This paper puts forward the concept of double semi-active vibration isolation systemutilizing the 'on-off' active damper and the 'on-off' active spring. Applying KBM Asympto-tic method, the vibration ...This paper puts forward the concept of double semi-active vibration isolation systemutilizing the 'on-off' active damper and the 'on-off' active spring. Applying KBM Asympto-tic method, the vibration of the system in case of weak semi-active control is studied. ln pcactice, there are two types of vibration isolation. One is to isolate the transmitting of the cyclicunbalanced force generated by the revolving machine to the surroundings. The other is to isolatethe transmitting of the vibration displacement of the surroundings to precise equipment. Deduc-ing the influence of the roadway unflatness on vehicles also belongs to this type. For the firsttype of isolation system, the damper always dissipates energy, and the total work done by the spring in a vibration cycle is zero. For the second type of isolation system, the work done by the damper sometimes is positive, and sometimes negative. The damper dissipates less energy. The work done by the spring in a vibration cycle isn't zero, and it is usually positive. ln thispaper, the vibration isolation is refered to the second type. .展开更多
Objective:Mesenchymal stem cells(MSCs)are important cells in bone tissue engineering.Bone morphogenetic protein-2(BMP-2)effectively treats bone defects and nonunion.The purpose of this study is to investigate whether ...Objective:Mesenchymal stem cells(MSCs)are important cells in bone tissue engineering.Bone morphogenetic protein-2(BMP-2)effectively treats bone defects and nonunion.The purpose of this study is to investigate whether BMP-2 promotes bone formation and femoral fracture healing by inhibiting inflammation and promoting osteogenic differentiation of MSCs,in order to provide an experimental basis for developing more efficient fracture treatment strategies.Methods:Bone marrow-derived MSCs(BMSCs)were isolated from rats and treated withOE-BMP-2,the 5′-adenosinemonophosphate-activated protein kinase(AMPK)signal agonist 5-aminoimidazole-4-carboxamide ribonucleotide(AICAR),and the inhibitor Compound C.Osteogenic differentiation was evaluated through an alkaline phosphatase(ALP)kit,Western blot,and Alizarin Red S(ARS)staining.A rat model of femoral fracture was constructed,and fracture healing in the rats was detected by X-ray,microcomputed tomography(CT),and pathological staining.The AMPK signaling pathway and inflammation levels in the BMSCs and fracture model rats were measured by Western blot and enzyme-linked immunosorbent assay(ELISA)kits.Results:After BMP-2 overexpression,the ALP activity in osteogenic BMSCs was significantly increased(increased to 253.64%),the levels of osteogenic differentiation proteins(Osterix and osteocalcin)and p-AMPK Thr172 protein were significantly increased,and the concentrations of inflammatory factorswere decreased.In rat fracture tissues,BMP-2 overexpression promoted the expression of p-AMPKThr172 protein and bone callus formation,increased bone volume(increased to 22.22%),reduced the number of fibrous components in the cartilage matrix,increased the numbers of osteoblasts and chondrocytes,increased the expression of osteogenic differentiation proteins,and reduced the content of inflammatory factors in the serum.After AICAR intervention,ALP activity and the expression of osteogenic differentiation proteins in BMSCs and fracture tissues further increased,and the level of inflammation decreased.However,the changes in osteogenic differentiation and inflammation levels were significantly reversed after Compound C intervention.Conclusion:BMP-2 activated the AMPK signaling pathway,inhibited the inflammatory response,and effectively promoted the osteogenic differentiation of BMSCs and femoral fracture healing in rats.展开更多
Eu3+-activated Gd2(MoO4)3 pseudo-pompon-like red-emitting phosphors were prepared by solid-state method. The structure, morphology, and luminescent properties of these powder samples were investigated by X-ray diffrac...Eu3+-activated Gd2(MoO4)3 pseudo-pompon-like red-emitting phosphors were prepared by solid-state method. The structure, morphology, and luminescent properties of these powder samples were investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), and fluorescent spectrophotometry, respectively. The as-obtained phosphors were single crystalline phase with orthorhombic unit cell. The particles of the powder samples had the length of 5-12 m and width of 3-7 m with flake shape and large surface area, which is suitable for manufacture of white LEDs. The phosphor could be efficiently excited by the incident light of 348-425 nm, well matched with the output wavelength of near-UV (In,Ga)N chip, and re-emitted an intense red light peaking at 615 nm. By combing this phosphor with a ~395 nm-emitting (In,Ga)N chip, a red LED was fabricated, so that the applicability of this novel phosphor to white LEDs was confirmed. It is considered to be an efficient red-emitting conversion phosphor for solid-state lighting based on (In,Ga)N LEDs.展开更多
Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early ...Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early distant dissemination and resistance to conventional chemotherapies. Kras mutation is a well-defined hallmark of pancreatic cancer, with over 95% of cases harbouring Kras mutations that give rise to constitutively active forms of Kras. As important down-stream effectors of Kras, p21-activated kinases(PAKs) are involved in regulating cell proliferation, apoptosis, invasion/migration and chemo-resistance. Immunotherapy is now emerging as a promising treatment modality in the era of personalized anti-cancer therapeutics. In this review, basic knowledge of PAK structure and regulation is briefly summarised and the pivotal role of PAKs in Kras-driven pancreatic cancer is highlighted in terms of tumour biology and chemoresistance. Finally, the involvement of PAKs in immune modulation in the tumour microenvironment is discussed and the potential advantages of targeting PAKs are explored.展开更多
The roles of intermediate conductance Ca2＋-activated K＋ channel （IKCal） in the pathogene- sis of hepatocellular carcinoma （HCC） were investigated. Immunohistochemistry and Western blotting were used to detect th...The roles of intermediate conductance Ca2＋-activated K＋ channel （IKCal） in the pathogene- sis of hepatocellular carcinoma （HCC） were investigated. Immunohistochemistry and Western blotting were used to detect the expression of IKCal protein in 50 HCC and 20 para-carcinoma tissue samples. Real-time PCR was used to detect the transcription level of IKCal mRNA in 13 HCC and 11 para-carcinoma tissue samples. The MTT assay was used to measure the function of IKCal in human HCC cell line HepG2 in vitro. TRAM-34, a specific blocker of IKCal, was used to intervene with the function of IKCal. As compared with para-carcinoma tissue, an over-expression of IKCal protein was detected in HCC tissue samples （P〈0.05）. The mRNA expression level of IKCal in HCC tissues was 2.17 times higher than that in para-carcinoma tissues. The proliferation of HepG2 cells was suppressed by TRAM-34 （0.5, 1.0, 2.0 and 4.0 pxnol/L） in vitro （P〈0.05）. Our results suggested that IKCal may play a role in the proliferation of human HCC, and IKCal blockers may represent a potential therapeutic strategy for HCC.展开更多
