Skin sensitization is a common adverse effect of a wide range of small reactive chemicals,leading to allergic contact dermatitis(ACD),the most frequent manifestation of immunotoxicity in humans.The prevalence of ACD i...Skin sensitization is a common adverse effect of a wide range of small reactive chemicals,leading to allergic contact dermatitis(ACD),the most frequent manifestation of immunotoxicity in humans.The prevalence of ACD is increasing,affecting up to 20%of the Western European population.This trend was particularly pronounced in high-risk occupational sectors,including healthcare,food services,metal and construction workers,and hairdressers[1].The skin sensitization adverse outcome pathway(AOP)comprises 11 elements,with four designated key events(KEs):formation of proteinhapten complexes(KE-1),inflammatory keratinocyte response(KE-2),dendritic cell(DC)activation(KE-3),and T-cell proliferation(KE-4)[2].As there is no cure for ACD,preventive strategies are of great relevance.In addition to avoiding exposure,preventive measures,such as the use of latex gloves,barrier creams,emollients,and moisturizers,often have limited effectiveness[3].展开更多
Diabetic liver injury is a widespread complication of diabetes and carries a high risk to liver function.Therefore,early diagnosis of diabetic liver injury is of great significance for providing quality of life for di...Diabetic liver injury is a widespread complication of diabetes and carries a high risk to liver function.Therefore,early diagnosis of diabetic liver injury is of great significance for providing quality of life for diabetic patients.Most of the activated dual-modal probes are usually activated by single factor stimulation,which greatly reduces the diagnostic accuracy of liver injury.Here,a novel cysteine(Cys)/homocysteine(Hcy)and viscosity-enhanced dual-modal probe DAL was developed for the first time to monitor diabetic liver injury and its repair process.In the presence of Cys/Hcy,the near-infrared fluorescence(NIRF)and photoacoustic(PA)signals of the probe DAL were activated,with further signal enhancement in high viscosity environments.This Cys/Hcy and viscosity cascade probe exhibits heightened sensitivity and enhanced anti-interference capabilities,contributing to the advancement of liver injury diagnosis accuracy.In addition,the probe DAL shows exceptional mitochondrial targeting ability,enabling sensitive monitoring of Cys/Hcy and viscosity alterations within mitochondria.Based on NIRF/PA dual-modal imaging technology,the probe was successfully used for the first time in a mouse diabetic liver injury model to evaluate the extent of liver damage and the repair process by tracking the levels of Cys/Hcy and viscosity.Therefore,the two-factor activated dual-modal probe developed in this study provides a powerful instrument for accurate diagnosis and efficacy evaluation of complications related to diabetes.展开更多
BACKGROUND Pancreatic cancer tissues mainly consist of fibrotic and dense stroma,which limits their therapeutic efficacy.The stromal fibroblasts of pancreatic tumors frequently express the secreted protein acidic and ...BACKGROUND Pancreatic cancer tissues mainly consist of fibrotic and dense stroma,which limits their therapeutic efficacy.The stromal fibroblasts of pancreatic tumors frequently express the secreted protein acidic and rich in cysteine(SPARC).AIM To assess the impact of SPARC and its oncological relevance in patients undergoing pancreatic cancer resection.METHODS Ninety-one pancreatic ductal adenocarcinoma specimens were obtained from patients with curative resection between January 2009 and December 2015 as a retrospective study.SPARC expression patterns were analyzed using immunohistochemistry.Oncological outcomes were analyzed based on SPARC expression patterns.Oncological outcomes,based on SPARC expression,were analyzed in The Cancer Genome Atlas-Pancreatic Adenocarcinoma cohort(retrieved from a public database).RESULTS Patients with stromal SPARC expression(sSPARC+)had poorer overall survival than that in those without it(sSPARC-)(P=0.035).However,among patients who received adjuvant treatment,no difference was observed in survival between the sSPARC+and the sSPARC-groups(P=0.14).In The Cancer Genome Atlas-Pancreatic Adenocarcinoma samples,the high SPARC expression group exhibited noticeably lower overall survival than that in the low expression group(cutoff:14.1295,P=0.0222).Furthermore,SPARC expression was strongly correlated with the percentage the CD10+stromal component(R2=0.804,P<0.001).CONCLUSION Adjuvant chemotherapy improves survivals in sSPARC+pancreatic cancer patients,indicating suggesting sSPARC expression as a prognostic biomarker and potential indicator for neoadjuvant treatment planning.展开更多
Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related mortality worldwide.This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms,wi...Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related mortality worldwide.This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms,with a particular focus on mitochondrial function and apoptosis.Methods:Differential expression analyses were performed across three datasets—The Cancer Genome Atlas(TCGA)-Liver Hepatocellular Carcinoma(LIHC),GSE36076,and GSE95698—to identify overlapping differentially expressed genes(DEGs).A prognostic risk model was then constructed.Cysteine/serine-rich nuclear protein 1(CSRNP1)expression levels in HCC cell lines were assessed via western blot(WB)and quantitative reverse transcription polymerase chain reaction(qRT-PCR).The effects of CSRNP1 knockdown or overexpression on cell proliferation,migration,and apoptosis were evaluated using cell counting-8(CCK-8)assays,Transwell assays,and flow cytometry.Mitochondrial ultrastructure was examined by transmission electron microscopy,and intracellular and mitochondrial reactive oxygen species(mROS)levels were measured using specific fluorescent probes.WB was used to assess activation of the c-Jun N-terminal kinase(JNK)/p38 mitogen-activated protein kinase(MAPK)pathway,and pathway dependence was examined using the ROS scavenger N-Acetylcysteine(NAC)and the JNK inhibitor SP600125.Results:A six-gene prognostic model was established,comprising downregulated genes(NR4A1 and CSRNP1)and upregulated genes(CENPQ,YAE1,FANCF,and POC5)in HCC.Functional experiments revealed that CSRNP1 knockdown promoted the proliferation of HCC cells and suppressed their apoptosis.Conversely,CSRNP1 overexpression impaired mitochondrial integrity,increased both mitochondrial and cytoplasmic ROS levels,and activated the JNK/p38 MAPK pathway.Notably,treatment with NAC or SP600125 attenuated CSRNP1-induced MAPK activation and apoptosis.Conclusion:CSRNP1 is a novel prognostic biomarker and tumor suppressor in HCC.It exerts anti-tumor effects by inducing oxidative stress and activating the JNK/p38 MAPK pathway in a ROS-dependent manner.These findings suggest that CSRNP1 may serve as a potential therapeutic target in the management of HCC.展开更多
