Protein phosphatase 2A activators reverse age-related behavioral changes by targeting neural cell senescence.

The contribution of cellular senescence to the behavioral changes observed in the elderly remains elusive. Here, we observed that aging is associated with a decline in protein phosphatase 2A (PP2A) activity in the brains of zebrafish and mice. Moreover, drugs activating PP2A reversed age-related behavioral changes. We developed a transgenic zebrafish model to decrease PP2A activity in the brain through knockout of the ppp2r2c gene encoding a regulatory subunit of PP2A. Mutant fish exhibited the behavioral phenotype observed in old animals and premature accumulation of neural cells positive for markers of cellular senescence, including senescence-associated ß-galactosidase, elevated levels cdkn2a/b, cdkn1a, senescence-associated secretory phenotype gene expression, and an increased level of DNA damage signaling. The behavioral and cell senescence phenotypes were reversed in mutant fish through treatment with the senolytic ABT263 or diverse PP2A activators as well as through cdkn1a or tp53 gene ablation. Senomorphic function of PP2A activators was demonstrated in mouse primary neural cells with downregulated Ppp2r2c. We conclude that PP2A reduction leads to neural cell senescence thereby contributing to age-related behavioral changes and that PP2A activators have senotherapeutic properties against deleterious behavioral effects of brain aging.

The landscape of aging.

Aging is characterized by a progressive deterioration of physiological integrity, leading to impaired functional ability and ultimately increased susceptibility to death. It is a major risk factor for chronic human diseases, including cardiovascular disease, diabetes, neurological degeneration, and cancer. Therefore, the growing emphasis on "healthy aging" raises a series of important questions in life and social sciences. In recent years, there has been unprecedented progress in aging research, particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes. In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases, we review the descriptive, conceptual, and interventive aspects of the landscape of aging composed of a number of layers at the cellular, tissue, organ, organ system, and organismal levels.

The non-telomeric evolutionary trajectory of TRF2 in zebrafish reveals its specific roles in neurodevelopment and aging.

The shelterin protein complex is required for telomere protection in various eukaryotic organisms. In mammals, the shelterin subunit TRF2 is specialized in preventing ATM activation at telomeres and chromosome end fusion in somatic cells. Here, we demonstrate that the zebrafish ortholog of TRF2 (encoded by the terfa gene) is protecting against unwanted ATM activation genome-wide. The terfa-compromised fish develop a prominent and specific embryonic neurodevelopmental failure. The heterozygous fish survive to adulthood but exhibit a premature aging phenotype. The recovery from embryonic neurodevelopmental failure requires both ATM inhibition and transcriptional complementation of neural genes. Furthermore, restoring the expression of TRF2 in glial cells rescues the embryonic neurodevelopment phenotype. These results indicate that the shelterin subunit TRF2 evolved in zebrafish as a general factor of genome maintenance and transcriptional regulation that is required for proper neurodevelopment and normal aging. These findings uncover how TRF2 links development to aging by separate functions in gene expression regulation and genome stability control.

The differential spatiotemporal expression pattern of shelterin genes throughout lifespan.

Shelterin forms the core complex of telomere proteins and plays critical roles in protecting telomeres against unwanted activation of the DNA damage response and in Emaintaining telomere length homeostasis. Although shelterin expression is believed to be ubiquitous for stabilization of chromosomal ends. Evidences suggest that some shelterin subunits have tissue-specific functions. However, very little is known regarding how shelterin subunit gene expression is regulated during development and aging. Using two different animal models, the mouse and zebrafish, we reveal herein that shelterin subunits exhibit distinct spatial and temporal expression patterns that do not correlate with the proliferative status of the organ systems examined. Together, this work shows that the shelterin subunits exhibit distinct spatiotemporal expression patterns, suggesting important tissue-specific functions during development and aging.

An Evaluation of Laboratory Efficiency in Shanghai Emergency by Turn Around Times Level.

