Background Polygalacturonase inhibiting proteins(PGIPs)play a pivotal role in plant defense against plant patho-gens by inhibiting polygalacturonase(PG),an enzyme produced by pathogens to degrade plant cell wall pecti...Background Polygalacturonase inhibiting proteins(PGIPs)play a pivotal role in plant defense against plant patho-gens by inhibiting polygalacturonase(PG),an enzyme produced by pathogens to degrade plant cell wall pectin.PGIPs,also known as leucine-rich repeat pathogenesis-related(PR)proteins,activate the host’s defense response upon interaction with PG,thereby reinforcing the host defense against plant pathogens attacks.In Egyptian or extra-long staple cotton(Gossypium barbadense),the interaction between PGIP and PG is one of the crucial steps in the defense mechanism against major pathogens such as Xanthomonas citri pv.malvacearum and Alternaria mac-rospora,which are responsible for bacterial leaf blight and leaf spot diseases,respectively.Results To unravel the molecular mechanisms underlying these PR proteins,we conducted a comprehensive study involving molecular modeling,protein-protein docking,site-specific double mutation(E169G and F242K),and molec-ular dynamics simulations.Both wild-type and mutated cotton PGIPs were examined in the interaction with the PG enzyme of a bacterial and fungal pathogen.Our findings revealed that changes in conformations of double-mutated residues in the active site of PGIP lead to the inhibition of PG binding.The molecular dynamics simulation studies provide insights into the dynamic behaviour and stability of the PGIP-PG complexes,shedding light on the intricate details of the inhibitory and exhibitory mechanism against the major fungal and bacterial pathogens of G.barbadense,respectively.Conclusions The findings of this study not only enhance our understanding of the molecular interactions between PGs of Xanthomonas citri pv.malvacearum and Alternaria macrospora and PGIP of G.barbadense but also pre-sent a potential strategy for developing the disease-resistant cotton varieties.By variations in the binding affinities of PGs through specific mutations in PGIP,this research offers promising avenues for the development of enhanced resistance to cotton plants against bacterial leaf blight and leaf spot diseases.展开更多
Objectives: To construct retroviral vectorsexpressing antisense polymeric RNAs targeted at the coresequence (+13-+47) of HIV-l TAR RNA, and to testthe anti-HIV properties of this construct in transducedCD4^+T cells. M...Objectives: To construct retroviral vectorsexpressing antisense polymeric RNAs targeted at the coresequence (+13-+47) of HIV-l TAR RNA, and to testthe anti-HIV properties of this construct in transducedCD4^+T cells. Methods: The polymeric TAR-Core DNAwas amplified by the"self-primers-template PCR"展开更多
It is difficult for the double suppression division algorithm of bee colony to solve the spatio-temporal coupling or have higher dimensional attributes and undertake sudden tasks.Using the idea of clustering,after clu...It is difficult for the double suppression division algorithm of bee colony to solve the spatio-temporal coupling or have higher dimensional attributes and undertake sudden tasks.Using the idea of clustering,after clustering tasks according to spatio-temporal attributes,the clustered groups are linked into task sub-chains according to similarity.Then,based on the correlation between clusters,the child chains are connected to form a task chain.Therefore,the limitation is solved that the task chain in the bee colony algorithm can only be connected according to one dimension.When a sudden task occurs,a method of inserting a small number of tasks into the original task chain and a task chain reconstruction method are designed according to the relative relationship between the number of sudden tasks and the number of remaining tasks.Through the above improvements,the algorithm can be used to process tasks with spatio-temporal coupling and burst tasks.In order to reflect the efficiency and applicability of the algorithm,a task allocation model for the unmanned aerial vehicle(UAV)group is constructed,and a one-to-one correspondence between the improved bee colony double suppression division algorithm and each attribute in the UAV group is proposed.Task assignment has been constructed.The study uses the self-adjusting characteristics of the bee colony to achieve task allocation.Simulation verification and algorithm comparison show that the algorithm has stronger planning advantages and algorithm performance.展开更多
The action between imidazolinyl-quaternary-ammonium-salt(IQAS) molecule and Fe atom was studied, and the influence of the alkyl group connected with N atom of imidazoline ring on corrosion inhibition efficiency was ex...The action between imidazolinyl-quaternary-ammonium-salt(IQAS) molecule and Fe atom was studied, and the influence of the alkyl group connected with N atom of imidazoline ring on corrosion inhibition efficiency was explored. Quantum chemical methods, HF/6-31 G and HF/Lan L2 dz, were applied successively to calculate the parameters such as front molecular orbit energy of IQASⅠ-Ⅳ and chemical adsorption for IQASⅠ-Ⅳ and Fe atom. The corrosion inhibition efficiency was measured with the weight loss method of carbon steel samples in acidic solution and oil field sewage. Based on the theoretical analyses and experimental results, it is concluded that N-Fe coordination bond is formed between IQAS molecule and Fe atom, corrosion inhibition efficiency is decreased in the following order(from large to small): IQAS Ⅳ, IQAS Ⅲ, IQAS Ⅱ, IQASⅠ.展开更多
The effect of egg shell powder(ES) as an environmental friendly inhibitor was studied for its corrosion inhibitive tendency on N08904 austenitic stainless steel in simulated saline(3.5% NaCl) solution using potentiody...The effect of egg shell powder(ES) as an environmental friendly inhibitor was studied for its corrosion inhibitive tendency on N08904 austenitic stainless steel in simulated saline(3.5% NaCl) solution using potentiodynamic polarization, weight loss, and SEM/EDX at room temperature. The experimental data explained the effective performance of ES with values of 57%-100% inhibition efficiency, at 2 g-10 g inhibitor concentration from weight loss tests due to the inhibition of stainless steel. The electrochemical action was as a result of the ionized particles which inhibit the compound influencing the redox reaction mechanism causing surface corrosion. ES's best performance was achieved when 6 g of the inhibitor concentration was added to the saline medium. Corrosion rate value decreased progressively with the presence of inhibitor because of anions adsorption at the interface of the metal film. Corrosion potential(Ecorr) value was found to decrease from-0.3991 V to-0.3447 V in the presence of inhibitor at 2 g concentration, decreasing gradually to-0.2048 at 6 g inhibitor concentration. The compounds identified in the ES completely adsorbed onto the surface of stainless steel as observed from the EDX analysis. The ES adsorption on stainless steel surface obeyed Langmuir adsorption isotherm. A corroded morphology with pits was observed in the SEM results without ES which contrast the images obtained with the presence of ES.展开更多
