Exosomal hsa_circ_0125310 promotes cell proliferation and fibrosis in diabetic nephropathy via sponging miR-422a and targeting the IGF1R/p38 axis.

Diabetic nephropathy (DN) is still on the rise worldwide, and millions of patients have to be treated through dialysis or transplant because of kidney failure caused by DN. Recent reports have highlighted circRNAs in the treatment of DN. Herein, we aimed to investigate the mechanism by which high glucose-induced exo-circ_0125310 promotes diabetic nephropathy progression. circ_0125310 is highly expressed in diabetic nephropathy and exosomes isolated from high glucose-induced mesangial cells (MCs). High glucose-induced exosomes promote the proliferation and fibrosis of MCs. However, results showed that the effects of exosomes on MCs can be reversed by the knockdown of circ_0125310. miR-422a, which targets IGF1R, was the direct target of circ_0125310. circ_0125310 regulated IGF1R/p38 axis by sponging miR-422a. Exo-circ_0125310 increased the luciferase activity of the WT-IGF1R reporter in the dual-luciferase reporter gene assays and upregulated the expression level of IGF1R and p38. Finally, in vivo research indicated that the overexpression of circ_0125310 promoted the diabetic nephropathy progression. Above results demonstrated that the high glucose-induced exo-circ_0125310 promoted cell proliferation and fibrosis in diabetic nephropathy via sponging miR-422a and targeting the IGF1R/p38 axis.

Circ-AKT3 inhibits the accumulation of extracellular matrix of mesangial cells in diabetic nephropathy via modulating miR-296-3p/E-cadherin signals.

Diabetic nephropathy is a leading cause of end-stage renal disease globally. The vital role of circular RNAs (circRNAs) has been reported in diabetic nephropathy progression, but the molecular mechanism linking diabetic nephropathy to circRNAs remains elusive. In this study, we investigated the significant function of circ-AKT3/miR-296-3p/E-cadherin regulatory network on the extracellular matrix accumulation in mesangial cells in diabetic nephropathy. The expression of circ-AKT3 and fibrosis-associated proteins, including fibronectin, collagen type I and collagen type IV, was assessed via RT-PCR and Western blot analysis in diabetic nephropathy animal model and mouse mesangial SV40-MES13 cells. Luciferase reporter assays were used to investigate interactions among E-cadherin, circ-AKT3 and miR-296-3p in mouse mesangial SV40-MES13 cells. Cell apoptosis was evaluated via flow cytometry. The level of circ-AKT3 was significantly lower in diabetic nephropathy mice model group and mouse mesangial SV40-MES13 cells treated with high-concentration (25 mmol/L) glucose. In addition, circ-AKT3 overexpression inhibited the level of fibrosis-associated protein, such as fibronectin, collagen type I and collagen type IV. Circ-AKT3 overexpression also inhibited the apoptosis of mouse mesangial SV40-MES13 cells treated with high glucose. Luciferase reporter assay and bioinformatics tools identified that circ-AKT3 could act as a sponge of miR-296-3p and E-cadherin was the miR-296-3p direct target. Moreover, circ-AKT3/miR-296-3p/E-cadherin modulated the extracellular matrix of mouse mesangial cells in high-concentration (25 mmol/L) glucose, inhibiting the synthesis of related extracellular matrix protein. In conclusion, circ-AKT3 inhibited the extracellular matrix accumulation in diabetic nephropathy mesangial cells through modulating miR-296-3p/E-cadherin signals, which might offer novel potential opportunities for clinical diagnosis targets and therapeutic biomarkers for diabetic nephropathy.

Loss of lncRNA MIAT ameliorates proliferation and fibrosis of diabetic nephropathy through reducing E2F3 expression.

Diabetic nephropathy (DN) is a serious kidney disease resulted from diabetes. Dys-regulated proliferation and extracellular matrix (ECM) accumulation in mesangial cells contribute to DN progression. In this study, we tested expression level of MIAT in DN patients and mesangial cells treated by high glucose (HG). Up-regulation of MIAT was observed in DN. Then, functional assays displayed that silence of MIAT by siRNA significantly repressed the proliferation and cycle progression in mesangial cells induced by HG. Meanwhile, we found that collagen IV, fibronectin and TGF-ß1 protein expression was obviously triggered by HG, which could be rescued by loss of MIAT. Then, further assessment indicated that MIAT served as sponge harbouring miR-147a. Moreover, miR-147a was decreased in DN, which exhibited an antagonistic effect of MIAT on modulating mesangial cell proliferation and fibrosis. Moreover, bioinformatics analysis displayed that E2F transcription factor 3 (E2F3) could act as direct target of miR-147a. We demonstrated that E2F3 was greatly increased in DN and the direct binding association between miR-147a and E2F3 was evidenced using luciferase reporter assay. In summary, our data explored the underlying mechanism of DN pathogenesis validated that MIAT induced mesangial cell proliferation and fibrosis via sponging miR-147a and regulating E2F3.

