OBJECTIVE:To observe the efficacy and safety of proton pump inhibitors combined with Compound digestive en-zyme tablet in the treatment of epigastric pain syndrome with abdominal distension. METHODS:156 patients with epigastric pain syndrome with abdominal distension were randomly divided into control group(75 cases)and observation group(81 cases). Con-trol group was given 40 mg Esomeprazole enteric-coated tablet for once half an hour before breakfast;observation group was addi-tionally given 243.6 mg Compound digestive enzyme tablet immediately after meal,3 times a day. The treatment course for both groups was 2 weeks. Clinical efficacy,clinical symptom score,pepsinogenⅠ(PGⅠ),pepsinogenⅡ(PGⅡ),2,4 h postprandial gastric emptying rate before and after treatment,and incidence of adverse reactions in 2 groups were observed. RESULTS:The to-tal effective rate in observation group was significantly higher than control group,the difference was statistically significant (P<0.05). There was no significant difference in the incidence of adverse reactions between 2 groups (P>0.05). Before treatment, there were no significant differences in the clinical symptom score,PGⅠ,PGⅡand 2,4 h postprandial gastric emptying rate(P>0.05). After treatment,clinical symptom score in 2 groups were significantly lower than before,and observation group was lower than control group;PGⅠ and PGⅡ in observation group were significantly higher than before and control group,the differences were statistically significant(P<0.05);and there were no significant differences in the 2,4 h postprandial gastric emptying rate be-tween 2 groups and PGⅠ and PGⅡ in control group before and after treatment(P>0.05). CONCLUSIONS:The efficacy of pro-ton pump inhibitors combined with Compound digestive enzyme tablet is superior to the proton pump inhibitors in the treatment of epigastric pain syndrome with abdominal distension,with similar safety.

Objective To investigate the relationship between regular exercise habit and coronary collaterals of patients with acute coronary syndrome (ACS).Methods TWo hundred and thirty-night patients diagnosed ACS and operated coronary angiography (CAG) showing severe coronary stenosis were enrolled hospitalized from May 2012 to October 2012.They were divided into regular exercise group (n =102) and irregular exercise group(n =137) according to the exercise frequency.The information of the general data,the information of CAG and other relevant index were collected.The coronary artery score was recorded according to the Censini and the coronary collateral class was made according to the Rentrop.Other characters in clinical and laboratory were recorded.Multi-factor regression analysis was used to analysis the influence factors of coronary collateral.Results The proportion of coronary collaterals (41.2％ (42/102)) in the regular exercise group was higher than that in the irregular exercise group (24.1％ (33/137)),and the difference was statistically significant(x2 =7.929,P =0.005).Lg(Gensini score) was (1.89 ± 0.18) the and (1.94 ± 0.19) in the regular exercise group,The left ventricular ejection fraction was 57.0％ (52.0％,60.0％) in the regular exercise group and 50.0％ (45.0％,57.0％) in the irregular exercise group,and the difference was statistically significant (Z =-5.152,P =0.000).Multi-factor regression analysis showed that regular exercise (OR =3.423,95％ CI:1.790-4.578),diabetes mellitus (OR =0.451,95％ CI:0.212-0.962),B-type natriuretic peptide (OR =2.412,95 ％ CI:1.271-4.578),non-ST-segment elevation ACS (OR =2.383,95％ CI:1.185-4.791),chest pain history (OR =2.207,95％ CI:1.175-4.145),Gensini score (OR =1.538,95％ CI:1.141-2.073) were independent influence factors of coronary collateral(P ＜ 0.05).After adjusting other factors,the patients with regular exercise had better coronary collaterals than that with irregular exercise (OR=3.423,95％CI:1.790-6.548,P ＜0.001).Conclusion The regular exercise can promote coronary collateral emergence for the patients with ACS.

