Dyclonine relieves the Parkinson's disease progression in rotenone-induced Drosophila model.

It has been estimated that there will be 930 million Parkinson's disease (PD) patients in 2030 in the whole world. However, no therapy has been effective for PD until now. Only levodopa is the available primary drug for the treatment of motor symptoms. Therefore, it is an urgent task to develop new drugs to inhibit the progression of PD and improve the quality of the patient's life. Dyclonine which was found to have antioxidant activity and would benefit patients with Friedreich's ataxia, is a commonly used local anesthetic. Here, we reported that dyclonine improved the motor ability and loss of dopaminergic neurons in the rotenone-induced Drosophila PD model for the first time. Furthermore, dyclonine upregulated the Nrf2/HO pathway, decreased the ROS and MDA levels, and inhibited the apoptosis of neurons in the brain of PD model flies. Hence, dyclonine might be an attractive FDA-approved drug for the exploration of effective PD therapy.

Downregulation of lncRNA SLC7A11-AS1 decreased the NRF2/SLC7A11 expression and inhibited the progression of colorectal cancer cells.

Colorectal cancer (CRC) is ranked as the second leading cause of cancer-related death worldwide. Many abnormally expressed long non-coding RNAs (lncRNAs) in CRC were identified with the development of next-generation sequencing, most functions of which are largely unclear. In this study, we report that the lncRNA SLC7A11-AS1 was significantly overexpressed in CRC by analyzing TCGA database and 6 pairs of clinical samples. High SLC7A11-AS1 level was related to poor CRC overall survival and SLC7A11-AS1 knockdown could inhibit the proliferation, migration and invasion of CRC cell lines. Furthermore, we found there was a positive correlation between the expression of SLC7A11-AS1 and its' sense transcript SLC7A11. In HCT-8 cells, SLC7A11-AS1 knockdown decreased expression of both SLC7A11 and the nuclear level of NRF2, which happens to be the activator of SLC7A11 transcription. Interestingly, in SLC7A11-AS1 overexpressed CRC tissues, SLC7A11 and NRF2 were also upregulated. Moreover, the ROS levels increased with SLC7A11-AS1 knockdown in HCT-8 cells. And the down regulated expression of SLC7A11 and lower ROS level causing by SLC7A11-AS1 knocked down could be relieved by overexpressed NRF2. These results suggested that upregulated SLC7A11-AS1 might promote the formation and progression of CRC by increasing the expression of NRF2 and SLC7A11, which decreases the ROS level in cancer cells. Therefore, SLC7A11-AS1 could be a potential therapeutic target and diagnostic marker of CRC.

Impact of age on the rotenone-induced sporadic Parkinson's disease model using Drosophila melanogaster.

Rotenone, a naturally occurring toxin, has been used to induce sporadic Parkinson's disease (PD) in Drosophila melanogaster for decades. However, the age of flies varies considerably between studies in this model. To investigate the impact of age on the rotenone-induced PD model, we collected male flies at the age of 1, 5, 7, and 10 days post-eclosion, respectively. Then, flies were immediately exposed to a feeding medium supplemented with 250 µM rotenone for seven days. The motor ability of Drosophila was detected by negative geotaxis assay, and the number of dopamine (DA) neurons and tyrosine hydroxylase (TH) expression levels were evaluated. The results showed that both the motor deficits and mortality increased with age. The flies older than five days showed typical PD features, including the loss of DA neurons, decreased TH expression levels, and decreased locomotive ability. However, 1-day-old flies displayed an unstable motor deficit and little TH expression changes after seven days of rotenone exposure. Lastly, after 7 days of exposure to rotenone, the death rate of flies rapidly increased with increasing starting age. The death rates of 1-, 5-, 7-, and 10-days old flies were 10.0%, 22.8%, 41.5%, and 50.4%, respectively. The findings of this study suggest that age is a crucial factor impacting the Drosophila PD model. This information provides a reference for the age selection to use this model for future studies.

Long-term sevoflurane exposure resulted in temporary rather than lasting cognitive impairment in Drosophila.