P21-activated kinases(PAKs) are central players in various oncogenic signaling pathways. The six PAK family members are classified into group Ⅰ(PAK1-3) and group Ⅱ(PAK4-6). Focus is currently shifting from group Ⅰ ...P21-activated kinases(PAKs) are central players in various oncogenic signaling pathways. The six PAK family members are classified into group Ⅰ(PAK1-3) and group Ⅱ(PAK4-6). Focus is currently shifting from group Ⅰ PAKs to group Ⅱ PAKs. Group Ⅱ PAKs play important roles in many fundamental cellular processes, some of which have particular significance in the development and progression of cancer. Because of their important functions, group Ⅱ PAKs have become popular potential drug target candidates. However, few group Ⅱ PAKs inhibitors have been reported, and most do not exhibit satisfactory kinase selectivity and "drug-like" properties. Isoform- and kinase-selective PAK inhibitors remain to be developed. This review describes the biological activities of group Ⅱ PAKs, the importance of group Ⅱ PAKs in the development and progression of gastrointestinal cancer, and smallmolecule inhibitors of group Ⅱ PAKs for the treatment of cancer.展开更多
A series of Sm^(3+)-doped La_(3)Si_(6)N_(11)phosphor materials we re synthesized by a high temperature solid-state reaction method.The crystal structure,micro structure,photoluminescence properties,decay curves as wel...A series of Sm^(3+)-doped La_(3)Si_(6)N_(11)phosphor materials we re synthesized by a high temperature solid-state reaction method.The crystal structure,micro structure,photoluminescence properties,decay curves as well as thermal quenching properties of the as-prepared phosphors were investigated systematically.The excitation spectra contain a wide asymmetric band below 350 nm originating from the host absorption,several sharp excitation peaks in the range of 300-550 nm corresponding to f-f transition of Sm^(3+).Under the excitation of 369 and 414 nm light,the phosphors exhibit strong narrow-band orangered emission peaked at 605 nm.The average decay time of La_(2.99)Si_(6)N_(11):0.01 Sm^(3+)sample is fitted to be0.38 ms and the CIE coordinates were calculated to be(0.6105,0.3833).For water resistance,La_(3)Si_(6)N_(11):Sm^(3+)is better than K_(2)SiF_(6):Mn^(4+)phosphor.After soaking in deionized water for 300 min,the La_(3)Si_(6)N_(11):Sm^(3+)sample retains approximately 80%of its initial relative emission intensity.When the temperature rises to 423 K(150℃),the emission intensity of La_(2.99)Si_(6)N_(11):0.01 Sm^(3+)sample remains 85%in co mparison to that of room tempe rature.The activation energy was calculated to be 0.63253 eV,which is higher than those of Sm^(3+)-activated oxide phosphors,indicating that the phosphor has relatively good thermal stability.展开更多
To investigate the relationship between intracellular free Ca^2＋ concentration （[Ca^2＋ ]i ） and calcium-activated chloride （Clca） channels of pulmonary artery smooth muscle cells （PASMCs） in rats under acute a...To investigate the relationship between intracellular free Ca^2＋ concentration （[Ca^2＋ ]i ） and calcium-activated chloride （Clca） channels of pulmonary artery smooth muscle cells （PASMCs） in rats under acute and chronic hypoxic conditions, acute hypoxia-induced contraction was observed in rat pulmonary artery by using routine blood vascular perfusion in vitro. The fluorescence Ca^2＋ indicator Fura-2/AM was used to observe [Ca^2＋ ]i of rat PASMCs under normal and chronic hypoxic condition. The effect of Clca channels on PASMCs proliferation was assessed by MTT assay. The Clca channel blockers niflumic acid （NFA） and indaryloxyacetic acid （IAA-94） exerted inhibitory effects on acute hypoxia-evoked contractions in the pulmonary artery. Under chronic hypoxic condition, [Ca^2＋ ]i was increased. Under normoxic condition, [Ca^2＋ If was （123.634-18.98） nmol/ L, and in hypoxic condition, [Ca^2＋]i wag （281. 754-16.48） nmol/L （P〈0. 01）. Under normoxic condition, [Ca^2＋ ]i showed no significant change and no effect on Clca channels was observed （P〉 0. 05）. Chronic hypoxia increased [Ca^2＋ ]i which opened Clca channels. The NFA and IAA-94 blocked the channels and decreased [Ca^2＋ ]i from （281.75± 16.48） nmot/L to （117.66 ±15.36） nmol/L （P〈0.01）. MTT assay showed that under chronic hypoxic condition NFA and IAA-94 decreased the value of absorbency （A value） from 0. 459±0. 058 to 0. 224±0. 025 （P〈0. 01）. Hypoxia increased [Ca^2＋ ]i which opened Cl~ channels and had a positive-feedback in [Ca^2＋ ]i. This may play an important role in hypoxic pulmonary hypertension. Under chronic hypoxic condition, Clca channel may play a part in the regulation of proliferation of PASMCs.展开更多
The study examined the inhibitory effect of Atractylodes macrocephala （AM） on the uterine contraction during premature delivery and explored its electrophysiological mechanism by studying the effects of AM on the C...The study examined the inhibitory effect of Atractylodes macrocephala （AM） on the uterine contraction during premature delivery and explored its electrophysiological mechanism by studying the effects of AM on the Ca^2＋-activated K^＋ currents of pregnant human myometrial smooth muscle cells with or without the treatment with intedeukin-6. Single cells were acutely isolated from pregnant human myometrial smooth muscles. Whole-cell Ca^2＋-activated K^＋ currents were recorded by using an Axopatchl-D amplifier. The cells were divided into three groups： group A in which AM was added into perfusate, group B, in which interleukin-6 was added into perfusate） and group C in which AM was added into perfusate after addition of interleukin-6. IL-6 10 ng/mL inhibited BKca by 36.9%±13.7% as compared with control （P〈0.01）. AM at 2 mg/mL raised BKca by 36.7%±22.6% or 45.2%±13.7% with or without the treatment of IL-6, respectively （P〈0.01）. It is concluded that AM was able to enhance the BKca of pregnant human myometrial smooth muscle cells treated or untreated with interleukin-6 and its effect on the BKca IL-treated cells was stronger that its effect on BKca of untreated cells. Our results suggested that AM can help to maintain the membrane potentials and the resting status of pregnant human myometrial smooth muscle cells.展开更多
Objective：To investigate the effects of calcium-activated chloride （ClCa） channels on proliferation of pulmonary artery smooth muscle cells（PASMCs） in rats under chronic hypoxic condition. Methods：The cultured P...Objective：To investigate the effects of calcium-activated chloride （ClCa） channels on proliferation of pulmonary artery smooth muscle cells（PASMCs） in rats under chronic hypoxic condition. Methods：The cultured PASMCs were placed under normoxic and chronic hypoxic conditions：The cells were observed by light and electron microscope; The cell cycles were observed by flow-cytometry; Immunocytochemistry staining was used to detect the expressions of PCNA, c-fos and c-jun of PASMCs; Cytoplasmic free Ca^2＋ concentration （[Ca^2＋]i） in PASMCs was investigated by fluorescent quantitation using fluorospectrophotometer. Results：The PASMCs were contractile phenotype under normoxic conditions. Observation by transmission electron microscope： In kytoplasm of contractile phenotype cells, myofilament bundles were abundant and the content of cell organs such as Golgi＇s bodies were rare. The PASMCs were synthetic phenotype under chronic hypoxic condition. There