Objective:To investigate the effect of rapamycin (Rapa) on apoptosis of acute myeloid leukemia THP-1 cells induced by idarubicin (IDA) and its molecular mechanism.Methods:The THP-1 cells were treated with 10, 20, 40 and 80 nmol/L Rapa for 1 h, and the cells without Rapa treatment were set up. Western blot was used to detect the conversion of autophagy marker LC3 protein in THP-1 cells (the ratio of LC3Ⅱ/LC3Ⅰ), flow cytometry was used to detect the apoptotic rate, and the pretreatment concentration of Rapa was determined. THP-1 cells were treated with different concentrations of IDA for 24 h, the cell proliferation inhibition rate of IDA for THP-1 cells was detected by CCK-8 method, and the half maximal inhibitory concentration ( IC50) was calculated. THP-1 cells with or without Rapa treatment were treated by IDA with the concentration of lower than IC50 for 24 h, CCK-8 method was used to detect cell proliferation inhibition rate, flow cytometry was used to detect cell apoptosis, real-time fluorescent quantitative polymerase chain reaction was used to detect the expression changes of autophagy-related genes Beclin-1, LC3 and p62, and Western blot was used to detect the conversion of autophagy marker LC3 protein. Results:The ratio of LC3Ⅱ/LC3Ⅰ in THP-1 cells treated by 20 nmol/L Rapa was higher than that in the untreated cells ( P=0.002 4). The apoptotic rate in THP-1 cells treated by 80 nmol/L Rapa was higher than that in the untreated cells ( P=0.007 3). According to the results of Western blot and flow cytometry, 20 nmol/L Rapa was selected as the pretreatment concentration. The IC50 of IDA for THP-1 cells treated with IDA for 24 h was 59.874 nmol/L. After treated with 50 nmol/L IDA for 24 h, the proliferation inhibitory [(69.67±5.03)% vs. (41.67±3.51)%] and apoptotic rates [(74.35±4.83)% vs. (41.25±5.24)%] in THP-1 cells pretreated by Rapa were higher than those in the unpretreated cells (both P<0.05); the Beclin-1 and LC3 mRNA expression levels and the ratio of LC3Ⅱ/LC3Ⅰ in THP-1 cells pretreated by Rapa were higher than those in the unpretreated cells, and the expression of p62 mRNA was lower than that in the unpretreated cells (all P<0.05). Conclusion:Rapa can enhance the apoptosis of THP-1 cells induced by a relative low dose of IDA, which may be achieved through inducing excessive autophagy in THP-1 cells.

Objective To study the expression of mitochondrial tumor suppressor gene 1 (MTUS1) mR-NA in papillary thyroid carcinoma(PTC).Methods Reverse transcription polymerase chain reaction(RT-PCR) was used to detect MTUS1 mRNA level in 68 cases of human PTC and the adjacent non-cancerous epithelium (NCE) specimens.Results The relative expression value of MTUS1 mRNA in PTC was 0.31 ± 0.09,while it was 0.65 ±0.12 in NCE.The difference had statistical significance between the 2 groups(t =2.39,P ＜0.05).In PTC,mRNA expression of MTUS1 gene was related to the pathological grade,and lymph node metastasis(P ＜ 0.05)while it was not related to patients' age,sex,differentiation degree,tumor size or TNM stage(P ＞ 0.05).Conclusion mRNA expression of MTUS1 gene is lower in PTC than in NCE,which may play an important role in carcinogenesis and progression of PTC.

Aim TostudytheeffectsofCuO,ZnOand TiO2 nanoparticles on the viability and metastatic po-tential of EC-9706 and EC-109 esophageal squamous carcinomacelllineinvitro.Methods Characteristics of CuO,ZnO and TiO2 nanoparticles were detected u-sing transmission electron microscope (TEM)and dy-namic light scattering (DLS ).EC-9706 and EC-109 cells were treated with different concentrations of CuO, ZnO and TiO2 (5 ~80 mg · L-1 ).The cell prolifera-tion was analyzed by MTT assay.The cell cycle and apoptotic rates were determined by flow cytometry (FCM).The cell invasion was assayed in Transwell chambers.The expression of Bcl-2 and caspase-3 pro-tein in cells was detected by Western blot method.Re-sults CuO,ZnOandTiO2nanoparticleswerespheri-cal with primary particle size 12,20. 6,12 nm.The particles were agglomerated in water and cell culture medium with negative charge.CuO and ZnO nanoparti-cles induced decreases in EC-9706 and EC-109 cell vi-ability dose-dependently.After exposed to increasing concentrations of CuO and ZnO nanoparticles,the cell cycle analysis revealed a decreasing proportion of cells in G2/Mand S phase,and up-regulation of the cells in G0/G1 phase.Apoptotic cells also increased along with decreased cell invasion upon CuO and ZnO treatment. Nanoparticles treatment after 48 h, the activated caspase-3 expression quantity increased significantly and the Bcl-2 expression quantity decreased obviously (P<0. 05 )compared with control group.TiO2 nanop-articles had no obvious effect on the EC-9706 and EC-109 cell proliferation,cell cycle,apoptosis and inva-sion.Conclusion ComparedwithTiO2,CuOand ZnO nanoparticles can inhibit EC-9706 and EC-109 cell viability and metastatic potential,the mechanism of action involves cell cycle arrest in G0/G1 phase and apoptosis.These findings can help the development of nanoparticles as anti-cancer therapeutics for esophageal cancer.

