs) are non-specifi c phosphohydrolases, and they are widely used in clinical diagnostics and biological studies. APs are widespread in nature and exhibit dif ferent structural formulations. Based on the diversity of biogenetic sources, APs exhibit temperature-propensity traits, and they are classifi ed as psychrophilic, mesophilic, and thermophilic. In this article, the characteristics of psychrophilic APs from marine organisms were described, accompanied by a simple description of APs from other organisms. This review will facilitate better utilization of marine APs in the biotechnology fi eld.展开更多
Obesity and the metabolic syndrome and their associated morbidities are major public health issues, whose prevalence will continue to increase in the foreseeable future. Aberrant signaling by the receptors for leptin ...Obesity and the metabolic syndrome and their associated morbidities are major public health issues, whose prevalence will continue to increase in the foreseeable future. Aberrant signaling by the receptors for leptin and insulin plays a pivotal role in development of the metabolic syndrome. More complete molecular-level understanding of how both of these key signaling pathways are regulated is essential for full characterization of obesity, the metabolic syndrome, and type lI diabetes, and for developing novel treatments for these diseases. Phosphorylation of proteins on tyrosine residues plays a key role in mediating the effects of leptin and insulin on their target cells. Here, we discuss the molecular methods by which protein tyrosine phosphatases, which are key physiological regulators of protein phosphorylation in vivo, affect signaling by the leptin and insulin receptors in their major target tissues.展开更多
Introduction Purple acid phosphatases （PAPs） comprise of a family of binuclear metal-containing hydrolases, some members of which have been isolated and characterized from animal, plant and fungal sources . PAPs ...Introduction Purple acid phosphatases （PAPs） comprise of a family of binuclear metal-containing hydrolases, some members of which have been isolated and characterized from animal, plant and fungal sources . PAPs not only catalyze the hydrolyses of a wide range of phosphate esters and anhydrides under acidic reaction conditions, but also catalyze the generation of hydroxyl radicals in a Fenton-like reaction, by virtue of the presence of a redox-active binuclear metal center. Inmammals,展开更多
Protein phosphorylation and dephosphorylation are two essential and vital cellular mechanisms that regulate many receptors and enzymes through kinases and phosphatases.Ca^2+- dependent kinases and phosphatases are res...Protein phosphorylation and dephosphorylation are two essential and vital cellular mechanisms that regulate many receptors and enzymes through kinases and phosphatases.Ca^2+- dependent kinases and phosphatases are responsible for controlling neuronal processing;balance is achieved through opposition.During molecular mechanisms of learning and memory,kinases generally modulate positively while phosphatases modulate negatively.This review outlines some of the critical physiological and structural aspects of kinases and phosphatases involved in maintaining postsynaptic structural plasticity.It also explores the link between neuronal disorders and the deregulation of phosphatases and kinases.展开更多
Pollen hydration represents the initial and critical step in pollen-stigma interactions and is necessary for successful plant fertilization.The FERONIA(FER)receptor kinase regulates pollen hydration by modulating stig...Pollen hydration represents the initial and critical step in pollen-stigma interactions and is necessary for successful plant fertilization.The FERONIA(FER)receptor kinase regulates pollen hydration by modulating stigmatic reactive oxygen species(ROS)accumulation through rapid alkalinization factor 23/33(RALF23/33)and pollen coat protein B-class peptide(PCP-B)signaling.However,the function and regulatory mechanism of FER’s receptor kinase activity in pollen hydration remain poorly understood.In this study,we found that the kinase-dead form of FER^(K565R) fails to restore stigmatic ROS accumulation and pollen hydration in the fer-4 mutant.By integrating RNA sequencing database analyses with yeast two-hybrid assays,we identified three type 2C phosphatases(PP2Cs)-protein phosphatase 2C clade H 1(PP2CH1)and cladeE Growth-Regulating 1 and 2(EGR1 and EGR2)-that interact with FER at the plasma membrane.These PP2Cs dephosphorylate FER at Ser695 and Thr696 within the activation segment,thereby inhibiting its kinase activity.Mutations at these two residues reduced ROS levels in the stigma and increased pollen hydration rates.Altogether,this study reveals a crucial regulatory mechanism of FER signaling,demonstrating that PP2CH1,EGR1,and EGR2 act as negative regulators of FER kinase activity to modulate stigmatic ROS accumulation and promote pollen hydration.展开更多
