Astaxanthin suppresses endoplasmic reticulum stress and protects against neuron damage in Parkinson's disease by regulating miR-7/SNCA axis.

Parkinson's disease (PD) is a common neurodegenerative disorder that featured by the loss of dopaminergic neurons. Astaxanthin (AST), an important antioxidant, is demonstrated to be a neuroprotective agent for PD. However, the underlying mechanisms of AST in PD remain largely unclear. In this study, we found that AST treatment significantly not only abolished the cell viability inhibition and apoptosis promotion induced by 1-methyl-4-phenylpyridinium (MPP+) in SH-SY5Y cells via inhibiting endoplasmic reticulum (ER) stress, but also reversed the MPP+ caused dysregulation of miR-7 and SNCA expression. MiR-7 knockdown and SNCA overexpression were achieved by treating SH-SY5Y cells with miR-7 inhibitor and pcDNA3.1-SNCA plasmids, respectively. MiR-7 could bind to and negatively regulate SNCA in SH-SY5Y cells. Treated SH-SY5Y cells with miR-7 inhibitor or pcDNA3.1-SNCA abrogated the protective effects of AST on MPP+ induced cytotoxicity. Knockdown of miR-7 aggravated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced neuron injury in vivo suggested by athletic performance, histopathological morphology, expression of tyrosine hydroxylase (TH) and TUNEL positvie cells, however, AST treatment could reverse these effects of miR-7 knockdown. Collectively, AST suppressed ER stress and protected against PD-caused neuron damage by targeting miR-7/SNCA axis, implying that AST might be a potential effective therapeutic agent for PD.

Development of disulfide-derived fructose-1,6-bisphosphatase (FBPase) covalent inhibitors for the treatment of type 2 diabetes.

Fructose-1,6-bisphosphatase (FBPase), as a key rate-limiting enzyme in the gluconeogenesis (GNG) pathway, represents a practical therapeutic strategy for type 2 diabetes (T2D). Our previous work first identified cysteine residue 128 (C128) was an important allosteric site in the structure of FBPase, while pharmacologically targeting C128 attenuated the catalytic ability of FBPase. Herein, ten approved cysteine covalent drugs were selected for exploring FBPase inhibitory activities, and the alcohol deterrent disulfiram displayed superior inhibitory efficacy among those drugs. Based on the structure of lead compound disulfiram, 58 disulfide-derived compounds were designed and synthesized for investigating FBPase inhibitory activities. Optimal compound 3a exhibited significant FBPase inhibition and glucose-lowering efficacy in vitro and in vivo. Furthermore, 3a covalently modified the C128 site, and then regulated the N125-S124-S123 allosteric pathway of FBPase in mechanism. In summary, 3a has the potential to be a novel FBPase inhibitor for T2D therapy.

High frequency of the SDK1:AMACR fusion transcript in Chinese prostate cancer.

Chromosomal rearrangements and fusion genes play important roles in tumor development and progression. Four high-frequency prostate cancer (CaP) specific fusion genes, SDK1:AMACR, RAD50:PDLIM4, CTAGE5:KHDRBS3 and USP9Y:TTTY15 have been reported in Chinese CaP samples through a transcriptome sequencing study. We previously reported that USP9Y:TTTY15 is a transcription-mediated chimeric RNA, which is expressed in both tumor and non-malignant samples, and here we attempted to confirm the existence of the other three fusion genes SDK1:AMACR, RAD50:PDLIM and CTAGE5:KHDRBS3. We detected SDK1:AMACR fusion transcript in 23 of 100 Chinese CaP samples, but did not detect RAD50:PDLIM4 and CTAGE5:KHDRBS3 transcripts in any of those samples. SDK1:AMACR fusion transcript is Chinese CaP specific, which was neither detected in non-malignant prostate tissues adjacent to cancer from Chinese patient nor in CaP samples from UK patients. However, we did not detect genomic rearrangement of SDK1 gene by fluorescence in situ hybridization analysis, indicating that SDK1:AMACR is also a transcription-mediated chimeric RNA. Quantitative analysis demonstrated that high level AMACR expression was associated with SDK1:AMACR fusion status (P=0.004), suggesting that SDK1:AMACR fusion transcript may promote prostate carcinogenesis through increasing AMACR expression. However, the fusion status was not significantly correlated with any poor disease progression clinical features. The identification of the SDK1:AMACR fusion transcript in CaP cases from China but not from UK further supports our previous observation that different genetic alterations contribute to CaP in China and Western countries, although many genetic changes are also shared. Further studies are required to establish if CaPs with SDK1:AMACR represent a distinct subtype.

Serum adiponectin levels may be associated with the pathogenesis of hepatocellular carcinoma.