were increased free ribosomes, dilated rough endoplasmic reticulums, highly developed Golgi complexes, decreased or disappeared thick filaments and dense body in kytoplasm of synthetic phenotype cells. After NFA and IAA-94, the situations were reversed The number of S ＋G2M PASMCs were significantly increased in chronic hypoxic condition; The NFA and IAA-94 were shown to significantly decrease them from （28.6±1.0）% to （16.0±1.6）% and the number of G0G1 PASMCs significantly increased from （71.4± 1.9）% to （83.9 ± 1.6）% （P〈 0.01）. In chronic hypoxic conditions, the expression of proliferating cell nucleus antigen was significantly increased; The NFA and IAA-94 were shown to significantly decrease it from （81 ± 6）% to （27 ± 7）%（P 〈 0.01）. The expression of c-fos and c-jun were significantly increased in＇chronic hypoxic conditions; The NFA and IAA-94 were shown to significantly decrease them from 0.15 ±0.02, 0.32 ± 0.05 to 0.05 ± 0.01, 0.12 ± 0.05, respectively （P〈 0.01）; Under chronic hypoxic conditions, [Ca^2＋]i was increased; The NFA and IAA-94 decreased it from （281.8±16,5）nmol/L to （117.7 ± 15.4）nmol/L（P 〈 0.01）. Conclusion：Hypoxia initiated the change of PASMCs from contractile to synthetic phenotype and increased proliferation of PASMCs. NFA and IAA-94 depressed cell proliferation by blocking ClCa channels in hypoxic condition. These may play an important role in proliferation of PASMCs under chronic hypoxic conditions.展开更多
Objective To determine whether Ca2+ activated Cl- current(Icl(Ca)) contributes to the functional remodeling of the failing heart.Methods Whole cell patch-clamp recording technique was employed to record the Icl(Ca) in...Objective To determine whether Ca2+ activated Cl- current(Icl(Ca)) contributes to the functional remodeling of the failing heart.Methods Whole cell patch-clamp recording technique was employed to record the Icl(Ca) in cardiac myocytes enzymatically isolatedfrom rapidly pacing induced canine failing hearts at room temperature and compared that of the normal hearts (Nor).Results Thecurrent density of DIDS(200M)sensitive Icl(Ca) induced by intracellular Ca2+ release trigged by L-type Ca2+ current(Ica,L)wassignificantly decreased in heart failare(HE)cells compared to Nor cells.At membrane voltage of 20mV,the Icl(Ca) density was 3.02±0.54 pA/pF in Nor(n=6)vs.1.31±0.25 pA/pF in HF(n=8)cells,(P＜0.01),while the averaged Ica,L density did not show differencebetween two groups.The time constant of current decay of Icl(Ca) was similar in both types of cells.On the other hand,in intra cellularCa2+ clamped mode,where the[Ca2+];was maintained at 100nmol/L,Icl(Ca) density be increased significantly in HF cells when themembrane voltage at+30mV or higher.Conclusions Our results suggest that Icl(Ca) density was decreased in pacing induced failingheart but the channel function be enhanced.Impaired Ca2+ handing in HF cells rather than reduced,Icl(Ca) channel function itself may havecaused this abnormality.The Icl(Ca) density reduction might contribute to the prolongation of action potential in failing heart.The Icl(Ca)channel function up-rugulation is likely to cause cardiac arrhythmia by inducing a delayed after depolarization,when Ca2+ overloadoccurred in diastolic failing heart cells.展开更多
The human endogenous retroviruses type W family envelope(HERV-W env)gene is located on chromosome 7q21-22.Our previous studies show that HERV-W env is elevated in schizophrenia and HERV-W env can increase cal-cium inf...The human endogenous retroviruses type W family envelope(HERV-W env)gene is located on chromosome 7q21-22.Our previous studies show that HERV-W env is elevated in schizophrenia and HERV-W env can increase cal-cium influx.Additionally,the 5-HTergie system and particularly 5-hydroxytryptamine(5-HT)receptors play a prominent role in the pathogenesis and treatment of schizophrenia.5-hydroxytryptamine receptor 4(5-HT4R)agonist can block calcium channels.However,the underlying relationship between HERV-W env and 5-HT4R in the etiology of schizophrenia has not been revealed.Here,we used enzyme-linked immunosorbent assay to detect the concentration of HERV-W env and 5-HT4R in the plasma of patients with schizophrenia and we found that there were decreased levels of 5-HT4R and a negative correlation between 5-HT4R and HERV-W env in schizophrenia.Overexpression of HERV-W env decreased the transcription and protein levels of 5-HT4R but increased small conductance Ca^(2+)-activated K^(+)type 2 channels(SK2)expression levels.Further studies revealed that HERV-w env could interact with 5-HT4R.Additionally,luciferase assay showed that an essential region(-364 to-176 from the transcription start site)in the SK2 promoter was required for HERV-W env-induced SK2 expression.Importantly,5-HT4R participated in the regulation of SK2 expression and promoter activity.Electrophysiological recordings suggested that HERV-Wenv could increase SK2 channel currents and the increase of SK2 currents was inhibited by 5-HT4R.In condusion,HERV-W env could activate SK2 channels via decreased 5-HT4R,which might exhibit a novel mechanism for HERV-Wenv to influence neuronal activity in schizophrenia.展开更多
Objective: To study the effect of isoflurane and ethanol on large conductance Ca 2+-activated K + channels(BK channels). Methods: The cRNA of mslo1 encoding BK channels was injected into Xenopus oocytes. Oocytes were ...Objective: To study the effect of isoflurane and ethanol on large conductance Ca 2+-activated K + channels(BK channels). Methods: The cRNA of mslo1 encoding BK channels was injected into Xenopus oocytes. Oocytes were incubated in ND96 (96 mmol/L NaCl, 2.0 mmol/L KCl, 1.8 mmol/L CaCl 2, 1.0 mmol/L MgCl 2, and 5.0 mmol/L HEPES, pH 7.4) at 4 ℃. Patch clamp recording (outside-out) were performed after 2-3 d. Isoflurane was administrated by the vaporizer driven by air, ethanol was applied by a closed, manual-controlled administration system. Different test potentials from 0 to 10 mV were given to observe changes of currents. Results: 0.7 mmol/L and 1.2 mmol/L of isoflurane could inhibit BK currents obviously at different command potentials, but 50 mmol/L, 100 mmol/L, or 200 mmol/L of ethanol had no any effect on BK currents. Conclusion: Clinical concentration of isoflurane can distinctly inhibit isolating BK currents.展开更多
Targeted construction of new covalent organic frameworks(COFs)with specific purposes and rationalities to build colorimetric assay platform for environmental pollutant monitoring have attracted increasing interest.How...Targeted construction of new covalent organic frameworks(COFs)with specific purposes and rationalities to build colorimetric assay platform for environmental pollutant monitoring have attracted increasing interest.However,it is still challenging due to lack of available coordination sites inside COFs pores and only a slight bonding ability for anchoring metal.In this work,a two-dimensional(2D)COFs(termed as Tz-COF)with high crystallinity,excellent chemical stability,and abundant sulfur coordination in its skeletons was synthesized and used for the confined growth of Au NPs.It was found that the Au NPs showed significant dispersibility for the support of Tz-COF.The proposed Tz-COF@Au NPs possessed outstanding Hg^(2+)-activated peroxidase-like activity benefited from physicochemical properties of gold amalgam and synergistic effect between COFs and Au NPs to oxidize chromogenic substrate.Based on highly efficient activity and distinctive color evolution,the strategy for detecting Hg^(2+)was developed and successfully applied to determine the content of Hg^(2+)in real environmental samples.This work manifests that a potential strategy to establish a colorimetric assay platform for environmental pollutant monitoring based on the targeted manufacturing of novel COFs with specific functions.展开更多