Green manuring is essential for improving soil quality and nutrient uptake.With the gradual depletion of phosphorus(P)resources,more attention is being paid to the role of green manures in cultivation systems,such as ...Green manuring is essential for improving soil quality and nutrient uptake.With the gradual depletion of phosphorus(P)resources,more attention is being paid to the role of green manures in cultivation systems,such as maize-green manure intercropping,to find possible pathways for enhancing soil P utilization.A maize-green manure intercropping experiment was started in 2009 to investigate the effects and mechanisms for enhancing P uptake and yield in maize.Three species of green manures(hairy vetch(HV),needle leaf pea(NP),sweet pea(SP))and a sole maize treatment(CK)were used,resulting in four treatments(CK,HVT,NPT,and SPT)in the experiment.During 2020-2023,the intercropping treatments enhanced maize yields in 2020 and 2021,particularly in HVT with increases of 13.7%(1.96 t ha^(-1))and 13.0%(2.13 t ha^(-1))compared with CK,respectively.Grain P accumulation of maize was significantly higher in the intercropping treatments than CK in 2020,2021,and 2023,and with an average increase of 10.6%over the four years(5.2% for NPT,10.8% for SPT and 15.9% for HVT)compared with CK.Intercropping promoted maize growth with a greater root length density and a higher organic acid release rate.HVT changed the soil properties more dramatically than the other treatments,with increases in the acid phosphatase and alkaline phosphatase activities of 29.8 and 38.5%,respectively,in the topsoil(0-15 cm),while the soil p H was reduced by 0.37 units compared to CK(p H=8.44).Intercropping treatments facilitated the conversion of non-labile P to mod-labile P and stimulated the growth of soil bacteria in the topsoil.Compared with CK,the relative abundance of Gemmatimonadota,known for accumulating polyphosphate,and Actinobacteriota,a prominent source of bioactive compounds,increased significantly in the intercropping treatments,especially in HVT and SPT.A PLS-PM analysis showed that intercropping promoted soil P mobilization and the enrichment of beneficial bacteria by regulating maize root morphology and physiology.Our results highlight that maize-green manure intercropping optimizes root traits,soil properties and bacterial composition,which contribute to greater maize P uptake and yield,providing an effective strategy for sustainable crop production.展开更多
PP1,PP2A and PP2B,belonging to the PPP family of Ser/Thr protein phosphatases,participate in regulating many important physiological processes,such as cell cycle control,regulation of cell growth and division regulati...PP1,PP2A and PP2B,belonging to the PPP family of Ser/Thr protein phosphatases,participate in regulating many important physiological processes,such as cell cycle control,regulation of cell growth and division regulation,etc.The sequence homology between them is relatively high,and ter-tiary structure is conserved.Because of the complexity of the structure of PP2A and the diversity of its regulatory subunits,its structure is less well known than those of PP1 and PP2B.The PP2A holoen-zyme consists of a heterodimeric core enzyme,comprising a scaffolding subunit and a catalytic sub-unit,as well as a variable regulatory subunit.In this study,the subunit compositions,similarities and differences between the Ser/Thr protein phsphatases structures are summarized.展开更多
: The regulation of stomatal movement is one of the most important signaling networks in plants. The H+-ATPase at the plasma membrane of guard cells plays a critical role in the stomata opening, while there are some c...: The regulation of stomatal movement is one of the most important signaling networks in plants. The H+-ATPase at the plasma membrane of guard cells plays a critical role in the stomata opening, while there are some conflicting results regarding the effectiveness of the plasma membrane H+-ATPase inhibitor, vanadate, in inhibiting stomata opening. We observed that 2 mmol/L vanadate hardly inhibited light-stimulated stomata opening in epidermal peels of Vicia faba L., but significantly inhibited dark- and ABA-induced stomatal closure. These results cannot be explained with the previous findings that H+-ATPase was inhibited by vanadate. In view of the fact that vanadate is an inhibitor of protein tyrosine phosphatases (PTPases), we investigated whether the stomatal movement regulated by vanadate is through the regulation of PTPase. As expected, phenylarsine oxide (PAO), a specific inhibitor of PTPase, has very similar effects and even more effective than vanadate. Typical PTPase activity was found in guard cells of V. faba; moreover, the phosphatase activity could be inhibited by both vanadate and PAO. These results not only provide a novel explanation for conflicting results about vanadate modulating stomatal movement, but also provide further evidence for the involvement of PTPases in modulating signal transduction of stomatal movement.展开更多
Protein tyrosine phosphorylation is a major posttranslational modification used by cells to regulate signal transduction and essentially participate in every aspect of cellular physiologic and pathogenic processes. Th...Protein tyrosine phosphorylation is a major posttranslational modification used by cells to regulate signal transduction and essentially participate in every aspect of cellular physiologic and pathogenic processes. The protein tyrosine phosphatase （PTP） super family of enzymes coordinately function with protein tyrosine kinases in signaling pathways that underlie a broad spectrum of fundamental physiological processes. Abnormal regulation of tyrosine phosphorylation or deregulation of phosphorylation is known to result in neoplastic or non-neoplastic diseases. Having evolved into separate families that are structurally and mechanistically distinct, PTPs have been implicated in a variety of diseases and efforts have been made to seek therapeutic clues from them. The phosphatases of regenerating liver （PRL） PRL-1, PRL-2, PRL-3 （also known as PTP4A1, PTP4A2, and PTP4A3, respectively） constitute a subfamily of the protein tyrosine phosphatases that have been suggested to play a key role in oncogenic and metastatic phenotypes.5 Here we review what is known about this novel class of small, prenylated phosphatases and its value in diagnosis and therapy of solid tumors.展开更多
