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.

[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.

[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.