The p21-activated kinase 4(PAK4),a key regulator of malignancy,is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy.Given the lack of high efficacy PAK4 inhibitors...The p21-activated kinase 4(PAK4),a key regulator of malignancy,is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy.Given the lack of high efficacy PAK4 inhibitors,we herein reported the identification of a novel inhibitor 13 bearing a tetrahydrobenzofuro[2,3-c]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC_(50) values of 0.38 and 0.50 mmol/L,respectively.This compound directly binds to PAK4 in a non-ATP competitive manner.In the mouse Pan02 model,compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg,accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue.Overall,compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo,thus making it worthy of further exploration.展开更多
Epidermal growth factor （EGF） may increase cell motility, an event implicated in cancer cell invasion and metastasis. However, the underlying mechanisms for EGF-induced cell motility remain elusive. In this study, w...Epidermal growth factor （EGF） may increase cell motility, an event implicated in cancer cell invasion and metastasis. However, the underlying mechanisms for EGF-induced cell motility remain elusive. In this study, we found that EGF treatment could activate Ras-related C3 botulinum toxin substrate 1 （Racl）, PI3K/Akt and p21- actived kinase （PAK1） along with cell migration. Ectopic expression of PAK1 K299R, a dominant negative PAK1 mutant, could largely abolish EGF-induced cell migration. Blocking PI3K/Akt signalling with LY294002 or Akt siRNA remarkably inhibited both EGF-induced PAK1 activation and cell migration. Furthermore, expression of dominant-negative Racl （T17N） could largely block EGF-induced PI3K/Akt-PAK1 activation and cell migration. Interestingly, EGF could induce a significant production of ROS, and N-acetyl-L-cysteine, a scavenger of ROS which abolished the EGF-induced ROS generation, cell migration, as well as activation of PI3K/Akt and PAK, but not Racl. Our study demonstrated that EGF-induced cell migration involves a cascade of signalling events, including activation of Racl, generation of ROS and subsequent activation of PI3K/Akt and PAK1.展开更多
Objective:To determine the potential molecular mechanisms underlying the therapeutic effect of curcumin on hepatocellular carcinoma(HCC)by network pharmacology and experimental in vitro validation.Methods:The predicti...Objective:To determine the potential molecular mechanisms underlying the therapeutic effect of curcumin on hepatocellular carcinoma(HCC)by network pharmacology and experimental in vitro validation.Methods:The predictive targets of curcumin or HCC were collected from several databases.the identified overlapping targets were crossed with Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analyses using the Database for Annotation,Visualization,and Integrated Discovery(DAVID)platform.Two of the candidate pathways were selected to conduct an experimental verification.The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium(MTT)assay was used to determine the effect of curcumin on the viability of Hep G2 and LO2 cells.The apoptosis and autophagy of Hep G2 cells were respectively detected by flow cytometry and transmission electron microscopy.Besides,western blot and real-time polymerase chain reaction(PCR)were employed to verify the p53 apoptotic pathway and adenosine 5’-monophosphate(AMP)-activated protein kinase(AMPK)autophagy pathway.Hep G2 cells were pretreated with pifithrin-α(PFT-α)and GSK690693 for further investigation.Results:The 167 pathways analyzed by KEGG included apoptosis,autophagy,p53,and AMPK pathways.The GO enrichment analysis demonstrated that curcumin was involved in cellular response to drug,regulation of apoptotic pathway,and so on.The in vitro experiments also confirmed that curcumin can inhibit the growth of Hep G2 cells by promoting the apoptosis of p53 pathway and autophagy through the AMPK pathway.Furthermore,the protein and messenger RNA(m RNA)of the two pathways were downregulated in the inhibitor-pretreated group compared with the experimental group.The damage-regulated autophagy modulator(DRAM)in the PFT-α-pretreated group was downregulated,and p62 in the GSK690693-pretreated group was upregulated.Conclusions:Curcumin can treat HCC through the p53 apoptotic pathway and the AMPK/Unc-51-like kinase 1(ULK1)autophagy pathway,in which the mutual transformation of autophagy and apoptosis may occur through DRAM and p62.展开更多
Blue-violet light can not only enhance the total content of biomass and glucoside but also enrich the taste of the fruit.Thus,it is meaningful to study the blue-violet luminescent materials for plant cultivation.In th...Blue-violet light can not only enhance the total content of biomass and glucoside but also enrich the taste of the fruit.Thus,it is meaningful to study the blue-violet luminescent materials for plant cultivation.In this study,titanium(IV)-activated CaYAlO4(CYAO) phosphors were synthesized by conventional hightemperature solid-state reaction.X-ray powder diffraction was employed to analyze the crystalstructure of CYAO.It is found that the doped Ti^4+ ions do not change obviously the crystal structure of phosphors.Upon 246 nm excitation,CaYAl1-xO4:xTi^4+phosphors exhibit broad blue-violet emission band peaking at 395 nm,which can be attributed to the charge transfer of Ti^4+-O^2-.Moreover,this phosphor exhibits strong thermal stability.The luminescence emission intensity at 150℃maintained about 91 mol% of its initial value at room temperature.Additionally,the electron transition process and concentration quenching mechanism of CaYAl1-xO4:xTi^4+are discussed in detail.The excellent luminescent properties indicate that CaYAl1-xO4:xTi^4+phosphor may have promising application in indoor plant cultivation.展开更多
文摘This paper puts forward the concept of double semi-active vibration isolation systemutilizing the 'on-off' active damper and the 'on-off' active spring. Applying KBM Asympto-tic method, the vibration of the system in case of weak semi-active control is studied. ln pcactice, there are two types of vibration isolation. One is to isolate the transmitting of the cyclicunbalanced force generated by the revolving machine to the surroundings. The other is to isolatethe transmitting of the vibration displacement of the surroundings to precise equipment. Deduc-ing the influence of the roadway unflatness on vehicles also belongs to this type. For the firsttype of isolation system, the damper always dissipates energy, and the total work done by the spring in a vibration cycle is zero. For the second type of isolation system, the work done by the damper sometimes is positive, and sometimes negative. The damper dissipates less energy. The work done by the spring in a vibration cycle isn't zero, and it is usually positive. ln thispaper, the vibration isolation is refered to the second type. .