Cysteine residues found in proteins have various functions such as metal binding, nitrosylation, and stabilization of structure. We have done a comparative, computational structural analysis of the cysteine residues i...Cysteine residues found in proteins have various functions such as metal binding, nitrosylation, and stabilization of structure. We have done a comparative, computational structural analysis of the cysteine residues in two proteins from bacteria to get some insight into the differences between metal binding cysteine residues and those involved in structure stabilization. The two target proteins in this study are the periplasmic mercury binding protein （MerP） and the 1-1eucine binding protein （LBP）. Both are periplasmic binding proteins from E. coli. We have shown key phenomenon that define cysteines as metal binding or structural in nature.展开更多
Aim Cysteine proteases are closely associated with many human and non-human pathological processes and are potential targets for metal ions especially Hg^2＋ and the related species. In the present work, on the basis ...Aim Cysteine proteases are closely associated with many human and non-human pathological processes and are potential targets for metal ions especially Hg^2＋ and the related species. In the present work, on the basis of to the general study on the effects of some metal ions on the activity of papain, a well-known representative of cysteine protease family, the inhibitory effects of Hg^2＋ and polysulfide complexes were studied. Results All the metal ions tested （Hg^2＋, Cu^2＋, Ag^＋, Au^3＋, Zn^2＋, Cd^2＋, Fe^3＋, Mn^2＋, Pb^2＋, Yb^3＋） inhibit the activity of papain anda good correlation between the inhibitory potency and softness-and-hardness was observed. Among the metals, Hg^2＋ was shown to be a potent inhibitor of papain with a Kiof 2 × 10^-7 mol·L^-1 among. Excessive amounts of glutathione and cysteine could reactivate the enzyme activity of papain deactivated by Hg^2＋. These evidences supported that Hg^2＋ might bind to the catalytic site of papain. Interestingly, Hg （Ⅱ） polysulfide complexes were for the first time found to inhibit papain with a Ki of 7 × 10^-6 mol·L^-1, whose potency is close to a well known mercury compound, thimerosal （Ki=2.7 × 10^-6）. In addition, Hg （Ⅱ） polysulfide complexes exhibit good permeability （ 1.9 × 10-5 cm· s^-1） to caco-2 monolayer. Conclusion These results suggested that mercury polysulfide complexes might be potential bioactive species in the interaction with cysteine proteases and other- SH-content proteins, providing a new clue to understand the mechanism of the toxicological and pharmacological actions of cinnabar and other insoluble mercury compounds.展开更多
With the progress of plant genome research, more than 50 plant metallothionein_like (MT_L) genes have been found, but only several MT_L proteins have been detected and no experimental structural information for MT_L p...With the progress of plant genome research, more than 50 plant metallothionein_like (MT_L) genes have been found, but only several MT_L proteins have been detected and no experimental structural information for MT_L proteins has been reported so far. Since detailed knowledge of the protein tertiary structure is required to understand its biological function, a method is needed to determine the structure of these proteins. In this study, the structural data of known mammal MT was used to determine the interatomic distance constraints of the CXC and CXXC motifs and the metal_sulfur chelating cluster. Then several possible MT conformations were predicted using a distance geometry algorithm. The statistical analysis was used to select those with much lower target function values and lower conformation energies as the predicted tertiary structural models of the cysteine_rich (CR) domains of these proteins. A suitable prediction method for modeling the CR domain of the plant MT_L protein was constructed. The accurately predicted result for the known structure of an MT protein from blue crab suggests that this method is practicable. The tertiary structures of CR domains of rape MT_L protein LSC54 was then modeled with this method.展开更多
Hyperhomocysteinemia and abnormal blood lipids are independent risk factors for stroke. However, whether both factors exert a synergistic effect in the onset of stroke remains unclear. The present study is a retrospec...Hyperhomocysteinemia and abnormal blood lipids are independent risk factors for stroke. However, whether both factors exert a synergistic effect in the onset of stroke remains unclear. The present study is a retrospective analysJs of 2 089 cases of stroke and 2 089 control cases of simple in- tervertebral disk protrusion using a paired multivariate logistic regression method. Adjusting for known confounding variables including the patients＇ age, gender, smoking status, alcohol con- sumption status, patient and family medical history, and clinical biochemical indices, elevated ho- mocysteine level was related to the onset of stroke. Patients with elevated homocysteJne levels and abnormal blood lipids showed a 40.9 % increase in the risk for stroke compared to patients with normal homocysteine levels and blood lipids （odds ratio 1.409; 95% confidence interval 1.127-1.761）. These results indicate that elevated homocysteine and abnormal blood lipids exert synergistic effects in the onset of stroke. Patients with elevated homocysteine levels and abnormal blood lipids are predisposed to stroke.展开更多
Secreted protein acidic and rich in cysteine(SPARC)is a matricellular protein highly expressed in bone tissue that acts as achemoattractant factor promoting the arrival of prostate cancer(PCa)cells to the bone marrow....Secreted protein acidic and rich in cysteine(SPARC)is a matricellular protein highly expressed in bone tissue that acts as achemoattractant factor promoting the arrival of prostate cancer(PCa)cells to the bone marrow.However,the contribution of SPARCduring the early stages of tumor progression remains unclear.In this study,we show that SPARC is highly expressed in PCa tissueswith a higher Gleason score.Through stable knockdown and overexpression of SPARC in PC3 and LNCaP cells,respectively,here wedem on strate that en doge nous SPARC induces the epithelial-mesenchymal tran sition(EMT),decreasing E-cadheri n and cytokeratin18 and increasing N-cadheri n and vime ntin.Moreover,SPARC in duces the expression of EMT regulatory tran scription factors Snailfamily transcriptional repressor 1(Snail),Snail family transcriptional repressor 2(Slug),and zinc finger E-box binding homeobox 1(Zeb1).In addition,SPARC knockdown in PC3 cells decreases migration and invasion in vitro,without modifying cell proliferation.Our results indicate that SPARC might facilitate tumor progression by modifying the cellular phenotype in cancer cells.展开更多
AIM: To investigate the potential role of oxidative stress and the possible therapeutic effects of N-acetyl cysteine (NAC), amifostine (AMF) and ascorbic acid (ASC) in methotrexate (MTX)-induced hepatotoxicity.