Long noncoding RNA Gm6135 functions as a competitive endogenous RNA to regulate toll-like receptor 4 expression by sponging miR-203-3p in diabetic nephropathy.

We aim to explore the relationship between Gm6135 and diabetic nephropathy. We detected the relative expression levels of Gm6135 and toll-like receptor 4 (TLR4) in diabetic nephropathy mice and high-glucose-cultured mouse mesangial cells SV40-MES-13 by the quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot detection. Cell proliferation and apoptosis were detected after small interfering RNA (siRNA) interference or plasmid overexpression of Gm6135/TLR4, and bioinformatics method was used to predict and screen miR-203 as an intermediate factor. Through dual-luciferase reporter gene, RNA pull-down, qRT-PCR, and western blot, the binding relationship between Gm6135, miR-203-3p, and TLR4 was confirmed. The possibility of the competing endogenous RNA mechanism was demonstrated by cell localization assays and rip assays. Finally, the proliferation of mouse mesangial cells SV40-MES-13 was detected after mimics and inhibitor of microRNA, which were reversed with TLR4 overexpression and siRNA. The results showed that the relative expression levels of Gm6135 and TLR4 in the kidney and high-glucose-cultured mouse mesangial cells of diabetic nephropathy mice increased significantly. Overexpression or downregulation of Gm6135/TLR4 significantly affected the proliferation and apoptosis of mouse mesangial cells. Gm6135 upregulates TLR4 by competitively binding to miR-203-3p.

SERPINH1 promoted the proliferation and metastasis of colorectal cancer by activating PI3K/Akt/mTOR signaling pathway.

BACKGROUND: Serpin peptidase inhibitor clade H member 1 (SERPINH1) was initially recognized as an oncogene implicated in various human malignancies. Nevertheless, the clinical relevance and functional implications of SERPINH1 in colorectal cancer (CRC) remain largely elusive. AIM: To investigate the effects of SERPINH1 on CRC cells and its specific mechanism. METHODS: Quantitative real-time polymerase chain reaction, western blotting analysis, The Cancer Genome Atlas data mining and immunohistochemistry were employed to examine SERPINH1 expression in CRC cell lines and tissues. A series of in-vitro assays were performed to demonstrate the function of SERPINH1 and its possible mechanisms in CRC. RESULTS: SERPINH1 demonstrated elevated expression levels in both CRC cells and tissues, manifested at both mRNA and protein tiers. Elevated SERPINH1 levels correlated closely with advanced T stage, lymph node involvement, and distant metastasis, exhibiting a significant association with poorer overall survival among CRC patients. Subsequent investigations unveiled that SERPINH1 overexpression notably bolstered CRC cell proliferation, invasion, and migration in vitro, while conversely, SERPINH1 knockdown elicited the opposite effects. Gene set enrichment analysis underscored a correlation between SERPINH1 upregulation and genes associated with cell cycle regulation. Our findings underscored the capacity of heightened SERPINH1 levels to expedite G1/S phase cell cycle progression via phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway activation, thereby facilitating CRC cell invasion and migration. CONCLUSION: These findings imply a crucial involvement of SERPINH1 in the advancement and escalation of CRC, potentially positioning it as a novel candidate for prognostic assessment and therapeutic intervention in CRC management.

Alisol B 23-acetate adjusts bile acid metabolisim via hepatic FXR-BSEP signaling activation to alleviate atherosclerosis.

