Objective:To assess the role of EGFR mutations on pemetrexed response in patients with advanced lung adenocarcino-ma. Method: Forty pulmonary adenocarcinoma patients with evaluable lesions were retrospectively screened .They had been treated with pemetrexed-included chemotherapy and had EGFR gene test results. The evaluation endpoints were overall response rate,disease control rate and progression free survival. Result:No significant statistical difference was seen in overall response rate(ORR) (44.4%VS 31.8%, respectively) and disease control rate(DCR) (88.9%VS 81.8%, respectively ) between EGFR wild group and EGFR muta-tion group, but patients in EGFR wild group had longer progression free survival(PFS) ( 8.9 months VS 5.3 months;P=0.046). Conclu-sion:EGFR mutation status can influence the efficacy of pemetrexed.

OBJECTIVE CYP2 family including CYP2C and CYP2J is the predominant arachidonic acid (AA) epoxygenase, and the epoxidation of AA produces four regioisomeric cis-epoxyeicosatrienoic acids (5,6-, 8,9-, 11,12-, and 14,15-EET). Human CYP2J2 is one of the main CYP isoforms expressed in brain, but CYP2C8 was present at a low level. The aim of this study is to investigate the roles of brain CYP2J in Parkinson disease. METHODS Rats received the right-unilaterally injection with concentrated LV-CYP2J3 or LV-EGFP in the substantia nigra (SN) at 3 d before LPS or 6-OHDA treatment. The animals were tested for rotational behavior with the dopaminergic agonist apomorphine dissolved in sterile saline at 14 and 21 d after LPS injection. The influence of CYP2J-dependent derivative, 14,15-EET, on the genes related with oxidative stress was assayed in SH-SY5Y cells. RESULTS CYP2J overexpression or 14,15-EET treatment significantly increased the levels of SOD1, CAT, GPX1, NRF2 and KEAP1 in neurons. TLR4- MyD88 signaling pathway was involved the down- regulation of CYP2J by LPS. The binding of p-CREB with the promoter of CYP2J was inhibited by the LPS treatment. The loss of dopami?nergic neurons in the right SN induced by LPS or 6- OHDA was significantly decreased by CYP2J3 transfection at 21 d after LPS injection. Compared with LPS or 6-OHDA group, the number of the rotation of rats was decreased by 42.6% and 60.7% by CYP2J3 transfection at 14 d after LPS or 6-OHDA injection;meanwhile, the rotation number was decreased by 12.7% and 21.3% at 21 d. The accumulation of alpha synuclein induced by LPS was significantly decreased by CYP2J3 transfection. The mRNA levels of SOD1, CAT, GPX1, NRF2 and KEAP1 in SN were decreased by LPS, which was attenuated by the injection of LV-CYP2J3. CONCLUSION Brain CYP2J can play a protective role in the damage of the inflammation and oxidative stress to the dopaminergic neurons. Brain CYP2J- dependent derivatives from AA may have therapeutic effects in Parkinson disease via the up- regulation of the antioxidant system in neurons.

OBJECTIVE Neuroinflammation plays a critical role in neurodegenerative disorders, although the inflammation may not the initiating factor. Parkinson disease (PD) is characterized patho?logically by the accumulation of alpha synuclein (α-syn) and the loss of the dopamine (DA) neurons in the substantia nigra (SN), which has been reported to be induced by the stereotaxic injection of lipopolysaccharide (LPS) to the SN region in rodents. This study is to investigate the therapeutic benefit of the inhibition of miR-873 in PD. METHODS Rats received the right-unilaterally injection with concentrated LV-sponge or LV-EGFP 3 d before LPS treatment, 7 or 14 d after LPS treatment. The animals were tested for rotational behavior with the dopaminergic agonist apomorphine dissolved in sterile saline at 21 d after LPS injection. The regulation of miR-873 on the genes related with cholesterol transport and inflammation was assayed in SH-SY5Y cells and U251 cells. RESULTS TLR4-MyD88 signaling pathway was involved the regulation of miR-873 by LPS. The luciferase assay showed that HMGCR, ABCA1 and A20 were down- stream genes of miR- 873. The transfection of miR- 873 decreased the cholesterol levels in cell membrane, but increased in lysosome in SH-SY5Y cells. Compared with the control SH-SY5Y cells, cholesterol levels were higher in lysosome with α-synuclein overexpression or LPS treatment. The transfection of miR-873 increased the α-syn levels in lysosome in cells with α-synuclein overexpression. The loss of dopaminergic neuorns induced by LPS was significantly respectively decreased by 22.8%, 35.6% and 57% after the inhibition of miR-873 at 3 d before LPS treatment, 7 or 14 d after LPS treatment. Compared with LPS-treated group, the number of the rotation of rats was decreased by 60.4%, 33.5% and 13.2% after the inhibition of miR-873 at 3 d before LPS treatment, 7 or 14 d after LPS treatment. The inhibition of miR-873 significantly decreased accumulation of α-syn. The mRNA levels of HMGCR, ABCA1 and A20 in SN were decreased by LPS treatment, which was attenuated by the injection of LV- sponge. CONCLUSION The selective regulation of miR- 873 can protect the dopaminergic neurons from the LPS-induced damage. The inhibition of miR-873 can attenuate the relocation of cholesterol in lysosome and the accumulation of α-syn in neurons induced by LPS via the regulation of HMGCR, ABCA1 and A20.