The synergistic inhibition effect of CeCl3(Ce)and serine(Ser)on the corrosion of carbon steel in a 3%NaCl solution was investigated by electrochemical methods and surface analysis.The results showed that both CeCl3 an...The synergistic inhibition effect of CeCl3(Ce)and serine(Ser)on the corrosion of carbon steel in a 3%NaCl solution was investigated by electrochemical methods and surface analysis.The results showed that both CeCl3 and Ser,when used alone,had limited inhibition effect toward carbon steel corrosion in the 3%NaCl solution.In contrast,the combination of CeCl3 with Ser produced a strong synergistic effect on the corrosion inhibition behavior of carbon steel,improving the inhibition efficiency significantly.The polarization curves showed that the mixture of CeCl3 and Ser acts as a cationic-type inhibitor.Scanning electron microscopy and Fourier transform infrared spectroscopy showed that the synergistic inhibition effect was due to complex formation between the cerium ions and amino acid molecules.展开更多
Inhibition mechanism between sodium （NaaAlF6） and sulfur on coke reactivity was investigated by simulating petroleum coke with low-impurity pitch coke and by impurity doping. The mechanism was discussed by scanning ...Inhibition mechanism between sodium （NaaAlF6） and sulfur on coke reactivity was investigated by simulating petroleum coke with low-impurity pitch coke and by impurity doping. The mechanism was discussed by scanning electron microscopy, energy-dispersive spectrometry, and X-ray powder diffraction. Results show that Na effectively inhibited S catalysis during carbon-air/CO2 reactions, and S inhibited the catalysis of Na during carbon- air reaction to a certain extent. A stable structure with a Na-to-S atomic ratio of 1.4 and a cyclic reaction system of ＂Na2SO3→ Na2S→Na2CO3→ Na2SO3＂ were likely the keys to producing this mutual inhibition.展开更多
The compound(4-chlorophenyl)-N-(4-methylphenyl)nitrone(4CPNMPN)has been selected as one of the new nitrone derivative for our study.The molecular structure of the compound was investigated based on frontier orbital an...The compound(4-chlorophenyl)-N-(4-methylphenyl)nitrone(4CPNMPN)has been selected as one of the new nitrone derivative for our study.The molecular structure of the compound was investigated based on frontier orbital analysis and natural bond orbital(NBO)theory.The present work also focuses on the inhibition efficiency of the compound.It is an attempt to find the correlation between the molecular structure of the compound and possible behaviour like corrosion inhibitors.The NBO analysis and the values of electric dipole moment(μ)of the investigated molecule were computed using DFT calculations.The molecule orbital contributions were studied by using the total(TDOS)density of states.The strong evidences that the compound can be used as an efficient nonlinear optical(NLO)of 4CPNMPN were demonstrated by considerable polarizability and hyperpolarizability values obtained at DFT levels.展开更多
Recently we have synthesized a novel small retinoid molecule WYC-209 that can effectively inhibit proliferation of malignant murine melanoma tumor-repopulating cells(TRCs).The molecule can induce 100%TRCs apoptosis at...Recently we have synthesized a novel small retinoid molecule WYC-209 that can effectively inhibit proliferation of malignant murine melanoma tumor-repopulating cells(TRCs).The molecule can induce 100%TRCs apoptosis at 10μM concentration.However,how WYC-209 induces TRCs apoptosis is still elusive.Here we demonstrate that WYC-209 at>6μM concentration started to induce TRCs apoptosis primarily via the caspase 3 pathway by releasing cytochrome c from mitochondria.Interestingly,we found that at concentrations<6μM WYC-209 induced TRCs to elevate dormancy marker COUP TF1 but induced no changes in apoptosis marker P53.Furthermore,proliferation markers Ki67 and PCNA decreased with the increase of WYC-209 concentrations,suggesting that low concentrations of WYC-209 inhibit TRCs growth by inducing cell dormancy instead of causing apoptosis.In addition,TRC traction forces were almost abolished when WYC-209 concentration was at 5μM,preceding the initiation of apoptosis.Our findings demonstrate that inhibition of TRCs by anti-cancer molecule WYC-209 is concentration-dependent and WYC-209 inhibits cellular force generation of the tumor-repopulating cells before inducing apoptosis.展开更多
OBJECTIVE Sheng Jiang San(SJS),a multi-herb formulation,is used in treating high fever,thirsty and anxiety in ancient China and it is sometimes used to treat seasonal influenza in modern.However,there is no evidenceba...OBJECTIVE Sheng Jiang San(SJS),a multi-herb formulation,is used in treating high fever,thirsty and anxiety in ancient China and it is sometimes used to treat seasonal influenza in modern.However,there is no evidencebased investigation and mechanism research to support SJS′s anti-influenza efficacy.This study aims to investigate the anti-influenza effect of SJS and its possible mechanisms.METHODS In this study,we examined the inhibitory effect of SJS against different influenza viruses on Madin-Darby canine kidney cells.Influenza virus infected BALB/c mice were employed as in vivo model to evaluate the efficacy.Mice challenged with A/PR/8/34(H1N1)were orally administrated SJS 1 g·kg^-1 daily for seven days and monitored for 14 d.The survival rate,body mass changes,lung index,lung viral load,histopathologic changes and immune-regulation of the mice were measured.The underlying anti-influenza virus mechanisms were studied by a series of biological assays in vitro to determine if hemagglutinin,ribonucleoprotein complex or nerauminidase were targets of SJS.RESULTS SJS exerted a broad spectrum of inhibitory effects on multiple influenza strains in a dose-dependent manner.And IC50 of SJS against A/WSN/33(H1N1)was lower than 35 mg·L^-1.SJS also protected 50%of mice from influenza virus PR8 infection.The lung index and the lung viral load of SJS treated mice were signifi⁃cantly decrease compared with untreated mice.SJS 2 g·L^-1 inhibited 80%of neuraminidase enzymatic activity.SJS also up-regulated TNF-αand IFN-αand down-regulated IL-2 of influenza virus induced mice.CONCLUSION SJS is a useful formulation for treating influenza virus infection.展开更多