BACKGROUND: Postmenopausal women have a high incidence of atherosclerosis. Phytosterols have been shown to have cholesterol-lowering properties. Alisa B 23-acetate (AB23A) is a biologically active plant sterol isolated from Chinese herbal medicine Alisma. However, the atherosclerosis effect of AB23A after menopause and its possible mechanism have not been reported yet. PURPOSE: To explore whether AB23A can prevent atherosclerosis by regulating farnesoid X receptor and subsequently increasing fecal bile acid and cholesterol excretion to reduce plasma cholesterol levels. METHODS: Aortic samples from premenopausal and postmenopausal women with ascending aortic arteriosclerosis were analyzed, and bilateral ovariectomized (OVX) female LDLR-/- mice and free fatty acid (FFA)-treated L02 cells were used to analyze the effect of AB23A supplementation therapy. RESULTS: AB23A increased fecal cholesterol and bile acids (BAs) excretion dependent on activation of hepatic farnesoid X receptor (FXR) in ovariectomized mice. AB23A inhibited hepatic cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) via inducing small heterodimer partner (SHP) expression. On the other hand, AB23A increased the level of hepatic chenodeoxycholic acid (CDCA), and activated the hepatic BSEP signaling. The activation of hepatic FXR-BSEP signaling by AB23A in ovariectomized mice was accompanied by the reduction of liver cholesterol, hepatic lipolysis, and bile acids efflux, and reduced the damage of atherosclerosis. In vitro, AB23A fixed abnormal lipid metabolism in L02 cells and increased the expression of FXR, BSEP and SHP. Moreover, the inhibition and silencing of FXR canceled the regulation of BSEP by AB23A in L02 cells. CONCLUSION: Our results shed light into the mechanisms behind the cholesterol-lowering of AB23A, and increasing FXR-BSEP signaling by AB23A may be a potential postmenopausal atherosclerosis therapy.

Knockdown of ZNF479 inhibits proliferation and glycolysis of gastric cancer cells through regulating ß-catenin/c-Myc signaling pathway.

Gastric cancer is the fifth most common malignancy and the third most deadly tumor in the world. Zinc finger protein 479 (ZNF479) has been demonstrated to play crucial roles in hepatocellular carcinoma. However, the function of ZNF479 in gastric cancer remains to be clarified. The current study aimed to investigate the role of ZNF479 in gastric cancer progression and elucidate the potential molecular mechanism. In this study, Cell Count Kit-8 and colony formation assays demonstrated that knockdown of ZNF479 inhibited cell proliferation in AGS and SGC-7901 cells. Of note, knockdown of ZNF479 hinders tumor growth of xenograft tumor mice. What is more, knockdown of ZNF479 inhibited glucose uptake, lactate production, adenosine triphosphate level, and extracellular acidification ratio; increased oxygen consumption ratio in gastric cancer cells; and decreased the expression of glycolytic proteins both in vitro and in vivo. Furthermore, analysis mechanism suggests that ZNF479 participated in the regulation of gastric cancer progression through affecting the ß-catenin/c-Myc signaling pathway. Collectively, ZNF479 plays a role as an oncogene through modulating ß-catenin/c-Myc signaling pathway in the development of gastric cancer, which provides a new research target for future studies.

[Reaserch Advance on Inhibitor Targeting at the B-Cell Receptor Pathway in Chronic Lymphocytic Leukemia --Review].

Abstract　　Disregulated BCR signaling pathway plays an important role in the occurence and progress of chronic lymphocytic leukemia (CLL). As key kinases of BCR pathway, the Bruton tyrosine kinase (BTK), phosphoinositide 3-kinase (PI3K) and spleen tyrosine kinase (SYK) have become the focus of CLL targeted therapy. Over the past decade, drugs targeting of BCR pathway for CLL treatment have been continuously developed, including BTK inhibitors, PI3K inhibitors and SYK inhibitors. To date, the BTK inhibitor Ibrutinib, PI3K inhibitors Idelalisib and Duvelisib have been approved for CLL treatment, and some novel inhibitors are still in clinical trials. These targeted drugs are much less toxic than chemoimmunotherapy and show better efficacy in certain high-risk patients such as del 17P. These inhibitors targeted BCR pathway are increasingly prominent in CLL treatment and gradually replace traditional chemoimmunotherapy.

[Research Advance on the Role of Spleen Tyrosine Kinase Inhibitors in Hematologic Malignancies].

