SC79, a novel Akt activator, protects dopaminergic neuronal cells from MPP+ and rotenone.

In pathogenesis of Parkinson's disease (PD), mitochondrial dysfunction causes substantial reactive oxygen species (ROS) production and oxidative stress, leading to dopaminergic (DA) neuronal cell death. Mitochondrial toxins, including MPP+ (1-methyl-4-phenylpyridinium ion) and rotenone, induce oxidative injury in cultured DA neuronal cells. The current study tested the potential effect of SC79, a first-in-class small-molecule Akt activator, against the process. In SH-SY5Y cells and primary murine DA neurons, SC79 significantly attenuated MPP+- and rotenone-induced viability reduction, cell death, and apoptosis. SC79 activated Akt signaling in DA neuronal cells. Akt inhibition (by LY294002 and MK-2206) or CRISPR-Cas9-mediated Akt1 knockout completely abolished SC79-induced DA neuroprotection against MPP+. Further studies demonstrated that SC79 attenuated MPP+- and rotenone-induced ROS production, mitochondrial depolarization, and lipid peroxidation in SH-SY5Y cells and primary DA neurons. Moreover, upregulation of Nrf2-dependent genes (HO1 and NQO1) and Nrf2 protein stabilization were detected in SC79-treated SH-SY5Y cells and primary DA neurons. Together we show that SC79 protects DA neuronal cells from mitochondrial toxins possibly via activation of Akt-Nrf2 signaling.

[Epidemiological studies on close contacts of smear-positive tuberculosis patients in Shijiazhuang city from 2007 to 2008].

OBJECTIVE: To analyze the incidence of tuberculosis (TB) in people who were in close contact with smear-positive TB patients. METHODS: A total of 19 159 subjects, including 17 334 family members and 1825 classmates of patients, in close contact with 6653 smear-positive TB patients in Shijiazhuang city from 2007 to 2008 were observed. All the classmates were tested by purified protein derivative (PPD) test and symptom screening, and all family members were screened by symptoms. All these subjects were trained with knowledge related to TB. The ones with positive PPD test and suspected TB symptoms were further examined by chest X-ray and sputum smear microscopy, and those without any symptom were followed up monthly throughout a two year period and were examined at any time if symptoms occurred. RESULTS: A total of 281 patients with pulmonary TB were diagnosed in 2 years, including 176 family members and 105 classmates in all close contacts. The smear-positive incidences were 1466.67/100 000. The incidences for 14 - 25 years old group and more than 75 years old group were 2907.18/100 000 (83/2855) and 2650.96/100 000 (18/679), which were higher than those for other groups. Two higher incidences were related to close contact time periods of 6 months (929.07/100 000, 178/19 159) and 13 - 18 months (369.12/100 000, 70/18 964). Three highest incidences were observed in the roommates (11 384.62/100 000, 37/325), classmates (4533.33/100 000, 68/1500) and couples (1624.17/100 000, 86/5295). CONCLUSION: Closer contact with smear-positive patients with TB may result in the higher chance of TB. Close contact for 6 months or 13 to 18 months caused more patients, and the 14 - 25 years old group and more than 75 years old group had higher incidences of TB.

Optimal indicator for changing the filter during the continuous renal replacement therapy in intensive care unit patients with acute kidney injury: A crossover randomized trial.

BACKGROUND: The study aims to investigate an optimal indicator for changing the filter during the continuous renal replacement therapy (CRRT) in intensive care unit (ICU) patients with acute kidney injury (AKI). METHODS: Patients with AKI requiring CRRT in an ICU were randomly divided into two groups for crossover trial, i.e., groups A and B. Patients in the group A were firstly treated with continuous veno-venous hemofiltration (CVVH), followed by continuous veno-venous hemodiafiltration (CVVHDF). Patients in the group B were firstly treated with CVVHDF followed by CVVH. Delivered doses of solutes with different molecular weights at the indicated time points between groups were compared. A correlation analysis between the delivered dose and pre-filter pressure (PPRE) and transmembrane pressure (PTM) was performed. Receiver operating characteristic (ROC) curves were constructed to evaluate the accuracy of PTM as an indicator for filter replacement. RESULTS: A total of 50 cases were analyzed, 27 in the group A and 23 in the group B. Delivered doses of different molecular-weight solutes significantly decreased before changing the filter in both modalities, compared with those at the initiation of treatment (all P<0.05). In the late stage of CRRT, the possible rebound of serum medium-molecular-weight solute concentration was observed. PTM was negatively correlated with the delivered dose of medium-molecular-weight solute in both modalities. The threshold for predicting the rebound of serum concentration of medium-molecular-weight solute by PTM was 146.5 mmHg (1 mmHg=0.133 kPa). CONCLUSIONS: The filter can be used as long as possible within the manufacturer's safe use time limits to remove small-molecular-weight solutes. PTM of 146.5 mmHg may be an optimal indicator for changing the filter in CRRT therapies to remove medium-molecular-weight solutes.