Cysteine(Cys)plays a pivotal role in many physiological and pathological processes,including detoxification and protein synthesis.The abnormal levels of Cys are linked to many diseases.In this study,a novel red-emitti...Cysteine(Cys)plays a pivotal role in many physiological and pathological processes,including detoxification and protein synthesis.The abnormal levels of Cys are linked to many diseases.In this study,a novel red-emitting off-on fluorescent probe Cys-TCF was masterly constructed for discriminative detection of Cys.After a series of experimental assessment,Cys-TCF displayed higher selectivity and sensitivity for Cys over other biothilols with a low detection limit(0.04μmol/L).More notably,the probe was also successfully applied to image Cys in live cells and live zebrafishes with low cytotoxicity.展开更多
BACKGROUND Aberrant methylation in DNA regulatory regions could downregulate tumor suppressor genes without changing the sequences.However,our knowledge of secreted protein acidic and rich in cysteine(SPARC)and its ab...BACKGROUND Aberrant methylation in DNA regulatory regions could downregulate tumor suppressor genes without changing the sequences.However,our knowledge of secreted protein acidic and rich in cysteine(SPARC)and its aberrant methylation in gastric cancer(GC)is still inadequate.In the present research,we performed fundamental research to clarify the precise function of methylation on SPARC and its significance in GC.AIM To investigate promoter methylation and the effects of the SPARC gene in GC cells and tissues and to evaluate its clinical significance.METHODS Plasmids that overexpressed the SPARC gene were transfected into human GC BGC-823 cells;non-transfected cells were used as a control group(NC group).Quantitative real-time polymerase chain reaction and western blotting(WB)were then used to detect the expression of SPARC.Methylation-specific polymerase chain reaction was executed to analyze the gene promoter methylation status.Cell viability was measured by the cell counting kit-8 assay.The migration and invasion ability of cells were detected by scratch assays and transwell chamber assays,respectively.Cell cycle events and apoptosis were observed with a flow cytometer.RESULTS The expression of SPARC mRNA in GC tissues and cells was significantly lower and showed differing degrees of hypermethylation,respectively,than that in normal adjacent tissues and control cells.Treatment with 5-Aza-2’-deoxycytidine(5-Aza-Cdr)was able to restore the expression of SPARC and reverse promoter hypermethylation.Overexpression of the SPARC gene significantly inhibited proliferation,migration,and invasion of GC cells,while also causing cell cycle arrest and apoptosis;the NC group exhibited the opposite effects.CONCLUSION This study demonstrated that SPARC could function as a tumor suppressor and might be silenced by promoter hypermethylation.Furthermore,in GC cells,SPARC inhibited migration,invasion,and proliferation,caused cell cycle arrest at the G0/G1 phase,and promoted apoptosis.展开更多
Triangular silver nanoprisms were prepared and applied to make colorimetric detection of cysteine based on our findings that cysteine could lead to the blue shift of the dipole plasmon resonance absorption, but other ...Triangular silver nanoprisms were prepared and applied to make colorimetric detection of cysteine based on our findings that cysteine could lead to the blue shift of the dipole plasmon resonance absorption, but other 19 kinds of natural amino acids could not. Cysteine with a concentration 160 nmol/L can result in a color change that can be discerned with naked eyes.展开更多
A novel wate r-soluble red-emissive AIE fluorescence probe for cysteine(Cys) in situ was prepared and the performance of selectivity and sensitivity has been carefully investigated in this study.The probe was establis...A novel wate r-soluble red-emissive AIE fluorescence probe for cysteine(Cys) in situ was prepared and the performance of selectivity and sensitivity has been carefully investigated in this study.The probe was established on the electrostatic interaction of sulfonate functionalized tetraphenylethene(TPE) and polycation generated by the reaction between a polymer bearing dinitrobenzenesulfonate groups and Cys.From the experimental results,it was easy to distinguish Cys from glutathione(GSH) and homocysteine(Hcy) with a detection limit of 73 nmol/L.The assay system also possessed strong antiinterference ability against multitudinous amino acids.The Stokes shift was 142 nm and the emission ranged from 550 nm to 850 nm.In addition,double responses in fluorescence and ultraviolet-visible spectra also make the red-emissive assay ideal for sensitive detection and quantification of Cys for most purposes,especially in-situ monitoring of Cys in aqueous medium.展开更多
AIM: To examine the effectiveness of human placental inhibitors, by injecting vitamin E to rats with transplanted Morris-5123 hepatoma, on the expression of cathepsins B and L in tumor, liver, lung and blood sera afte...AIM: To examine the effectiveness of human placental inhibitors, by injecting vitamin E to rats with transplanted Morris-5123 hepatoma, on the expression of cathepsins B and L in tumor, liver, lung and blood sera after transplantation of Morris 5123 hepatoma. METHODS: Animals were divided into 10 groups receiving three different concentrations of vitamin E and inhibitors along or in combination and compared with negative control (healthy rats) and positive control (tumor rats). Effectiveness of treatment was evaluated with regard to survival time, tumor response and determination of the activities of proteolytic enzymes and their inhibitors using flurogenic substrates. RESULTS: Cathepsins B and L activities were elevated by 16-fold in comparison with negative control tissues, and their endogenous inhibitor activity decreased by 1.2-fold before treatment. In several cases, tumors completely disappeared following vitamin E plus human placental cyteine protease inhibitor (CPI) compared with controls. The number of complete tumor responses was higher when 20 m/kg vitamin E plus 400 μg of CPI was used, i.e. 7/10 rats survived more than two mo. Cathepsins B and L were expressed significantly in tumor, liver, lung tissues and sera in parallel to the increasing of the endogenous inhibitor activity compared with the controls after treatment(P<0.0001) CONCLUSION: The data indicate formation of metastasis significantly reduced in treated rats, which might provide a therapeutic basis for anti-cancer therapy.展开更多