Abstract　　Spleen tyrosine kinase (SYK) is not only a key kinase in the B-cell receptor (BCR) signaling pathway, but also a critical component of other signal transduction pathways such as Fc receptor, complement receptor and integrin. Abnormal activation of SYK closely related to the occurrence and development of hematological malignancies, thus targeting SYK has become a research hotspot. Several SYK inhibitors including Fostamatinib, Entospletinib and Cerdulatinib were being evaluated in clincal trials. As a second generation SYK inhibitor, Entospletinib has achieved good efficacy in lymphoid and myeloid hematologic tumors. Furthermore, Entospletinib can significantly relieve hematopoietic stem cell transplantation(HCT) related graft versus host disease (GVHD). In this review the role of SYK inhibitors in treatment of hematological malignancies is summarized brifely.

[Reaserch Advance on Bruton Tyrosine Kinase Inhibitors in the Treatment of B-Cell Tumors--Review].

Abstract　　In recent years, development of the targeted drugs according to the biological characteristics of tumors have provided more treatment options for tumor patients. It was found that the overactivation or abnormality of B cell receptor (BCR) signal pathway closely related to the occurrence and development of various B cell tumors, such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). As a key kinase in the BCR pathway, BTK inhibitors have obvious anti-tumor effect when its activity is being inhibitered. Currently, BTK inhibitors developed include the first-generation Ibrutinib and the second-generation Acalabrutinib, which can be targeted at the inhibition of BTK and its downstream signaling pathway, and have important therapeutic value for a variety of B-cell tumors, such as CLL and partial non-Hodgkin's lymphoma (NHL). However, its side effects and drug-resistance also gradually emerged, effective drug combination therapy has shown a certain clinical activity. This reviews summarizes briefly the mechanism and status of BTK inhibitors in the treatment of various B-cell tumors.

[Research Progress of m6A-Methylation in Acute Leukemia-Review].

OBJECTIVE: Epigenetic abnormalities play an important role in the pathogenesis of hematological malignancies, especially acute leukemia (AL). Similar to DNA methylation and histone modifications, RNA methylation is another important epigenetic modification. m6A methylation is one of the most prevalent and extensively studied RNA methylation. m6A methylation is involved in many biological and pathological process. Recent studies have found that m6A methylation is involved in the occurrence, development and drug-resistance of AL. This review focuses on the research progress of m6A methylation in AL.

[Randomized Controlled Clinical Trials of Treatment of Knee Osteoarthritis of Yang-deficiency Pattern by Acupuncture Plus Moxibustion].

OBJECTIVE: To compare the therapeutic effect of acupuncture plus moxibustion and simple acupuncture in the treatment of patients with knee osteoarthritis (KOA) of yang-deficiency syndrome. METHODS: Fifty-eight KOA patients with yang-deficiency syndrome were chosen and randomly divided into acupuncture plus moxibustion group (n＝30) and acupuncture group (n＝28). Neixiyan (EX-LE 4), Dubi (ST 35), Liangqiu (ST 34), Heding (EX-LE 2), Xuehai (SP 10), Yanglingquan (GB 34) on the affected side of the body were punctured with filiform needles or/and stimulated with moxibustion using seed-sized moxa cones. The treatment was conducted once daily for 10 days, followed with another 10 days after 2 days interval. The pain severity was evaluated by using visual analogue scale (VAS), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were used to measure the KOA pain, stiffness and function before and after the treatment, and 1 month after the treatment. The therapeutic effect was also evaluated according to the "Standards for Diagnosis and Therapeutic Effect Evaluation of Diseases/Syndromes of Traditional Chinese Medicine" (issued by the State Administration of Traditional Chinese Medicine of China in 1994). RESULTS: Twenty days and 1 month after the treatment, the scores of VAS, and KOA pain, stiffness and motor function of WOMAC were significantly decreased in both groups in comparison with their own pre-treatment (P<0.01), and were obviously lower in the acupuncture plus moxibustion group than in the acupuncture group (P<0.05, P<0.01). Of the 28 and 30 cases in the acupuncture and acupuncture plus moxibustion groups, 7 and 12 experienced marked improvement, 12 and 16 were effective, 9 and 2 ineffective, with the therapeutic effect being 67.86% and 93.33%, respectively. The therapeutic effect of acupuncture plus moxibustion was apparently superior to that of simple acupuncture (P<0.05). CONCLUSION: Acupuncture plus moxibustion is significantly superior to simple acupuncture therapy in relieving symptoms of KOA patients, and also has a better post-effect.

Abnormality of spontaneous brain activities in patients with chronic neck and shoulder pain: A resting-state fMRI study.

