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Background and Purpose: Overexpression of astrocytic lactoferrin (Lf) was observed in the brain of Alzheimer's disease (AD) patients, whereas the role of astrocytic Lf in AD progression remains unexplored. In this study, we aimed to evaluate the effects of astrocytic Lf on AD progression. Experimental Approach: Male APP/PS1 mice with astrocytes overexpressing human Lf were developed to evaluate the effects of astrocytic Lf on AD progression. N2a‐sw cells also were employed to further uncover the mechanism of astrocytic Lf on β‐amyloid (Aβ) production. Key Results: Astrocytic Lf overexpression increased protein phosphatase 2A (PP2A) activity and reduced amyloid precursor protein (APP) phosphorylation, Aβ burden and tau hyperphosphorylation in APP/PS1 mice. Mechanistically, astrocytic Lf overexpression promoted the uptake of astrocytic Lf into neurons in APP/PS1 mice, and conditional medium from astrocytes overexpressing Lf inhibited p‐APP (Thr668) expression in N2a‐sw cells. Furthermore, recombinant human Lf (hLf) significantly enhanced PP2A activity and inhibited p‐APP expression, whereas inhibition of p38 or PP2A activities abrogated the hLf‐induced p‐APP down‐regulation in N2a‐sw cells. Additionally, hLf promoted the interaction of p38 and PP2A via p38 activation, thereby enhancing PP2A activity, and low‐density lipoprotein receptor‐related protein 1 (LRP1) knockdown significantly reversed the hLf‐induced p38 activation and p‐APP down‐regulation. Conclusions and Implications: Our data suggested that astrocytic Lf promoted neuronal p38 activation, via targeting to LRP1, subsequently promoting p38 binding to PP2A to enhance PP2A enzyme activity, which finally inhibited Aβ production via APP dephosphorylation. In conclusion, promoting astrocytic Lf expression may be a potential strategy against AD. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase‐3α/β (GSK3α/β) is a critical kinase for Tau hyperphosphorylation which contributes to neurodegeneration. Despite the termination of clinical trials for GSK3α/β inhibitors in Alzheimer's disease (AD) treatment, there is a pressing need for novel therapeutic strategies targeting GSK3α/β. Here, we identified the compound AS1842856 (AS), a specific forkhead box protein O1 (FOXO1) inhibitor, reduced intracellular GSK3α/β content in a FOXO1‐independent manner. Specifically, AS directly bound to GSK3α/β, promoting its translocation to the multivesicular bodies (MVBs) and accelerating exocytosis, ultimately decreasing intracellular GSK3α/β content. Expectedly, AS treatment effectively suppressed Tau hyperphosphorylation in cells exposed to okadaic acid or expressing the TauP301S mutant. Furthermore, AS was visualized to penetrate the blood–brain barrier (BBB) using an imaging mass microscope. Long‐term treatment of AS enhanced cognitive function in P301S transgenic mice by mitigating Tau hyperphosphorylation through downregulation of GSK3α/β expression in the brain. Altogether, AS represents a novel small‐molecule GSK3α/β inhibitor that facilitates GSK3α/β exocytosis, holding promise as a therapeutic agent for GSK3α/β hyperactivation‐associated disorders. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases worldwide. The occult nature of the onset and the uncertainty of the etiology largely impede the development of therapeutic strategies for AD. Previous studies revealed that the disorder of energy metabolism in the brains of AD patients appears far earlier than the typical pathological features of AD, suggesting a tight association between energy crisis and the onset of AD. Energy crisis in the brain is known to be induced by the reductions in glucose uptake and utilization, which may be ascribed to the diminished expressions of cerebral glucose transporters (GLUTs), insulin resistance, mitochondrial dysfunctions, and lactate dysmetabolism. Notably, the energy sensors such as peroxisome proliferators-activated receptor (PPAR), transcription factor EB (TFEB), and AMP-activated protein kinase (AMPK) were shown to be the critical regulators of autophagy, which play important roles in regulating beta-amyloid (Aβ) metabolism, tau phosphorylation, neuroinflammation, iron dynamics, as well as ferroptosis. In this study, we summarized the current knowledge on the molecular mechanisms involved in the energy dysmetabolism of AD and discussed the interplays existing between energy crisis, autophagy, and ferroptosis. In addition, we highlighted the potential network in which autophagy may serve as a bridge between energy crisis and ferroptosis in the progression of AD. A deeper understanding of the relationship between energy dysmetabolism and AD may provide new insight into developing strategies for treating AD; meanwhile, the energy crisis in the progression of AD should gain more attention., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: To investigate the roles of PKC-α/ezrin signals in phagocytosis crisis of retinal pigment epithelium (RPE) cells in light damage model., Methods: Light induced mice RPE injury model was established by continuously irradiating cool white light at different exposure time (0, 4, 8h light intensity: 4.18×10 -6 J/cm 2 ). In vitro , human ARPE-19 cells treated with the doses and intensity (1.57×10 -6 J/cm 2 ) of laser irradiation. Histology analysis was evaluated by hematoxylin and eosin (HE) staining. In vivo RPE phagocytosis was quantified by measuring the accumulation of photoreceptor outer segments in the sub-retinal space. In vitro RPE phagocytosis was assessed by calculating the relative fluorescence intensity of FITC-labeled microspheres in ARPE-19 cells. To further investigate the molecular mechanism, the activation of PKC-α/ezrin signal was evaluated by Western blot in vivo and in vitro ., Results: HE staining revealed that the thickness of outer nuclear layer decreased significantly after 4 and 8h light exposure. By immunostaining with rhodopsin, a significant greater accumulation of photoreceptor outer segment was noticed after light injury. In vitro , light injured RPE cells had less phagocytic activity in a dose dependent manner than that of the normal control ( P <0.01). Western blot suggested the activation of PKC-α/ezrin signaling was down-regulated in a dose-dependent manner after light exposure., Conclusion: Our data suggest that light induced phagocytic crisis of RPE cells may result from the down-regulation of PKC-α/ezrin signaling.

