Objective Melatonin has been shown to have neuroprotective effects.This study is aimed at observing the effects of copper deposition on cognitive function in a toxic milk(TX)mouse model of Wilson disease(WD),and investigating the effects and mechanisms of action of Gandou Bushen Decoction(GDBSD)on melatonin synthesis and pineal function in the WD model mice.Methods A total of 30 homozygous TX mice were randomly assigned to 3 groups(n=10 in each group),including a WD group,a GDBSD group,and a dimercaptosuccinic acid(DMSA)group.A total of 10 DL mice were included in the normal control(NC)group.The structure and copper content of pineal gland tissues,oxidative stress and apoptosis-related markers,and serum melatonin levels were evaluated using hematoxylin-eosin(HE)staining,enzyme-linked immunosorbent assay(ELISA),flow cytometry,and Western blot.Results Compared with the NC group,the WD group exhibited decreased learning and cognitive abilities(P＜0.05),damaged pineal gland structure,increased copper content,reactive oxygen species(ROS)levels,and mitochondrial damage rate in the pineal gland(P＜0.01),altered levels of melatonin and oxidative stress-related markers(P＜0.05),upregulated expression levels of pro-apoptotic proteins Bax and Caspase-3,and decreased expression of the anti-apoptotic protein Bcl-2(P＜0.01).After treatment with GDBSD and DMSA,the SIRT3/FOXO3α signaling pathway was activated,the copper content in the pineal gland was reduced,and oxidative stress and apoptosis-related damages were improved,leading to an improvement in learning and memory abilities(P＜0.05).Conclusion GDBSD can alleviate cognitive impairments in WD mice caused by pineal gland copper deposition by inhibiting oxidative stress and apoptosis in the pineal gland.The underlying molecular mechanism is associated with the regulation of the SIRT3/FOXO3α signaling pathway.

Objective To investigate whether activation of mitochondrial acetal dehydrogenase 2(ALDH2)alleviates hypoxic pulmonary hypertension by regulating the SIRT1/PGC-1α signaling pathway.Methods Thirty 8-week-old C57 BL/6 mice were randomized into control,hypoxia,and hypoxia+Alda-1(an ALDH2 activator)group(n=10),and the mice in the latter two groups,along with 10 ALDH2 knockout(ALDH2-/-)mice,were exposed to hypoxia(10%O2,90%N2)with or without daily intraperitoneal injection of Alda-1 for 4 weeks.The changes in right ventricular function and pressure(RVSP)of the mice were evaluated by echocardiography and right ventricular catheter test,and pulmonary artery pressure was estimated based on RVSP.Pulmonary vascular remodeling,right ventricular injury,myocardial α-SMA expression,distal pulmonary arteriole muscle normalization,right ventricular cross-sectional area,myocardial cell hypertrophy,and right cardiac hypertrophy index were assessed with HE staining,immunofluorescence staining and WGA staining,and the expressions of ALDH2,SIRT1,PGC-1α,P16INK4A and P21CIP1 were detected.In pulmonary artery smooth muscle cells with hypoxic exposure,the effect of Alda-1 and EX527 on cell senescence and protein expressions was evaluated using β-galactose staining and Western blotting.Results The wild-type mice with hypoxic exposure showed significantly increased RVSP,right ventricular free wall thickness and myocardial expressions of P16INK4A and P21CIP1,which were effectively lowered by treatment with Alda-1 but further increased in ALDH2-/-mice.In cultured pulmonary artery smooth muscle cells,hypoxic exposure significantly increased senescent cell percentage and cellular expressions of P16INK4A and P21CIP1,which were all lowered by treatment with Alda-1,but its effect was obviously attenuated by EX527 treatment.Conclusion ALDH2 alleviates hypoxia-induced senescence of pulmonary artery smooth muscle cells by upregulating the SIRT1/PGC-1α signaling pathway to alleviate pulmonary hypertension in mice.