Sevoflurane is the primary inhaled anesthetic used in pediatric surgery. It has been the focus of research since animal models studies found that it was neurotoxic to the developing brain two decades ago. However, whether pediatric general anesthesia can lead to permanent cognitive deficits remained a subject of heated debate. Therefore, our study aims to determine the lifetime neurotoxicity of early long-time sevoflurane exposure using a short-life-cycle animal model, Drosophila melanogaster. To investigate this question, we measured the lifetime changes of two-day-old flies' learning and memory abilities after anesthesia with 3 % sevoflurane for 6 h by the T-maze memory assay. We evaluated the apoptosis, levels of ATP and ROS, and related genes in the fly head. Our results suggest that 6 h 3 % sevoflurane exposure at a young age can only induce transient neuroapoptosis and cognitive deficits around the first week after anesthesia. But this brain damage recedes with time and vanishes in late life. We also found that the mRNA level of caspases and Bcl-2, ROS level, and ATP level increased during this temporary neuroapoptosis process. And mRNA levels of antioxidants, such as SOD2 and CAT, increased and decreased simultaneously with the rise and fall of the ROS level, indicating a possible contribution to the recovery from the sevoflurane impairment. In conclusion, our results suggest that one early prolonged sevoflurane-based general anesthesia can induce neuroapoptosis and learning and memory deficit transiently but not permanently in Drosophila.

Identification of Down-Regulated ADH1C is Associated With Poor Prognosis in Colorectal Cancer Using Bioinformatics Analysis.

Colorectal cancer (CRC) is the second most deadly cancer in the whole world, with the underlying mechanisms largely indistinct. Therefore, we aimed to identify significant pathways and genes involved in the initiation, formation and poor prognosis of CRC using bioinformatics methods. In this study, we compared gene expression profiles of CRC cases with those from normal colorectal tissues from three chip datasets (GSE33113, GSE23878 and GSE41328) to identify 105 differentially expressed genes (DEGs) that were common to the three datasets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the highest proportion of up-regulated DEGs was involved in extracellular region and cytokine-cytokine receptor interaction pathways. Integral components of membrane and bile secretion pathways were identified as containing down-regulated DEGs. 13 hub DEGs were chosen and their expression were further validated by GEPIA. Only four DEGs (ADH1C, CLCA4, CXCL8 and GUCA2A) were associated with a significantly lower overall survival after the prognosis analysis. Lower ADH1C protein level and higher CXCL8 protein level were verified by immunohistochemical staining and western blot in clinical CRC and normal colorectal tissues. In conclusion, our study indicated that the extracellular tumor microenvironment and bile metabolism pathways play critical roles in the formation and progression of CRC. Furthermore, we confirmed ADH1C being down-regulated in CRC and reported ADH1C as a prognostic predictor for the first time.

Involvement of Mitochondrial Dynamics and Mitophagy in Sevoflurane-Induced Cell Toxicity.

General anesthesia is a powerful and indispensable tool to ensure the accomplishment of surgical procedures or clinical examinations. Sevoflurane as an inhalational anesthetic without unpleasant odor is commonly used in clinical practice, especially for pediatric surgery. However, the toxicity caused by sevoflurane has gained growing attention. Mitochondria play a key role in maintaining cellular metabolism and survival. To maintain the stability of mitochondrial homeostasis, they are constantly going through fusion and fission. Also, damaged mitochondria need to be degraded by autophagy, termed as mitophagy. Accumulating evidence proves that sevoflurane exposure in young age could lead to cell toxicity by triggering the mitochondrial pathway of apoptosis, inducing the abnormalities of mitochondrial dynamics and mitophagy. In the present review, we focus on the current understanding of mitochondrial apoptosis, dynamics and mitophagy in cell function, the implications for cell toxicity in response to sevoflurane, and their underlying potential mechanisms.

Th17/Treg imbalance in patients with severe acute pancreatitis: Attenuated by high-volume hemofiltration treatment.

