The autophagy–lysosomal system in subarachnoid haemorrhage

The autophagy–lysosomal pathway is a self‐catabolic process by which dysfunctional or unnecessary intracellular components are degraded by lysosomal enzymes. Proper function of this pathway is critical for maintaining cell homeostasis and survival. Subarachnoid haemorrhage (SAH) is one of the most devastating forms of stroke. Multiple pathogenic mechanisms, such as inflammation, apoptosis, and oxidative stress, are all responsible for brain injury and poor outcome after SAH. Most recently, accumulating evidence has demonstrated that the autophagy–lysosomal pathway plays a crucial role in the pathophysiological process after SAH. Appropriate activity of autophagy–lysosomal pathway acts as a pro‐survival mechanism in SAH, while excessive self‐digestion results in cell death after SAH. Consequently, in this review article, we will give an overview of the pathophysiological roles of autophagy–lysosomal pathway in the pathogenesis of SAH. And approaching the molecular mechanisms underlying this pathway in SAH pathology is anticipated, which may ultimately allow development of effective therapeutic strategies for SAH patients through regulating the autophagy–lysosomal machinery.     

Embryological Studies of Codonopsis pilosula Nannf.

This paper reports the studies of megasporogenesis and microsporogenesis, development of female and male gametophytes, fertilization, and development of embryo and endosperm, The anther wall consists of four layers, i.e. epidermis, endothecium, middle layer and tapetum. Part of the tapetum cells originates from the primary parietal cells, and the other part comes from the basic tissue of the anther partition. Tapeta? cells are uninucleate or binucleate, and belong to the secretory type. Microsporocyte originates directly from the primary sporogenous cell, Cytokinesis is of the simultaneous type. Arrangement of microspores in tetrad is isobilateral. Mature pollen grain is of the 2-celled type. The ovary is tricarpellum, trilocular with many ovules. The ovule is mono-integinous, tenui-nucellar and anatropous. The embryo sac originates from the single-archesporial cell. The one chalazal megaspore in linear tetrad is the functional megaspore. The development of embryo sac is of the Polygonum type. Before fertilization, two polar nuclei fuse in to a secondary nucleus and the antipodal cells degenerate. Fertilization is porogamy, fusion of one sperm with secondary nucleus is faster than that of one sperm with egg nucleus. The development of endosperm is of the cellular type. The first three divisions of endosperm ceils are regular. Two endosperm cells near the ends of chalaza and the micropyle develop into haustorium without division. The haustoria gradually degenerate at the late stage of globular embryo. The mature seeds contain abundant endosperm. The development of embryo is of the Solanad type. The suspensor consists of 12–20 cells. The optimum development of the suspensor is at the early stage of the globular embryo. It begins to degenerate after late globular stage. The embryo develops from proembryo, heartshaped embryo, dicotyledenous- to mature embryo.     

Correlations between glycolysis with clinical traits and immune function in bladder urothelial carcinoma

Background: Glycolysis was a representative hallmark in the tumor microenvironment (TME), and we aimed to explore the correlations between glycolysis with immune activity and clinical traits in bladder urothelial carcinoma (BLCA).Methods: Our study obtained glycolysis scores for each BLCA samples from TCGA by a single-sample gene set enrichment analysis (ssGSEA) algorithm, based on a glycolytic gene set. The relationship between glycolysis with prognosis, clinical characteristics, and immune function were investigated subsequently.Results: We found that enhanced glycolysis was associated with poor prognosis and metastasis in BLCA. Moreover, glycolysis had a close correlation with immune function, and enhanced glycolysis increased immune activities. In other words, glycolysis had a positive correlation with immune activities. Immune checkpoints such as IDO1, CD274, were up-regulated in high-glycolysis group as well.Conclusion: We speculated that in BLCA, elevated glycolysis enhanced immune function, which caused tumor cells to overexpress immune checkpoints to evade immune surveillance. Inhibition of glycolysis might be a promising assistant for immunotherapy in bladder cancer.     

