Midbrain dopamine oxidation links ubiquitination of glutathione peroxidase 4 to ferroptosis of dopaminergic neurons.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the gradual loss of midbrain dopaminergic neurons in association with aggregation of α-synuclein. Oxidative damage has been widely implicated in this disease, though the mechanisms involved remain elusive. Here, we demonstrated that preferential accumulation of peroxidized phospholipids and loss of the antioxidant enzyme glutathione peroxidase 4 (GPX4) were responsible for vulnerability of midbrain dopaminergic neurons and progressive motor dysfunctions in a mouse model of PD. We also established a mechanism wherein iron-induced dopamine oxidation modified GPX4, thereby rendering it amenable to degradation via the ubiquitin-proteasome pathway. In conclusion, this study unraveled what we believe to be a novel pathway for dopaminergic neuron degeneration during PD pathogenesis, driven by dopamine-induced loss of antioxidant GPX4 activity.

[Correlation between expression of forkhead box M1 (FOXM1) and clinicopathological features and prognosis in patients with non-small cell lung cancer (NSCLC)].

OBJECTIVE: To investigate the expression of forkhead box M1 (FOXM1) and its correlation with clinicopathological features and prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: The expression of FOXM1 in 68 cases of NSCLC was detected by immunohistochemistry. The FOXM1 expression in 6 tumor tissues (3 cases with negative and 3 cases with positive expression of FOXM1) was analyzed by Western blotting to confirm the immunohistochemical results. The correlation of the expression of FOXM1 with clinicopathalogical features and overall survival of the NSCLC patients was analyzed. RESULTS: The expression of FOXM1 protein was detected in the nuclei or cytoplasms of the tumor cells. The positive expression rate of FOXM1 was 36.8% (25/68). Western blotting confirmed the immunohistochemical results. The expression level of FOXM1 in advanced stage cancer was significantly higher than that in early stage NSCLC (P = 0.001). The median OS was 23.0 months in patients with negative expression of FOXM1 and 13.0 months in those with positive expression (P = 0.001). Univariate analysis revealed that histological grade, lymph nodes status, TNM stage and FOXM1 expression were significantly associated with prognosis in the NSCLC patients (P < 0.05). The Cox multivariate analysis demonstrated that lymph nodes status, TNM stage and FOXM1 expression were independent poor prognostic factors (P < 0.05). CONCLUSION: The expression status of FOXM1 in NSCLC is an independent prognostic factor and negatively correlated with prognosis.

Identification of plasma microRNA-21 as a biomarker for early detection and chemosensitivity of non-small cell lung cancer.

Studies have shown cell-free microRNA (miRNA) circulating in the serum and plasma with specific expression in cancer, indicating the potential of using miRNAs as biomarkers for cancer diagnosis and therapy. This study was to investigate whether plasma miRNA-21 (miR-21) can be used as a biomarker for the early detection of non-small cell lung cancer (NSCLC) and to explore its association with clinicopathologic features and sensitivity to platinum-based chemotherapy. We used real-time RT-PCR to investigate the expression of miR-21 in the plasma of 63 NSCLC patients and 30 healthy controls and correlated the findings with early diagnosis, pathologic parameters, and treatment. Thirty-five patients (stages IIIB and IV) were evaluable for chemotherapeutic responses: 11 had partial response (PR); 24 had stable and progressive disease (SD+ PD). Plasma miR-21 was significantly higher in NSCLC patients than in age- and sex-matched controls (P < 0.001). miR-21 was related to TNM stage (P < 0.001), but not related to age, sex, smoking status, histological classification, lymph node status, and metastasis (all P > 0.05). This marker yielded a receiver operating characteristic (ROC) curve area of 0.775 (95% CI: 0.681- 0.868) with 76.2% sensitivity and 70.0% specificity. Importantly, miR-21 plasma levels in PR samples were several folds lower than that in SD plus PD samples (P = 0.049), and were close to that in healthy controls (P = 0.130). Plasma miR-21 can serve as a circulating tumor biomarker for the early diagnosis of NSCLC and is related to the sensitivity to platinum-base chemotherapy.

Reduction of Plasma MicroRNA-21 is Associated with Chemotherapeutic Response in Patients with Non-small Cell Lung Cancer.