Microcalorimetry was used to study the inhibitory or antibiotic action of six kinds of the model compounds of purple acid phosphatases on a strain of Aerobacter aerogenes . Difference in their capacities to inhibit...Microcalorimetry was used to study the inhibitory or antibiotic action of six kinds of the model compounds of purple acid phosphatases on a strain of Aerobacter aerogenes . Difference in their capacities to inhibit the metabolism of this bacterium was observed. The extent and duration of the inhibitory effect on the metabolism as judged from the growth rate constant, k , and the half inhibitory concentration, IC 50 , varied with the different drugs. The rate constant k of A. aerogenes (in the log phase) in the presence of the compounds decreased with the increasing of concentrations. The experimental results reveal that the order of the antibiotic activity of the compounds is: LD 1>LD 2>LD 3>XF 1>LD 4～LD 5.展开更多
NF-kappaB plays a critical role in cell survival,apoptosis,and inflammatory responses.Serine/threoninespecific phosphatases(PPs)represent the second major class of enzymes that catalyze the dephosphorylation of protei...NF-kappaB plays a critical role in cell survival,apoptosis,and inflammatory responses.Serine/threoninespecific phosphatases(PPs)represent the second major class of enzymes that catalyze the dephosphorylation of proteins.The roles of PPs regulating NF-kappaB activities are poorly understood.Here we describe an RNAi-based screen to identify the PPs that involve in regulating NFkappaB signaling.Thirty-four candidate PPs siRNAs were synthesized and primarily screened by NF-kappaB reporter gene assay in HeLa cells.PHLPP,one of the protein phosphatase type 2C family members(PP2C),was identified as a positive regulator of NF-kappaB signaling.Knock-down of PHLPP dramatically attenuated TNFα-stimulated NF-kappaB transcriptional activation.Knockdown of PHLPP led to enhancement of NF-kappaB/p65 nuclear import and retention,but decreased TNFα-induced phosphorylation at Ser276 on p65.This critical phosphorylation was also drastically reduced by knock-down of PKCalpha and Akt1,two important serine/threonine kinases dephosphorylated by PHLPP.The results together suggest that PHLPP-Akt-PKC may represent an important signaling loop that activates NF-kappaB/p65 signaling through critical serine phosphorylation.展开更多
Demyelinating diseases of the central nervous system are common,yet few effective strategies for myelin repair and remyelination are available.An increasing number of studies highlight the role of microRNAs(miRNAs)as ...Demyelinating diseases of the central nervous system are common,yet few effective strategies for myelin repair and remyelination are available.An increasing number of studies highlight the role of microRNAs(miRNAs)as key regulators of demyelination.miRNA mimics and inhibitors,which are currently in preclinical development,have shown promise as novel therapeutic agents.However,the mechanisms by which they protect myelin are not fully understood.Using a mouse model of acute central nervous system demyelination induced by infection with Angiostrongylus cantonensis,we investigated alterations in miRNA expression in the mouse brain.Our findings revealed a significant early-stage increase in the levels of miR-200,particularly miR-200a and miR-200c.Subsequent analysis demonstrated that combined miR-200a and miR-200c overexpression improved neurobehavioral outcomes and attenuated demyelination in Angiostrongylus cantonensis-infected mice.Further lipid metabolomic profiling indicated that miR-200a and miR-200c synergistically inhibited the production of phosphatase and tensin homolog(PTEN)and activated the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway,as confirmed by double luciferase reporter assay and western blotting.Additionally,in vitro experiments showed that miR-200a and miR-200c protected oligodendrocyte precursor cells from lipopolysaccharide-induced damage and enhanced their survival.Our study indicates the critical role of miR-200a and miR-200c in protecting against central nervous system demyelination by targeting PTEN and modulating key survival pathways.Furthermore,our findings suggest that miR-200a and miR-200c are promising diagnostic biomarkers of and therapeutic targets for treating demyelination-related disorders.展开更多
Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The...Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5(GAS5) is a member of the 5′-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5×FAD) mice, APPswe/PSEN1dE9(APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β) and phosphatase and tensin homologue deleted on chromosome 10(PTEN) expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies, suggesting a candidate therapeutic target in Alzheimer's disease.展开更多
Induction and secretion of acid phosphatases （APases） is thought to be an adaptive mechanism that helps plants survive and grow under phosphate （Pi） deprivation, in Arabidopsis, there are 29 purple acid phosphata...Induction and secretion of acid phosphatases （APases） is thought to be an adaptive mechanism that helps plants survive and grow under phosphate （Pi） deprivation, in Arabidopsis, there are 29 purple acid phosphatase （AtPAP） genes. To systematically investigate the roles of different AtPAPs, we first identified knockout or knock-down T-DNA lines for all 29 AtPAP genes. Using these atpap mutants combined with in-gel and quantitative APase enzyme assays, we demonstrated that AtPAP12 and AtPAP26 are two major intracellular and secreted APases in Arabidopsis while AtPAPlo is mainly a secreted APase. On Pi-deficient （P-） medium or P- medium supplemented with the organophosphates ADP and fructose-6-phosphate （Fru-6-P）, growth of atpaplo was significantly reduced whereas growth of atpap12 was only moderately reduced, and growth of atpap26 was nearly equal to that of the wild type （WT）. Overexpression of the AtPAP12 or AtPAP26 gene, however, caused plants to grow better on P- or P- medium supplemented with ADP or Fru-6-P. Interest-ingly, Pi levels are essentially the same for the WT and overexpressing lines, although these two types of plants have significantly different growth phenotypes. These results suggest that the APases may have other roles besides enhancing internal Pi recycling or releasing Pi from external organophosphates for plant uptake.展开更多