Targeted Overexpression of α-Synuclein by rAAV2/1 Vectors Induces Progressive Nigrostriatal Degeneration and Increases Vulnerability to MPTP in Mouse

Mutations, duplication and triplication of α-synuclein genes are linked to familial Parkinson’s disease (PD), and aggregation of α-synuclein (α-syn) in Lewy bodies (LB) is involved in the pathogenesis of the disease. The targeted overexpression of α-syn in the substantia nigra (SN) mediated by viral vectors may provide a better alternative to recapitulate the neurodegenerative features of PD. Therefore, we overexpressed human wild-type α-syn using rAAV2/1 vectors in the bilateral SN of mouse and examined the effects for up to 12 weeks. Delivery of rAAV-2/1-α-syn caused significant nigrostriatal degeneration including appearance of dystrophic striatal neurites, loss of nigral dopaminergic (DA) neurons and dissolving nigral neuron bodies in a time-dependent manner. In addition, the α-syn overexpressed mice also developed significant deficits in motor function at 12 weeks when the loss of DA neurons exceeded a threshold of 50%. To investigate the sensitivity to neurotoxins in mice overexpressing α-syn, we performed an MPTP treatment with the subacute regimen 8 weeks after rAAV injection. The impact of the combined genetic and environmental insults on DA neuronal loss, striatal dopamine depletion, dopamine turnover and motor dysfunction was markedly greater than that of either alone. Moreover, we observed increased phosphorylation (S129), accumulation and nuclear distribution of α-syn after the combined insults. In summary, these results reveal that the overexpressed α-syn induces progressive nigrostriatal degeneration and increases the susceptibility of DA neurons to MPTP. Therefore, the targeted overexpression of α-syn and the combination with environmental toxins may provide valuable models for understanding PD pathogenesis and developing related therapies.     

Bioavailability and antioxidant effect of epigallocatechin gallate administered in purified form versus as green tea extract in healthy individuals

Tea polyphenols have strong in vitro antioxidant activity. Due to their limited bioavailability, however, their contribution to in vivo antioxidant activity may depend on the form of administration. A human intervention study was performed to evaluate the bioavailability and antioxidant capacity of (-)-epigallocatechin-3-gallate (EGCG) administered as a single large dose in the form of either purified EGCG or as green tea extract (Polyphenon E). Plasma concentrations of tea polyphenols were determined by high-performance liquid chromatography (HPLC) analysis combined with coulometric array electrochemical detection (ECD). We found no differences in plasma EGCG concentrations and trolox equivalents determined by the trolox equivalent antioxidant capacity assay after administration of either form of EGCG. However, we found that the plasma antioxidant activity was significantly affected by changes in the plasma urate concentration, which may have interfered with the effect of tea polyphenols on the antioxidant activity. In addition, lymphocyte 8-hydroxydeoxyguanosine to deoxyguanosine (8-OHdG/10(6)dG) ratios were determined by HPLC with ECD. The 8-OHdG/10(6)dG ratios did not change significantly during the 24 h following both EGCG interventions but correlated significantly within individuals determined during the two interventions separated by 1 week. In summary, changes in plasma uric acid due to dietary intake were significantly correlated to the plasma antioxidant activity and exerted a stronger influence on the plasma antioxidant activity compared with the EGCG intervention. In future studies of dietary effects on the plasma antioxidant capacity, changes in plasma uric acid will need to be closely monitored.     

Regulatory effect of vasoactive intestinal peptide on the balance of Treg and Th17 in collagen-induced arthritis

Vasoactive intestinal peptide (VIP) is a well-known anti-inflammatory neuropeptide. The capacity of VIP can be exhibited through inhibiting inflammatory responses, shifting the Th1/Th2 balance in favor of anti-inflammatory Th2 immunity and inducing regulatory T cells (Tregs) with suppressive activity. In addition to pro-inflammatory Th1 response, Th17 are also believed to play important roles in the pathogenesis of rheumatoid arthritis (RA). In this study, we used collagen-induced arthritis (CIA) model in Wistar rats to investigate the role of VIP in the balance of CD4⁺ CD25⁺ Tregs and Th17 on RA. Data presented here showed that administration of VIP decreased incidence and severity of CIA. Disease suppression was associated with the upregulation of CD4⁺ CD25⁺ Tregs, downregulation of Th17- and Th1-type response and influence on the RANK/RANKL/OPG system. The results provide novel evidence that the therapeutic effects of VIP on CIA rats were associated with the balance of CD4⁺ CD25⁺ Tregs and Th17.     

Efficacy of Procyanidins against In Vivo Cellular Oxidative Damage: A Systematic Review and Meta-Analysis

Aims

In this study, the efficacy of proanthocyanidins (PCs) against oxidative damage was systematically reviewed to facilitate their use in various applications.