BACKGROUND: To investigate the effect of high-volume hemofiltration (HVHF) on Th17/Treg imbalance in patients with severe acute pancreatitis (SAP). METHODS: Forty-two patients with SAP were randomly received 24 hours of continuous HVHF (n = 21) or without HVHF (n = 21). At day 28, all 42 patients were divided into survival group (n = 32) and non-survival group (n = 10). Venous blood samples collected at 0, 6, 12, and 24 hours during HVHF treatment (or equivalent time in non-HVHF group) were assessed by flow cytometry to detect Th17 and Treg cells. Concentrations of IL-6, IL-17, IL-10, and TGF-ß1 were detected by enzyme-linked immunosorbent assay. RESULTS: Th17%, Treg%, Th17/Treg, and levels of related cytokines were significantly higher in SAP patients than healthy controls (P < .05), and these changes were more pronounced in SAP patients with multiple organ failure than those with single organ failure (P < .05). After HVHF treatment, Th17%, Treg%, Th17/Treg, IL-6, IL-17, and IL-10 significantly reduced (P < .05), while there were no significant changes in non-HVHF group (P > .05). In addition, acute physiology and chronic health evaluation II and sequential organ failure assessment scores decreased markedly after HVHF treatment. Baselines of Th17%, Treg%, Th17/Treg, and related cytokines were significantly higher in non-survival group than survival group. Both acute physiology and chronic health evaluation I score and IL-6 level were positively correlated with Th17% before and after HVHF treatment (P < .01). CONCLUSIONS: Th17/Treg imbalance is present in SAP and may be correlated with its severity and prognosis. HVHF effectively attenuates the Th17/Treg imbalance in SAP patients. The beneficial effect of HVHF on Th17/Treg imbalance is possibly associated with removing excess inflammatory mediators.

A case report of Takayasu arteritis with aortic dissection as initial presentation.

RATIONALE: The initial symptoms and signs of Takayasu arteritis vary due to the heterogeneity of affected vessels. Moreover, the vascular lesions are difficult to detect at initial presentation, making diagnosis even more challenging. Although cases of aortic dissection with arteritis history have been reported, Takayasu arteritis in men with aortic dissection as initial presentation is very rare. PATIENT CONCERNS: A 37-year-old man presenting with persistent chest and back pain for 6 days was transferred to our hospital for further treatment. Left hand pulse was absent and right lower limb pulse was feeble. Blood pressure was 144/83 mmHg in the right arm but only 114/62 mmHg in the left arm. DIAGNOSES: Computed tomography angiography revealed aortic dissection (DeBakey type III b) from the descending aorta to the distal abdominal aorta. INTERVENTIONS: High-dose glucocorticoid therapy and immunosuppressive therapy have been used to control inflammatory reaction during acute period of Takayasu arteritis. Endovascular graft exclusion (EVGE) surgery was performed to cover the primary entry tear and re-expand true lumen during inactive stage. OUTCOMES: His pain symptoms improved progressively and he was followed in our outpatient clinic after discharged from hospital, without recurrence. LESSONS: Timely therapy (glucocorticoid and immunosuppressive) and corrective surgery (endovascular graft exclusion) for Takayasu arteritis with aortic dissection at the inactive stage is essential and beneficial.

Population and allelic variation of A-to-I RNA editing in human transcriptomes.

BACKGROUND: A-to-I RNA editing is an important step in RNA processing in which specific adenosines in some RNA molecules are post-transcriptionally modified to inosines. RNA editing has emerged as a widespread mechanism for generating transcriptome diversity. However, there remain significant knowledge gaps about the variation and function of RNA editing. RESULTS: In order to determine the influence of genetic variation on A-to-I RNA editing, we integrate genomic and transcriptomic data from 445 human lymphoblastoid cell lines by combining an RNA editing QTL (edQTL) analysis with an allele-specific RNA editing (ASED) analysis. We identify 1054 RNA editing events associated with cis genetic polymorphisms. Additionally, we find that a subset of these polymorphisms is linked to genome-wide association study signals of complex traits or diseases. Finally, compared to random cis polymorphisms, polymorphisms associated with RNA editing variation are located closer spatially to their respective editing sites and have a more pronounced impact on RNA secondary structure. CONCLUSIONS: Our study reveals widespread cis variation in RNA editing among genetically distinct individuals and sheds light on possible phenotypic consequences of such variation on complex traits and diseases.

Th17/regulatory T cell imbalance in sepsis patients with multiple organ dysfunction syndrome: attenuated by high-volume hemofiltration.