Trehalose is the principal sugar circulating in the hemolymph of insects,and trehalose synthesis is catalyzed by trehalose-6-phosphate synthase(TPS)and trehalose-6-phosphate phosphatase(TPP).Insect TPS is a fused enzy...Trehalose is the principal sugar circulating in the hemolymph of insects,and trehalose synthesis is catalyzed by trehalose-6-phosphate synthase(TPS)and trehalose-6-phosphate phosphatase(TPP).Insect TPS is a fused enzyme containing both TPS do-main and TPP domain.Thus,many insects do not possess TPP genes as TPSs have re-placed the function of TPPs.However,TPPs are widely distributed across the dipteran insects,while the roles they play remain largely unknown.In this study,3 TPP genes from notorious dipteran pest Bactrocera minax(BmiTPPB,BmiTPPCl,and BmiTPPC2)were identified and characterized.The different temporal-spatial expression patterns of 3 BmiTPPs implied that they exert different functions in B.minax.Recombinant BmiTPPs were heterologously expressed in yeast cells,and all purified proteins exhibited enzy-matic activities,despite the remarkable disparity in performance between BmiTPPB and BmiTPPCs.RNA interference revealed that all BmiTPPs were successfully downregulated after double-stranded RNA injection,leading to decreased trehalose content and increased glucose content.Also,suppression of BmiTPPs significantly affected expression of down-stream genes and increased the mortality and malformation rate.Collectively,these results indicated that all 3 BmiTPPs in B.minax are involved in trehalose synthesis and metamor-phosis.Thus,these genes could be evaluated as insecticidal targets for managing B.minax,andevenforotherdipteranpests.展开更多
基金supported by the National Natural Sci ence Foundation of China(No.31672543)the Zhejiang Province“Sannongliufang”Science and Technology Coopera tion Project(No.2020SNLF007),China.
文摘Toxoplasma gondii is a single-celled parasite that infects nearly all warm-blooded animals,including humans(Montoya and Liesenfeld,2004).It occurs worldwide and can persist for a lifetime in mammals.Humans get infected by eating undercooked meat of animals containing the tissue cysts of this parasite.In immune-competent individuals,T.
基金China-France Scientific end Technical Cooperation (No.1996-134)Bioengineering Key Laboratory of Henan Province
文摘INTRODUCTIONOnly the liver has the great capability ofregeneration in mammal.Few hepatocytes are inthe phase of division in the normal liver of an adultmammal (including human beings),but theremaining hepatocytes can be induced to proliferatequickly by partial hepatectomy (PH),and,to somedegree,they stop dividing and re-differentiate intocells functioning as hepatocytes.This shows
基金support by program for New Century Excellent Talents in University (NCET)National Natural Science Foundation of China(No.305722321)Lab of Organic Functional Molecules,the Sino-French Institute of ECNU for supports.
文摘Two series of tanshinone ⅡA derivatives were synthesized and evaluated for their antitumor activities as Cdc25 phosphatase inhibitors. Most of them demonstrated potent Cdc25 inhibitory activity and powerful cytotoxicity against A549 tumor cell line, producing IC50 values in very low micromolar range. At last, the preliminary SAR was discussed.
基金Supported by Grants SAF2006-06963, SAF2009-09500 and Consolider CSD-2007-00020 to Sastre J BFU2007-63120 and CSD2006-49 to López-Rodas G
文摘Acute pancreatitis is an inflammation of the pancreas that may lead to systemic inflammatory response syndrome and death due to multiple organ failure. Acinar cells, together with leukocytes, trigger the inflammatory cascade in response to local damage of the pancreas. Amplification of the inflammatory cascade requires up-regulation of proinflammatory cytokines and this process is mediated not only by nuclear factor κB but also by chromatinmodifying complexes and chromatin remodeling. Among the different families of histone acetyltransferases, the p300/CBP family seems to be particularly associated with the inflammatory process. cAMP activates gene expression via the cAMP-responsive element (CRE) and the transcription factor CRE-binding protein (CREB). CREB can be phosphorylated and activated by different kinases, such as protein kinase A and MAPK, and then it recruits the histone acetyltransferase co-activator CREB-binding protein (CBP) and its homologue p300. The recruitment of CBP/p300 and changes in the level of histone acetylation are required for transcription activation. Transcriptional repression is also a dynamic and essential mechanism of down-regulation of genes for resolution of inflammation, which seems to be mediated mainly by protein phosphatases (PP1, PP2A and MKP1) and histone deacetylases(HDACs) .Class HDACs are key transcriptional regulators whose activities are controlled via phosphorylationdependent nucleo/cytoplasmic shuttling. PP2A is responsible for dephosphorylation of class HDACs, triggeringnuclear localization and repression of target genes, whereas phosphorylation triggers cytoplasmic localization leading to activation of target genes. The potential benefit from treatment with phosphodiesterase inhibitors and histone deacetylase inhibitors is discussed.