Methods

A meta-analysis was performed by two researchers. Each investigator independently searched electronic databases, including Cochrane, PubMed, Springer, Web of Science, China National Knowledge Infrastructure (CKNI), China Science and Technology Journal Database (CSTJ), and WanFang Data, and analyzed published data from 29 studies on the effects of PCs against oxidative damage. Oxidative stress indexes included superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), and total antioxidative capacity (T-AOC).

Results

Compared with the oxidative damage model group, PCs effectively improved the T-AOC, SOD, GSH, GPx, and CAT levels, and reduced the MDA levels; these differences were statistically significant (P < 0.05). In studies that used the gavage method, SOD (95% CI, 2.33–4.00) and GPx (95% CI, 2.10–4.05) were 3.16-fold and 3.08-fold higher in the PC group than in the control group, respectively. In studies that used the feeding method, SOD (95% CI, 0.32–1.74) and GPx (95% CI, -0.31 to 1.65) were 1.03-fold and 0.67-fold higher in the PC group than in the control group, respectively. Statistically significant differences in the effects of PCs (P < 0.00001) were observed between these two methods. MDA estimated from tissue samples (95% CI, -5.82 to -2.60) was 4.32-fold lower in the PC group than in the control group. In contrast, MDA estimated using serum samples (95% CI, -4.07 to -2.06) was 3.06-fold lower in the PC group than in the control group. The effect of PCs on MDA was significantly greater in tissue samples than in serum samples (P = 0.02).

Conclusion

PCs effectively antagonize oxidative damage and enhance antioxidant capacity. The antagonistic effect may be related to intervention time, intervention method, and the source from which the indexes are estimated.     

A nuclear export signal and phosphorylation regulate Dok1 subcellular localization and functions

Dok1 is believed to be a mainly cytoplasmic adaptor protein which down-regulates mitogen-activated protein kinase activation, inhibits cell proliferation and transformation, and promotes cell spreading and cell migration. Here we show that Dok1 shuttles between the nucleus and cytoplasm. Treatment of cells with leptomycin B (LMB), a specific inhibitor of the nuclear export signal (NES)-dependent receptor CRM1, causes nuclear accumulation of Dok1. We have identified a functional NES (348LLKAKLTDPKED359) that plays a major role in the cytoplasmic localization of Dok1. Src-induced tyrosine phosphorylation prevented the LMB-mediated nuclear accumulation of Dok1. Dok1 cytoplasmic localization is also dependent on IKKbeta. Serum starvation or maintaining cells in suspension favor Dok1 nuclear localization, while serum stimulation, exposure to growth factor, or cell adhesion to a substrate induce cytoplasmic localization. Functionally, nuclear NES-mutant Dok1 had impaired ability to inhibit cell proliferation and to promote cell spreading and cell motility. Taken together, our results provide the first evidence that Dok1 transits through the nucleus and is actively exported into the cytoplasm by the CRM1 nuclear export system. Nuclear export modulated by external stimuli and phosphorylation may be a mechanism by which Dok1 is maintained in the cytoplasm and membrane, thus regulating its signaling functions.     

The Association between Leptin Level and Breast Cancer: A Meta-Analysis

Background

Contradictory results have been reported regarding the association between leptin level and breast cancer. Therefore, a meta-analysis was performed to investigate this issue.

Methods

Published literature from PubMed and the Chinese National Knowledge Infrastructure (CNKI) Database was retrieved. This study was performed based on different cases and control groups. The combined effect () with 95% confidence interval (CI) was calculated using fixed-effects or random-effects model analysis.

Results

Overall, the mean serum leptin level of case groups was significantly higher than that of control groups. A) For 9 studies comparing breast cancer cases and healthy controls the combined effect was 0.58 with 95% CI (0.48, 0.68). B) For 4 studies comparing premenopausal breast cancer cases and healthy controls the was 0.32 (0.12, 0.52). C) For 5 studies comparing postmenopausal cases and healthy controls the was 0.65 (0.46, 0.84). D) For 4 studies comparing breast cancer cases and breast benign controls the was 0.38 (0.17, 0.59). E) For 2 studies comparing premenopausal breast cancer cases and breast benign controls the was 0.33 (-0.25, 0.91). F) For 6 studies comparing postmenopausal breast cancer cases and breast benign controls the was 0.39 (0.19, 0.60). G) For 4 studies comparing lymph node metastasis positive cases and negative controls the was 0.72 (0.45, 1.00). H) For 3 studies comparing breast benign cases and healthy controls the was 0.71 (0.41, 1.01).

Conclusion

This meta-analysis suggests that leptin level plays a role in breast cancer and has potential for development as a diagnostic tool.