BACKGROUND: We assessed the Th17 (T-helper cell)/Treg (Regulatory T cell) imbalance in sepsis patients with multiple organ dysfunction syndrome (MODS) and the clinical benefits of continuous high-volume hemofiltration (HVHF). METHODS: 48 sepsis patients, including 22 patients with MODS (MODS group, n = 22) and 26 without (non-MODS group, n = 26), and 20 healthy volunteer controls were enrolled. The patients in MODS group were randomly divided into the continuous blood purification (CBP) group (n = 11) receiving conventional comprehensive treatment plus high-volume hemofiltration and the non-CBP group (n = 11) receiving conventional comprehensive treatment only. At day 28, all 48 patients were divided into the survival group (n = 36) and the non-survival group (n = 12). Venous blood samples, collected at 0, 6, 12 and 24 hours during hemofiltration (or equivalent times in the non-CBP group), were assessed by flow cytometry to detect the Th17 and Treg cells in peripheral blood. Serum cytokines (such as IL-6, IL-17, IL-23, IL-10 and TGF-ß1) were detected by enzyme-linked immune sorbent assay (ELISA). RESULTS: Th17%, Treg%, Th17/Treg, IL-6, IL-17, IL-23, IL-10 and TGF-ß1 were significantly higher in MODS and non-MODS group than in the health control (p<0.05), while Th17%, Treg%, Th17/Treg and measured cytokines were significantly higher in the MODS group compared to the non-MODS group (p<0.05). After HVHF treatment, Th17%, Treg%, Th17/Treg, IL-6, IL-17, and IL-10 were significantly reduced (p<0.05), while there were no significant changes in the non-CBP group (p>0.05). In addition, APACHE II and SOFA scores decreased markedly after HVHF treatment. Baseline Th17%, Treg%, Th17/Treg, IL-6, IL-17, IL-23, IL-10 and TGF-ß1 were significantly higher in the non-survival group compared to the survival group. Both Th17% and Th17/Treg were positivity correlated with concentration of IL-6 and APACHE II score (p<0.01). CONCLUSIONS: The level of Th17/Treg imbalance in sepsis is related to the occurrence and prognosis of MODS. High-volume hemofiltration can attenuate the Th17/Treg imbalance in sepsis patients, possibly by removing inflammatory mediators.

Proteomic analysis of the cerebrospinal fluid of Parkinson's disease patients pre- and post-deep brain stimulation.

AIMS: To investigate alterations in protein expression associated with deep brain stimulation (DBS) in an attempt to elucidate possible mechanisms of action . METHODS: Cerebrospinal fluid (CSF), obtained from six Parkinson's disease (PD) patients (pre- and post-DBS) and from six normal healthy controls, was studied for differentially expressed proteins. 2-D DIGE, in combination with MALDI-TOF and TOF-TOF Mass Spectrometry (MS) or ESI-MS, was used to identify the changed proteins (3 PD patients and 3 controls). Selected proteins were further studied using western blotting (6 PD patients and 6 controls). RESULTS: Twenty-one proteins were identified after MS and protein database interrogation. Apart from apolipoprotein A-I (apoA-I), the expression levels of complement C4 (C4), IgA, tetranectin, and extracellular superoxide dismutase (EC-SOD), detected by western blotting, correlated well with the 2-D DIGE results. In the follow-up period, the expression levels of C4, apoA-I and IgA were stable whereas EC-SOD and tetranectin were significantly elevated. In addition, when DBS was ceased in one patient due to a suicide attempt, the levels of EC-SOD and tetranectin significantly decreased. CONCLUSION: Our preliminary results suggest that variations in the expression levels of EC-SOD and tetranectin in CSF is related to DBS.

Comparative proteomic analysis of differentially expressed proteins in human pancreatic cancer tissue.

BACKGROUND: Pancreatic cancer is one of the most common malignant tumors. Early diagnosis of pancreatic cancer is difficult because of the latent onset and lack of good biomarkers. This study aimed to look for and identify differentially expressed proteins in tissues of pancreatic cancer and adjacent noncancerous tissues by proteomic approaches so as to provide information about possible pancreatic cancer markers and therapeutic targets. METHODS: Proteins extracted from 3 paired adjacent noncancerous and cancerous pancreatic tissue specimens were separated by two-dimensional gel electrophoresis (2-DE). The protein spots exhibiting statistical alternations between the two groups through computerized image analysis were then identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). In addition, Western blotting and immunohistochemistry were performed to verify the expression of certain candidate proteins. RESULTS: Twelve proteins were significantly upregulated and 4 were downregulated between cancerous and paired adjacent noncancerous pancreatic tissues. Several proteins (S100A11, Ig gamma-1 chain C region, GSTO1 and peroxiredoxin 4) were found for the first time to be associated with pancreatic cancer. Differential expression of some identified proteins was further confirmed by Western blotting analysis and/or immunohistochemical analysis. CONCLUSIONS: Comparative proteomic analysis using 2-DE and MALDI-TOF-MS is an effective method for identifying differentially expressed proteins that may be the potential diagnostic biomarkers and therapeutic targets for pancreatic cancer.