A simple flow injection spectrophotometric method is reported for the determination of cysteine,N-acetyl cysteine and glutathione based on the reduction of Fe（Ⅲ）/ferricyanide,the in situ reduced ions are reacted wi...A simple flow injection spectrophotometric method is reported for the determination of cysteine,N-acetyl cysteine and glutathione based on the reduction of Fe（Ⅲ）/ferricyanide,the in situ reduced ions are reacted with unreduced portion of ferricyanide/Fe（Ⅲ） to form soluble Prussian blue,which is monitored at 735 nm.The calibration graphs are linear in the concentration ranges of（1―100）×10-6 mol/L for cysteine and N-acetyl cysteine,and（1―50）×10-6 mol/L for glutathione.The relative standard deviations of 1.8%,2.5% and 1.9% were found for eleven replicate analyses of 5×10-6 mol/L cysteine,N-acetyl cysteine and glutathione.The limits of detection（3σ blank） at 5×10-7 mol/L for cysteine,and 3×10-7 mol/L for N-acetyl cysteine and glutathione were obtained.The proposed method allowed 60 injections/h.The effects of common substances present in pharmaceuticals and human physiological fluids were examined.The method was applied to determining cysteine in pharmaceutical formulations with the recoveries in a range of 97% to 106% and the results obtained are agreed well with labeled values.展开更多
Curcuminoid difluoroboron has attractive performance as a promising near-infrared（NIR） fluorescent dye. In this contribution, we designed and synthesized a mitochondria-targeted NIR fluorescent probe DFB1 based on d...Curcuminoid difluoroboron has attractive performance as a promising near-infrared（NIR） fluorescent dye. In this contribution, we designed and synthesized a mitochondria-targeted NIR fluorescent probe DFB1 based on difluoroboron curcuminoid scaffold for the detection of Cys（cysteine）. DFB1 employs a curcumin analog as the NIR fluorophore, an acrylate group containing a, b-unsaturated ketone as a functional trigger moiety for Cys, and a triphenylphosphonium（TPP） cation moiety for specifically targeting mitochondria. The remarkable shift of DFB1 with Cys was observed from 470 nm to 590 nm in absorption spectra and from 560 nm to 680 nm in emission spectra. Notably, DFB1 manifests significantly dual-channel and turn-on NIR fluorescent signals simultaneously in response to Cys concentration,which make it favorable for monitoring endogenous Cys activity in vivo. This probe has high sensitivity and selectivity for the detection of Cys over homocysteine（Hcy） and glutathione（GSH）. This specific response for Cys was based on differences kinetics of intramolecular adduct/cyclizations. More importantly, biological experiments indicated that this probe could be utilized for the detection of endogenous mitochondrial Cys in living cells.展开更多
A coumarin-based compound（1） was designed and synthesized as a new turn-on fluorescent probe for the detection of cysteine. The probe exhibited higher selectivity towards the target molecule over other thiol and ami...A coumarin-based compound（1） was designed and synthesized as a new turn-on fluorescent probe for the detection of cysteine. The probe exhibited higher selectivity towards the target molecule over other thiol and amino acids at pH 7.2 in aqueous media CH_3CN-HEPES（0.02 mol/L, pH 7.2, 1：9, v/v）. The reaction mechanism is attributed to the cysteine-induced S_NAr substitution-rearrangement reaction. Remarkable enhancement of up to 20-fold in fluorescence intensity was achieved in the detection of cysteine. When applied for the fluorescence imaging of cysteine, the compound 1 emitted a green fluorescence in Hi5 cell cytoplasm. The in vivo imaging of Caenorhabditis elegans had further confirmed the cysteine detection by compound 1.展开更多
A sensitive and selective chemiluminescence (CL) method was developed for the determination of cysteine. This method is based on that the weak CL of cysteine oxidized with cerium (IV) can be greatly enhanced by quinin...A sensitive and selective chemiluminescence (CL) method was developed for the determination of cysteine. This method is based on that the weak CL of cysteine oxidized with cerium (IV) can be greatly enhanced by quinine, and the total cysteine in human serum can be detected through simply diluting with water, showing a simpler analytical characteristic.展开更多
AIM: Cysteine peptidase (CP) and its inhibitor (CPI) are a matrix protease that may be associated with colorectal carcinoma invasion and progression, and vitamin E is also a stimulator of the immunological system. Our...AIM: Cysteine peptidase (CP) and its inhibitor (CPI) are a matrix protease that may be associated with colorectal carcinoma invasion and progression, and vitamin E is also a stimulator of the immunological system. Our purpose was to determine the correlation between the expression of cysteine peptidases and their endogenous inhibitors,and the level of vitamin E in sera of patients with colorectal cancer in comparison with healthy individuals.METHODS: The levels of cysteine peptidases and their inhibitors were determined in the sera of patients with primary and metastatic colorectal carcinoma and healthy individuals using fluorogenic substrate, and the level of vitamin E was determined by HPLC.RESULTS: The levels of cysteine peptidases and their inhibitors were significantly higher in the metastatic colorectal cancer patients than that in the healthy controls (P＜0.05).The activity of CP increased 2.2-fold, CPI 2.8-fold and vitamin E decreased 3.4-fold in sera of patients with metastasis in comparison with controls. The level of vitamin E in healthy individuals was higher, whereas the activity of cysteine peptidases and their inhibitors associated with complexes was lower than that in patients with cancer of the digestive tract.CONCLUSION: These results suggest that the serum levels of CP and their inhibitors could be an indicator of the prognosis for patients with metastatic colorectal cancer. Vitamin E can be administered prophylactically to prevent digestive tract neoplasmas.展开更多