Objective:To explore the antitumor effect of ADU-S100/doxorubicin in situ vaccine on diffuse large B-cell lymphoma (DLBCL) and its mechanism.Methods:The 6-week-old female BALB/c mice were selected, and the bilateral murine subcutaneous B-cell lymphoma model was established with murine B-cell lymphoma A20 cells. The subcutaneous tumor-bearing mice were randomly divided into untreated group (without treatment), ADU-S100 in situ vaccine treatment group (intratumoral injection of interferon gene stimulating factor agonist ADU-S100), doxorubicin in situ vaccine treatment group (intratumoral injection of doxorubicin), and ADU-S100/doxorubicin in situ vaccine treatment group (intratumoral injection of ADU-S100 and doxorubicin) by using random number table method, with 5 mice in each group. The right tumors of the bilateral subcutaneous tumor-bearing mice were defined as proximal tumors, and the left tumors of the bilateral subcutaneous tumor-bearing mice were defined as distal tumors. Only the proximal tumors were treated via the intratumoral route, and the distal tumors were not treated. On day 23 after tumor inoculation, the percentages of CD11c + dendritic cells (DC), CD8 + CD11c + DC and CD80 + CD11c + DC in the spleen of mice in each group were detected by flow cytometry. The splenocytes of mice in each group were stimulated with A20 tumor cell lysate in vitro, the percentages of 5'-ethynyl-2'-deoxyuridine-positive (EdU +) cells and tumor necrosis factor-α-positive (TNF-α +) cells in CD8 + T cells in each in situ vaccine treatment group were detected by flow cytometry, and the killing effect of cytotoxic T lymphocyte (CTL) in each group was measured by using the lactate dehydrogenase (LDH) cytotoxicity assay kit. The mice treated with ADU-S100/doxorubicin in situ vaccine were intraperitoneally injected with anti-mouse CD8α (clone 53-6.7) mAb or isotype control on days 7, 12 and 17 after tumor inoculation to eliminate CD8 + cells. On day 23 after tumor inoculation, the proximal and distal tumor volumes of mice in the ADU-S100/doxorubicin in situ vaccine combined with anti-mouse CD8α (clone 53-6.7) mAb or isotype control treatment group were measured, the percentages of CD8 + T cells and CD8 + CD11c + DC in the spleen of tumor-bearing mice in these two groups were detected by flow cytometry, and the infiltration of CD8 + T cells in the tumor tissues from these two groups was detected by immunohistochemistry (IHC) staining. Results:On days 11, 14, 17, 20 and 23 after tumor inoculation, the proximal and distal tumor volumes of mice in each treated group were lower than those in the untreated group (all P < 0.05). The proportions of CD11c + DC in the spleen of the untreated group, ADU-S100 in situ vaccine treatment group, doxorubicin in situ vaccine treatment group and ADU-S100/doxorubicin in situ vaccine treatment group were (4.92±0.63)%, (7.54±0.84)%, (7.45±0.86)% and (11.63±0.85)%, respectively, and the difference was statistically significant ( F = 72.30, P < 0.001); the proportions of CD8 + CD11c + DC were (1.36±0.34)%, (4.02±0.43)%, (4.22±0.61)% and (6.11±0.73)%, respectively, and the difference was statistically significant ( F = 76.09, P < 0.001); the proportions of CD80 + CD11c + DC were (0.51±0.24)%, (1.69±0.23)%, (1.82±0.25)% and (4.09±0.39)%, respectively, and the difference was statistically significant ( F = 167.40, P < 0.001). The CTL responses and the proportion of EdU + cells and TNF-α + cells in CD8 + T cells in each in situ vaccine treatment group were higher than those in the untreated group (all P < 0.05). Furthermore, the enhanced CTL responses and the increased proportion of EdU + cells and TNF-α + cells in CD8 + T cells were observed in the ADU-S100/doxorubicin in situ vaccine treatment group as compared to the ADU-S100 in situ vaccine treatment group and doxorubicin in situ vaccine treatment group (all P < 0.05). The proportions of CD8 + T cells and CD8 + CD11c + DC in the spleen of mice treated with ADU-S100/doxorubicin in situ vaccine and anti-mouse CD8α mAb were lower than those in ADU-S100/doxorubicin in situ vaccine and isotype control group (both P < 0.05) and both proximal and distal tumor volumes of mice treated with ADU-S100/doxorubicin in situ vaccine and anti-mouse CD8α mAb were larger than those in ADU-S100/doxorubicin in situ vaccine and isotype control group (both P < 0.05). Conclusions:ADU-S100/doxorubicin in situ vaccine can induce profound regression of proximal tumors in bilateral murine subcutaneous B-cell lymphoma model and generate systemic immune responses capable of partially inhibiting distant tumor growth, and the antitumor efficacy of ADU-S100/doxorubicin in situ vaccine may require CD8 + CD11c + DC-mediated CD8 + T cell immune responses.