The aim of the meta-analysis described below was to investigate the correlation between serum levels of adiponectin (ADPN) and the pathogenesis of hepatocellular carcinoma (HCC). Relevant studies about serum ADPN levels and the pathogenesis of HCC were identified by searching electric databases and by manual search. The included studies were selected in strict accordance with the inclusion and exclusion criteria. Detailed criteria were described in "Materials and methods" section. Statistical analyses were conducted with the STATA 12.0 statistical software (StataCorp, College Station, TX, USA). A total of nine studies were incorporated into this meta-analysis after careful consideration, including 705 HCC patients and 1390 healthy controls. This meta-analysis demonstrated that the serum ADPN levels in HCC patients were significantly higher than those in healthy controls (standard mean difference (SMD) = 0.97, 95% confidence intervals (CI) = 0.02∼1.93, P < 0.05). The result of subgroup analysis by ethnicity revealed that serum ADPN levels in Caucasians and Asians were both obviously higher than those in healthy controls (Caucasians: SMD = 0.51, 95% CI = 0.30∼0.73, P < 0.001; Asians: SMD = 0.49, 95% CI = 0.06∼0.91, P < 0.05), but in Africans, the differences between HCC patients and controls had no statistical significance (SMD = 2.64, 95% CI = -3.01∼8.30, P = 0.36). The evidence obtained by this meta-analysis suggests that serum ADPN levels are associated with the pathogenesis of HCC. Further conclusion might be that increased serum levels of ADPN can inhibit tumor growth and play a protective role in the development of HCC.

Association between EXOC3L2 rs597668 polymorphism and Alzheimer's disease.

BACKGROUND: EXOC3L2 gene rs597668 polymorphism was identified to be significantly associated with Alzheimer's disease (AD) in Caucasian population. However, recent studies reported consistent and inconsistent results in Caucasian and Asian populations. AIMS: In order to assess this association, we performed a meta-analysis of rs597668 polymorphism using RevMan (v.5.1) software. METHODS: We searched PubMed and Google scholar databases and selected 4 independent publications, which included 16 independent studies. We conducted sensitivity analysis and evaluated the publication bias. In the end, we calculated the odds ratio (OR) using fixed effect model (Mantel-Haenszel). RESULTS: We observed significant association between rs597668 polymorphism and AD using allele model (P = 0.006, OR = 1.09, 95% CI 1.03-1.16) and the dominant model (P = 0.008, OR = 1.11, 95% CI 1.03-1.21). DISCUSSION AND CONCLUSIONS: To our knowledge, this is the first study that assesses the association between rs597668 polymorphism and AD by meta-analysis. We believe that our findings will be very useful for future genetic studies in AD.

[The effect of continuous hemofiltration in the treatment of traumatic patients with refractory acute cephalocele after craniotomy].

OBJECTIVE: To investigate the effect and the possible mechanism of continuous hemofiltration in the treatment of traumatic patients with refractory acute cephalocele. METHODS: Continuous venous-venous hemofiltration (CVVH) was applied to 9 traumatic patients with refractory acute cephalocele after craniotomy. The changes in patients' physical signs, electrolytes, blood gas analysis, biochemical and blood clotting indexes as well as the outcome were observed. RESULTS: (1) The later the CVVH started, the worse the disorders became such as unstable body temperature, respiratory rate, heart rate, blood pressure and abnormal blood gas analysis. The most significant abnormality emerged with a delay of 12 hours. The above abnormalities returned to normal and kept stable within 12 hours of CVVH. CVVH maintained body temperature in hypothermic state, and serum lactic acid was kept at a low level without disturbance of blood coagulation function. (2) The duration between occurrence of cephalocele and beginning of CVVH was 2-16 hours, with a mean of (5.4±5.1) hours, the duration of CVVH was 23-129 hours, with a mean of (75.7±34.3) hours, and the net volume of liquid balance (NVLB) was -1.2-3.1 L, with a mean of (0.76±1.46) L. Height of encephalocele over skull window (HEOSW) was 51.8±10.0 mm and 51.0±10.0 mm before and 72 hours after CVVH. NVLB and HEOSW did not show obvious correlation with the prognosis of the patients. (3) Four patients survived, and 2 patients showed satisfactory outcome with Glasgow outcome scale (GOS) over 12 after follow-up for 3 months, and 2 patients showed improvement with GOS of 8 but in vegetative state 3 months later. Five patients died of respiratory failure and multiple organ dysfunction syndrome (MODS) 9-35 days after the termination of CVVH. CONCLUSIONS: CVVH was safe and effective in certain extent in the treatment of refractory acute cephalocele. The direct causes of death of the patients were complications instead of the cephalocele itself. The outcomes of the patients were related to the time of beginning of CVVH and the duration of CVVH, and there was nothing to do with the NVLB and the HEOSW. The study implicated that the effect of CVVH on these patients was not brain-dehydration solely. It also exerted certain effect on regulating water-electrolyte balance, acid-base balance and body temperature.