Osteoarthritis(OA)is an inflammatory disease involving the joints that is prevalent in the global aging population.The purpose of this study is to determine whether irisin can attenuate osteoarthritis(OA)progression i...Osteoarthritis(OA)is an inflammatory disease involving the joints that is prevalent in the global aging population.The purpose of this study is to determine whether irisin can attenuate osteoarthritis(OA)progression in anterior cruciate ligament transection(ACLT)mice models and the mechanism of irisin therapy effect on OA by increase the resistance of apoptosis in MLO-Y4 cells induced by mechanical stretch in vitro.Methods For in vivo study,3-month-old male C57BL/6 J mice were randomized to three groups,sham-operated,anterior cruciate ligament transection(ACLT)-operated treated with vehicle,and ACLT-operated treated with irisin by intraperitoneal injection once a week.Cartilage erosion was observed by HE staining.Osteoarthritis Research Society International(OARSI)scores were evaluated according to the safranin O stai-ning.The microstructure of tibia cortical bone,trabecular bone,and subchondral bone was analyzed by micro-CT and the bone histomorphometry has been administrated including mineral apposition rate(MAR).Edu staining and cck-8 were used for the detection of the proliferation of MLO-Y4 cells.For mechanical stress,cells were seeded on the collagen-I coated chamber subjected with a peak biaxial stretch of 20%at 1 Hz for 16 hours to induce apoptosis.Flow cytometry was used for the detection of apoptosis and cell cycle.TUNNEL was used for staining the apoptotic cells and rt-PCR was applied for quantifying the expression of mRNA such as Bax,Bcl-2,SOST,c-myc,Opg.Western blot was utilized to confirm the mechanism of how irisin decrease the osteocyte apoptosis.Results In vivo,irisin can attenuate articular cartilage degeneration.Irisin maintains the proportion of hyaline cartilage and calcified cartilage and keep fewer cartilage erosions in ACLT-operated mice.For immunohistochemical(IHC)staining,irisin reduced the expression of caspase3,Bax and matrix metalloproteinase-13 in both cartilage and subchondral bone.Irisin-treated ACLT group shows higher Trabecular number(Tb.N)and bone volume fraction(BV/TV)compared to the vehicle-treated ACLT group.In vitro, irisin significantly increased the proliferation of MLO-Y4 cells detected by Edu and Ki67 staining,and irisin can protect the cells from both mechanical stretchinduced apoptosis detected by FITC-PI flow cytometry and maintain the cell activity by regulating the expression of Bax,Bcl-2,and c-myc.Transcriptome sequencing shows that irisin significantly activates the MAPK signaling pathway and we confirm the result by western blot:irisin effectively activates the Erk signaling pathway through phosphorylation and has a certain activation effect on p38 signaling pathway,no activation was observed for FAK signaling pathway.Conclusions Irisin can attenuate the progression of OA by decrease the apoptosis of osteocyte,which can improve the microarchitecture of subchondral bone.Erk pathway activation plays an important role in reducing the apoptosis of osteocyte.展开更多
Aim Previous studies showed that the inhibition of proteasome activity could significantly improve cardi- ac hypertrophy, but its mechanism is not clear. Increased glycogen synthase kinase-3 （GSK-3） activity can als...Aim Previous studies showed that the inhibition of proteasome activity could significantly improve cardi- ac hypertrophy, but its mechanism is not clear. Increased glycogen synthase kinase-3 （GSK-3） activity can also improve cardiac hypertrophy. However, the relationship between proteasome and GSK-3 has not been reported in cardiomyocyte In this study, we will investigate the effect of proteasome inhibition on cardiomyocyte hypertrophy, GSK-3 activity and the underlying mechanism. Methods Primary neonatal rat cardiomyocytes were divided into 4 groups： Control, Ang H （100 nmol · L^-1 48 h） Ang Ⅱ （ 100 nmol · L^-1） ＋ MG132 （0.05 μmol · L^-1） MG132 （0.05 μmol · L^-1） ,Ang 11 （100 nmol · L^-1 ） ＋ MG132 ＋ LiC1 （ 10 mmol · L^-1 ）, LiC1. Proteasome activitiy was detected by fluorescent peptide substrate. Cardiomyocyte surface area, ANF mRNA expression, and the rate of protein synthesis were observed as myocardial hypertrophy index. GSK-3, Akt, AMPKoL, and Histone3 （H3） were detected by Western Blot. The expression of GATA4 in the cytoplasm and nucleus was observed by im- munofluorescence. Results （1） Compared with the control group, myocardial ANF mRNA expression, the rate of protein synthesis and cell surface area were all increased in Ang H group. The chymotrypsin-like, trypsin-like and caspase-like activities of proteasome were all increased significantly. The phosphorylated level of both GSK-3α（ p- GSK-3α） （ Ser21 ） and GSK-3β （p-GSK-3β ） （Ser9） increased, i. e they were inactivated. （2） Compared with the Ang II group, myocardial ANF mRNA expression, the rate of protein synthesis and cell surface area were all decreased after proteasome inhibition. And p-GSK-3 （Ser21） and p-GSK-3β （Ser9） was respondingly decreased, （3） Proteasome inhibition also resulted in the decrease of p-Akt （Ser473） and p-AMPKa （Thr172）7 which in- creased in cardiomyocyte hypertrophy. Immunofluorescence showed that GATA4 was mainly distributed in the nu- cleus after Ang II treatment, while it was obviously increased in the cytoplasm after proteasome inhibition. After the GSK-3 inhibitor-LiC1 was given, the above indicators were reversed. （4） p-Histone3 was also increased in cardio- myocyte hypertrophy and MG132 reduced its level, but LiC1 treatment had no significant effect on its level. Con- clusion Proteasome inhibition reduces cardiomyocyte hypertrophy through increase of GSK-3a/b activity, which may be related with the decrease of Akt and AMPKa activities, and the decrease of nucleus location of GATA4, but p-histone3 is not involved.展开更多
A plasmid expressing antisense MDRl cDNAsegment was introduced into KB<sub>v200</sub> which inductedmultiple drugs to VCT （vincristine, 175 fold-resistancehigher than that in original KB cells） and ADM（...A plasmid expressing antisense MDRl cDNAsegment was introduced into KB<sub>v200</sub> which inductedmultiple drugs to VCT （vincristine, 175 fold-resistancehigher than that in original KB cells） and ADM（adriamycin, 14. 5 fold） resulting over-expression ofMDRl. We used the primers for antisense RNA asfollowing: upstream 5′OGAATTCTGAAACCTGTAAGCAGCAACC 3′: downstream展开更多
Previous studies have shown that the bcl-2protooncogene encodes a mitochondrial protein thatpromotes cell survival by blocking programmed celldeath. High levels of bcl-2 expression were found inmurine myeloid leukemic...Previous studies have shown that the bcl-2protooncogene encodes a mitochondrial protein thatpromotes cell survival by blocking programmed celldeath. High levels of bcl-2 expression were found inmurine myeloid leukemic cell lines resistant to apoptosisinduced by variety of agents. In addition artificialelevation of bcl-2 expression in a human pre-B leukemiccell line resulted in enhanced resistance to chemo-therapcutic drugs. We reported here on the effect ofbcl-2 antisense phosphorothiate展开更多
To evaluate the influence of various Cr(Ⅵ) concentrations (0.05, 0.25, 0.50, 1.00 and 2.00 g/kg) on the activity of soil enzymes, the activities of catalase, polyphenol oxidase, dehydrogenase, alkaline phosphatase in...To evaluate the influence of various Cr(Ⅵ) concentrations (0.05, 0.25, 0.50, 1.00 and 2.00 g/kg) on the activity of soil enzymes, the activities of catalase, polyphenol oxidase, dehydrogenase, alkaline phosphatase in soils were investigated in the incubation experiment with a period of 35 d. The results indicate that all the tested Cr(Ⅵ) concentrations significantly inhibit dehydrogenase activity by over 70% after 35 d. The activity of alkaline phosphatase is slightly inhibited during the whole experiment except for on the day 7. Cr(Ⅵ) has no obvious effect on the activity of catalase in soil. On the contrary, Cr(Ⅵ) stimulates the activity of polyphenol oxidase. The results suggest that dehydrogenase activity can be used as an indicator for assessing the severity of chromium pollution.展开更多