基金supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) and extramural NIH funding(JLM-DE12889 and AR53102)
文摘Cementum is critical for anchoring the insertion of periodontal ligament fibers to the tooth root. Several aspects of cementogenesis remain unclear, including differences between acellular cementum and cellular cementum, and between cementum and bone. Biomineralization is regulated by the ratio of inorganic phosphate （Pi） to mineral inhibitor pyrophosphate （PPi）, where local Pi and PPi concentrations are controlled by phosphatases including tissue-nonspecific alkaline phosphatase （TNAP） and ectonucleotide pyrophosphatase/phosphodiesterase 1 （NPP1）. The focus of this study was to define the roles of these phosphatases in cementogenesis. TNAP was associated with earliest cementoblasts near forming acellular and cellular cementum. With loss of TNAP in the Alpl null mouse, acellular cementum was inhibited, while cellular cementum production increased, albeit as hypomineralized cementoid. In contrast, NPP1 was detected in cementoblasts after acellular cementum formation, and at low levels around cellular cementum. Loss of NPP1 in the Enppl null mouse increased acellular cementum, with little effect on cellular cementum. Developmental patterns were recapitulated in a mouse model for acellular cementum regeneration, with early TNAP expression and later NPP1 expression. In vitro, cementoblasts expressed Alpl gene/protein early, whereas Enppl gene/protein expression was significantly induced only under mineralization conditions. These patterns were confirmed in human teeth, including widespread TNAP, and NPP1 restricted to cementoblasts lining acellular cementum. These studies suggest that early TNAP expression creates a low PPi environment promoting acellular cementum initiation, while later NPP1 expression increases PPi, restricting acellular cementum apposition. Alterations in PPi have little effect on cellular cementum formation, though matrix mineralization is affected.
基金Supported by the National Natural Science Foundation for Creative Research Groups(No.41221004)the Natural Science Foundation of Shandong Province(No.ZR2011DQ005)+6 种基金the Key Laboratory of Marine Ecology and Environmental Science and Engineering,SOA(No.MESE-2013-03)the Key Laboratory for Ecological Environment in Coastal Areas,State Oceanic Administration(No.201306)the Major International Joint Research Project of NSFC(No.41320104008)the Changjiang Scholars Program,Ministry of Education of Chinathe Taishan Scholars Program of Shandong Provincethe Key Lab of Marine Bioactive Substance and Modern Analytical Technique,SOA(No.MBSMAT-2013-05)This is MCTL Contribution No.81
文摘Alkaline phosphatases(APs) are non-specifi c phosphohydrolases, and they are widely used in clinical diagnostics and biological studies. APs are widespread in nature and exhibit dif ferent structural formulations. Based on the diversity of biogenetic sources, APs exhibit temperature-propensity traits, and they are classifi ed as psychrophilic, mesophilic, and thermophilic. In this article, the characteristics of psychrophilic APs from marine organisms were described, accompanied by a simple description of APs from other organisms. This review will facilitate better utilization of marine APs in the biotechnology fi eld.
基金supported by the Israel Science Foundation(#786/13)the Fritz Thyssen Stiftung(Germany),and by the Kekst Family Institute for Medical Genetics and the David and Fela Shapell Family Center for Genetic Disorders Research at the Weizmann Institute
文摘Obesity and the metabolic syndrome and their associated morbidities are major public health issues, whose prevalence will continue to increase in the foreseeable future. Aberrant signaling by the receptors for leptin and insulin plays a pivotal role in development of the metabolic syndrome. More complete molecular-level understanding of how both of these key signaling pathways are regulated is essential for full characterization of obesity, the metabolic syndrome, and type lI diabetes, and for developing novel treatments for these diseases. Phosphorylation of proteins on tyrosine residues plays a key role in mediating the effects of leptin and insulin on their target cells. Here, we discuss the molecular methods by which protein tyrosine phosphatases, which are key physiological regulators of protein phosphorylation in vivo, affect signaling by the leptin and insulin receptors in their major target tissues.
文摘Introduction Purple acid phosphatases （PAPs） comprise of a family of binuclear metal-containing hydrolases, some members of which have been isolated and characterized from animal, plant and fungal sources . PAPs not only catalyze the hydrolyses of a wide range of phosphate esters and anhydrides under acidic reaction conditions, but also catalyze the generation of hydroxyl radicals in a Fenton-like reaction, by virtue of the presence of a redox-active binuclear metal center. Inmammals,
文摘Protein phosphorylation and dephosphorylation are two essential and vital cellular mechanisms that regulate many receptors and enzymes through kinases and phosphatases.Ca^2+- dependent kinases and phosphatases are responsible for controlling neuronal processing;balance is achieved through opposition.During molecular mechanisms of learning and memory,kinases generally modulate positively while phosphatases modulate negatively.This review outlines some of the critical physiological and structural aspects of kinases and phosphatases involved in maintaining postsynaptic structural plasticity.It also explores the link between neuronal disorders and the deregulation of phosphatases and kinases.