基金support was provided by the European Regional Development Fund(ERDF),through the Centro 2020 Regional Operational Programme,Portugal(Project No.:CENTRO-01-0145-FEDER-000012(HealthyAging2020))through the COMPETE 2020-Operational Programme for Competitiveness and Internationalisation and Portuguese National Funds via Fundaçao para a Ciencia e a Tecnologia,Portugal(Project Nos.:POCI-01-0145-FEDER-029369 UIDB/04539/2020,iBiMED UIDB/04501/2020,DOI identifier https://doi.org/10.54499/UIDB/04501/2020 and project reference UIDP/04501/2020,DOI identifier https://doi.org/10.54499/UIDP/04501/2020,and LA/P/0058/2020)supported by Fundaçao para a Ciencia e a Tecnologia through the individual PhD fellowships,Portugal(Grant Nos.:PD/BDE/142926/2018 and SFRH/BD/110717/2015)。
文摘Skin sensitization is a common adverse effect of a wide range of small reactive chemicals,leading to allergic contact dermatitis(ACD),the most frequent manifestation of immunotoxicity in humans.The prevalence of ACD is increasing,affecting up to 20%of the Western European population.This trend was particularly pronounced in high-risk occupational sectors,including healthcare,food services,metal and construction workers,and hairdressers[1].The skin sensitization adverse outcome pathway(AOP)comprises 11 elements,with four designated key events(KEs):formation of proteinhapten complexes(KE-1),inflammatory keratinocyte response(KE-2),dendritic cell(DC)activation(KE-3),and T-cell proliferation(KE-4)[2].As there is no cure for ACD,preventive strategies are of great relevance.In addition to avoiding exposure,preventive measures,such as the use of latex gloves,barrier creams,emollients,and moisturizers,often have limited effectiveness[3].
基金financially supported by the National Natural Science Foundation of China(Nos.21877048,22077048,and 22277014)Guangxi Natural Science Foundation(Nos.2021GXNSFDA075003,AD21220061)the Startup Fund of Guangxi University(No.A3040051003).
文摘Diabetic liver injury is a widespread complication of diabetes and carries a high risk to liver function.Therefore,early diagnosis of diabetic liver injury is of great significance for providing quality of life for diabetic patients.Most of the activated dual-modal probes are usually activated by single factor stimulation,which greatly reduces the diagnostic accuracy of liver injury.Here,a novel cysteine(Cys)/homocysteine(Hcy)and viscosity-enhanced dual-modal probe DAL was developed for the first time to monitor diabetic liver injury and its repair process.In the presence of Cys/Hcy,the near-infrared fluorescence(NIRF)and photoacoustic(PA)signals of the probe DAL were activated,with further signal enhancement in high viscosity environments.This Cys/Hcy and viscosity cascade probe exhibits heightened sensitivity and enhanced anti-interference capabilities,contributing to the advancement of liver injury diagnosis accuracy.In addition,the probe DAL shows exceptional mitochondrial targeting ability,enabling sensitive monitoring of Cys/Hcy and viscosity alterations within mitochondria.Based on NIRF/PA dual-modal imaging technology,the probe was successfully used for the first time in a mouse diabetic liver injury model to evaluate the extent of liver damage and the repair process by tracking the levels of Cys/Hcy and viscosity.Therefore,the two-factor activated dual-modal probe developed in this study provides a powerful instrument for accurate diagnosis and efficacy evaluation of complications related to diabetes.
基金Supported by Faculty Research Grant from Yonsei University College of Medicine,No.6-2017-0155.
文摘BACKGROUND Pancreatic cancer tissues mainly consist of fibrotic and dense stroma,which limits their therapeutic efficacy.The stromal fibroblasts of pancreatic tumors frequently express the secreted protein acidic and rich in cysteine(SPARC).AIM To assess the impact of SPARC and its oncological relevance in patients undergoing pancreatic cancer resection.METHODS Ninety-one pancreatic ductal adenocarcinoma specimens were obtained from patients with curative resection between January 2009 and December 2015 as a retrospective study.SPARC expression patterns were analyzed using immunohistochemistry.Oncological outcomes were analyzed based on SPARC expression patterns.Oncological outcomes,based on SPARC expression,were analyzed in The Cancer Genome Atlas-Pancreatic Adenocarcinoma cohort(retrieved from a public database).RESULTS Patients with stromal SPARC expression(sSPARC+)had poorer overall survival than that in those without it(sSPARC-)(P=0.035).However,among patients who received adjuvant treatment,no difference was observed in survival between the sSPARC+and the sSPARC-groups(P=0.14).In The Cancer Genome Atlas-Pancreatic Adenocarcinoma samples,the high SPARC expression group exhibited noticeably lower overall survival than that in the low expression group(cutoff:14.1295,P=0.0222).Furthermore,SPARC expression was strongly correlated with the percentage the CD10+stromal component(R2=0.804,P<0.001).CONCLUSION Adjuvant chemotherapy improves survivals in sSPARC+pancreatic cancer patients,indicating suggesting sSPARC expression as a prognostic biomarker and potential indicator for neoadjuvant treatment planning.
基金funded by Shanghai Yangpu District Science and Technology Commission(Grant No.YPQ202303(Xuejing Lin))Shanghai Yangpu Hospital Foundation(Grant No.Se1202420(Wenchao Wang)and Ye1202423(Juan Huang)).