To study the inhibiting effects of S-Nitroso-Glutathione （GSNO） on sporulation process of Eimeria tenella （E. tenella） oocysts by detecting the sporulation rate, GSNO as nitric oxide donor was used to treat E. ten...To study the inhibiting effects of S-Nitroso-Glutathione （GSNO） on sporulation process of Eimeria tenella （E. tenella） oocysts by detecting the sporulation rate, GSNO as nitric oxide donor was used to treat E. tenella oocysts sporulated for different times; Several kinds of antioxidants and oxidants were used to investigate the inhibitory effects of GSNO on sporogony process of E. tenella oocysts. The results showed that GSNO still inhibited the oocysts sporulated 10 h, but had few inhibiting effect on the oocysts sporulated for 14 h; the antioxidants, such as Vitamin C （VC）, mannitol and sodium salicylate, could not eliminate the inhibitory effects of GSNO on oocysts; neither did the ferrous sulfate （FeSO4） nor Dithiothreitol （DTT）. However, the oxidants, potassium dichromate （K2Cr2OT） and potassium permanganate （KMnO4） could obviously repress the effects of GSNO on oocysts. At present, the inhibitory mechanism of GSNO on unsporulated oocysts was still unclear.展开更多
Objective Apoptosis is recognized as an important mechanism in contrast-induced nephropathy(CIN).Acupuncture and moxibustion,the auxiliary treatment in China,are effective interventions for cell apoptosis in many isch...Objective Apoptosis is recognized as an important mechanism in contrast-induced nephropathy(CIN).Acupuncture and moxibustion,the auxiliary treatment in China,are effective interventions for cell apoptosis in many ischemic diseases.In our previous study,we found acupuncture and moxibustion could prevent CIN.The objective of this research is to study the mechanism of acupuncture and moxibustion on tubular epithelial cell apoptosis in diabetic CIN rats.展开更多
OBJECTIVE Microglial activation-mediated neuroinflammation plays an important pathological basis in the progression of many neurodegenerative diseases.Activated microglia cells show a metabolic shift from oxidative ph...OBJECTIVE Microglial activation-mediated neuroinflammation plays an important pathological basis in the progression of many neurodegenerative diseases.Activated microglia cells show a metabolic shift from oxidative phos⁃phorylation to aerobic glycolysis.However,the molecular mechanism underlying the role of glycolysis in microglial activation and progres⁃sion of neuroinflammatory diseases have not yet been fully understood.METHODS The anti-inflammatory effects and its underlying mecha⁃nisms of glycolytic inhibition in vitro were exam⁃ined in lipopolysaccharide(LPS)activated BV-2 microglial cells or primary microglial cells by enzyme-linked immunosorbent assay(ELISA),quantitative reverse transcriptase polymerase chain reaction(RT-PCR),Western blotting,immunoprecipitation,Flow cytometry and nuclear factor kappa B(NF-κB)luciferase reporter assays.In vivo,the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-or LPS-induced Par⁃kinson disease(PD)models were constructed to explored the anti-inflammatory and neuropro⁃tective effects of glycolytic inhibitor.RESULTS Inhibition of glycolysis by specific inhibitors[2-DG and 3-bromopyruvic acid(3-BPA)],knockdown of glucose transporter type 1(Glut-1)or hexoki⁃nase(HK)Ⅱabolished LPS-induced expres⁃sion of proinflammatory genes in microglia cells.Mechanistic studies demonstrated that glyco⁃lytic inhibitors significantly inhibited LPS-induced mTOR phosphorylation,IKKβphosphorylation,IκB phosphorylation,IκB degradation,nuclear translocation of P65 and NF-κB luciferase activity.Furthermore,LPS-induced P65 acetyla⁃tion on lysine 310,which is mediated by NAD-dependent protein deacetylase sirtuin-1 and is critical for NF-kB activation,were inhibited by glycolytic inhibitors.A coculture study revealed that 2-DG reduced the cytotoxicity of activated microglia toward MES23.5 dopaminergic neuron cells with no direct protective effect.In vivo,2-DG significantly ameliorated MPTP or LPS induced DA neuron loss and glial cell activation.CONCLUSION Glycolysis is actively involved in microglial activation.Inhibition of glycolysis can ameliorate microglial activation-related neuroinflammatory diseases.展开更多
OBJECTIVE Prepulse inhibition(PPI)of the acoustic startle response provides a measure of sensorimotor gating system mecha⁃nisms,which is known to be impaired in schizo⁃phrenia patients.We assessed the effects of the 5...OBJECTIVE Prepulse inhibition(PPI)of the acoustic startle response provides a measure of sensorimotor gating system mecha⁃nisms,which is known to be impaired in schizo⁃phrenia patients.We assessed the effects of the 5-HT2A/2C receptor agonist(±)2,5-dimethoxy-4-methylamphetamine(DOM),the NMDA receptor antagonist ketamine,the dopamine receptor ago⁃nist methamphetamine(Meth)on PPI and the startle magnitude in SD rats.METHODS AND RESULTS Systemic administration of the three compounds all dose-dependently reduced PPI.However,as far as startle magnitude,only DOM at the doses of 3 mg·kg-1 reduced that,while both ketamine and Meth did not change the startle magnitudes.Furthermore,to determine whether 5-HT2A receptor mediate this effect,the non-spe⁃cific 5-HT2 receptor antagonist cyproheptadine,specific 5-HT2A receptor antagonist ketanserin and specific 5-HT2C receptor antagonist SB242084 were tested.Cyproheptadine,ketan⁃serin and SB242084 did not alter startle ampli⁃tude by themselves in SD rats and only ketanserin slightly increased PPI at higher dose(3 mg·kg-1).PPI impairment induced by DOM was restored by pretreatment of cyproheptadine(1 mg·kg-1)and ketanserin(1 mg·kg-1),while not by pretreat⁃ment of SB242084(1 mg·kg-1).Damage of PPI induced by ketamine and Meth was not reversed by cyproheptadine(1 and 5 mg·kg-1).CONCLU⁃SION The receptor mechanisms underlying the disruption of PPI caused by DOM,ketamine and Meth were different from each other,at least 5-HT2A receptor was not the junction receptor for which the three chemicals acted.展开更多