Objective To investigate whether activation of mitochondrial acetal dehydrogenase 2(ALDH2)alleviates hypoxic pulmonary hypertension by regulating the SIRT1/PGC-1α signaling pathway.Methods Thirty 8-week-old C57 BL/6 mice were randomized into control,hypoxia,and hypoxia+Alda-1(an ALDH2 activator)group(n=10),and the mice in the latter two groups,along with 10 ALDH2 knockout(ALDH2-/-)mice,were exposed to hypoxia(10%O2,90%N2)with or without daily intraperitoneal injection of Alda-1 for 4 weeks.The changes in right ventricular function and pressure(RVSP)of the mice were evaluated by echocardiography and right ventricular catheter test,and pulmonary artery pressure was estimated based on RVSP.Pulmonary vascular remodeling,right ventricular injury,myocardial α-SMA expression,distal pulmonary arteriole muscle normalization,right ventricular cross-sectional area,myocardial cell hypertrophy,and right cardiac hypertrophy index were assessed with HE staining,immunofluorescence staining and WGA staining,and the expressions of ALDH2,SIRT1,PGC-1α,P16INK4A and P21CIP1 were detected.In pulmonary artery smooth muscle cells with hypoxic exposure,the effect of Alda-1 and EX527 on cell senescence and protein expressions was evaluated using β-galactose staining and Western blotting.Results The wild-type mice with hypoxic exposure showed significantly increased RVSP,right ventricular free wall thickness and myocardial expressions of P16INK4A and P21CIP1,which were effectively lowered by treatment with Alda-1 but further increased in ALDH2-/-mice.In cultured pulmonary artery smooth muscle cells,hypoxic exposure significantly increased senescent cell percentage and cellular expressions of P16INK4A and P21CIP1,which were all lowered by treatment with Alda-1,but its effect was obviously attenuated by EX527 treatment.Conclusion ALDH2 alleviates hypoxia-induced senescence of pulmonary artery smooth muscle cells by upregulating the SIRT1/PGC-1α signaling pathway to alleviate pulmonary hypertension in mice.

Lung cancer is one of the most common cancers in the world, and its treatment strategy is mainly surgery combined with radiotherapy and chemotherapy. However, long-term chemotherapy will result in drug resistance, which is also one of the difficulties in the treatment of lung cancer. Ferroptosis is an iron-dependent and lipid peroxidation-driven non-apoptotic cell death cascade, occurring when there is an imbalance of redox homeostasis in the cell. Nuclear factor erythroid 2-related factor 2 (Nrf2) is key for cellular antioxidant responses. Numerous studies suggest that Nrf2 assumes an extremely important role in regulation of ferroptosis, for its various functions in iron, lipid, and amino acid metabolism, and so on. In this review, a brief overview of the research progress of ferroptosis over the past decade will be presented. In particular, the mechanism of ferroptosis and the regulation of ferroptosis by Nrf2 will be discussed, as well as the role of the Nrf2 pathway and ferroptosis in tumor drug resistance, which will provide new research directions for the treatment of drug-resistant lung cancer patients.
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Humans ; Ferroptosis ; NF-E2-Related Factor 2/genetics* ; Lung Neoplasms/genetics* ; Drug Resistance, Neoplasm ; Iron

The morbidity and mortality of lung cancer ranks among the top cancers in the world. Non-small cell lung cancer (NSCLC) is the main pathological type of lung cancer, with limited treatment options and poor prognosis. The nuclear factor E2-related factor 2 (NRF2) signaling pathway is highly mutated and activated in NSCLC, and promotes the malignant progression of lung cancer through various mechanisms. NRF2-targeted therapy will provide new treatment strategies for patients with NSCLC. This article will review the basic structure and response pathways of the NRF2 pathway, the mechanism of NRF2 regulating lung cancer cell proliferation, and the research and development progress of NRF2 inhibitors.
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Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; NF-E2-Related Factor 2/metabolism* ; Lung Neoplasms/pathology* ; Gene Expression Regulation, Neoplastic ; Signal Transduction ; Cell Proliferation

Iron overload, as a pathological feature of many nervous system diseases, can cause oxidative stress and lead to abnormal iron metabolism and injury of nerve cells. Hypoxia inducible factor (HIF) can participate in brain iron metabolism by regulating brain iron uptake, storage, excretion and intracellular regulation. So, HIF is expected to become a therapeutic target to inhibit brain iron overload in nervous system diseases. This paper reviews the physiological/pathological mechanism of HIF in regulating brain iron metabolism, in order to provide new treatment ideas and methods for nervous system diseases characterized by brain iron overload.

Objective:To explore the correlation between the index of hemodynamics in perinatal period and retinopathy of prematurity(ROP), so as to provide basis for the better prevention and treatment of ROP.Methods:From May 2017 to April 2019, the preterm infants were admitted to the Neonatal Intensive Care Unit of the First Affiliated Hospital of Zhengzhou University at birth and were hospitalized for more than 2 weeks, gestational age ≤ 35 weeks and birth weight ≤ 2 500 g. They were selected as the study objects.The perinatal data including heart rate, blood pressure, patent ductus arteriosus, ventricular septal defect, and NT-proBNP level on the 1 st, 7 th and 14 th day, respectively after birth were collected.They were divided into ROP group and non ROP group according to the results of the retinopathy screening report.The influencing factors of ROP were screened out by univariate analysis and multivariate regression analysis. Results:A total of 1 119 subjects were included, 105 infants with ROP were detected, and the prevalence of ROP was 9.4%.Among them, 12 cases of pre-threshold lesion type 1 and threshold lesions required treatment, accoun-ting for 1.07% of screened preterm infants .Univariate analysis and multivariate regression analysis revealed that gestational age, birth weight, total oxygen therapy time, and intrauterine growth restriction were all factors affecting ROP, and 2 hemodynamic related indicators, such as the level of NT-proBNP in plasma on the 14 th day after birth, and placenta previa or abruption were also related to ROP( OR=0.604, 0.647, 1.276, 2.361, 1.688 and 2.506, respectively, all P<0.05). Conclusion:The hemodynamic changes in perinatal period may be involved in the formation of ROP, and it is necessary to further clarify its mechanism.