基金funded by the Qinghai Province Natural Science Foundation Youth Project Grant No.2022-ZJ-968Q.
文摘Objective:Mesenchymal stem cells(MSCs)are important cells in bone tissue engineering.Bone morphogenetic protein-2(BMP-2)effectively treats bone defects and nonunion.The purpose of this study is to investigate whether BMP-2 promotes bone formation and femoral fracture healing by inhibiting inflammation and promoting osteogenic differentiation of MSCs,in order to provide an experimental basis for developing more efficient fracture treatment strategies.Methods:Bone marrow-derived MSCs(BMSCs)were isolated from rats and treated withOE-BMP-2,the 5′-adenosinemonophosphate-activated protein kinase(AMPK)signal agonist 5-aminoimidazole-4-carboxamide ribonucleotide(AICAR),and the inhibitor Compound C.Osteogenic differentiation was evaluated through an alkaline phosphatase(ALP)kit,Western blot,and Alizarin Red S(ARS)staining.A rat model of femoral fracture was constructed,and fracture healing in the rats was detected by X-ray,microcomputed tomography(CT),and pathological staining.The AMPK signaling pathway and inflammation levels in the BMSCs and fracture model rats were measured by Western blot and enzyme-linked immunosorbent assay(ELISA)kits.Results:After BMP-2 overexpression,the ALP activity in osteogenic BMSCs was significantly increased(increased to 253.64%),the levels of osteogenic differentiation proteins(Osterix and osteocalcin)and p-AMPK Thr172 protein were significantly increased,and the concentrations of inflammatory factorswere decreased.In rat fracture tissues,BMP-2 overexpression promoted the expression of p-AMPKThr172 protein and bone callus formation,increased bone volume(increased to 22.22%),reduced the number of fibrous components in the cartilage matrix,increased the numbers of osteoblasts and chondrocytes,increased the expression of osteogenic differentiation proteins,and reduced the content of inflammatory factors in the serum.After AICAR intervention,ALP activity and the expression of osteogenic differentiation proteins in BMSCs and fracture tissues further increased,and the level of inflammation decreased.However,the changes in osteogenic differentiation and inflammation levels were significantly reversed after Compound C intervention.Conclusion:BMP-2 activated the AMPK signaling pathway,inhibited the inflammatory response,and effectively promoted the osteogenic differentiation of BMSCs and femoral fracture healing in rats.
基金Project supported by the Natural Science Research Project of the Jiangsu Higher Education Institutions (08KJD150014)the QingLan Project of the Jiangsu Province (2008)the Basic Research Fund of Jiangsu Teachers University of Technology (KYY09031)
文摘Eu3+-activated Gd2(MoO4)3 pseudo-pompon-like red-emitting phosphors were prepared by solid-state method. The structure, morphology, and luminescent properties of these powder samples were investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), and fluorescent spectrophotometry, respectively. The as-obtained phosphors were single crystalline phase with orthorhombic unit cell. The particles of the powder samples had the length of 5-12 m and width of 3-7 m with flake shape and large surface area, which is suitable for manufacture of white LEDs. The phosphor could be efficiently excited by the incident light of 348-425 nm, well matched with the output wavelength of near-UV (In,Ga)N chip, and re-emitted an intense red light peaking at 615 nm. By combing this phosphor with a ~395 nm-emitting (In,Ga)N chip, a red LED was fabricated, so that the applicability of this novel phosphor to white LEDs was confirmed. It is considered to be an efficient red-emitting conversion phosphor for solid-state lighting based on (In,Ga)N LEDs.
基金Pancare Foundation (https://www.pancare.org.au) for supporting the pancreatic cancer research program in the Department of Surgery, University of Melbournesupported by Melbourne International Fee Remission Scholarship (MIFRS)+1 种基金Melbourne International Research Scholarship (MIRS)the Moshe Sambor Scholarship (Pancare Foundation)
文摘Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early distant dissemination and resistance to conventional chemotherapies. Kras mutation is a well-defined hallmark of pancreatic cancer, with over 95% of cases harbouring Kras mutations that give rise to constitutively active forms of Kras. As important down-stream effectors of Kras, p21-activated kinases(PAKs) are involved in regulating cell proliferation, apoptosis, invasion/migration and chemo-resistance. Immunotherapy is now emerging as a promising treatment modality in the era of personalized anti-cancer therapeutics. In this review, basic knowledge of PAK structure and regulation is briefly summarised and the pivotal role of PAKs in Kras-driven pancreatic cancer is highlighted in terms of tumour biology and chemoresistance. Finally, the involvement of PAKs in immune modulation in the tumour microenvironment is discussed and the potential advantages of targeting PAKs are explored.
基金supported by grants from the National Natural Science Foundation of China (No. 81072001)the Natural Science Foundation of Hubei Province, China (No.2011CDB556)
文摘The roles of intermediate conductance Ca2＋-activated K＋ channel （IKCal） in the pathogene- sis of hepatocellular carcinoma （HCC） were investigated. Immunohistochemistry and Western blotting were used to detect the expression of IKCal protein in 50 HCC and 20 para-carcinoma tissue samples. Real-time PCR was used to detect the transcription level of IKCal mRNA in 13 HCC and 11 para-carcinoma tissue samples. The MTT assay was used to measure the function of IKCal in human HCC cell line HepG2 in vitro. TRAM-34, a specific blocker of IKCal, was used to intervene with the function of IKCal. As compared with para-carcinoma tissue, an over-expression of IKCal protein was detected in HCC tissue samples （P〈0.05）. The mRNA expression level of IKCal in HCC tissues was 2.17 times higher than that in para-carcinoma tissues. The proliferation of HepG2 cells was suppressed by TRAM-34 （0.5, 1.0, 2.0 and 4.0 pxnol/L） in vitro （P〈0.05）. Our results suggested that IKCal may play a role in the proliferation of human HCC, and IKCal blockers may represent a potential therapeutic strategy for HCC.