[Early treatment of atelectasis by bronchoscopy in craniotomy patients].

OBJECTIVE: To investigate the safety and effects of early bronchoscopy on atelectasis of the ventilation patients, whom had experienced craniotomy for severe cranial trauma and hemorrhage. METHODS: Fifty-five patients suffered from severe cranial trauma and hemorrhage with Glascow coma scores (GCS) less than 8 complicated by atelectasis after craniotomy were early given sputum suction by bronchoscope via extratracheal intubation and broncho-alveolar lavage (BAL) during tracheal intubation and mechanical ventilation. During the treatment, patients' consciousness, vital signs and arterial blood gas were closely monitored. The relevant data, before, during (5, 10, and 25 minutes), bronchoscopy treatment completed and 30 minutes after bronchoscopy, were recorded and analyzed. RESULTS: Eighty-two time of bronchoscopies and 111 time of local BALs in 55 patients were completed and were effective for atelectasis. The patient's GCS (5.6±2.5 vs. 5.4±2.6, P>0.05), heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), blood oxygenous saturation (SaO(2)) were not deteriorated during bronchoscopy. Compared with pre-bronchoscopy, the HR and SBP decreased (HR: 88.2±14.2 bpm vs. 98.2±18.3 bpm, SBP: 110.6±18.2 mm Hg vs. 118.4±18.5 mm Hg, both P<0.05), and SaO(2) increased (0.982±0.022 vs. 0.945±0.035, P<0.05), pH, arterial partial pressure of oxygen (PaO(2)) and arterial partial pressure of carbon dioxide (PaCO(2)) had no significant changes during bronchoscopy. There was obviously increased in PaO(2) (84.5±14.4 mm Hg, 81.6±18.2 mm Hg vs. 76.2±15.4 mm Hg, both P<0.05), and decreased in PaCO(2) (27.0±12.8 mm Hg, 29.3±18.2 mm Hg vs. 36.5±11.6 mm Hg, both P<0.05) respectively, significantly decreased in alveolar arterial pressure of oxygen difference [P ((A-a))O(2)] at 10 minutes and 25 minutes, and at the time bronchoscopy treatment completed and the time 30 minutes after compared with before bronchoscopy (36.1±4.7 mm Hg, 32.4±6.2 mm Hg, 32.5±5.2 mm Hg, 31.2±7.2 mm Hg vs. 38.5±5.6 mm Hg, all P<0.05). All patients had not encounter side effects related with bronchoscopy and ventilation. CONCLUSION: The bronchoscope via extratracheal intubation for sputum suction and BAL were safe and effective treatment to the patients suffered from severe cranial trauma or hemorrhage complicated by atelectasis after craniotomy during mechanical ventilation, without obvious changes of the vital signs.

Application of fiberoptic bronchscopy in patients with acute exacerbations of chronic obstructive pulmonary disease during sequential weaning of invasive-noninvasive mechanical ventilation.

BACKGROUND: Early withdrawal of invasive mechanical ventilation (IMV) followed by noninvasive MV (NIMV) is a new strategy for changing modes of treatment in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) with acute respiratory failure (ARF). Using pulmonary infection control window (PIC window) as the switch point for transferring from invasive to noninvasive MV, the time for early extubation can be more accurately judged, and therapy efficacy can be improved. This study aimed to prospectively investigate the clinical effectiveness of fiberoptic bronchscopy (FOB) in patients with AECOPD during sequential weaning of invasive-noninvasive MV. METHODS: Since July 2006 to January 2011, 106 AECOPD patients with ARF were treated with comprehensive medication and IMV after hospitalization. Patients were randomly divided into two groups according to whether fiberoptic bronchoscope is used (group A, n=54) or not (group B, n=52) during sequential weaning from invasive to noninvasive MV. In group A, for sputum suction and bronchoalveolar lavage (BAL), a fiberoptic bronchoscope was put into the airway from the outside of an endotracheal tube, which was accompanied with uninterrupted use of a ventilator. After achieving PIC window, patients of both groups changed to NIMV mode, and weaned from ventilation. The following listed indices were used to compare between the groups after treatment: 1) the occurrence time of PIC, the duration of MV, the length of ICU stay, the success rate of weaning from MV for the first time, the rate of reventilation and the occurrence rate of ventilator-associated pneumonia (VAP); 2) the convenience and safety of FOB manipulation. The results were compared using Student's t test and the Chi-square test. RESULTS: The occurrence time of PIC was (5.01±1.49) d, (5.87±1.87) d in groups A and B, respectively (P<0.05); the duration of MV was (6.98±1.84) d, (8.69±2.41) d in groups A and B, respectively (P<0.01); the length of ICU stay was (9.25±1.84) d, (11.10±2.63) d in groups A and B, respectively (P<0.01); the success rate of weaning for the first time was 96.30%, 76.92% in groups A and B, respectively (P<0.01); the rate of reventilation was 5.56%, 19.23% in groups A and B, respectively (P<0.05); and the occurrence rate of VAP was 3.70%, 23.07% in groups A and B, respectively (P<0.01). Moreover, it was easy and safe to manipulate FOB, and no side effect was observed. CONCLUSIONS: The application of FOB in patients with AECOPD during sequential weaning of invasive-noninvasive MV is effective in ICU. It can decrease the duration of MV and the length of ICU stay, increase the success rate from weaning MV for the first time, reduce the rate of reventilation and the occurrence rate of VAP. In addition, such a method is convenient and safe in patients of this kind.