OBJECTIVE The inhibitory effect of active ingredients of Tripterygium wilfordii Hook.F.(TWHF)(celastrol,triptolide,triptonide,wilforlide A,wilforgine and wilforine)on human carboxylester⁃ase 1(CES1)and CES2 was detect...OBJECTIVE The inhibitory effect of active ingredients of Tripterygium wilfordii Hook.F.(TWHF)(celastrol,triptolide,triptonide,wilforlide A,wilforgine and wilforine)on human carboxylester⁃ase 1(CES1)and CES2 was detected to investigate the herb-drug interactions(HDIs)of TWHF.METHODS Human liver microsomes catalysed hydrolysis of 2-(2-benzoyl-3-methoxyphenyl)benzothi⁃azole(BMBT)and fluorescein diacetate(FD)were used as the probe reaction to phenotype the activity of CES1 and CES2,respectively.The residual activities of CES1 and CES2 were detected by ultrahigh performance liquid chromatography(UPLC)after intervention with celastrol,triptolide,triptonide,wilforlide A,wilforgine and wilforine(100μmol·L^(-1)).Kinetics analysis,involving half inhibitory concentra⁃tion(IC_(50)),inhibition type and kinetic parameter(Ki),and in vitro-in vivo extrapolation(IVIVE),was carried out to predict the HDIs between these compounds and CES-metabolizing drugs.Molecular docking was performed to analyze the ligand-enzyme interaction.RESULTS Out of the six main con⁃stituents of TWHF,only celastrol exhibited strong inhibition towards both CES1 and CES2,with the inhibitory rates of 97.45%(P<0.05)and 95.62%(P<0.05),respectively.The IC_(50)was 9.95 and 4.02 mol·L^(-1),respectively,and the types of inhibition were all non-competitive inhibition.Based on the kinetics analysis,the Ki values were calculated to be 5.10 and 10.55μmol·L^(-1)for the inhibition of celastrol on CES1 and CES2,respectively.IVIVE indicated that celastrol might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting CES1.Molecular docking results showed that hydrogen bonds and hydrophobic contacts contributed to the interaction of celastrol and CESs.CONCLUSION The inhibitory effect of celastrol on CES1 and CES2 might cause HDIs with clinical drugs hydrolysed by CESs.展开更多
基金CABin grant(F.no.Agril.Edn.4-1/2013-A&P)Indian Council of Agricul-tural Research,Ministry of Agriculture and Farmers’Welfare,Govt.of India and Department of Biotechnology,Govt.of India for BIC project grant(BT/PR40161/BTIS/137/32/2021)。
文摘Background Polygalacturonase inhibiting proteins(PGIPs)play a pivotal role in plant defense against plant patho-gens by inhibiting polygalacturonase(PG),an enzyme produced by pathogens to degrade plant cell wall pectin.PGIPs,also known as leucine-rich repeat pathogenesis-related(PR)proteins,activate the host’s defense response upon interaction with PG,thereby reinforcing the host defense against plant pathogens attacks.In Egyptian or extra-long staple cotton(Gossypium barbadense),the interaction between PGIP and PG is one of the crucial steps in the defense mechanism against major pathogens such as Xanthomonas citri pv.malvacearum and Alternaria mac-rospora,which are responsible for bacterial leaf blight and leaf spot diseases,respectively.Results To unravel the molecular mechanisms underlying these PR proteins,we conducted a comprehensive study involving molecular modeling,protein-protein docking,site-specific double mutation(E169G and F242K),and molec-ular dynamics simulations.Both wild-type and mutated cotton PGIPs were examined in the interaction with the PG enzyme of a bacterial and fungal pathogen.Our findings revealed that changes in conformations of double-mutated residues in the active site of PGIP lead to the inhibition of PG binding.The molecular dynamics simulation studies provide insights into the dynamic behaviour and stability of the PGIP-PG complexes,shedding light on the intricate details of the inhibitory and exhibitory mechanism against the major fungal and bacterial pathogens of G.barbadense,respectively.Conclusions The findings of this study not only enhance our understanding of the molecular interactions between PGs of Xanthomonas citri pv.malvacearum and Alternaria macrospora and PGIP of G.barbadense but also pre-sent a potential strategy for developing the disease-resistant cotton varieties.By variations in the binding affinities of PGs through specific mutations in PGIP,this research offers promising avenues for the development of enhanced resistance to cotton plants against bacterial leaf blight and leaf spot diseases.
文摘Objectives: To construct retroviral vectorsexpressing antisense polymeric RNAs targeted at the coresequence (+13-+47) of HIV-l TAR RNA, and to testthe anti-HIV properties of this construct in transducedCD4^+T cells. Methods: The polymeric TAR-Core DNAwas amplified by the"self-primers-template PCR"
基金This work was supported by the National Natural Science and Technology Innovation 2030 Major Project of Ministry of Science and Technology of China(2018AAA0101200)the National Natural Science Foundation of China(61502522,61502534)+4 种基金the Equipment Pre-Research Field Fund(JZX7Y20190253036101)the Equipment Pre-Research Ministry of Education Joint Fund(6141A02033703)Shaanxi Provincial Natural Science Foundation(2020JQ-493)the Military Science Project of the National Social Science Fund(WJ2019-SKJJ-C-092)the Theoretical Research Foundation of Armed Police Engineering University(WJY202148).
文摘It is difficult for the double suppression division algorithm of bee colony to solve the spatio-temporal coupling or have higher dimensional attributes and undertake sudden tasks.Using the idea of clustering,after clustering tasks according to spatio-temporal attributes,the clustered groups are linked into task sub-chains according to similarity.Then,based on the correlation between clusters,the child chains are connected to form a task chain.Therefore,the limitation is solved that the task chain in the bee colony algorithm can only be connected according to one dimension.When a sudden task occurs,a method of inserting a small number of tasks into the original task chain and a task chain reconstruction method are designed according to the relative relationship between the number of sudden tasks and the number of remaining tasks.Through the above improvements,the algorithm can be used to process tasks with spatio-temporal coupling and burst tasks.In order to reflect the efficiency and applicability of the algorithm,a task allocation model for the unmanned aerial vehicle(UAV)group is constructed,and a one-to-one correspondence between the improved bee colony double suppression division algorithm and each attribute in the UAV group is proposed.Task assignment has been constructed.The study uses the self-adjusting characteristics of the bee colony to achieve task allocation.Simulation verification and algorithm comparison show that the algorithm has stronger planning advantages and algorithm performance.
基金Project (05A002) supported by Scientific Research Fundation of Hunan Provincial Education Depart ment project(04JJY40010) supported by the Natural Science Foundation of Hunan Province
文摘The action between imidazolinyl-quaternary-ammonium-salt(IQAS) molecule and Fe atom was studied, and the influence of the alkyl group connected with N atom of imidazoline ring on corrosion inhibition efficiency was explored. Quantum chemical methods, HF/6-31 G and HF/Lan L2 dz, were applied successively to calculate the parameters such as front molecular orbit energy of IQASⅠ-Ⅳ and chemical adsorption for IQASⅠ-Ⅳ and Fe atom. The corrosion inhibition efficiency was measured with the weight loss method of carbon steel samples in acidic solution and oil field sewage. Based on the theoretical analyses and experimental results, it is concluded that N-Fe coordination bond is formed between IQAS molecule and Fe atom, corrosion inhibition efficiency is decreased in the following order(from large to small): IQAS Ⅳ, IQAS Ⅲ, IQAS Ⅱ, IQASⅠ.