OBJECTIVE CYP2D is one of the most abundant subfamily of CYPs in the brain, especially in the cerebellum. Brain CYP2D is responsible for the metabolism of endogenous neurotransmitters such as tyramine and serotonin. Our previous studies have shown brain CYP2D can be regulated by exogenous and endogenous substances with tissue- specificity. The purpose of this study is to examine the effects of cerebral CYP2D on the mice behavior and the regulatory mechanism of brain CYP2D by growth hormone. METHODS Mice received the stereotaxic injection with CYP2D inhibitor quinine in deep cerebellar nuclei of cerebellum. The animals were tested with rotarod apparatus, balance beam, water maze, elevated plus maze and open field. The changes in CYP2D22, PPARαand PPARγ in brain regions and liver were assayed in male growth hormone receptor knockout mice, SH-SY5Y cells and HepG2 cells. RESULTS The inhibition of cerebellum CYP2D significantly affected the spatial learning and exploring ability of mice. Compared with WT mice, CYP2D expression was lower in brain regions from GHR(-/- ) male mice; however, hepatic CYP2D level was similar. Pulsatile GH decreased PPARα mRNA level, and increased mRNA levels of CYP2D6 and PPARα in SH- SY5Y cells. In HepG2 cells, pulsatile GH resulted in decreases in PPARα and PPARγ mRNA levels, but not CYP2D6. PPARα inhibitor induced CYP2D6 mRNA and protein by 1.32-fold and 1.43-fold in SH-SY5Y cells. PPARγ inhibitor decreased CYP2D6 mRNA and protein by 74.76% and 40.93%. PPARα agonist decreased the level of CYP2D22 mRNA in liver and cerebellum, while PPARγ agonist rosiglitazone resulted in diametrically increases. The luciferase assay showed that PPARγ actived the CYP2D6 gene promoter while PPARα inhibited its function. Pulsatile GH declined the binding of PPARα with CYP2D6 promoter by 40%, promoted the binding of PPARγ with CYP2D6 promoter by approximate 60%. The levels of brain and liver PPARα expression in male GHR(-/- ) mice is obviously higher than those in WT mice. The level of PPARγ in male GHR(-/- ) mice was decreased in the frontal cortex and hippocampus, while remained stable in the cerebellum and striatum; meanwhile, PPARγ was increased in the liver. CONCLUSION Brain CYP2D may be involved in learning and memory functions of central system. Masculine GH secretion altered the PPARs expression and the binding of PPARs to CYP2D promoter, leading to the elevated brain CYP2D in a tissue- specific manner. Growth hormone may specifically alter the metabolic and synthetic of important endogenous substances in the central nervous system (such as serotonin) through the specific regulation of brain CYP2D expression.