[Changes in plasma content of matrix metallo proteinase-9 in acute cerebral infarction patients before and after thrombolytic therapy and its significance].

OBJECTIVE: To investigate the changes in the content of plasma matrix metallo proteinase-9 (MMP-9) in patients with acute cerebral infarction before and after thrombolytic therapy and its clinical significance. METHODS: The levels of MMP-9 were determined in 34 patients with acute cerebral infarction before and after thrombolytic therapy, and 34 healthy individuals served as healthy control. RESULTS: Compared with the healthy controls, the levels of plasma MMP-9 before thrombolytic therapy were not significantly increased [(13.47±3.09) ng/L vs. (12.89±10.22) ng/L, P >0.05]. In contrast, MMP-9 values were significantly increased after thrombolytic therapy [(22.06±12.53) ng/L] compared with that in either before or healthy control group (both P<0.05). MMP-9 values were significantly higher in patients with hemorrhage after thrombolytic therapy (incidence rate was 26.5%, 9/34) compared with before treatment [(24.02±15.41) ng/L vs. (14.28±2.33) ng/L, P<0.05], and the values of MMP-9 were higher than those of patients without hemorrhage [(20.42±9.57) ng/L], but there was no statistically significant difference ( P >0.05). In patients with complete revascularization (revascularization rate was 58.8%, 20/34), MMP-9 level was markedly higher than before thrombolytic therapy after thrombolytic therapy [(19.26±7.94) ng/L vs. (13.63±3.02) ng/L, P<0.05], and the values of MMP-9 were higher than the no-revascularization patients [(18.97±4.23) ng/L], but there was no statistically significant difference ( P >0.05). CONCLUSION: Thrombolytic therapy activated MMP-9, and MMP-9 increased the risk of hemorrhage after thrombolytic therapy, and it participated in the mechanisms of hemorrhagic tendency after thrombolysis.

[Study of the protection and mechanism of IGF-1 on tau protein hyperphosphorylation in PC12 cells induced by Abeta(1-40)].

OBJECTIVE: To investigate the effect and the molecular mechanism of insulin-like growth factor 1 (IGF-1) on the level of tau protein phosphorylation in PC12 cells induced by aggregated beta-amyloid protein(1-40) (Abeta(1-40)). METHODS: MTT assay was used to measure the survival rate of PC12 cells, Western blot was applied to detect tau phosphorylation level, total tau, glycogen synthase kinase-3beta (GSK-3beta), and phosphorylation of GSK-3beta Ser9 for observing the effect of IGF-1 or LiCl, a specific inhibitor of GSK-3beta, on Abeta-induced tau protein phosphorylation in PC12 cells. RESULTS: Different concentrations of IGF-1 could improve the survival rate of PC12 cells compared with that of Abeta(1-40) group (P < 0.05), and the best protective effect was observed in 1 microg/mL IGF-1 group. The levels of tau protein phosphorylation in the sites of Ser396, Ser(199/202) and the amount of whole tau increased after 3 h exposure and reached the maximum level after 12 h exposure to Abeta(1-40), meanwhile, the expressions of the amount of whole GSK-3beta was also increased (P < 0.05), but a decreased phosphorylation of GSK-3betaSer9 was observed (P < 0.05). Pretreatment with several dose of IGF-1 or LiCl, markedly reduced Abeta(1-40)-induced tau hyperphosphorylation and the expression of GSK-3beta (P < 0.05), but the expression of phosphorylation of GSK-3betaSer9 was increased (P < 0.05). CONCLUSION: The levels of tau protein phosphorylation in the sites of Ser396, Ser(199/202) and the amount of whole tau increased by Abeta(1-40) in PC12 cells, GSK-3beta activation by Abeta(1-40) may lead to extensive tau phosphorylation. IGF-1 could attenuate Abeta(1-40)-induced tau protein hyperphosphorylation by inhibiting the activation of GSK-3beta.