文摘The effect of egg shell powder(ES) as an environmental friendly inhibitor was studied for its corrosion inhibitive tendency on N08904 austenitic stainless steel in simulated saline(3.5% NaCl) solution using potentiodynamic polarization, weight loss, and SEM/EDX at room temperature. The experimental data explained the effective performance of ES with values of 57%-100% inhibition efficiency, at 2 g-10 g inhibitor concentration from weight loss tests due to the inhibition of stainless steel. The electrochemical action was as a result of the ionized particles which inhibit the compound influencing the redox reaction mechanism causing surface corrosion. ES's best performance was achieved when 6 g of the inhibitor concentration was added to the saline medium. Corrosion rate value decreased progressively with the presence of inhibitor because of anions adsorption at the interface of the metal film. Corrosion potential(Ecorr) value was found to decrease from-0.3991 V to-0.3447 V in the presence of inhibitor at 2 g concentration, decreasing gradually to-0.2048 at 6 g inhibitor concentration. The compounds identified in the ES completely adsorbed onto the surface of stainless steel as observed from the EDX analysis. The ES adsorption on stainless steel surface obeyed Langmuir adsorption isotherm. A corroded morphology with pits was observed in the SEM results without ES which contrast the images obtained with the presence of ES.
基金Project(2017210101002066)supported by the Crosswise Project of Liaoning province,China
文摘The synergistic inhibition effect of CeCl3(Ce)and serine(Ser)on the corrosion of carbon steel in a 3%NaCl solution was investigated by electrochemical methods and surface analysis.The results showed that both CeCl3 and Ser,when used alone,had limited inhibition effect toward carbon steel corrosion in the 3%NaCl solution.In contrast,the combination of CeCl3 with Ser produced a strong synergistic effect on the corrosion inhibition behavior of carbon steel,improving the inhibition efficiency significantly.The polarization curves showed that the mixture of CeCl3 and Ser acts as a cationic-type inhibitor.Scanning electron microscopy and Fourier transform infrared spectroscopy showed that the synergistic inhibition effect was due to complex formation between the cerium ions and amino acid molecules.
基金Projects(51374253,51574289)supported by the National Natural Science Foundation of China
文摘Inhibition mechanism between sodium （NaaAlF6） and sulfur on coke reactivity was investigated by simulating petroleum coke with low-impurity pitch coke and by impurity doping. The mechanism was discussed by scanning electron microscopy, energy-dispersive spectrometry, and X-ray powder diffraction. Results show that Na effectively inhibited S catalysis during carbon-air/CO2 reactions, and S inhibited the catalysis of Na during carbon- air reaction to a certain extent. A stable structure with a Na-to-S atomic ratio of 1.4 and a cyclic reaction system of ＂Na2SO3→ Na2S→Na2CO3→ Na2SO3＂ were likely the keys to producing this mutual inhibition.
文摘The compound(4-chlorophenyl)-N-(4-methylphenyl)nitrone(4CPNMPN)has been selected as one of the new nitrone derivative for our study.The molecular structure of the compound was investigated based on frontier orbital analysis and natural bond orbital(NBO)theory.The present work also focuses on the inhibition efficiency of the compound.It is an attempt to find the correlation between the molecular structure of the compound and possible behaviour like corrosion inhibitors.The NBO analysis and the values of electric dipole moment(μ)of the investigated molecule were computed using DFT calculations.The molecule orbital contributions were studied by using the total(TDOS)density of states.The strong evidences that the compound can be used as an efficient nonlinear optical(NLO)of 4CPNMPN were demonstrated by considerable polarizability and hyperpolarizability values obtained at DFT levels.
基金supported by funds from Huazhong University of Science and Technology
文摘Recently we have synthesized a novel small retinoid molecule WYC-209 that can effectively inhibit proliferation of malignant murine melanoma tumor-repopulating cells(TRCs).The molecule can induce 100%TRCs apoptosis at 10μM concentration.However,how WYC-209 induces TRCs apoptosis is still elusive.Here we demonstrate that WYC-209 at>6μM concentration started to induce TRCs apoptosis primarily via the caspase 3 pathway by releasing cytochrome c from mitochondria.Interestingly,we found that at concentrations<6μM WYC-209 induced TRCs to elevate dormancy marker COUP TF1 but induced no changes in apoptosis marker P53.Furthermore,proliferation markers Ki67 and PCNA decreased with the increase of WYC-209 concentrations,suggesting that low concentrations of WYC-209 inhibit TRCs growth by inducing cell dormancy instead of causing apoptosis.In addition,TRC traction forces were almost abolished when WYC-209 concentration was at 5μM,preceding the initiation of apoptosis.Our findings demonstrate that inhibition of TRCs by anti-cancer molecule WYC-209 is concentration-dependent and WYC-209 inhibits cellular force generation of the tumor-repopulating cells before inducing apoptosis.
文摘OBJECTIVE Sheng Jiang San(SJS),a multi-herb formulation,is used in treating high fever,thirsty and anxiety in ancient China and it is sometimes used to treat seasonal influenza in modern.However,there is no evidencebased investigation and mechanism research to support SJS′s anti-influenza efficacy.This study aims to investigate the anti-influenza effect of SJS and its possible mechanisms.METHODS In this study,we examined the inhibitory effect of SJS against different influenza viruses on Madin-Darby canine kidney cells.Influenza virus infected BALB/c mice were employed as in vivo model to evaluate the efficacy.Mice challenged with A/PR/8/34(H1N1)were orally administrated SJS 1 g·kg^-1 daily for seven days and monitored for 14 d.The survival rate,body mass changes,lung index,lung viral load,histopathologic changes and immune-regulation of the mice were measured.The underlying anti-influenza virus mechanisms were studied by a series of biological assays in vitro to determine if hemagglutinin,ribonucleoprotein complex or nerauminidase were targets of SJS.RESULTS SJS exerted a broad spectrum of inhibitory effects on multiple influenza strains in a dose-dependent manner.And IC50 of SJS against A/WSN/33(H1N1)was lower than 35 mg·L^-1.SJS also protected 50%of mice from influenza virus PR8 infection.The lung index and the lung viral load of SJS treated mice were signifi⁃cantly decrease compared with untreated mice.SJS 2 g·L^-1 inhibited 80%of neuraminidase enzymatic activity.SJS also up-regulated TNF-αand IFN-αand down-regulated IL-2 of influenza virus induced mice.CONCLUSION SJS is a useful formulation for treating influenza virus infection.