Aim: To determine the optimal type of surgery for late-stage gastric cancer with hepatic metastases., Methods: We retrospectively analyzed 49 gastrectomies for late-stage gastric cancer conducted in the First Hospital Affiliated to Henan University of Science and Technology between September 2003 and September 2010. All gastrectomy operations were divided into two groups: radical resection (gastrectomy and simultaneous resection of hepatic metastases, n = 31), and palliative resection (gastrectomy without hepatic resection, n = 18). All 49 patients had chemotherapy catheter implantation in the hepatic artery via the gastroduodenal artery. Postoperative complications and cumulative survival rates of the two groups were compared and analyzed., Results: There was no significant difference in the number of perioperative complications between the radical and palliative resection groups (6 and 3 cases, respectively, P > 0.05). The incidence of long-term complications including ileus (3 in the radical resection and 2 in the palliative resection groups) and anastomosis (2 cases in each group) was not significantly different (P > 0.05). The cumulative survival rate was significantly lower in the palliative resection group (P < 0.05)., Conclusion: Radical gastrectomy with resection of hepatic metastases and hepatoarterial catheter implantation is the recommended surgery for late-stage gastric cancer patients with hepatic metastases.

Panax ginseng is traditionally used as a remedy for cancer, inflammation, stress and aging, and ginsenoside‑Rg5 is a major bioactive constituent of steamed ginseng. The present study aimed to evaluate whether ginsenoside‑Rg5 had any marked cytotoxic, apoptotic or DNA‑damaging effects in human cervical cancer cells. Five human cervical cancer cell lines (HeLa, MS751, C33A, Me180 and HT‑3) were used to investigate the cytotoxicity of ginsenoside‑Rg5 using a 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay. Additionally, the effects of ginsenoside‑Rg5 on the apoptosis of HeLa and MS751 cells were detected using DNA ladder assays and flow cytometry. DNA damage was assessed in the HeLa and MS751 cells using alkaline comet assays and by detection of γH2AX focus formation. The HeLa and MS751 cells were significantly more sensitive to ginsenoside‑Rg5 treatment compared with the C‑33A, HT‑3 and Me180 cells. As expected, ginsenoside‑Rg5 induced significant concentration‑ and time‑dependent increases in apoptosis. In addition, ginsenoside‑Rg5 induced significant concentration‑dependent increases in the level of DNA damage compared with the negative control. Consistent with the comet assay data, the percentage of γH2AX‑positive HeLa and MS751 cells also revealed that ginsenoside‑Rg5 caused DNA double‑strands to break in a concentration‑dependent manner. In conclusion, ginsenoside‑Rg5 had marked genotoxic effects in the HeLa and MS751 cells and, thus, demonstrates potential as a genotoxic or cytotoxic drug for the treatment of cervical cancer.

In order to analyze the relationships between aboveground biomass and environmental factors along an altitude gradient of Bayanbulak alpine grassland on the southern slope of Tianshan Mountain, nine plots were selected, with each at 100 m interval of altitude. The results showed that Stipa purpurea and Festuca ovina communities distributed at the altitude from 2460 to 2760 m, and the aboveground biomass were 52.2-75.9 g x m(-2). Kobresia capillifolia + S. purpurea communities distributed at altitude 2860 m, and the aboveground biomass was 53.2 g x m(-2). K. capillifolia, Aichemilla tianschanica and Carex stenocarpa distributed at the altitude from 2860 to 3260 m, and the aboveground biomass was 62.1-107.4 g x m(-2). The mean relative humidity in July and August had greater effects on the aboveground biomass. Altitude had a negative correlation with the aboveground biomass of gramineous functional group, but a positive correlation with that of sedge functional group. The mean air temperature in July and August was the key factor affecting the aboveground biomass of gramineous and sedge functional groups, and the stepwise regression equations were Y = 13.467X - 97.284 and Y = 171.699 - 15.331X, respectively (X represented mean air temperature, and Y represented aboveground biomass). Altitude was negatively correlated with mean air temperature and soil pH value (P < 0.01), and positively correlated with mean relative humidity (P < 0.01) and soil available nitrogen and water content (P < 0.05).