基金Supported by National Natural Science Foundation of ChinaNo.90813038+2 种基金No.31271389No.31371424No.31171360 and No.81230077
文摘P21-activated kinases(PAKs) are central players in various oncogenic signaling pathways. The six PAK family members are classified into group Ⅰ(PAK1-3) and group Ⅱ(PAK4-6). Focus is currently shifting from group Ⅰ PAKs to group Ⅱ PAKs. Group Ⅱ PAKs play important roles in many fundamental cellular processes, some of which have particular significance in the development and progression of cancer. Because of their important functions, group Ⅱ PAKs have become popular potential drug target candidates. However, few group Ⅱ PAKs inhibitors have been reported, and most do not exhibit satisfactory kinase selectivity and "drug-like" properties. Isoform- and kinase-selective PAK inhibitors remain to be developed. This review describes the biological activities of group Ⅱ PAKs, the importance of group Ⅱ PAKs in the development and progression of gastrointestinal cancer, and smallmolecule inhibitors of group Ⅱ PAKs for the treatment of cancer.
基金the Doctoral Scientific Research Foundation of Jiangxi University of Science and Technology(3401223311)Science and Technology Research Project of Jiangxi Provincial Education Department(GJJ160636)+1 种基金National Natural Science Foundation of China(51962005)Natural Science Foundation of Jiangxi Province of China(20192BAB206010)。
文摘A series of Sm^(3+)-doped La_(3)Si_(6)N_(11)phosphor materials we re synthesized by a high temperature solid-state reaction method.The crystal structure,micro structure,photoluminescence properties,decay curves as well as thermal quenching properties of the as-prepared phosphors were investigated systematically.The excitation spectra contain a wide asymmetric band below 350 nm originating from the host absorption,several sharp excitation peaks in the range of 300-550 nm corresponding to f-f transition of Sm^(3+).Under the excitation of 369 and 414 nm light,the phosphors exhibit strong narrow-band orangered emission peaked at 605 nm.The average decay time of La_(2.99)Si_(6)N_(11):0.01 Sm^(3+)sample is fitted to be0.38 ms and the CIE coordinates were calculated to be(0.6105,0.3833).For water resistance,La_(3)Si_(6)N_(11):Sm^(3+)is better than K_(2)SiF_(6):Mn^(4+)phosphor.After soaking in deionized water for 300 min,the La_(3)Si_(6)N_(11):Sm^(3+)sample retains approximately 80%of its initial relative emission intensity.When the temperature rises to 423 K(150℃),the emission intensity of La_(2.99)Si_(6)N_(11):0.01 Sm^(3+)sample remains 85%in co mparison to that of room tempe rature.The activation energy was calculated to be 0.63253 eV,which is higher than those of Sm^(3+)-activated oxide phosphors,indicating that the phosphor has relatively good thermal stability.
文摘To investigate the relationship between intracellular free Ca^2＋ concentration （[Ca^2＋ ]i ） and calcium-activated chloride （Clca） channels of pulmonary artery smooth muscle cells （PASMCs） in rats under acute and chronic hypoxic conditions, acute hypoxia-induced contraction was observed in rat pulmonary artery by using routine blood vascular perfusion in vitro. The fluorescence Ca^2＋ indicator Fura-2/AM was used to observe [Ca^2＋ ]i of rat PASMCs under normal and chronic hypoxic condition. The effect of Clca channels on PASMCs proliferation was assessed by MTT assay. The Clca channel blockers niflumic acid （NFA） and indaryloxyacetic acid （IAA-94） exerted inhibitory effects on acute hypoxia-evoked contractions in the pulmonary artery. Under chronic hypoxic condition, [Ca^2＋ ]i was increased. Under normoxic condition, [Ca^2＋ If was （123.634-18.98） nmol/ L, and in hypoxic condition, [Ca^2＋]i wag （281. 754-16.48） nmol/L （P〈0. 01）. Under normoxic condition, [Ca^2＋ ]i showed no significant change and no effect on Clca channels was observed （P〉 0. 05）. Chronic hypoxia increased [Ca^2＋ ]i which opened Clca channels. The NFA and IAA-94 blocked the channels and decreased [Ca^2＋ ]i from （281.75± 16.48） nmot/L to （117.66 ±15.36） nmol/L （P〈0.01）. MTT assay showed that under chronic hypoxic condition NFA and IAA-94 decreased the value of absorbency （A value） from 0. 459±0. 058 to 0. 224±0. 025 （P〈0. 01）. Hypoxia increased [Ca^2＋ ]i which opened Cl~ channels and had a positive-feedback in [Ca^2＋ ]i. This may play an important role in hypoxic pulmonary hypertension. Under chronic hypoxic condition, Clca channel may play a part in the regulation of proliferation of PASMCs.
文摘The study examined the inhibitory effect of Atractylodes macrocephala （AM） on the uterine contraction during premature delivery and explored its electrophysiological mechanism by studying the effects of AM on the Ca^2＋-activated K^＋ currents of pregnant human myometrial smooth muscle cells with or without the treatment with intedeukin-6. Single cells were acutely isolated from pregnant human myometrial smooth muscles. Whole-cell Ca^2＋-activated K^＋ currents were recorded by using an Axopatchl-D amplifier. The cells were divided into three groups： group A in which AM was added into perfusate, group B, in which interleukin-6 was added into perfusate） and group C in which AM was added into perfusate after addition of interleukin-6. IL-6 10 ng/mL inhibited BKca by 36.9%±13.7% as compared with control （P〈0.01）. AM at 2 mg/mL raised BKca by 36.7%±22.6% or 45.2%±13.7% with or without the treatment of IL-6, respectively （P〈0.01）. It is concluded that AM was able to enhance the BKca of pregnant human myometrial smooth muscle cells treated or untreated with interleukin-6 and its effect on the BKca IL-treated cells was stronger that its effect on BKca of untreated cells. Our results suggested that AM can help to maintain the membrane potentials and the resting status of pregnant human myometrial smooth muscle cells.