Objective To investigate the effects of compound radix angelicae sinensis injection on oocyte and segmentation sphere injured by subacute exposure to diesel exhaust particles (DEP) in female mice. Methods Two hundred and ten 21-day-old ICR female mice were randomly divided into 5 groups: the control group (group A), DEP group (group B), DEP+low-dose group (group C),DEP±middle-dose group (group D) and DEP+high-dose group (group E). There were 42 mice in each group. The mice were inoculated with 30 μ1 DEP suspension at 12.0 μg/μl (group B-E) or the same volume of vehicle (PBS, group A) on pharynx posterior wall by sample pipettor beginning at day 21 and repeated every 3 days for 4 times. The mice were sacrificed three days after the last exposure.Compound radix angelicae sinensis injection containing 75 (group C), 150 (group D) and 300 (group E)grams of crude drug, respectively, which was intraperitoneally administered for each mouse daily from the day of the first DEP inoculation till the day before sacrifice, consecutively for 12 days. The general conditions were observed, and the body weight and ovary/body weight ratio were tested. Superoxide dismutase (SOD) activity, malondialdehyde (MDA) and reduced glutathione (GSH) contents in ovarian tissues were assayed. Rates of survival, germinal vesicle breakdown, extrusion of the first polar body and in-vitro fertilization, and quantity of mitochondrial DNA for oocytes were investigated.Ultrastructural changes of oocytes were observed. Results ( 1 ) No significant difference of the body weight was found among all the groups (P＞0. 05). The ovary weight, ovary/body weight ratio, ovary SOD and GSH content were significantly decreased in groups B [( 1.5 ± 0. 6) mg, ( 7.2 ± 2. 5) × 10-5 ,(192. 10±23.67) nU/mg prot and (262.40 ± 31.60) nmol/mg prot], and C [( 1.7 ± 0. 2) mg,(8.9±0.6)× 10-5, (198.92±24.27) nU/mg prot and (271.66±14.58) nmol/mg prot] and D [(2. 1±0. 2) mg, (9. 8±1. 1)×10-5, (214. 37±27. 19) nU/mg prot and (285. 93±9. 55) nmol/mg prot] as comparing to groupA [(3. 3±1. 5) mg, (15.4±7.3)×10-5, (292. 30 ± 40. 03) nU/mg prot and (367.98±24.59) nmol/mg prot (P＜ 0. 05 or P＜0.01); and significantly increased in group E [(3. 7±1.1) mg, (18. 7±5. 4)× 10-5, (279. 10±12. 63) nU/mg prot ]and (353. 59±10. 61) nmol/mg prot]comparing to group B (P＜0. 01). MDA content was signi-ficantly increased for groups B, C and D [(3. 88±0.35) nmol/mg prot, (3. 62 ± 0. 19) nmol/mg prot and (2. 63 ± 0. 34) nmol/mg prot] comparing to group A [(2. 18±0. 44) nmol/mg prot](P＜0. 05 or ＜0. 01, respectively); and significantly decreased for group D and E (2. 35±0. 37 nmol/mg prot) comparing to group B (P＜0. 01). (2) In all observed time points, oocyte survival rate in group B and C, extrusion rate of the first polar body and in-vitro fertilization rate in group B, C and D were significantly lower than in group A (P ＜ 0. 05 or ＜0. 01), and all those in group E were significantly higher than in group B (P＜0. 05). Rates of germinal vesicle breakdown were 100% in all five groups. (3) Logarithmic values of mitochondrial DNA copy numbers in group C, D and E were significantly lower than in group A; whereas significantly higher in group C and D than in group B (P＜0.01). (4) Normal appearance for oocytes in group A was seen. In groups B and C, a number of cytoplasmic organelles were dramatically degenerated in part of the oocytes and some necrotic oocytes were seen. Large body of mitochondria in the oocytes swelled and vacuolized in group D, while such changes dincished to a lesser extent and scope in group E. Conclusions Compound radix angelicae sinensis injection exerts a favorable curative and protective effect on oocyte and segmentation sphere injured by subacute DEP exposure in female mice.