文摘Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related mortality worldwide.This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms,with a particular focus on mitochondrial function and apoptosis.Methods:Differential expression analyses were performed across three datasets—The Cancer Genome Atlas(TCGA)-Liver Hepatocellular Carcinoma(LIHC),GSE36076,and GSE95698—to identify overlapping differentially expressed genes(DEGs).A prognostic risk model was then constructed.Cysteine/serine-rich nuclear protein 1(CSRNP1)expression levels in HCC cell lines were assessed via western blot(WB)and quantitative reverse transcription polymerase chain reaction(qRT-PCR).The effects of CSRNP1 knockdown or overexpression on cell proliferation,migration,and apoptosis were evaluated using cell counting-8(CCK-8)assays,Transwell assays,and flow cytometry.Mitochondrial ultrastructure was examined by transmission electron microscopy,and intracellular and mitochondrial reactive oxygen species(mROS)levels were measured using specific fluorescent probes.WB was used to assess activation of the c-Jun N-terminal kinase(JNK)/p38 mitogen-activated protein kinase(MAPK)pathway,and pathway dependence was examined using the ROS scavenger N-Acetylcysteine(NAC)and the JNK inhibitor SP600125.Results:A six-gene prognostic model was established,comprising downregulated genes(NR4A1 and CSRNP1)and upregulated genes(CENPQ,YAE1,FANCF,and POC5)in HCC.Functional experiments revealed that CSRNP1 knockdown promoted the proliferation of HCC cells and suppressed their apoptosis.Conversely,CSRNP1 overexpression impaired mitochondrial integrity,increased both mitochondrial and cytoplasmic ROS levels,and activated the JNK/p38 MAPK pathway.Notably,treatment with NAC or SP600125 attenuated CSRNP1-induced MAPK activation and apoptosis.Conclusion:CSRNP1 is a novel prognostic biomarker and tumor suppressor in HCC.It exerts anti-tumor effects by inducing oxidative stress and activating the JNK/p38 MAPK pathway in a ROS-dependent manner.These findings suggest that CSRNP1 may serve as a potential therapeutic target in the management of HCC.
文摘Cysteine residues found in proteins have various functions such as metal binding, nitrosylation, and stabilization of structure. We have done a comparative, computational structural analysis of the cysteine residues in two proteins from bacteria to get some insight into the differences between metal binding cysteine residues and those involved in structure stabilization. The two target proteins in this study are the periplasmic mercury binding protein （MerP） and the 1-1eucine binding protein （LBP）. Both are periplasmic binding proteins from E. coli. We have shown key phenomenon that define cysteines as metal binding or structural in nature.
文摘Aim Cysteine proteases are closely associated with many human and non-human pathological processes and are potential targets for metal ions especially Hg^2＋ and the related species. In the present work, on the basis of to the general study on the effects of some metal ions on the activity of papain, a well-known representative of cysteine protease family, the inhibitory effects of Hg^2＋ and polysulfide complexes were studied. Results All the metal ions tested （Hg^2＋, Cu^2＋, Ag^＋, Au^3＋, Zn^2＋, Cd^2＋, Fe^3＋, Mn^2＋, Pb^2＋, Yb^3＋） inhibit the activity of papain anda good correlation between the inhibitory potency and softness-and-hardness was observed. Among the metals, Hg^2＋ was shown to be a potent inhibitor of papain with a Kiof 2 × 10^-7 mol·L^-1 among. Excessive amounts of glutathione and cysteine could reactivate the enzyme activity of papain deactivated by Hg^2＋. These evidences supported that Hg^2＋ might bind to the catalytic site of papain. Interestingly, Hg （Ⅱ） polysulfide complexes were for the first time found to inhibit papain with a Ki of 7 × 10^-6 mol·L^-1, whose potency is close to a well known mercury compound, thimerosal （Ki=2.7 × 10^-6）. In addition, Hg （Ⅱ） polysulfide complexes exhibit good permeability （ 1.9 × 10-5 cm· s^-1） to caco-2 monolayer. Conclusion These results suggested that mercury polysulfide complexes might be potential bioactive species in the interaction with cysteine proteases and other- SH-content proteins, providing a new clue to understand the mechanism of the toxicological and pharmacological actions of cinnabar and other insoluble mercury compounds.
文摘With the progress of plant genome research, more than 50 plant metallothionein_like (MT_L) genes have been found, but only several MT_L proteins have been detected and no experimental structural information for MT_L proteins has been reported so far. Since detailed knowledge of the protein tertiary structure is required to understand its biological function, a method is needed to determine the structure of these proteins. In this study, the structural data of known mammal MT was used to determine the interatomic distance constraints of the CXC and CXXC motifs and the metal_sulfur chelating cluster. Then several possible MT conformations were predicted using a distance geometry algorithm. The statistical analysis was used to select those with much lower target function values and lower conformation energies as the predicted tertiary structural models of the cysteine_rich (CR) domains of these proteins. A suitable prediction method for modeling the CR domain of the plant MT_L protein was constructed. The accurately predicted result for the known structure of an MT protein from blue crab suggests that this method is practicable. The tertiary structures of CR domains of rape MT_L protein LSC54 was then modeled with this method.
基金supported by a grant from Medical Science DataSharing Network,Ministry of Science and Technology,China,No.2005DKA32403Military Medical Scientific Research grants,No.11BJZ32,No.12BJZ271 and No.10BJZ202
文摘Hyperhomocysteinemia and abnormal blood lipids are independent risk factors for stroke. However, whether both factors exert a synergistic effect in the onset of stroke remains unclear. The present study is a retrospective analysJs of 2 089 cases of stroke and 2 089 control cases of simple in- tervertebral disk protrusion using a paired multivariate logistic regression method. Adjusting for known confounding variables including the patients＇ age, gender, smoking status, alcohol con- sumption status, patient and family medical history, and clinical biochemical indices, elevated ho- mocysteine level was related to the onset of stroke. Patients with elevated homocysteJne levels and abnormal blood lipids showed a 40.9 % increase in the risk for stroke compared to patients with normal homocysteine levels and blood lipids （odds ratio 1.409; 95% confidence interval 1.127-1.761）. These results indicate that elevated homocysteine and abnormal blood lipids exert synergistic effects in the onset of stroke. Patients with elevated homocysteine levels and abnormal blood lipids are predisposed to stroke.