OBJECTIVETo identify novel common mutations among patients with non-syndromic hearing loss (NSHL).

METHODSHigh-throughput gene capture technology was used to analyze 18 patients with NSHL in whom common mutations of deafness genes including GJB2, SLC26A4, GJB3, and mtDNA were excluded. Suspected mutation was verified with Sanger sequencing.

RESULTSNext generation sequencing has identified 62 mutations in 29 genes associated with hearing loss, which included 54 missense mutations, 4 splicing mutations, 3 deletional mutations, and 1 nonsense mutation. Mutations occurring more than twice in the 18 patients were verified by Sanger sequencing. This has confirmed 15 mutations in 8 genes, including 3 missense mutations (p.C2184G, p.L2825P, p.H1888Y) which have not been reported previously. Meanwhile, p.L445W, p.D866N, and IVS919-2A>G were common causative mutations.

CONCLUSIONA number of common causative mutations, e.g., p.L445W, p.D866N, IVS919-2A>G, have been identified by high-throughput capture technology, which may facilitate the research and genetic diagnosis for hearing loss.

DNA, Mitochondrial ; genetics ; Deafness ; genetics ; Female ; Hearing Loss ; genetics ; High-Throughput Nucleotide Sequencing ; methods ; Humans ; Male ; Mutation ; genetics

Objective To investigate the expression of zinc finger protein 382(ZNF382)in diffuse large B-cell lymphoma(DLBCL)tissue and its relationship with clinical pathological characteristics and prognosis of DLBCL patients.Methods A total of 57 DLBCL patients admitted to the Department of Hematology,Luoyang Central Hospital from January 2014 to December 2018 were selected as the research subjects.The biopsy pathological specimens and clinical data of DLBCL patients were collected;another 20 patients of reactive proliferative lymph node tissue preserved in the Department of Pathology,Luoyang Central Hospital were taken as the control group.The expression of ZNF382 in DLBCL tissue and reactive proliferative lymph node tissue was detected by En vision two-step method.The difference of ZNF382 expression was compared between DLBCL tissue and reactive proliferative lymph node tissue.The correlations of ZNF382 expression with the clinical features such as age,gender,primary tumor site,Ann Arbor stage,international prognostic index(IPI)score,Hans typing,B-symptoms,bone marrow infiltration,giant masses,Eastern Cooperative Oncology Group(ECOG)score,β2-microglobulin(β2-MG),serum lactate dehydrogenase(LDH),Ki67,and chemotherapy regimen of DLBCL patients were analyzed by univariate analysis;the survival curve was drawed by Kaplan Meier method,and the univariate and multivariate survival analysis were performed by log-rank tests and Cox proportional risk regression models.Results The expression level of ZNF382 in DLBCL tissue was significantly lower than that in reactive proliferative lymph node tissue(Z=-5.056,P＜0.01).The expression level of ZNF382 was correlated with IPI score,Ann Arbor stage,Hans typing,B-symptoms,bone marrow infiltration and giant masses of DLBCL patients(P＜0.05);the expression level of ZNF382 was not associated to gender,age,primary site,ECOG score,β2-MG,serum LDH,Ki67,and whether the chemotherapy regimen combined with rituximab or not of DLBCL patients(P＞0.05).Among the 57 DLBCL patients,the treatment was effective in 36 patients(63.20％)and ineffective in 21 patients(36.80％);the expression level of ZNF382 in tumor tissue of DLBCL patients with effective treatment was significantly higher than that of DLBCL patients with ineffective treatment(Z=-2.895,P＜0.05).The 2-year event free survival rate of DLBCL patients in the ZNF382 high expression group was significantly higher than that in the ZNF382 low expression group(x2=17.955,P＜0.001).The results of univariate survival analysis showed that female,primary lymph nodes,B-symptoms,bone marrow infiltration,giant masses,IPI score≥3,elevated β2-MG,Ki67＞70％,non-germinal center B-cell-like lymphoma,Ann Arbor stageⅢ-Ⅳ and low expression of ZNF382 were risk factors for poor prognosis in DLBCL patients(P＜0.05).The results of multivariate analysis showed that primary lymph nodes,Ann Arbor stage Ⅲ-Ⅳ and low expression of ZNF382 were independent influencing factors for poor prognosis in DLBCL patients(P＜0.05).Conclusion ZNF382 protein is low expressed in the tumor tissues of DLBCL patients,which is closely related to the occurrence,development and prognosis of DLBCL;and it can be used as an indicator for evaluating the prognosis of DLBCL.