基金supported by grants from the National Natural Science Foundation of China(32425008 and 32230009)the Science and Technology Commission of Shanghai Municipality(24N12800100)the Beijing Life Science Academy(2024400CB0050).
文摘Pollen hydration represents the initial and critical step in pollen-stigma interactions and is necessary for successful plant fertilization.The FERONIA(FER)receptor kinase regulates pollen hydration by modulating stigmatic reactive oxygen species(ROS)accumulation through rapid alkalinization factor 23/33(RALF23/33)and pollen coat protein B-class peptide(PCP-B)signaling.However,the function and regulatory mechanism of FER’s receptor kinase activity in pollen hydration remain poorly understood.In this study,we found that the kinase-dead form of FER^(K565R) fails to restore stigmatic ROS accumulation and pollen hydration in the fer-4 mutant.By integrating RNA sequencing database analyses with yeast two-hybrid assays,we identified three type 2C phosphatases(PP2Cs)-protein phosphatase 2C clade H 1(PP2CH1)and cladeE Growth-Regulating 1 and 2(EGR1 and EGR2)-that interact with FER at the plasma membrane.These PP2Cs dephosphorylate FER at Ser695 and Thr696 within the activation segment,thereby inhibiting its kinase activity.Mutations at these two residues reduced ROS levels in the stigma and increased pollen hydration rates.Altogether,this study reveals a crucial regulatory mechanism of FER signaling,demonstrating that PP2CH1,EGR1,and EGR2 act as negative regulators of FER kinase activity to modulate stigmatic ROS accumulation and promote pollen hydration.
基金supported financially by the National Key Research&Development Program of China(2021YFD1700200)the National Natural Science Foundation of China(32402686)+3 种基金the Earmarked Fund for China Agriculture Research System(CARS-22)the Fundamental Research Funds for Central Non-profit Scientific Institution,China(1610132022013)the Science and Technology Innovation Project of Chinese Academy of Agricultural Sciencesthe China National Crop Germplasm Resources Platform for Green Manure(NICGR-2024-19)。
文摘Green manuring is essential for improving soil quality and nutrient uptake.With the gradual depletion of phosphorus(P)resources,more attention is being paid to the role of green manures in cultivation systems,such as maize-green manure intercropping,to find possible pathways for enhancing soil P utilization.A maize-green manure intercropping experiment was started in 2009 to investigate the effects and mechanisms for enhancing P uptake and yield in maize.Three species of green manures(hairy vetch(HV),needle leaf pea(NP),sweet pea(SP))and a sole maize treatment(CK)were used,resulting in four treatments(CK,HVT,NPT,and SPT)in the experiment.During 2020-2023,the intercropping treatments enhanced maize yields in 2020 and 2021,particularly in HVT with increases of 13.7%(1.96 t ha^(-1))and 13.0%(2.13 t ha^(-1))compared with CK,respectively.Grain P accumulation of maize was significantly higher in the intercropping treatments than CK in 2020,2021,and 2023,and with an average increase of 10.6%over the four years(5.2% for NPT,10.8% for SPT and 15.9% for HVT)compared with CK.Intercropping promoted maize growth with a greater root length density and a higher organic acid release rate.HVT changed the soil properties more dramatically than the other treatments,with increases in the acid phosphatase and alkaline phosphatase activities of 29.8 and 38.5%,respectively,in the topsoil(0-15 cm),while the soil p H was reduced by 0.37 units compared to CK(p H=8.44).Intercropping treatments facilitated the conversion of non-labile P to mod-labile P and stimulated the growth of soil bacteria in the topsoil.Compared with CK,the relative abundance of Gemmatimonadota,known for accumulating polyphosphate,and Actinobacteriota,a prominent source of bioactive compounds,increased significantly in the intercropping treatments,especially in HVT and SPT.A PLS-PM analysis showed that intercropping promoted soil P mobilization and the enrichment of beneficial bacteria by regulating maize root morphology and physiology.Our results highlight that maize-green manure intercropping optimizes root traits,soil properties and bacterial composition,which contribute to greater maize P uptake and yield,providing an effective strategy for sustainable crop production.
基金the National Basic Research Program of China(973)(Grant No.2004CB719906)the National Natural Science Foundation of China(30470393)
文摘PP1,PP2A and PP2B,belonging to the PPP family of Ser/Thr protein phosphatases,participate in regulating many important physiological processes,such as cell cycle control,regulation of cell growth and division regulation,etc.The sequence homology between them is relatively high,and ter-tiary structure is conserved.Because of the complexity of the structure of PP2A and the diversity of its regulatory subunits,its structure is less well known than those of PP1 and PP2B.The PP2A holoen-zyme consists of a heterodimeric core enzyme,comprising a scaffolding subunit and a catalytic sub-unit,as well as a variable regulatory subunit.In this study,the subunit compositions,similarities and differences between the Ser/Thr protein phsphatases structures are summarized.