Objective: To analyze the trend of adolescent health risk behaviors in Shanghai, and to provide reference for the comprehensive intervention of middle school students health risk behaviors. Methods: Based on the health risk behavior questionnaire of Chinese Center for Disease Control and Prevention, the questionnaire was adapted according to the actual monitoring needs. It was divided into junior high school version and senior high school version. From 2004 to 2019, using the method of multistage stratified cluster random sampling, 59 209 middle school students who completed the questionnaire in 6 surveys were selected for analysis. Results: From 2004 to 2019, in the 7 days prior to the survey, 9.2%-50.6% of middle school students drank a glass of soda more than or equal to once a day and 54.2%-76.1% of middle school students reported eating dessert twice or more. Within 7 days, 48.3%-60.7% of middle school students had≥60 min of exercise per day for less than or equal to 3 days, and 16.1%- 35.2% of middle school students reported too much extracurricular activities, and the reporting rate increased year by year with the annual percent change ( APC ) of 5.15%( t =9.28, P <0.01). The reporting rate of long time online learning was 6.0%-13.6%, which showed an upward trend among high school students, with the APC of 5.35%( t =3.14, P <0.05). The reporting rate of middle school students pedestrian safety problems decreased from 69.1% in 2004 to 27.6% in 2019, with the APC of -6.28%( t =-8.18, P <0.01), but the reporting rate of cycling safety problems have increased in recent years. The reporting rate of intentional injury behaviors decreased by year such as fighting, bullying, etc. The reporting rate of initial smoking age ≤13 years old decreased, but attempted drinking behavior increased in junior middle school students, and the APC was 1.61%( t =3.48, P <0.05). A total of 1.6%-3.4% of middle school students had an Internet addiction behavior tendency. The detection rate of Internet addiction tendency was increasing in high school students and girls, and APC was 6.59% and 10.29% respectively( t =6.37, 8.62, P <0.01). Conclusion From 2004 to 2019, unintentional injury behavior, intentional injury behavior and substance addiction behavior of middle school students in Shanghai have improved. However, unhealthy diet and physical inactivity are still high. In the follow up. It need to focus on adverse diet and lack of physical activity behavior and take comprehensive intervention measures to control them.

OBJECTIVETo study the effects of Angelica sinensis Polysaccharides (ASP) on the hepatic drug metabolism enzymes activities in normal mice and those prednisolone (PSL)-induced liver injury.

METHODThe activities of phase II enzymes (GSH-related enzymes) and cytochrome P450 enzymes were measured by biochemical method.

RESULTASP increased the activities of glutathione S-transferase in liver microsomes and mitochondria. The cytochrome P450 content, NADPH-cytochrome c reductase, aminopyrine N-demethylase, and aniline hydroxylase activities in liver microsomes were also increased. PSL significantly increased serum ALT levels, and decreased the liver mitochondrial glutathione content. At the same time, other enzymes activities were all increased. When mice were treated with ASP 2.0 g.kg-1, the PSL-induced changes on cytochrome P450 enzymes, glutathione S-transferase, and GSH content were restored.

CONCLUSIONASP can modulate the activities of drug metabolism enzymes.

Aminopyrine N-Demethylase ; metabolism ; Angelica sinensis ; chemistry ; Aniline Hydroxylase ; metabolism ; Animals ; Chemical and Drug Induced Liver Injury ; enzymology ; etiology ; Cytochrome P-450 Enzyme System ; metabolism ; Glutathione Transferase ; metabolism ; Male ; Mice ; Microsomes, Liver ; enzymology ; Mitochondria, Liver ; enzymology ; NADPH-Ferrihemoprotein Reductase ; metabolism ; Plants, Medicinal ; chemistry ; Polysaccharides ; isolation & purification ; pharmacology ; Prednisolone

Comparative Genomic Hybridization ; methods ; Female ; Humans ; Infant ; Wolf-Hirschhorn Syndrome ; diagnosis