文摘Secreted protein acidic and rich in cysteine(SPARC)is a matricellular protein highly expressed in bone tissue that acts as achemoattractant factor promoting the arrival of prostate cancer(PCa)cells to the bone marrow.However,the contribution of SPARCduring the early stages of tumor progression remains unclear.In this study,we show that SPARC is highly expressed in PCa tissueswith a higher Gleason score.Through stable knockdown and overexpression of SPARC in PC3 and LNCaP cells,respectively,here wedem on strate that en doge nous SPARC induces the epithelial-mesenchymal tran sition(EMT),decreasing E-cadheri n and cytokeratin18 and increasing N-cadheri n and vime ntin.Moreover,SPARC in duces the expression of EMT regulatory tran scription factors Snailfamily transcriptional repressor 1(Snail),Snail family transcriptional repressor 2(Slug),and zinc finger E-box binding homeobox 1(Zeb1).In addition,SPARC knockdown in PC3 cells decreases migration and invasion in vitro,without modifying cell proliferation.Our results indicate that SPARC might facilitate tumor progression by modifying the cellular phenotype in cancer cells.
文摘AIM: To investigate the potential role of oxidative stress and the possible therapeutic effects of N-acetyl cysteine (NAC), amifostine (AMF) and ascorbic acid (ASC) in methotrexate (MTX)-induced hepatotoxicity.
基金financial supports from the National Natural Science Foundation of China (Nos.21708017,21572093,21778028)Lanzhou University (the Fundamental Research Funds for the Central Universities,No.lzujbky-2018-64)Natural Science Foundation of Gansu Province (No.17JR5RA193)
文摘Cysteine(Cys)plays a pivotal role in many physiological and pathological processes,including detoxification and protein synthesis.The abnormal levels of Cys are linked to many diseases.In this study,a novel red-emitting off-on fluorescent probe Cys-TCF was masterly constructed for discriminative detection of Cys.After a series of experimental assessment,Cys-TCF displayed higher selectivity and sensitivity for Cys over other biothilols with a low detection limit(0.04μmol/L).More notably,the probe was also successfully applied to image Cys in live cells and live zebrafishes with low cytotoxicity.
基金Supported by the Natural Science Foundation of Liaoning Province,No.201602817
文摘BACKGROUND Aberrant methylation in DNA regulatory regions could downregulate tumor suppressor genes without changing the sequences.However,our knowledge of secreted protein acidic and rich in cysteine(SPARC)and its aberrant methylation in gastric cancer(GC)is still inadequate.In the present research,we performed fundamental research to clarify the precise function of methylation on SPARC and its significance in GC.AIM To investigate promoter methylation and the effects of the SPARC gene in GC cells and tissues and to evaluate its clinical significance.METHODS Plasmids that overexpressed the SPARC gene were transfected into human GC BGC-823 cells;non-transfected cells were used as a control group(NC group).Quantitative real-time polymerase chain reaction and western blotting(WB)were then used to detect the expression of SPARC.Methylation-specific polymerase chain reaction was executed to analyze the gene promoter methylation status.Cell viability was measured by the cell counting kit-8 assay.The migration and invasion ability of cells were detected by scratch assays and transwell chamber assays,respectively.Cell cycle events and apoptosis were observed with a flow cytometer.RESULTS The expression of SPARC mRNA in GC tissues and cells was significantly lower and showed differing degrees of hypermethylation,respectively,than that in normal adjacent tissues and control cells.Treatment with 5-Aza-2’-deoxycytidine(5-Aza-Cdr)was able to restore the expression of SPARC and reverse promoter hypermethylation.Overexpression of the SPARC gene significantly inhibited proliferation,migration,and invasion of GC cells,while also causing cell cycle arrest and apoptosis;the NC group exhibited the opposite effects.CONCLUSION This study demonstrated that SPARC could function as a tumor suppressor and might be silenced by promoter hypermethylation.Furthermore,in GC cells,SPARC inhibited migration,invasion,and proliferation,caused cell cycle arrest at the G0/G1 phase,and promoted apoptosis.
基金the financial support of the Ministry of Science and Technology of the People's Republic of China(No.2006CB 933100).
文摘Triangular silver nanoprisms were prepared and applied to make colorimetric detection of cysteine based on our findings that cysteine could lead to the blue shift of the dipole plasmon resonance absorption, but other 19 kinds of natural amino acids could not. Cysteine with a concentration 160 nmol/L can result in a color change that can be discerned with naked eyes.
基金financial support from the National Key Research and Development Program of China (No. 2017YFA0701303)the National Natural Science Foundation of China (Nos.51873097 and 21674058)。
文摘A novel wate r-soluble red-emissive AIE fluorescence probe for cysteine(Cys) in situ was prepared and the performance of selectivity and sensitivity has been carefully investigated in this study.The probe was established on the electrostatic interaction of sulfonate functionalized tetraphenylethene(TPE) and polycation generated by the reaction between a polymer bearing dinitrobenzenesulfonate groups and Cys.From the experimental results,it was easy to distinguish Cys from glutathione(GSH) and homocysteine(Hcy) with a detection limit of 73 nmol/L.The assay system also possessed strong antiinterference ability against multitudinous amino acids.The Stokes shift was 142 nm and the emission ranged from 550 nm to 850 nm.In addition,double responses in fluorescence and ultraviolet-visible spectra also make the red-emissive assay ideal for sensitive detection and quantification of Cys for most purposes,especially in-situ monitoring of Cys in aqueous medium.
文摘AIM: To examine the effectiveness of human placental inhibitors, by injecting vitamin E to rats with transplanted Morris-5123 hepatoma, on the expression of cathepsins B and L in tumor, liver, lung and blood sera after transplantation of Morris 5123 hepatoma. METHODS: Animals were divided into 10 groups receiving three different concentrations of vitamin E and inhibitors along or in combination and compared with negative control (healthy rats) and positive control (tumor rats). Effectiveness of treatment was evaluated with regard to survival time, tumor response and determination of the activities of proteolytic enzymes and their inhibitors using flurogenic substrates. RESULTS: Cathepsins B and L activities were elevated by 16-fold in comparison with negative control tissues, and their endogenous inhibitor activity decreased by 1.2-fold before treatment. In several cases, tumors completely disappeared following vitamin E plus human placental cyteine protease inhibitor (CPI) compared with controls. The number of complete tumor responses was higher when 20 m/kg vitamin E plus 400 μg of CPI was used, i.e. 7/10 rats survived more than two mo. Cathepsins B and L were expressed significantly in tumor, liver, lung tissues and sera in parallel to the increasing of the endogenous inhibitor activity compared with the controls after treatment(P<0.0001) CONCLUSION: The data indicate formation of metastasis significantly reduced in treated rats, which might provide a therapeutic basis for anti-cancer therapy.