基金supported by the National Natural Science Foundation of China ( 31670957)
文摘Osteoarthritis(OA)is an inflammatory disease involving the joints that is prevalent in the global aging population.The purpose of this study is to determine whether irisin can attenuate osteoarthritis(OA)progression in anterior cruciate ligament transection(ACLT)mice models and the mechanism of irisin therapy effect on OA by increase the resistance of apoptosis in MLO-Y4 cells induced by mechanical stretch in vitro.Methods For in vivo study,3-month-old male C57BL/6 J mice were randomized to three groups,sham-operated,anterior cruciate ligament transection(ACLT)-operated treated with vehicle,and ACLT-operated treated with irisin by intraperitoneal injection once a week.Cartilage erosion was observed by HE staining.Osteoarthritis Research Society International(OARSI)scores were evaluated according to the safranin O stai-ning.The microstructure of tibia cortical bone,trabecular bone,and subchondral bone was analyzed by micro-CT and the bone histomorphometry has been administrated including mineral apposition rate(MAR).Edu staining and cck-8 were used for the detection of the proliferation of MLO-Y4 cells.For mechanical stress,cells were seeded on the collagen-I coated chamber subjected with a peak biaxial stretch of 20%at 1 Hz for 16 hours to induce apoptosis.Flow cytometry was used for the detection of apoptosis and cell cycle.TUNNEL was used for staining the apoptotic cells and rt-PCR was applied for quantifying the expression of mRNA such as Bax,Bcl-2,SOST,c-myc,Opg.Western blot was utilized to confirm the mechanism of how irisin decrease the osteocyte apoptosis.Results In vivo,irisin can attenuate articular cartilage degeneration.Irisin maintains the proportion of hyaline cartilage and calcified cartilage and keep fewer cartilage erosions in ACLT-operated mice.For immunohistochemical(IHC)staining,irisin reduced the expression of caspase3,Bax and matrix metalloproteinase-13 in both cartilage and subchondral bone.Irisin-treated ACLT group shows higher Trabecular number(Tb.N)and bone volume fraction(BV/TV)compared to the vehicle-treated ACLT group.In vitro, irisin significantly increased the proliferation of MLO-Y4 cells detected by Edu and Ki67 staining,and irisin can protect the cells from both mechanical stretchinduced apoptosis detected by FITC-PI flow cytometry and maintain the cell activity by regulating the expression of Bax,Bcl-2,and c-myc.Transcriptome sequencing shows that irisin significantly activates the MAPK signaling pathway and we confirm the result by western blot:irisin effectively activates the Erk signaling pathway through phosphorylation and has a certain activation effect on p38 signaling pathway,no activation was observed for FAK signaling pathway.Conclusions Irisin can attenuate the progression of OA by decrease the apoptosis of osteocyte,which can improve the microarchitecture of subchondral bone.Erk pathway activation plays an important role in reducing the apoptosis of osteocyte.
文摘Aim Previous studies showed that the inhibition of proteasome activity could significantly improve cardi- ac hypertrophy, but its mechanism is not clear. Increased glycogen synthase kinase-3 （GSK-3） activity can also improve cardiac hypertrophy. However, the relationship between proteasome and GSK-3 has not been reported in cardiomyocyte In this study, we will investigate the effect of proteasome inhibition on cardiomyocyte hypertrophy, GSK-3 activity and the underlying mechanism. Methods Primary neonatal rat cardiomyocytes were divided into 4 groups： Control, Ang H （100 nmol · L^-1 48 h） Ang Ⅱ （ 100 nmol · L^-1） ＋ MG132 （0.05 μmol · L^-1） MG132 （0.05 μmol · L^-1） ,Ang 11 （100 nmol · L^-1 ） ＋ MG132 ＋ LiC1 （ 10 mmol · L^-1 ）, LiC1. Proteasome activitiy was detected by fluorescent peptide substrate. Cardiomyocyte surface area, ANF mRNA expression, and the rate of protein synthesis were observed as myocardial hypertrophy index. GSK-3, Akt, AMPKoL, and Histone3 （H3） were detected by Western Blot. The expression of GATA4 in the cytoplasm and nucleus was observed by im- munofluorescence. Results （1） Compared with the control group, myocardial ANF mRNA expression, the rate of protein synthesis and cell surface area were all increased in Ang H group. The chymotrypsin-like, trypsin-like and caspase-like activities of proteasome were all increased significantly. The phosphorylated level of both GSK-3α（ p- GSK-3α） （ Ser21 ） and GSK-3β （p-GSK-3β ） （Ser9） increased, i. e they were inactivated. （2） Compared with the Ang II group, myocardial ANF mRNA expression, the rate of protein synthesis and cell surface area were all decreased after proteasome inhibition. And p-GSK-3 （Ser21） and p-GSK-3β （Ser9） was respondingly decreased, （3） Proteasome inhibition also resulted in the decrease of p-Akt （Ser473） and p-AMPKa （Thr172）7 which in- creased in cardiomyocyte hypertrophy. Immunofluorescence showed that GATA4 was mainly distributed in the nu- cleus after Ang II treatment, while it was obviously increased in the cytoplasm after proteasome inhibition. After the GSK-3 inhibitor-LiC1 was given, the above indicators were reversed. （4） p-Histone3 was also increased in cardio- myocyte hypertrophy and MG132 reduced its level, but LiC1 treatment had no significant effect on its level. Con- clusion Proteasome inhibition reduces cardiomyocyte hypertrophy through increase of GSK-3a/b activity, which may be related with the decrease of Akt and AMPKa activities, and the decrease of nucleus location of GATA4, but p-histone3 is not involved.
文摘A plasmid expressing antisense MDRl cDNAsegment was introduced into KB<sub>v200</sub> which inductedmultiple drugs to VCT （vincristine, 175 fold-resistancehigher than that in original KB cells） and ADM（adriamycin, 14. 5 fold） resulting over-expression ofMDRl. We used the primers for antisense RNA asfollowing: upstream 5′OGAATTCTGAAACCTGTAAGCAGCAACC 3′: downstream
文摘Previous studies have shown that the bcl-2protooncogene encodes a mitochondrial protein thatpromotes cell survival by blocking programmed celldeath. High levels of bcl-2 expression were found inmurine myeloid leukemic cell lines resistant to apoptosisinduced by variety of agents. In addition artificialelevation of bcl-2 expression in a human pre-B leukemiccell line resulted in enhanced resistance to chemo-therapcutic drugs. We reported here on the effect ofbcl-2 antisense phosphorothiate
基金Projects(2006AA06Z374, 2007AA021304) supported by the National High-Tech Research and Development Program of ChinaProject(2008SK2007) supported by the Key Program of Science and Technology of Hunan Province, China
文摘To evaluate the influence of various Cr(Ⅵ) concentrations (0.05, 0.25, 0.50, 1.00 and 2.00 g/kg) on the activity of soil enzymes, the activities of catalase, polyphenol oxidase, dehydrogenase, alkaline phosphatase in soils were investigated in the incubation experiment with a period of 35 d. The results indicate that all the tested Cr(Ⅵ) concentrations significantly inhibit dehydrogenase activity by over 70% after 35 d. The activity of alkaline phosphatase is slightly inhibited during the whole experiment except for on the day 7. Cr(Ⅵ) has no obvious effect on the activity of catalase in soil. On the contrary, Cr(Ⅵ) stimulates the activity of polyphenol oxidase. The results suggest that dehydrogenase activity can be used as an indicator for assessing the severity of chromium pollution.