文摘Objective：To investigate the effects of calcium-activated chloride （ClCa） channels on proliferation of pulmonary artery smooth muscle cells（PASMCs） in rats under chronic hypoxic condition. Methods：The cultured PASMCs were placed under normoxic and chronic hypoxic conditions：The cells were observed by light and electron microscope; The cell cycles were observed by flow-cytometry; Immunocytochemistry staining was used to detect the expressions of PCNA, c-fos and c-jun of PASMCs; Cytoplasmic free Ca^2＋ concentration （[Ca^2＋]i） in PASMCs was investigated by fluorescent quantitation using fluorospectrophotometer. Results：The PASMCs were contractile phenotype under normoxic conditions. Observation by transmission electron microscope： In kytoplasm of contractile phenotype cells, myofilament bundles were abundant and the content of cell organs such as Golgi＇s bodies were rare. The PASMCs were synthetic phenotype under chronic hypoxic condition. There were increased free ribosomes, dilated rough endoplasmic reticulums, highly developed Golgi complexes, decreased or disappeared thick filaments and dense body in kytoplasm of synthetic phenotype cells. After NFA and IAA-94, the situations were reversed The number of S ＋G2M PASMCs were significantly increased in chronic hypoxic condition; The NFA and IAA-94 were shown to significantly decrease them from （28.6±1.0）% to （16.0±1.6）% and the number of G0G1 PASMCs significantly increased from （71.4± 1.9）% to （83.9 ± 1.6）% （P〈 0.01）. In chronic hypoxic conditions, the expression of proliferating cell nucleus antigen was significantly increased; The NFA and IAA-94 were shown to significantly decrease it from （81 ± 6）% to （27 ± 7）%（P 〈 0.01）. The expression of c-fos and c-jun were significantly increased in＇chronic hypoxic conditions; The NFA and IAA-94 were shown to significantly decrease them from 0.15 ±0.02, 0.32 ± 0.05 to 0.05 ± 0.01, 0.12 ± 0.05, respectively （P〈 0.01）; Under chronic hypoxic conditions, [Ca^2＋]i was increased; The NFA and IAA-94 decreased it from （281.8±16,5）nmol/L to （117.7 ± 15.4）nmol/L（P 〈 0.01）. Conclusion：Hypoxia initiated the change of PASMCs from contractile to synthetic phenotype and increased proliferation of PASMCs. NFA and IAA-94 depressed cell proliferation by blocking ClCa channels in hypoxic condition. These may play an important role in proliferation of PASMCs under chronic hypoxic conditions.
文摘Objective To determine whether Ca2+ activated Cl- current(Icl(Ca)) contributes to the functional remodeling of the failing heart.Methods Whole cell patch-clamp recording technique was employed to record the Icl(Ca) in cardiac myocytes enzymatically isolatedfrom rapidly pacing induced canine failing hearts at room temperature and compared that of the normal hearts (Nor).Results Thecurrent density of DIDS(200M)sensitive Icl(Ca) induced by intracellular Ca2+ release trigged by L-type Ca2+ current(Ica,L)wassignificantly decreased in heart failare(HE)cells compared to Nor cells.At membrane voltage of 20mV,the Icl(Ca) density was 3.02±0.54 pA/pF in Nor(n=6)vs.1.31±0.25 pA/pF in HF(n=8)cells,(P＜0.01),while the averaged Ica,L density did not show differencebetween two groups.The time constant of current decay of Icl(Ca) was similar in both types of cells.On the other hand,in intra cellularCa2+ clamped mode,where the[Ca2+];was maintained at 100nmol/L,Icl(Ca) density be increased significantly in HF cells when themembrane voltage at+30mV or higher.Conclusions Our results suggest that Icl(Ca) density was decreased in pacing induced failingheart but the channel function be enhanced.Impaired Ca2+ handing in HF cells rather than reduced,Icl(Ca) channel function itself may havecaused this abnormality.The Icl(Ca) density reduction might contribute to the prolongation of action potential in failing heart.The Icl(Ca)channel function up-rugulation is likely to cause cardiac arrhythmia by inducing a delayed after depolarization,when Ca2+ overloadoccurred in diastolic failing heart cells.
基金supported by the National Natural Science Foundation of China(Nos.81971943,81772196,31470264,81271820,30870789,and 30300117)the Stanley Foundation from the Stanley Medical Research Institute(SMRI),United States(No.06R-1366)We acknowledge the Medicine Research Center for Structural Biology of Wuhan University for providing the confocal microscopy(Leica-LCS-SP8-STED).
文摘The human endogenous retroviruses type W family envelope(HERV-W env)gene is located on chromosome 7q21-22.Our previous studies show that HERV-W env is elevated in schizophrenia and HERV-W env can increase cal-cium influx.Additionally,the 5-HTergie system and particularly 5-hydroxytryptamine(5-HT)receptors play a prominent role in the pathogenesis and treatment of schizophrenia.5-hydroxytryptamine receptor 4(5-HT4R)agonist can block calcium channels.However,the underlying relationship between HERV-W env and 5-HT4R in the etiology of schizophrenia has not been revealed.Here,we used enzyme-linked immunosorbent assay to detect the concentration of HERV-W env and 5-HT4R in the plasma of patients with schizophrenia and we found that there were decreased levels of 5-HT4R and a negative correlation between 5-HT4R and HERV-W env in schizophrenia.Overexpression of HERV-W env decreased the transcription and protein levels of 5-HT4R but increased small conductance Ca^(2+)-activated K^(+)type 2 channels(SK2)expression levels.Further studies revealed that HERV-w env could interact with 5-HT4R.Additionally,luciferase assay showed that an essential region(-364 to-176 from the transcription start site)in the SK2 promoter was required for HERV-W env-induced SK2 expression.Importantly,5-HT4R participated in the regulation of SK2 expression and promoter activity.Electrophysiological recordings suggested that HERV-Wenv could increase SK2 channel currents and the increase of SK2 currents was inhibited by 5-HT4R.In condusion,HERV-W env could activate SK2 channels via decreased 5-HT4R,which might exhibit a novel mechanism for HERV-Wenv to influence neuronal activity in schizophrenia.
文摘Objective: To study the effect of isoflurane and ethanol on large conductance Ca 2+-activated K + channels(BK channels). Methods: The cRNA of mslo1 encoding BK channels was injected into Xenopus oocytes. Oocytes were incubated in ND96 (96 mmol/L NaCl, 2.0 mmol/L KCl, 1.8 mmol/L CaCl 2, 1.0 mmol/L MgCl 2, and 5.0 mmol/L HEPES, pH 7.4) at 4 ℃. Patch clamp recording (outside-out) were performed after 2-3 d. Isoflurane was administrated by the vaporizer driven by air, ethanol was applied by a closed, manual-controlled administration system. Different test potentials from 0 to 10 mV were given to observe changes of currents. Results: 0.7 mmol/L and 1.2 mmol/L of isoflurane could inhibit BK currents obviously at different command potentials, but 50 mmol/L, 100 mmol/L, or 200 mmol/L of ethanol had no any effect on BK currents. Conclusion: Clinical concentration of isoflurane can distinctly inhibit isolating BK currents.
基金supported by the National Natural Science Foundation of China(Nos.22274021,21974021 and 22036001).
文摘Targeted construction of new covalent organic frameworks(COFs)with specific purposes and rationalities to build colorimetric assay platform for environmental pollutant monitoring have attracted increasing interest.However,it is still challenging due to lack of available coordination sites inside COFs pores and only a slight bonding ability for anchoring metal.In this work,a two-dimensional(2D)COFs(termed as Tz-COF)with high crystallinity,excellent chemical stability,and abundant sulfur coordination in its skeletons was synthesized and used for the confined growth of Au NPs.It was found that the Au NPs showed significant dispersibility for the support of Tz-COF.The proposed Tz-COF@Au NPs possessed outstanding Hg^(2+)-activated peroxidase-like activity benefited from physicochemical properties of gold amalgam and synergistic effect between COFs and Au NPs to oxidize chromogenic substrate.Based on highly efficient activity and distinctive color evolution,the strategy for detecting Hg^(2+)was developed and successfully applied to determine the content of Hg^(2+)in real environmental samples.This work manifests that a potential strategy to establish a colorimetric assay platform for environmental pollutant monitoring based on the targeted manufacturing of novel COFs with specific functions.