Molecular Responses and Degradation Mechanisms of the Herbicide Diuron in Rice Crops.

Diuron [DU; 3-(3,4-dichlorophenyl)-1,1-dimethylurea], a widely used herbicide for weed control, arouses ecological and health risks due to its environment persistence. Our findings revealed that DU at 0.125-2.0 mg L-1 caused oxidative damage to rice. RNA-sequencing profiles disclosed a globally genetic expression landscape of rice under DU treatment. DU mediated downregulated gene encoding photosynthesis and biosynthesis of protein, fatty acid, and carbohydrate. Conversely, it induced the upregulation of numerous genes involved in xenobiotic metabolism, detoxification, and anti-oxidation. Furthermore, 15 DU metabolites produced by metabolic genes were identified, 7 of which include two Phase I-based and 5 Phase II-based derivatives, were reported for the first time. The changes of resistance-related phytohormones, like JA, ABA, and SA, in terms of their contents and molecular-regulated signaling pathways positively responded to DU stress. Our work provides a molecular-scale perspective on the response of rice to DU toxicity and clarifies the biotransformation and degradation fate of DU in rice crops.

MicroRNA-6862 inhibition elevates sphingosine kinase 1 and protects neuronal cells from MPP+-induced apoptosis.

MPP+ (1-methyl-4-phenylpyridinium)-induced dopaminergic neuronal cell apoptosis is associated with sphingosine kinase 1 (SphK1) inhibition. We here tested the potential effect of microRNA-6862 (miR-6862), a novel SphK1-targeting miRNA, on MPP+-induced cytotoxicity in neuronal cells. MiR-6862 locates in the cytoplasm of SH-SY5Y neuronal cells. It directly binds to SphK1 mRNA. In SH-SY5Y cells and HCN-2 cells, ectopic overexpression of miR-6862 decreased SphK13'-untranslated region luciferase reporter activity and downregulated its expression. miR-6862 inhibition exerted opposite activity and elevated SphK1 expression. In neuronal cells, MPP+-induced cell death was significantly inhibited through miR-6862 inhibition. Conversely, ectopic overexpression of miR-6862 or CRISPR/Cas9-induced SphK1 knockout augmented MPP+-induced apoptosis in the neuronal cells. Importantly, antagomiR-6862 failed to inhibit MPP+-induced apoptosis in SphK1-knockout SH-SY5Y cells. These results suggest that inhibition of miR-6862 induces SphK1 elevation and protects neuronal cells from MPP+-induced cell death.

PGK1 inhibitor CBR-470-1 protects neuronal cells from MPP+.

The neurotoxin MPP+ (1-methyl-4-phenylpyridinium ion) disrupts mitochondrial function leading to oxidative stress and neuronal death. Here we examine whether activation of the Keap1-Nrf2 cascade can protect SH-SY5Y neuroblastoma cells from MPP+-induced cytotoxicity. Treatment of SH-SY5Y cells with CBR-470-1, an inhibitor of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1), leads to methylglyoxal modification of Keap1, Keap1-Nrf2 disassociation, and increased expression of Nrf2 responsive genes. Pretreatment with CBR-470-1 potently attenuated MPP+-induced oxidative injury and SH-SY5Y cell apoptosis. CBR-470-1 neuroprotection is dependent upon Nrf2, as Nrf2 shRNA or CRISPR/Cas9-mediated Nrf2 knockout, abolished CBR-470-1-induced SH-SY5Y cytoprotection against MPP+. Consistent with these findings, PGK1 depletion or knockout mimicked CBR-470-1-induced actions and rendered SH-SY5Y cells resistant to MPP+-induced cytotoxicity. Furthermore, activation of the Nrf2 cascade by CRISPR/Cas9-induced Keap1 knockout protected SH-SY5Y cells from MPP+. In Keap1 or PGK1 knockout SH-SY5Y cells,CBR-470-1 failed to offer further cytoprotection against MPP+. Collectively PGK1 inhibition by CBR-470-1 protects SH-SY5Y cells from MPP+ via activation of the Keap1-Nrf2 cascade.

Compound 13 activates AMPK-Nrf2 signaling to protect neuronal cells from oxygen glucose deprivation-reoxygenation.