Objective:To investigate the correlation between serum levels of heme oxygenase-1 (HO-1) and lipoxin A4 (LXA4) and diabetic nephropathy, and to analyze the value of HO-1 and LXA4 in the diagnosis of diabetic nephropathy.Methods:A prospective cohort study was conducted in 185 patients with type 2 diabetes admitted to the Department of Endocrinology, Yan'an Hospital Affiliated to Kunming Medical University from January 2016 to January 2020. There were 96 cases with diabetic nephropathy (nephropathy group) and 89 cases without diabetic nephropathy (non nephropathy group). According to the stage of chronic kidney disease,the nephrotic group was divided into three subgroups: stage 1-2 group (31 cases), stage 3-4 group (40 cases) and stage 5 group (25 cases). Another 82 healthy volunteers were selected as the control group.Serum HO-1, LXA4, oxidative stress,inflammatory factors, glucose metabolism and renal function were detected. Pearson analysis of HO-1, LXA4 and oxidative stress, inflammatory factors, glucose metabolism and renal function index correlation, binary logistic regression analysis of diabetic nephropathy factors.Results:The serum HO-1 ((0.60 ± 0.20) μg/L) and LXA4 levels ((435.12 ± 22.42) ng/L) in nephrotic group were lower than those in non nephrotic ((0.72 ± 0.23) μg/L, (498.21 ± 29.48) ng/L)( t=29.351, 24.135, all P<0.05). The serum HO-1 and LXA4 levels in the 5 stage group were lower than those in the 3-4 stage and 1-2 stage group (all P<0.05). The serum HO-1 and LXA4 levels in the 3-4 stage group were lower than those in the 1-2 stage group (all P<0.05). Pearson correlation analysis showed that HO-1 was positively correlated with total antioxidant capacity (T-AOC), superoxide dismutase (SOD) and estimated glomerular filtration rate (EGFR) ( r=0.516, 0.602, 0.617; all P<0.05), and was positively correlated with malondialdehyde (MDA) and homeostasis model insulin resistance (homeostasis model insulin resistance) Model assessment insulin resistance (HOMA-IR), urinary albumin creatinine ratio (UACR) LXA4 was negatively correlated with T-AOC, SOD and EGFR ( r=-0.559, 0.597, 0.637; all P<0.05), and positively correlated with MDA, IL-6, TGF-β1, HOMA-IR and UACR There was a negative correlation ( r=-0.498, -0.623, -0.725; all P<0.05). Binary logistic regression analysis showed that malondialdehyde ( OR=1.587, 95% CI 1.402-1.603, P=0.016), TGF-β1 ( OR=1.679, 95% CI 1.642-1.739, P=0.012), HOMA-IR ( OR=1.699、95% CI 1.534-1.739, P=0.009) were risk factors of diabetic nephropathy (all P<0.05). HO-1 ( OR=0.506, 95% CI 0.423-0.653, P<0.001) and LXA4 ( OR=0.492, 95% CI 0.409-0.535, P<0.001) were protective factors for DN ( P<0.001). After adjusting for MDA, TGF-β1 and HOMA-IR, HO-1 ( OR=0.485, 95% CI:0.402-0.564, P<0.001) and LXA4 ( OR=0.416, 95% CI:0.386-0.475, P<0.001) were still associated with DN. ROC analysis showed that the area under curve (AUC) of HO-1 and LXA4 were 0.820 (95% CI:0.760-0.880, P<0.001) and 0.763 (95% CI:0.691-0.836, P<0.001), respectively. The sensitivity and specificity were 71.88%, 80.90%, 75.00% and 84.27%, respectively. Conclusion:The decrease of serum LXA4 and HO-1 levels is closely related to diabetic nephropathy, which can be used as a biological indicator for the diagnosis of diabetic nephropathy.

An ultra performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method was developed for the determination of 11 kinds of aminoglycosides (AGs), including paromomycin, spectinomycin, tobramycin, gentamycin, kanamycin, hygromycin B, apramycin, streptomycin, dihydrostreptomycin,amikacin and neomycin in aquatic products. Samples were extracted by phosphate buffer solution, and purified on molecularly imprinted polymers (MIP) solid phase extraction column. After separated by Obelisc R chromatographic column, AGs were detected by UPLC-MS/MS. It showed a good linearity relationship in the AGs concentration range of 1.0-1000 ng/mL with the correlation coefficient R2>0.994. The limit of detection (LOD,S/N≥3) was ranged from 1.0 μg/kg to 10.0 μg/kg,and the limit of quantitation (LOQ,S/N≥10) was ranged from 2.0 μg/kg to 20.0 μg/kg. Besides, the average recoveries presented 78.4%-109.6% with the relative standard deviation (RSD, n=6) of 2.3%-14.9%. This method was successfully applied to the simultaneous determination of 11 kinds of AGs with high sensitivity in aquatic products.