文摘A simple flow injection spectrophotometric method is reported for the determination of cysteine,N-acetyl cysteine and glutathione based on the reduction of Fe（Ⅲ）/ferricyanide,the in situ reduced ions are reacted with unreduced portion of ferricyanide/Fe（Ⅲ） to form soluble Prussian blue,which is monitored at 735 nm.The calibration graphs are linear in the concentration ranges of（1―100）×10-6 mol/L for cysteine and N-acetyl cysteine,and（1―50）×10-6 mol/L for glutathione.The relative standard deviations of 1.8%,2.5% and 1.9% were found for eleven replicate analyses of 5×10-6 mol/L cysteine,N-acetyl cysteine and glutathione.The limits of detection（3σ blank） at 5×10-7 mol/L for cysteine,and 3×10-7 mol/L for N-acetyl cysteine and glutathione were obtained.The proposed method allowed 60 injections/h.The effects of common substances present in pharmaceuticals and human physiological fluids were examined.The method was applied to determining cysteine in pharmaceutical formulations with the recoveries in a range of 97% to 106% and the results obtained are agreed well with labeled values.
基金supported by the National Natural Science Foundation of China for Excellent Young Scholars (No. 21622602)Distinguished Young Scholars (No. 21325625)+2 种基金 Oriental Scholarship, Fok Ying Tong Education Foundation (No. 142014)the Fundamental Research Funds for the Central Universities (Nos. WJ1616008, WK1013002)the State Key Laboratory of Fine Chemicals (No. KF1509)
文摘Curcuminoid difluoroboron has attractive performance as a promising near-infrared（NIR） fluorescent dye. In this contribution, we designed and synthesized a mitochondria-targeted NIR fluorescent probe DFB1 based on difluoroboron curcuminoid scaffold for the detection of Cys（cysteine）. DFB1 employs a curcumin analog as the NIR fluorophore, an acrylate group containing a, b-unsaturated ketone as a functional trigger moiety for Cys, and a triphenylphosphonium（TPP） cation moiety for specifically targeting mitochondria. The remarkable shift of DFB1 with Cys was observed from 470 nm to 590 nm in absorption spectra and from 560 nm to 680 nm in emission spectra. Notably, DFB1 manifests significantly dual-channel and turn-on NIR fluorescent signals simultaneously in response to Cys concentration,which make it favorable for monitoring endogenous Cys activity in vivo. This probe has high sensitivity and selectivity for the detection of Cys over homocysteine（Hcy） and glutathione（GSH）. This specific response for Cys was based on differences kinetics of intramolecular adduct/cyclizations. More importantly, biological experiments indicated that this probe could be utilized for the detection of endogenous mitochondrial Cys in living cells.
基金supported by the National Natural Science Foundation of China (Nos. 21462050 and 21672185)the Foundation of the Department of Science and Technology of Yunnan Province of China (Nos. 2013HB062, 2014HB008, 2016FB020,2016FB023)the Program for Excellent Youth Talents, Yunnan University (No. XT412003)
文摘A coumarin-based compound（1） was designed and synthesized as a new turn-on fluorescent probe for the detection of cysteine. The probe exhibited higher selectivity towards the target molecule over other thiol and amino acids at pH 7.2 in aqueous media CH_3CN-HEPES（0.02 mol/L, pH 7.2, 1：9, v/v）. The reaction mechanism is attributed to the cysteine-induced S_NAr substitution-rearrangement reaction. Remarkable enhancement of up to 20-fold in fluorescence intensity was achieved in the detection of cysteine. When applied for the fluorescence imaging of cysteine, the compound 1 emitted a green fluorescence in Hi5 cell cytoplasm. The in vivo imaging of Caenorhabditis elegans had further confirmed the cysteine detection by compound 1.
基金the NNSF of China(No.20175031,No.20035010)CAS(CMS-CX200104).
文摘A sensitive and selective chemiluminescence (CL) method was developed for the determination of cysteine. This method is based on that the weak CL of cysteine oxidized with cerium (IV) can be greatly enhanced by quinine, and the total cysteine in human serum can be detected through simply diluting with water, showing a simpler analytical characteristic.
文摘AIM: Cysteine peptidase (CP) and its inhibitor (CPI) are a matrix protease that may be associated with colorectal carcinoma invasion and progression, and vitamin E is also a stimulator of the immunological system. Our purpose was to determine the correlation between the expression of cysteine peptidases and their endogenous inhibitors,and the level of vitamin E in sera of patients with colorectal cancer in comparison with healthy individuals.METHODS: The levels of cysteine peptidases and their inhibitors were determined in the sera of patients with primary and metastatic colorectal carcinoma and healthy individuals using fluorogenic substrate, and the level of vitamin E was determined by HPLC.RESULTS: The levels of cysteine peptidases and their inhibitors were significantly higher in the metastatic colorectal cancer patients than that in the healthy controls (P＜0.05).The activity of CP increased 2.2-fold, CPI 2.8-fold and vitamin E decreased 3.4-fold in sera of patients with metastasis in comparison with controls. The level of vitamin E in healthy individuals was higher, whereas the activity of cysteine peptidases and their inhibitors associated with complexes was lower than that in patients with cancer of the digestive tract.CONCLUSION: These results suggest that the serum levels of CP and their inhibitors could be an indicator of the prognosis for patients with metastatic colorectal cancer. Vitamin E can be administered prophylactically to prevent digestive tract neoplasmas.