OBJECTIVE: To examine plasma microRNA-21 (miR-21) level in patients with non-small cell lung cancer (NSCLC) and its potential correlation with chemotherapeutic response. METHODS: 77 NSCLC patients and 36 age and sex-matched healthy controls were included. Plasma miR-21 concentration was examined using a quantitative real-time reverse transcription polymerase chain reaction assay (qRT-PCR). Potential correlation between plasma mir-21 concentrations with chemotherapeutic responses was analyzed in 35 patients with advanced NSCLC (stages IIIB and IV). RESULTS: Plasma miR-21 was significantly higher in NSCLC patients relative to the healthy controls (P<0.0001). As a biomarker, plasma mir-21 had a receiver operating characteristic (ROC) curve area of 0.729 with 61.04% sensitivity and 83.33% specificity. Chemotherapeutic response in the 35 patients with advanced NSCLC (stages IIIB and IV) included partial response (PR) (n=11), stable disease and progression disease (SD+PD) (n=24). The overall response rate (CR+PR) was 31.4%. Plasma miR-21 in patients who achieved PR was significantly lower than those who did not respond (SD+PD) (P=0.0487), and comparable to that of the healthy controls (P=0.2744). CONCLUSION: Plasma miR-21 is a good biomarker for NSCLC, and could be used to predict responses to chemotherapy.

PTA wastewater molecular toxicity detected with gene chip.

The purified terephthalic acid (PTA) petrochemical wastewater molecular toxicity detected by use of Mouse Genome 430A 2.0 GeneChip was conducted in this research. The toxic dose to male mice was 0.03 g/(kg x d) of PTA in the wastewater. The mice liver total RNA was isolated as the temple for synthesis of cDNA and then the cDNA as the temple for synthesis of cRNA. Hybridizing the cRNA with the target genes on the gene chip, there were 232 genes expression levels up-regulated and 74 genes down-regulated discovered obviously. The foremost 40 genes for both the highest and the lowest expression levels involved endogenetic steroid and hormone metabolism, immune system, the leukocyte activity and inflammation, detoxification in liver, reproduction and growth hormone, regulation immune factors of anti-tumor and anti-infection and cancer to the mice sampled. The data suggest the PTA wastewater contained over 5 aromatics and their toxicities integrated were much higher than the pure chemical PTA. And the pure chemical PTA toxicities data cannot be used to evaluate the toxicity of the PTA wastewater instead.

Purified terephthalic acid wastewater biodegradation and toxicity.

The biodegradation and toxicity of the purified terephthalic acid (PTA) processing wastewater was researched at NJYZ pilot with the fusant strain Fhhh in the carrier activated sludge process (CASP). Sludge loading rate (SLR) for Fhhh to COD of the wastewater was 1.09 d(-1) and to PTA in the wastewater was 0.29 d(-1). The results of bioassay at the pilot and calculation with software Ebis3 showed that the 48h-LC50 (median lethal concentration) to Daphnia magna for the PTA concentration in the wastewater was only 1/10 of that for the chemical PTA. There were 5 kinds of benzoate pollutants and their toxicities existing in the wastewater at least. The toxicity parameter value of the pure chemical PTA cannot be used to predicate the PTA wastewater toxicity. The toxicity of the NJYZ PTA wastewater will be discussed in detail in this paper.

Pilot regulation of MnP-SA for treating PTA wastewater.

In the pilot study of treating the purified terephthalic acid (PTA) wastewater with the functional Strain Fhhh in the carrier activated sludge process (CASP), the ratio of COD: TN: TP and the concentrations of Cu, Mn, Se and Zn were controlled to improve the manganese peroxidase (MnP) levels for increasing the treatment efficiency. When the ratio of COD: TN: TP was 100: 0.36: 0.15 and the concentrations of Cu, Mn, Se and Zn were 0.54, 5.07, 0.00 and 0.08 mg/L, the MnP specific activity (MnP-SA) reached 689 U/L, and the sludge loading rate to COD(SLRC) was 1.09 d(-l), which was 4--7 fold of that in other processes reported. The data indicated that improving MnP level could enhance the degradability of Fhhh. And the potentials of Fhhh and CASP will be also discussed in this paper.

[Effectiveness for medicine wastewater treatment biotechnology].

The effectiveness for the XZEH medicine wastewater treatment biotechnology was conducted. The results show that it needs to increase 28% of the aeration tank volume in order to meet the effluent COD concentration at the first grade wastewater discharge standard level in China. If the engineered strain Xhhh and informatics software (Ebis) were used, the specific degradation rate of Xhhh strain may be higher 128% than that of the natural bacterium XZ strain and the aeration tank needed may be 51% decreased. This should be a potential technical patch for improving the biotechnological effectiveness and making the effluent at the first grade discharge standard.