Downregulated AEG-1 together with inhibited PI3K/Akt pathway is associated with reduced viability of motor neurons in an ALS model.

Astrocyte elevated gene-1 (AEG-1) has been reported to regulate the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and is also regulated by it. This study investigated how AEG-1 participates in the survival pathway of motor neurons in amyotrophic lateral sclerosis (ALS). We found reduced levels of AEG-1 in ALS motor neurons, both in vivo and in vitro, compared to wild type controls. Moreover, AEG-1 silencing demonstrated inhibition of the PI3K/Akt pathway and increased cell apoptosis. Additionally, the PI3K/Akt pathway in mSOD1 cells was unresponsive under serum deprivation conditions compared to wtSOD1 cells. These results suggest that AEG-1 deficiency, together with the inhibited PI3K/Akt pathway was associated with decreased viability of ALS motor neurons. However, the mRNA levels of AEG-1 were still lower in mSOD1 cells compared to the control groups, though the signaling pathway was activated by application of a PI3-K activator. This suggests that in ALS motor neurons, some unknown interruption exists in the PI3K/Akt/CREB/AEG-1 feedback loop, thus attenuating the protection by this signaling pathway. Together, these findings support that AEG-1 is a critical factor for cell survival, and the disrupted PI3K/Akt/CREB/AEG-1cycle is involved in the death of injured motor neurons and pathogenesis of ALS.

Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid.

BACKGROUND: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important roles in neurological diseases. In this study, we explored whether Homer1b/c was involved in SOD1 mutation-linked ALS. RESULTS: In vitro studies showed that the SOD1 G93A mutation induced an increase of Homer1b/c expression at both the mRNA and protein levels in NSC34 cells. Knockdown of Homer1b/c expression using its short interfering RNA (siRNA) (si-Homer1) protected SOD1 G93A NSC34 cells from apoptosis. The expressions of Homer1b/c and apoptosis-related protein Bax were also suppressed, while Bcl-2 was increased by lithium and valproic acid (VPA) in SOD1 G93A NSC34 cells. In vivo, both the mRNA and protein levels of Homer1b/c were increased significantly in the lumbar spinal cord in SOD1 G93A transgenic mice compared with wild type (WT) mice. Moreover, lithium and VPA treatment suppressed the expression of Homer1b/c in SOD1 G93A mice. CONCLUSION: The suppression of SOD1 G93A mutation-induced Homer1b/c upregulation protected ALS against neuronal apoptosis, which is a novel mechanism of the neuroprotective effect of lithium and VPA. This study provides new insights into pathogenesis and treatment of ALS.

Spy1, a unique cell cycle regulator, alters viability in ALS motor neurons and cell lines in response to mutant SOD1-induced DNA damage.

Increasing evidence indicates that DNA damage and p53 activation play major roles in the pathological process of motor neuron death in amyotrophic lateral sclerosis (ALS). Human SpeedyA1 (Spy1), a member of the Speedy/Ringo family, enhances cell proliferation and promotes tumorigenesis. Further studies have demonstrated that Spy1 promotes cell survival and inhibits DNA damage-induced apoptosis. We showed that the Spy1 expression levels were substantially decreased in ALS motor neurons compared with wild-type controls both in vivo and in vitro by qRT-PCR, western blotting, and Immunoassay tests. In addition, we established that over-expression of human SOD1 mutant G93A led to a decreased expression of Spy1. Furthermore, DNA damage response was activated in SOD1G93A-transfected cells (mSOD1 cells). Moreover, decreased Spy1 expression reduced cell viability and further activated the DNA damage response in mSOD1 cells. In contrast, increased Spy1 expression improved cell viability and inhibited the DNA damage response in mSOD1 cells. These results suggest that Spy1 plays a protective role in ALS motor neurons. Importantly, these findings provide a novel direction for therapeutic options for patients with ALS as well as for trial designs, such as investigating the role of oncogenic proteins in ALS.

The Chinese version of the SLEQOL is a reliable assessment of health-related quality of life in Han Chinese patients with systemic lupus erythematosus.

To assess the health-related quality of life (HRQOL) of Han Chinese people with systemic lupus erythematosus (SLE) using a Chinese version of the Systemic Lupus Erythematosus-Specific Quality of Life Questionnaire (SLEQOL-C) and explore the factors influencing HRQOL of people with SLE. Participants were Han Chinese people with SLE. The SLEQOL-C and 36-item Short Form Health Survey (SF-36) were used to estimate the HRQOL. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and fatigue using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Participant factors included age, gender, educational background, disease duration, erythrocyte sedimentation rate (ESR), and complement C3 and C4 levels. The results showed that higher SLEQQL-C scores correlated with lower SF-36 both measures are essential for HRQQL prediction. The SLEQOL-C scores were correlated with educational level,age, FACIT-F score, SLEDAI score, and ESR, which suggests that poor educational background, old-age, and increased fatigue, disease activity, and ESR might represent poor HRQOL. Although disease duration did not significantly correlate with the scores on the SLEQOL-C; those whose disease duration was 12-24 months had higher SLEQOL-C summary scores and physical functioning, symptoms, and treatment subscale scores than did those whose duration was less than 6 months. The FACIT-F score, education level, age, disease duration, SLEDAI score, and ESR contributed to SLEQOL-C scores. The SLEQOL-C is reliable for assessing HRQOL of Han Chinese people with SLE. Fatigue, educational level, age, disease duration, ESR, and disease activity mainly influenced HRQOL of SLE patients.

Multiple imaging and excellent anticancer efficiency of an upconverting nanocarrier mediated by single near infrared light.

It is difficult to meet the requirements of clinical diagnosis through a single imaging technique. Similarly, satisfactory therapy efficacy is also hard to achieve by a single therapeutic modality. It is therefore highly desirable and interesting to simultaneously achieve multimodal imaging and therapies in one single structure. In this study, we developed a core-shell-satellite NaGdF4:Yb,Er,Mn,Co@mSiO2-CuS structure using up-conversion luminescent (UCL) NaGdF4:Yb,Er,Mn,Co as the core, mesoporous silica as the layer, and the photoactive CuS nanoparticles as the satellites. The further linked photosensitizer (ZnPc) and doxorubicin hydrochloride (DOX) allow the system to have photodynamic therapy (PDT) and chemotherapy functions. The doping of Co2+ ions in the core endows the carrier with T2-weighted magnetic resonance imaging (MRI) properties, and the co-doping of Mn2+ ions can efficiently enhance the red emission which further improves the PDT efficiency by reacting with the attached ZnPc upon near-infrared (NIR) light irradiation. The nanoplatform exhibits excellent anti-tumor efficiency due to a synergistic effect arising from combined PDT, photo-thermal therapy (PTT) and chemotherapy, which has been evidenced by in vitro and in vivo results. Due to the multimodal imaging (MRI, CT, and UCL) properties, the drug delivery process and therapeutic efficacy can be monitored in real time and assessed, thus achieving the target of imaging-guided therapy.