ObjectiveThis study was designed to explore the effect of MG53 on cardiac function affected by acute doxorubicin （DOX）-induced cardiotoxicity （DIC） in mice and its possible mechanism. MethodsIn vivo， C57BL/6 mice were injected intraperitoneally with twenty mg/kg DOX for one week to induce the acute DIC. In vitro， neonatal rat cardiomyocytes （NRCs） were treated with 1 μmol/L DOX to induce DIC. A small animal ultrasound imaging system was used to evaluate cardiac function， and the left ventricular changes in ejection fraction （EF） and fraction shortening （FS） were measured. qPCR technology was used to evaluate cardiac remodeling related factors ANP， BNP and α-MHC， autophagy-related factors Beclin1 and LC3， and apoptosis-related factor CASPASE3. Autophagy-related protein levels of Beclin1， LC3 and apoptosis-related protein levels of caspase3 were assessed by Western Blot. Transmission electron microscopy （TEM） was used to detect autophagosomes in heart tissues. TUNEL assay kit was used to detect apoptosis in neonatal murine cardiomyocytes. ResultsThe small animal ultrasound imaging revealed cardiac function was significantly reduced by doxorubicin in the DOX group and DOX+AAV9-NC group compared with the sham group （EF： Sham： 86.06 ± 2.08 vs. DOX：58.97 ± 1.62， P < 0.000 1； Sham： 86.06 ± 2.08 vs. DOX+AAV9-NC： 59.00 ± 1.86， P < 0.000 1. FS： Sham： 45.47 ± 1.95 vs. DOX：30.68 ± 1.21， P < 0.000 1； Sham： 45.47 ± 1.95 vs. DOX+AAV9-NC： 30.79 ± 1.13， P < 0.000 1）. However， the overexpression of MG53 with adeno-associated virus9 （AAV9） ameliorated cardiac dysfunction （EF： DOX+AAV9-MG53： 66.93 ± 1.78 vs. DOX+AAV9-NC： 59.00 ± 1.86， P < 0.000 1. FS： DOX+AAV9-MG53： 36.35 ± 1.33 vs. DOX+AAV9-NC： 30.79 ± 1.13， P < 0.000 1）. TEM showed autophagosomes were increased in the DOX+AAV9-MG53 group compared with the DOX group and DOX+AAV9-NC. qPCR results suggested that MG53 down-regulated the mRNA expression of cardiac remodeling related genes. Additionally， Western blot results confirmed that the protein level of caspases3 was decreased and Beclin1 and LC3 expression was increased in the DOX+AAV9-MG53 group compared with those in the DOX group and DOX+AAV9-NC group （caspase： DOX+AAV9-MG53： 1.49 ± 0.13 vs. DOX+AAV9-NC： 2.49 ± 0.46， P = 0.000 2； Beclin-1： DOX+AAV9-MG53：0.82 ± 0.02 vs. DOX+AAV9-NC： 0.62 ± 0.05， P < 0.000 1； LC3： DOX+AAV9-MG53： 0.83 ± 0.04 vs. DOX+AAV9-NC： 0.40 ± 0.05， P < 0.000 1）. In contrast， knockdown of MG53 significantly up-regulated the protein level of Caspase3 and significantly down-regulated the protein level of Beclin1 and LC3 （caspase： DOX+si-MG53： 4.52 ± 0.28 vs. DOX+si-NC： 3.37 ± 0.08， P < 0.000 1； Beclin-1： DOX+si-MG53： 0.34 ± 0.06 vs. DOX+si-NC： 0.54 ± 0.07， P = 0.026 2； LC3： DOX+si-MG53： 0.41 ± 0.12 vs. DOX+si-NC： 0.70 ± 0.07， P = 0.001 5）. TUNEL analysis showed overexpression of MG53 significantly inhibited the apoptosis of cardiomyocytes （DOX+Ad-MG53： 9.41 ± 0.53 vs. DOX+Ad-NC： 29.34 ± 7.29， P < 0.000 1）， and knockdown of MG53 significantly facilitate the apoptosis of cardiomyocytes （DOX+si-MG53： 71.34 ± 5.90 vs. DOX+si-NC： 32.19 ± 9.91， P < 0.000 1）. ConclusionMG53 inhibits cardiac apoptosis and enhances autophagy， which delays cardiac remodeling and ameliorates cardiac dysfunction.