Objective To explore whether stimulator of interferon genes(STING)agonist ADU-S100 could enhance the antitumor immune response of a chitosan(CS)nanoparticle-mediated DNA vaccine containing a tumor-specific antigen Dickkopf-related protein 1(DKK1)in multiple myeloma(MM).Methods CS-DNA nanoparticles were prepared by using the compound coprecipitation method.The particle sizes and Zeta potential of the CS-DNA nanoparticles were measured by using the Zetasizer Nano-ZS laser particle size analyzer.The DNA protection effect and in vivo DNA expression efficiency of the CS-DNA nanoparticles were assessed by using gel retardation assay and Western blot,respectively.The lentiviruses expressing human DKK1(hDKK1)genes were used to establish MPC-11 cells(MPC-11-hDKK1)which stably expressed hDKK1,and the MPC-11-hDKK1 cells were subcutaneously given to mice to construct tumor models.The tumor-bearing mice were randomly divided into a control group(intramuscular injection of CS-pcDNA3.1),an ADU-S100 immunization group(subcutaneous injection of ADU-S100),a CS-pDKK1 immunization group(intramuscular injection of CS-pDKK1)and an ADU-S1OO/CS-pDKK1 co-immunization group(intramuscular injection of CS-pDKK1+subcutaneous injection of ADU-S100),with 5 mice in each group.The tumor-bearing mice in each group were immunized 3 times at 10-day intervals according to the corresponding immunization schedule.The size of tumor was measured every week.On day 42 after MPC-11-hDKK1 cell inoculation,the tumor weight of mice in each immunization group was measured;the percentages of CD11c+dendritic cell(DC),CD8+CD11c+DC and major histocompatibility complex class Ⅱ(MHCII)+CD11c+DC subsets in the spleen of mice in each immunization group were detected by using flow cytometry.The splenocytes of mice in each group were stimulated with recombinant hDKK-1 protein in vitro,the percentage of EdU+cells in CD8+T lymphocytes in each immunization group was detected by using flow cytometry,and the killing effect of cytotoxic T lymphocyte(CTL)in each group was assessed by using the lactate dehydrogenase(LDH)cytotoxicity assay kit.Results The particle size and Zeta potential of the CS-DNA nanoparticles were(204.3±2.31)nm and(15.47±1.01)mV,respectively.Gel retardation assay showed that DNA enveloped in CS nanoparticles could be completely retarded.Western blot analysis indicated that CS-DNA nanoparticles could be effectively expressed in vivo.The relative expression of DKK1 protein was significantly higher in MPC-11-hDKK1 cells than in MPC-11-Ctrl cells(P＜0.05).On days 7 and 14 after MPC-11-hDKK1 cell inoculation,there was no significant difference in tumor volume of mice between the ADU-S100 immunization group,CS-pDKK1 immunization group,ADU-S100/CS-pDKK1 co-immunization group and the control group(P＞0.05);on days 21,28,35 and 42 after MPC-11-hDKK1 cell inoculation,the tumor volumes of mice in the ADU-S100 immunization group,CS-pDKK1 immunization group and ADU-S100/CS-pDKK1 co-immunization group were significantly lower than those in the control group(P＜0.05);the tumor volume of mice in the ADU-S100/CS-pDKK1 co-immunization group was significantly lower than that in the ADU-S100 immunization group and CS-pDKK1 immunization group(P＜0.05).On day 42 after MPC-11-hDKK1 cell inoculation,the tumor weight of mice in the ADU-S100 immunization group,CS-pDKK1 immunization group and ADU-S1 OO/CS-pDKK1 co-immunization group was significantly lower than that in the control group(P＜0.05);the tumor weight of mice in the ADU-S100/CS-pDKK1 co-immunization group was significantly lower than that in the ADU-S100 immunization group and CS-pDKK1 immunization group(P＜0.05).The proportions of CD11c+DC,CD8+CD11c+DC and MHCII+CD11c+DC subsets in the spleen of mice in the ADU-S100 immunization group,CS-pDKK1 immunization group and ADU-S100/CS-pDKK1 co-immunization group were significantly higher than those in the control group(P＜0.05).The proportions of CD11c+DC,CD8+CD11c+DC and MHCII+CD11c+DC subsets in the spleen of mice in the ADU-S100/CS-pDKK1 co-immunization group were significantly higher than those in the ADU-S100 immunization group and CS-pDKK1 immunization group(P＜0.05).The CTL killing effect and the proportion of EdU+cells in CD8+T lymphocytes in the ADU-S100 immunization group,CS-pDKK1 immunization group and ADU-S1OO/CS-pDKK1 co-immunization group were significantly higher than those in the control group(P＜0.05);the CTL killing effect and the proportion of EdU+cells in CD8+T lymphocytes in the ADU-S100/CS-pDKK1 co-immunization group were significantly higher than those in the ADU-S100 immunization group and CS-pDKK1 immunization group(P＜0.05).Conclusion STING agonist ADU-S100 can significantly improve the antitumor immunity of the CS-pDKK1 nanoparticle vaccine in MM,and this vaccine strategy provides a potential treatment approach for MM.