Objectives Chronic gneck and shoulder pain (CNSP) is a common clinical symptom of cervical spondylotic radiculopathy. Several studies using resting-state functional magnetic resonance imaging (rs-fMRI) have reported that most chronic pain diseases are accompanied by structural and functional changes in the brain. However, few rs-fMRI studies have examined CNSP. The current study investigated cerebral structural and functional changes in CNSP patients. Methods In total, 25 CNSP patients and 20 healthy volunteers participated in the study. 3D-T1W and rs-fMRI images were acquired. Voxel-based morphometry analysis was applied to structural images, and regional homogeneity (ReHo) was extracted from rs-fMRI. Statistical analysis was performed on post-processing images and ReHo parameter maps. Results The results revealed no significant differences in brain structure between the two groups. In the patient group, ReHo values were significantly increased in the bilateral middle frontal gyrus and decreased in the left insula, superior frontal gyrus, middle cingulate gyrus, supplementary motor area, right postcentral gyrus, and superior parietal lobule. Conclusions This initial structural and rs-fMRI study of CNSP revealed characteristic features of spontaneous brain activity of CNSP patients. These findings may be helpful for increasing our understanding of the neuropathology of CNSP.

Altered functional connectivity of the periaqueductal gray in chronic neck and shoulder pain.

Chronic neck and shoulder pain with cervical spondylotic radiculopathy (CNSP-CSR) is one of the most common clinical chronic pain diseases. This study aimed to investigate the abnormal patterns in functional connectivity (FC) pertaining to the periaqueductal gray matter (PAG) in patients with CNSP-CSR. A seed-based FC analysis was carried out for the right ventrolateral PAG and a correlation analysis was carried out with pain intensity, duration, and the extracted mean z scores. The PAG FC was significantly positively associated with the right orbital inferior frontal gyrus, supramarginal gyrus/postcentral gyrus, putamen, and the left anterior cingulate cortex, and significant negative FC was observed in the right lingual gyrus/occipital cortex in patients with CNSP-CSR. A significant negative correlation was found between the pain intensity and the mean z scores in the left anterior cingulate cortex. Our study provides evidence to show that patients with CNSP-CSR have abnormal FC in the PAG-centered pain modulation network. Knowledge of this abnormal FC might lead to a better understanding of the mechanism underlying CNSP-CSR, especially the descending pain modulation system involved in chronic pain.

The prognostic value of lymph nodes count on survival of patients with node-negative gastric cancer.

The retrieved lymph node (LN) count has been validated as a prognostic factor in various cancers. However, the interaction between LN counts and patients' prognosis in gastric cancer with negative-LN metastasis is not fully studied. Surveillance, Epidemiology, and End Results Program (SEER)-registered gastric cancer patients were used for analysis in this study. Patients operated on for gastric cancer at N0 stage between 2004 and 2012 were identified from the SEER database. The association between the LN counts and survival was assessed using the Cox proportional hazards model. Patients were stratified into 1-4, 5-13, and > 13 subgroups according to LN count cut-off values determined by X-tile program, with the 5-year cause specific survival (CSS) rate of 64.8%, 72.5%, and 79.4%, respectively. LN count was also validated as an independently prognostic factor in multivariate Cox analysis (P < 0.001). In addition, nomograms including LN counts on CSS were established according to all significant factors, and the c-index was 0.703 (95% CI: 0.672-0.734). Further study indicated that patients with no LN metastasis had a decreased risk of death for each patient with LN examined up to approximately 14 LNs. Collectively, our study firmly demonstrated that the number of the retrieved LNs count was an independent prognostic factor for gastric cancer with no LN metastasis. The higher the LN count, the better the survival would be; the best CSS was observed on the LN count more than 14.

Inhibition of long non-coding RNA TUG1 on gastric cancer cell transference and invasion through regulating and controlling the expression of miR-144/c-Met axis.