文摘To study the inhibiting effects of S-Nitroso-Glutathione （GSNO） on sporulation process of Eimeria tenella （E. tenella） oocysts by detecting the sporulation rate, GSNO as nitric oxide donor was used to treat E. tenella oocysts sporulated for different times; Several kinds of antioxidants and oxidants were used to investigate the inhibitory effects of GSNO on sporogony process of E. tenella oocysts. The results showed that GSNO still inhibited the oocysts sporulated 10 h, but had few inhibiting effect on the oocysts sporulated for 14 h; the antioxidants, such as Vitamin C （VC）, mannitol and sodium salicylate, could not eliminate the inhibitory effects of GSNO on oocysts; neither did the ferrous sulfate （FeSO4） nor Dithiothreitol （DTT）. However, the oxidants, potassium dichromate （K2Cr2OT） and potassium permanganate （KMnO4） could obviously repress the effects of GSNO on oocysts. At present, the inhibitory mechanism of GSNO on unsporulated oocysts was still unclear.
文摘Objective Apoptosis is recognized as an important mechanism in contrast-induced nephropathy(CIN).Acupuncture and moxibustion,the auxiliary treatment in China,are effective interventions for cell apoptosis in many ischemic diseases.In our previous study,we found acupuncture and moxibustion could prevent CIN.The objective of this research is to study the mechanism of acupuncture and moxibustion on tubular epithelial cell apoptosis in diabetic CIN rats.
文摘OBJECTIVE Microglial activation-mediated neuroinflammation plays an important pathological basis in the progression of many neurodegenerative diseases.Activated microglia cells show a metabolic shift from oxidative phos⁃phorylation to aerobic glycolysis.However,the molecular mechanism underlying the role of glycolysis in microglial activation and progres⁃sion of neuroinflammatory diseases have not yet been fully understood.METHODS The anti-inflammatory effects and its underlying mecha⁃nisms of glycolytic inhibition in vitro were exam⁃ined in lipopolysaccharide(LPS)activated BV-2 microglial cells or primary microglial cells by enzyme-linked immunosorbent assay(ELISA),quantitative reverse transcriptase polymerase chain reaction(RT-PCR),Western blotting,immunoprecipitation,Flow cytometry and nuclear factor kappa B(NF-κB)luciferase reporter assays.In vivo,the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-or LPS-induced Par⁃kinson disease(PD)models were constructed to explored the anti-inflammatory and neuropro⁃tective effects of glycolytic inhibitor.RESULTS Inhibition of glycolysis by specific inhibitors[2-DG and 3-bromopyruvic acid(3-BPA)],knockdown of glucose transporter type 1(Glut-1)or hexoki⁃nase(HK)Ⅱabolished LPS-induced expres⁃sion of proinflammatory genes in microglia cells.Mechanistic studies demonstrated that glyco⁃lytic inhibitors significantly inhibited LPS-induced mTOR phosphorylation,IKKβphosphorylation,IκB phosphorylation,IκB degradation,nuclear translocation of P65 and NF-κB luciferase activity.Furthermore,LPS-induced P65 acetyla⁃tion on lysine 310,which is mediated by NAD-dependent protein deacetylase sirtuin-1 and is critical for NF-kB activation,were inhibited by glycolytic inhibitors.A coculture study revealed that 2-DG reduced the cytotoxicity of activated microglia toward MES23.5 dopaminergic neuron cells with no direct protective effect.In vivo,2-DG significantly ameliorated MPTP or LPS induced DA neuron loss and glial cell activation.CONCLUSION Glycolysis is actively involved in microglial activation.Inhibition of glycolysis can ameliorate microglial activation-related neuroinflammatory diseases.
文摘OBJECTIVE Prepulse inhibition(PPI)of the acoustic startle response provides a measure of sensorimotor gating system mecha⁃nisms,which is known to be impaired in schizo⁃phrenia patients.We assessed the effects of the 5-HT2A/2C receptor agonist(±)2,5-dimethoxy-4-methylamphetamine(DOM),the NMDA receptor antagonist ketamine,the dopamine receptor ago⁃nist methamphetamine(Meth)on PPI and the startle magnitude in SD rats.METHODS AND RESULTS Systemic administration of the three compounds all dose-dependently reduced PPI.However,as far as startle magnitude,only DOM at the doses of 3 mg·kg-1 reduced that,while both ketamine and Meth did not change the startle magnitudes.Furthermore,to determine whether 5-HT2A receptor mediate this effect,the non-spe⁃cific 5-HT2 receptor antagonist cyproheptadine,specific 5-HT2A receptor antagonist ketanserin and specific 5-HT2C receptor antagonist SB242084 were tested.Cyproheptadine,ketan⁃serin and SB242084 did not alter startle ampli⁃tude by themselves in SD rats and only ketanserin slightly increased PPI at higher dose(3 mg·kg-1).PPI impairment induced by DOM was restored by pretreatment of cyproheptadine(1 mg·kg-1)and ketanserin(1 mg·kg-1),while not by pretreat⁃ment of SB242084(1 mg·kg-1).Damage of PPI induced by ketamine and Meth was not reversed by cyproheptadine(1 and 5 mg·kg-1).CONCLU⁃SION The receptor mechanisms underlying the disruption of PPI caused by DOM,ketamine and Meth were different from each other,at least 5-HT2A receptor was not the junction receptor for which the three chemicals acted.
文摘OBJECTIVE The inhibitory effect of active ingredients of Tripterygium wilfordii Hook.F.(TWHF)(celastrol,triptolide,triptonide,wilforlide A,wilforgine and wilforine)on human carboxylester⁃ase 1(CES1)and CES2 was detected to investigate the herb-drug interactions(HDIs)of TWHF.METHODS Human liver microsomes catalysed hydrolysis of 2-(2-benzoyl-3-methoxyphenyl)benzothi⁃azole(BMBT)and fluorescein diacetate(FD)were used as the probe reaction to phenotype the activity of CES1 and CES2,respectively.The residual activities of CES1 and CES2 were detected by ultrahigh performance liquid chromatography(UPLC)after intervention with celastrol,triptolide,triptonide,wilforlide A,wilforgine and wilforine(100μmol·L^(-1)).Kinetics analysis,involving half inhibitory concentra⁃tion(IC_(50)),inhibition type and kinetic parameter(Ki),and in vitro-in vivo extrapolation(IVIVE),was carried out to predict the HDIs between these compounds and CES-metabolizing drugs.Molecular docking was performed to analyze the ligand-enzyme interaction.RESULTS Out of the six main con⁃stituents of TWHF,only celastrol exhibited strong inhibition towards both CES1 and CES2,with the inhibitory rates of 97.45%(P<0.05)and 95.62%(P<0.05),respectively.The IC_(50)was 9.95 and 4.02 mol·L^(-1),respectively,and the types of inhibition were all non-competitive inhibition.Based on the kinetics analysis,the Ki values were calculated to be 5.10 and 10.55μmol·L^(-1)for the inhibition of celastrol on CES1 and CES2,respectively.IVIVE indicated that celastrol might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting CES1.Molecular docking results showed that hydrogen bonds and hydrophobic contacts contributed to the interaction of celastrol and CESs.CONCLUSION The inhibitory effect of celastrol on CES1 and CES2 might cause HDIs with clinical drugs hydrolysed by CESs.