Objective:To explore the interventional effect of β-sitosterol on ovalbumin(OVA)-induced allergic asthma rats and its potential mechanism.Methods:SD male rats were randomly divided into normal group(CON),model group(M),positive drug dexamethasone group(DEX,0.075 mg/kg)and β-sitosterol group(Sit,50 mg/kg).A rat model of allergic asthma was estab-lished by intraperitoneal injection of OVA with aluminum hydrogen solution,and nebulized inhalation of OVA to stimulate.Rats were given intragastric administration 30 min before aerosol challenge,and after continuous administration for 7 days,the indicators of cough and asthma and tracheal phenol red excretion were detected.HE staining was used to observe pathological changes of lung tis-sue.Flow cytometry was used to detect reactive oxygen species(ROS)generation,apoptosis level and ratios of Th17 and Treg cells in peripheral blood.Biochemical method was used to detect contents of MDA,and activities of T-SOD and GSH-Px in rat lung tissues.ELISA was used to detect levels of Th17 and Treg-related cytokines(TNF-α,IL-4,IL-6,IL-17A,and IL-35).Results:Compared with model group,β-sitosterol significantly prolonged the incubation period of cough and gasp in rats with allergic asthma,reduced the frequency of cough and gasping,and promoted the excretion of phenol red in trachea;significantly reduced inflammatory infiltration in lung tissue of asthmatic rats;observably reduced MDA content in lung tissue,ROS of primary lung cell and apoptosis levels of asthmatic rats,increased the activities of T-SOD and GSH-Px;markedly reduced proportion of Th17 cells and levels of pro-inflammatory cyto-kines TNF-α,IL-4,IL-6 and IL-17A,increased proportion of Treg cells and levels of anti-inflammatory cytokine IL-35.Conclusion:β-sitosterol can ameliorate airway inflammation and oxidative damage in OVA-induced allergic asthmatic rats,and its mecha-nism may be related to the regulation of β-sitosterol on Th17/Treg immune imbalance and oxidative stress response.