OBJECTIVE: To discuss the expression of long noncoding RNA TUG1 (lncRNA-TUG1) in gastric carcinoma (GC) and its effects on the transferring and invading capacity of gastric carcinoma cells. METHODS: Forty cases of carcinoma tissue and para-carcinoma tissue were selected from GC patients who underwent surgical removal in Zhejiang Provincial Hospital of Chinese Traditional Medicine and Wenzhou Central Hospital from January, 2013 to December, 2014; the expressing level of lncRNA-TUG1 in GC and para-C tissues was detected by applying the qRT-PCR technique. The correlation between lncRNA-TUG1 expression and patients' clinical data was classified and analyzed. SGC-7901 cells were transfected using lncRNA-TUG1 specific siRNA. Changes of the transferring and invading capacity of siRNA-transfected SGC-7901 cells were scratch-tested and transwell-detected. qRT-PCR was applied to detect the expression level of microRNA-144 after lncRNA-TUG1 was silenced. Changes of c-Met mRNA and protein expressions was detected by qRT-PCR and western-blot test. RESULTS: The expression level of lncRNA-TUG1 in GC tissue was significant higher than that in para-C tissue (P < 0.05) and the high expression level of lncRNA-TUG1 in GC tissue was significantly correlated with tumor lymph nodes metastasis and advance TNM phasing (P < 0.05). The transferring and invading capacity of SGC-7901 cells was highly inhibited after being transfected by lncRNA-TUG1 specific siRNA (P < 0.05). The results of qRT-PCR and western-blot proved that the expression of microRNA-144 was significantly boosted and the expression level of c-Met mRNA and protein was inhibited after lncRNA-TUG1 was silenced (P < 0.05). CONCLUSIONS: lncRNA-TUG1 shows an up-regulated expression in GC tissue and that bears a correlation with clinicopathological features of malignant tumor. lncRNA-TUG1 can promote the transferring and invading capacity of GC by inhibiting the pathway of microRNA-144/c-Met.

Difference in thermotolerance between green and red color variants of the Japanese sea cucumber, Apostichopus japonicus Selenka: Hsp70 and heat-hardening effect.

We studied thermal tolerance limits, heat-hardening, and Hsp70 to elucidate the difference in thermotolerance between two color variants of the sea cucumber Apostichopus japonicus. Green and Red variants occupy different habitats and have different aestivation responses to high temperature in summer. In the absence of heat-hardening, the variants showed no difference in the temperature at which 50% of the individuals died: Green, 31.49 degrees C; Red, 31.39 degrees C. However, Green specimens acquired higher thermotolerance than Red after a prior sublethal heat exposure. After 72 h of recovery from a heat-hardening treatment (30 degrees C for 2 h), the survival of Green variants was more than 50% and that of Red was less than 5% when they were treated at 33 degrees C for 2 h. Levels of mRNA and protein for Hsp70 were significantly higher in Green than Red after the heat shock of 30 degrees C, and the stability of hsp70 mRNA of Green was significantly higher than that of Red. Our findings suggest that within the same species, different variants that have similar thermal limits in the absence of heat-hardening can acquire different thermotolerances after a prior sublethal heat shock. The difference in induced thermotolerance between Green and Red is closely related to the expression pattern of Hsp70, which was partly governed by the stability of hsp70 mRNA.

Oxidative damage increased in presenilin1/presenilin2 conditional double knockout mice.

OBJECTIVE: This report aims to describe the oxidative damage profile in brain of presenilin1 and presenilin2 conditional double knockout mice (dKO) at both early and late age stages, and to discuss the correlation between oxidative stress and the Alzheimer-like phenotypes of dKO mice. METHODS: The protein level of Abeta(42) in dKO cortex and free 8-OHdG level in urine were measured by ELISA. Thiobarbituric acid method and spectrophotometric DNPH assay were used to determine the lipid peroxidation and protein oxidation in cortex, respectively. SOD and GSH-PX activities were assessed by SOD Assay Kit-WST and GSH-PX assay kit, separately. RESULTS: Significant decrease of Abeta(42) was verified in dKO cortex at 6 months as compared to control mice. Although lipid peroxidation (assessed by MDA) was increased only in dKO cortex at 3 months and protein oxidation (assessed by carbonyl groups) was basically unchanged in dKO cortex, ELISA analysis revealed that free 8-OHdG, which was an indicator of DNA lesion, was significantly decreased in urine of dKO mice from 3 months to 12 months. Activities of SOD and GSH-PX in dKO and control cortices showed no statistical difference except a significant increase of GSH-PX activity in dKO mice at 9 months. CONCLUSION: Oxidative damage, especially DNA lesion, was correlated with the neurodegenerative symptoms that appeared in dKO mice without the deposition of Abeta(42). Triggers of oxidative damage could be the inflammatory mediators released by activated microglia and astrocytes.