基金国家自然科学基金，Doctor's Fund of College and University Education
文摘: The regulation of stomatal movement is one of the most important signaling networks in plants. The H+-ATPase at the plasma membrane of guard cells plays a critical role in the stomata opening, while there are some conflicting results regarding the effectiveness of the plasma membrane H+-ATPase inhibitor, vanadate, in inhibiting stomata opening. We observed that 2 mmol/L vanadate hardly inhibited light-stimulated stomata opening in epidermal peels of Vicia faba L., but significantly inhibited dark- and ABA-induced stomatal closure. These results cannot be explained with the previous findings that H+-ATPase was inhibited by vanadate. In view of the fact that vanadate is an inhibitor of protein tyrosine phosphatases (PTPases), we investigated whether the stomatal movement regulated by vanadate is through the regulation of PTPase. As expected, phenylarsine oxide (PAO), a specific inhibitor of PTPase, has very similar effects and even more effective than vanadate. Typical PTPase activity was found in guard cells of V. faba; moreover, the phosphatase activity could be inhibited by both vanadate and PAO. These results not only provide a novel explanation for conflicting results about vanadate modulating stomatal movement, but also provide further evidence for the involvement of PTPases in modulating signal transduction of stomatal movement.
文摘Protein tyrosine phosphorylation is a major posttranslational modification used by cells to regulate signal transduction and essentially participate in every aspect of cellular physiologic and pathogenic processes. The protein tyrosine phosphatase （PTP） super family of enzymes coordinately function with protein tyrosine kinases in signaling pathways that underlie a broad spectrum of fundamental physiological processes. Abnormal regulation of tyrosine phosphorylation or deregulation of phosphorylation is known to result in neoplastic or non-neoplastic diseases. Having evolved into separate families that are structurally and mechanistically distinct, PTPs have been implicated in a variety of diseases and efforts have been made to seek therapeutic clues from them. The phosphatases of regenerating liver （PRL） PRL-1, PRL-2, PRL-3 （also known as PTP4A1, PTP4A2, and PTP4A3, respectively） constitute a subfamily of the protein tyrosine phosphatases that have been suggested to play a key role in oncogenic and metastatic phenotypes.5 Here we review what is known about this novel class of small, prenylated phosphatases and its value in diagnosis and therapy of solid tumors.
文摘Microcalorimetry was used to study the inhibitory or antibiotic action of six kinds of the model compounds of purple acid phosphatases on a strain of Aerobacter aerogenes . Difference in their capacities to inhibit the metabolism of this bacterium was observed. The extent and duration of the inhibitory effect on the metabolism as judged from the growth rate constant, k , and the half inhibitory concentration, IC 50 , varied with the different drugs. The rate constant k of A. aerogenes (in the log phase) in the presence of the compounds decreased with the increasing of concentrations. The experimental results reveal that the order of the antibiotic activity of the compounds is: LD 1>LD 2>LD 3>XF 1>LD 4～LD 5.
基金This research was supported by the National High Technology Research and Development Program of China(863 Program)(No.2006AA02Z191),the Bureau of Science and Technology of Guangzhou,China(No.2007Z1-E4041)Guangzhou Economic&Technological Development District(GETDD S&T Project)(2007G-P029).
文摘NF-kappaB plays a critical role in cell survival,apoptosis,and inflammatory responses.Serine/threoninespecific phosphatases(PPs)represent the second major class of enzymes that catalyze the dephosphorylation of proteins.The roles of PPs regulating NF-kappaB activities are poorly understood.Here we describe an RNAi-based screen to identify the PPs that involve in regulating NFkappaB signaling.Thirty-four candidate PPs siRNAs were synthesized and primarily screened by NF-kappaB reporter gene assay in HeLa cells.PHLPP,one of the protein phosphatase type 2C family members(PP2C),was identified as a positive regulator of NF-kappaB signaling.Knock-down of PHLPP dramatically attenuated TNFα-stimulated NF-kappaB transcriptional activation.Knockdown of PHLPP led to enhancement of NF-kappaB/p65 nuclear import and retention,but decreased TNFα-induced phosphorylation at Ser276 on p65.This critical phosphorylation was also drastically reduced by knock-down of PKCalpha and Akt1,two important serine/threonine kinases dephosphorylated by PHLPP.The results together suggest that PHLPP-Akt-PKC may represent an important signaling loop that activates NF-kappaB/p65 signaling through critical serine phosphorylation.
基金supported by the National Natural Science Foundation of China,Nos.82372277(to ZW),82272361(to XS),82271395(to GL)Guangdong Province Basic and Applied Basic Research Fund Project,No.2024A1515010615(to XS)+1 种基金Guangdong Province Natural Youth Promotion Project,No.2314070000241(to GL)Guangzhou Science and Technology Project,No.2025A04J4740(to GL).