基金support from the China National Innovation of Science and Technology-2030(Program of Brain Science and Brain-Inspired Intelligence Technology,2021ZD0204004)the National Natural Science Foundation of China(Grants Nos.82273767,82073073,82122045,and 82273948)+3 种基金the Major Projects for Shanghai Zhang jiang National Independent Innovation of China(ZJ2021-ZD-007)Innovative research team of high-level local universities in Shanghai(SHSMU-ZDCX20210802,China)the Project of Shanghai Institute of Materia Medica,CAS(SIMM0120231001,China)the High-level Innovative Research Institute,Department of Science and Technology of Guangdong Province(2021B0909050003,China).
文摘The p21-activated kinase 4(PAK4),a key regulator of malignancy,is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy.Given the lack of high efficacy PAK4 inhibitors,we herein reported the identification of a novel inhibitor 13 bearing a tetrahydrobenzofuro[2,3-c]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC_(50) values of 0.38 and 0.50 mmol/L,respectively.This compound directly binds to PAK4 in a non-ATP competitive manner.In the mouse Pan02 model,compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg,accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue.Overall,compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo,thus making it worthy of further exploration.
基金supported by grants from the National Natural Science Foundation of China (No. 30872926)the Program for AdvancedTalents within Six Industries of Jiangsu Province (08-D) to Dr. Luo Gu+1 种基金the Science Development Foundation of Nanjing Medical University (No. 2010NJMUZ35)the Research Program funded by Schoolof Basic Medical Science, Nanjing Medical University to Dr. Jun Du
文摘Epidermal growth factor （EGF） may increase cell motility, an event implicated in cancer cell invasion and metastasis. However, the underlying mechanisms for EGF-induced cell motility remain elusive. In this study, we found that EGF treatment could activate Ras-related C3 botulinum toxin substrate 1 （Racl）, PI3K/Akt and p21- actived kinase （PAK1） along with cell migration. Ectopic expression of PAK1 K299R, a dominant negative PAK1 mutant, could largely abolish EGF-induced cell migration. Blocking PI3K/Akt signalling with LY294002 or Akt siRNA remarkably inhibited both EGF-induced PAK1 activation and cell migration. Furthermore, expression of dominant-negative Racl （T17N） could largely block EGF-induced PI3K/Akt-PAK1 activation and cell migration. Interestingly, EGF could induce a significant production of ROS, and N-acetyl-L-cysteine, a scavenger of ROS which abolished the EGF-induced ROS generation, cell migration, as well as activation of PI3K/Akt and PAK, but not Racl. Our study demonstrated that EGF-induced cell migration involves a cascade of signalling events, including activation of Racl, generation of ROS and subsequent activation of PI3K/Akt and PAK1.
基金supported by the General Project of Shaanxi Science and Technology Plan(No.2021JM-472)the Key Laboratory Project of Education Department of Shaanxi Province(Nos.21JS014 and 21JS007)+1 种基金the Subject Innovation Team of Shaanxi University of Chinese Medicine(No.2019YL14)the Postgraduate Student’s Innovation Project of Shaanxi University of Chinese Medicine(No.2021-09),China。
文摘Objective:To determine the potential molecular mechanisms underlying the therapeutic effect of curcumin on hepatocellular carcinoma(HCC)by network pharmacology and experimental in vitro validation.Methods:The predictive targets of curcumin or HCC were collected from several databases.the identified overlapping targets were crossed with Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analyses using the Database for Annotation,Visualization,and Integrated Discovery(DAVID)platform.Two of the candidate pathways were selected to conduct an experimental verification.The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium(MTT)assay was used to determine the effect of curcumin on the viability of Hep G2 and LO2 cells.The apoptosis and autophagy of Hep G2 cells were respectively detected by flow cytometry and transmission electron microscopy.Besides,western blot and real-time polymerase chain reaction(PCR)were employed to verify the p53 apoptotic pathway and adenosine 5’-monophosphate(AMP)-activated protein kinase(AMPK)autophagy pathway.Hep G2 cells were pretreated with pifithrin-α(PFT-α)and GSK690693 for further investigation.Results:The 167 pathways analyzed by KEGG included apoptosis,autophagy,p53,and AMPK pathways.The GO enrichment analysis demonstrated that curcumin was involved in cellular response to drug,regulation of apoptotic pathway,and so on.The in vitro experiments also confirmed that curcumin can inhibit the growth of Hep G2 cells by promoting the apoptosis of p53 pathway and autophagy through the AMPK pathway.Furthermore,the protein and messenger RNA(m RNA)of the two pathways were downregulated in the inhibitor-pretreated group compared with the experimental group.The damage-regulated autophagy modulator(DRAM)in the PFT-α-pretreated group was downregulated,and p62 in the GSK690693-pretreated group was upregulated.Conclusions:Curcumin can treat HCC through the p53 apoptotic pathway and the AMPK/Unc-51-like kinase 1(ULK1)autophagy pathway,in which the mutual transformation of autophagy and apoptosis may occur through DRAM and p62.
基金supported by the National Natural Science Foundation of China(21706060,51703061)Natural Science Foundation of Hunan Province(2017JJ3103)+1 种基金Youth Project of Hunan Education Department(17B1118)Hunan Provincial Engineering Technology Research Center for Optical Agriculture(2018TP2003).
文摘Blue-violet light can not only enhance the total content of biomass and glucoside but also enrich the taste of the fruit.Thus,it is meaningful to study the blue-violet luminescent materials for plant cultivation.In this study,titanium(IV)-activated CaYAlO4(CYAO) phosphors were synthesized by conventional hightemperature solid-state reaction.X-ray powder diffraction was employed to analyze the crystalstructure of CYAO.It is found that the doped Ti^4+ ions do not change obviously the crystal structure of phosphors.Upon 246 nm excitation,CaYAl1-xO4:xTi^4+phosphors exhibit broad blue-violet emission band peaking at 395 nm,which can be attributed to the charge transfer of Ti^4+-O^2-.Moreover,this phosphor exhibits strong thermal stability.The luminescence emission intensity at 150℃maintained about 91 mol% of its initial value at room temperature.Additionally,the electron transition process and concentration quenching mechanism of CaYAl1-xO4:xTi^4+are discussed in detail.The excellent luminescent properties indicate that CaYAl1-xO4:xTi^4+phosphor may have promising application in indoor plant cultivation.