Oxygen glucose deprivation-reoxygenation (OGD-R) causes the production of reactive oxygen species (ROS) and oxidative injury in neuronal cells. We tested the potential neuroprotective function of compound 13 (C13), a novel AMP-activated protein kinase (AMPK) activator, against OGD-R. We show that C13 pretreatment protected SH-SY5Y neuronal cells and primary hippocampal neurons from OGD-R. C13 activated AMPK signaling in SH-SY5Y cells and primary neurons. It significantly inhibited OGD-R-induced apoptosis activation in neuronal cells. Conversely, AMPKα1 shRNA or knockout reversed C13-mediated neuroprotection against OGD-R. C13 potently inhibited OGD-R-induced ROS production and oxidative stress in SH-SY5Y cells and primary neurons. Furthermore, C13 induced Keap1 downregulation and Nrf2 activation, causing Nrf2 stabilization, nuclear accumulation, and expression of Nrf2-dependent genes. Nrf2 silencing or knockout in SH-SY5Y cells abolished C13-mediated neuroprotection against OGD-R. In conclusion, C13 activates AMPK-Nrf2 signaling to protect neuronal cells from OGD-R.

Hypothermic properties of dexmedetomidine provide neuroprotection in rats following cerebral ischemia-reperfusion injury.

Dexmedetomidine (Dex) is a sedative and analgesic agent that is widely administered to patients admitted to the intensive care unit, and has been demonstrated to result in hypothermia. Many patients have been revealed to benefit from therapeutic hypothermia, which can mitigate cerebral ischemia/reperfusion (I/R) injury following successful cardiopulmonary resuscitation. However, studies investigating the efficacy of Dex in I/R treatment is lacking. The present study aimed to investigate the efficacy of Dex in mitigating neuronal damage, and to determine the possible mechanism of its effects in a rat model of cardiac arrest (CA). CA was induced in Sprague-Dawley rats by asphyxiation for 5 min. Following successful resuscitation, the surviving rats were randomly divided into two treatment groups; one group was intraperitoneally administered with Dex (D group), whereas the control group was treated with normal saline (N group). Critical parameters, including core temperature and blood pressure were monitored following return of spontaneous circulation (ROSC). Arterial blood samples were collected at 10 min after surgery (baseline) 30 and 120 min post-ROSC; and neurological deficit scores (NDS) of the rats were taken 12 or 24 h after ROSC prior to euthanasia. The hippocampal tissue was then removed for analysis by histology, electron microscopy and western blotting. Rats in the D group exhibited a lower core temperature and higher NDS scores compared with the N group (P<0.05). In addition, Dex injection resulted in reduced expression of apoptotic and autophagy-associated factors in the hippocampus (P<0.05). Dex treatment induced hypothermia and improved neurological function in rats after ROSC following resuscitation from CA by inhibiting neuronal apoptosis and reducing autophagy, which suggested that Dex may be a potential therapy option for patients with CA.

4-(Dimethyl-amino)benzaldehyde.

The title compound, C(9)H(11)NO, crystallizes with two independent but essentially identical mol-ecules in the asymmetric unit, which are linked via a C-H⋯π inter-action. In both mol-ecules, the aldehyde and dimethyl-amine groups are essentially coplanar with the attached benzene ring. In the crystal structure, C-H⋯O hydrogen bonds link one type of independent mol-ecules into a chain along the a axis. In addition, the structure is stabilized by π-π stacking inter-actions involving the benzene rings [centroid-to-centroid distance = 3.697 (2) Å].

Gene therapy for human alpha1-antitrypsin deficiency in an animal model using SV40-derived vectors.

BACKGROUND & AIMS: In most genetic diseases, the goal of gene therapy is to deliver a particular transgene; however, sometimes a deleterious gene product must be eliminated. Because of the promise of recombinant simian virus 40 (rSV40) vectors, we tested their ability to deliver a transgene and to target a transcript for destruction by direct administration of the vectors to the liver of an animal model for human alpha1-antitrypsin (alpha1-AT) deficiency. METHODS: Therapy of human alpha1-AT deficiency requires stable transduction of resting hepatocytes, both to deliver wild-type alpha1-AT and to inhibit production of mutant alpha1-AT. Transgenic mice carrying the mutant human alpha1-AT PiZ allele were treated through an indwelling portal vein catheter with a simian virus 40 (SV40)-derived vector carrying a ribozyme designed to target the human transcript. RESULTS: Treated transgenic mice showed marked decreases of human alpha1-AT messenger RNA and the protein in the liver, and serum levels of human alpha1-AT were decreased to 50% +/- 5% of pretreatment values 3-16 weeks after transduction. Moreover, when normal mice were treated with an SV40-derived vector containing a modified human alpha1-AT complementary DNA engineered to be resistant to cleavage by the alpha1-AT ribozyme, they expressed human alpha1-AT messenger RNA and protein in their livers and serum levels of human alpha1-AT remained >1 microg/mL for 1 year. CONCLUSIONS: These results represent the initial steps toward a novel approach to the gene therapy of alpha1-AT deficiency.