文摘Demyelinating diseases of the central nervous system are common,yet few effective strategies for myelin repair and remyelination are available.An increasing number of studies highlight the role of microRNAs(miRNAs)as key regulators of demyelination.miRNA mimics and inhibitors,which are currently in preclinical development,have shown promise as novel therapeutic agents.However,the mechanisms by which they protect myelin are not fully understood.Using a mouse model of acute central nervous system demyelination induced by infection with Angiostrongylus cantonensis,we investigated alterations in miRNA expression in the mouse brain.Our findings revealed a significant early-stage increase in the levels of miR-200,particularly miR-200a and miR-200c.Subsequent analysis demonstrated that combined miR-200a and miR-200c overexpression improved neurobehavioral outcomes and attenuated demyelination in Angiostrongylus cantonensis-infected mice.Further lipid metabolomic profiling indicated that miR-200a and miR-200c synergistically inhibited the production of phosphatase and tensin homolog(PTEN)and activated the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway,as confirmed by double luciferase reporter assay and western blotting.Additionally,in vitro experiments showed that miR-200a and miR-200c protected oligodendrocyte precursor cells from lipopolysaccharide-induced damage and enhanced their survival.Our study indicates the critical role of miR-200a and miR-200c in protecting against central nervous system demyelination by targeting PTEN and modulating key survival pathways.Furthermore,our findings suggest that miR-200a and miR-200c are promising diagnostic biomarkers of and therapeutic targets for treating demyelination-related disorders.
基金supported by the National Natural Science Foundation of China,Nos. 82173806 and U1803281Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science,Nos. 2021-I2M-1-030 and 2022-I2M-2-002Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences,No. 2022-JKCS-08 (all to RL)。
文摘Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5(GAS5) is a member of the 5′-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5×FAD) mice, APPswe/PSEN1dE9(APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β) and phosphatase and tensin homologue deleted on chromosome 10(PTEN) expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies, suggesting a candidate therapeutic target in Alzheimer's disease.
基金supported by the National Natural Science Foundation of China (31370290 to D.L. and 30971554 to X.D.)the Ministry of Agriculture of China (2014ZX0800932B to D.L.)
文摘Induction and secretion of acid phosphatases （APases） is thought to be an adaptive mechanism that helps plants survive and grow under phosphate （Pi） deprivation, in Arabidopsis, there are 29 purple acid phosphatase （AtPAP） genes. To systematically investigate the roles of different AtPAPs, we first identified knockout or knock-down T-DNA lines for all 29 AtPAP genes. Using these atpap mutants combined with in-gel and quantitative APase enzyme assays, we demonstrated that AtPAP12 and AtPAP26 are two major intracellular and secreted APases in Arabidopsis while AtPAPlo is mainly a secreted APase. On Pi-deficient （P-） medium or P- medium supplemented with the organophosphates ADP and fructose-6-phosphate （Fru-6-P）, growth of atpaplo was significantly reduced whereas growth of atpap12 was only moderately reduced, and growth of atpap26 was nearly equal to that of the wild type （WT）. Overexpression of the AtPAP12 or AtPAP26 gene, however, caused plants to grow better on P- or P- medium supplemented with ADP or Fru-6-P. Interest-ingly, Pi levels are essentially the same for the WT and overexpressing lines, although these two types of plants have significantly different growth phenotypes. These results suggest that the APases may have other roles besides enhancing internal Pi recycling or releasing Pi from external organophosphates for plant uptake.
基金supported by Natural Science Foundation of Chongqing(cstc202ljcyj-msxmX1054)the Fundamental Research Funds forthe Central Universities(XDJK2018C092).
文摘Trehalose is the principal sugar circulating in the hemolymph of insects,and trehalose synthesis is catalyzed by trehalose-6-phosphate synthase(TPS)and trehalose-6-phosphate phosphatase(TPP).Insect TPS is a fused enzyme containing both TPS do-main and TPP domain.Thus,many insects do not possess TPP genes as TPSs have re-placed the function of TPPs.However,TPPs are widely distributed across the dipteran insects,while the roles they play remain largely unknown.In this study,3 TPP genes from notorious dipteran pest Bactrocera minax(BmiTPPB,BmiTPPCl,and BmiTPPC2)were identified and characterized.The different temporal-spatial expression patterns of 3 BmiTPPs implied that they exert different functions in B.minax.Recombinant BmiTPPs were heterologously expressed in yeast cells,and all purified proteins exhibited enzy-matic activities,despite the remarkable disparity in performance between BmiTPPB and BmiTPPCs.RNA interference revealed that all BmiTPPs were successfully downregulated after double-stranded RNA injection,leading to decreased trehalose content and increased glucose content.Also,suppression of BmiTPPs significantly affected expression of down-stream genes and increased the mortality and malformation rate.Collectively,these results indicated that all 3 BmiTPPs in B.minax are involved in trehalose synthesis and metamor-phosis.Thus,these genes could be evaluated as insecticidal targets for managing B.minax,andevenforotherdipteranpests.