OBJECTIVE: China launched a health care reform policy due to the aging population and rapid urbanization. However, emergency overcrowding is not improved. We assessed the laboratory efficiency of emergency department (ED) in Shanghai hospitals. METHODS: We recorded the turn around times for processing laboratory biomarkers to assess laboratory efficiency at 17 EDs in national/regional hospitals. We compared TAT between national and regional hospitals and between central and ED laboratories to analyze the relationship between the laboratory efficiency and the ED overcrowding. RESULTS: All the participating hospitals have an emergency laboratory. The median TAT for c-TNT was 61 min (46-76 min) at regional EDs compared with 64 min (46-87 min) at national EDs; therefore, the TAT at regional EDs were more efficient (P < 0.05). The TAT were longer (65 min (53-85 min)) at ED labs than (60 min (42-83 min)) at central labs (P < 0.05), independent of the hospital tier and working period. We discovered that only 9% of investigated samples at Tier II EDs and 5% at Tier III EDs were assayed by point-of-care (POC) instruments. CONCLUSION: Our TAT level is approaching the recommended international standard. However, the TAT evaluation from ED laboratories demonstrates that their existence does not decrease the waiting time for laboratory reports compared to central laboratory. Thus, they have not yet approached a level to share the burden of the ED overcrowding. Further arrangement should be assigned to separate the function of emergency laboratory and central laboratory. It is worth deploying the POC assay in the ED, which will save twice the TAT level. The idea of evaluating routine laboratory efficiency by TAT at ED is fast, convenient, although it does not represent the general level of laboratory efficiency.

Vitamin C treatment attenuates hemorrhagic shock related multi-organ injuries through the induction of heme oxygenase-1.

BACKGROUND: Vitamin C (VitC) has recently been shown to exert beneficial effects, including protecting organ function and inhibiting inflammation, in various critical care conditions, but the specific mechanism remains unclear. Induction of heme oxygenase (HO)-1, a heat shock protein, has been shown to prevent organ injuries in hemorrhagic shock (HS) but the relationship between VitC and HO-1 are still ill-defined so far. Here we conducted a systemic in vivo study to investigate if VitC promoted HO-1 expression in multiple organs, and then tested if the HO-1 induction property of VitC was related to its organ protection and anti-inflammatory effect. METHODS: Firstly, to determine the HO-1 induction property of VitC, the HO-1 level were measured in tissues including kidney, liver and lung of the normal and HS model of Sprague-Dawley (SD) rats after VitC treatment (100 mg/kg body weight). Secondly, to testify if VitC prevented HS related organ injuries via inducing HO-1, the HS model of rats were separately pre- and post-treated with VitC, and some of them also received Zinc protoporphyrin (Znpp), a specific HO-1 inhibitor. The HO-1 activity in tissues was tested; the organ injuries (as judged by histological changes in tissues and the biochemical indicators level in serum) and inflammatory response in tissues (as judged by the level of pro-inflammatory cytokines Tumor necrosis factor-α and Interleukin-6 ) were analyzed. RESULTS: The HO-1 mRNA and protein level in kidney, liver, and lung were highly induced by VitC treatement under normal and HS conditions. The HO-1 activity in tissues was enhanced by both VitC pre- and post-treatment, which was shown to improve the organ injuries and inhibit the inflammatory response in the HS model of rats. Of note, the beneficial effects of VitC were abolished after HO-1 activity was blocked by Znpp. CONCLUSIONS: VitC led to a profound induction of HO-1 in multiple organs including the kidney, liver and lung, and this property might be responsible for the organ protection and inflammation inhibitory effects of both pre- and post-treatment with VitC in HS.

The clinical situation of point-of-care testing and its future development at the emergency department in Shanghai.

We assessed the efficiency of point-of-care (POC) tests in the emergency department (ED) by comparing them with the international standard. We recorded the turnaround times (TATs) for processing laboratory biomarkers to assess laboratory efficiency from 17 EDs in national/regional hospitals. We also compared patient components between national and regional hospitals. Although the 17 enrolled hospitals expanded their EDs, they contained only five POC machines among them. The P50 (P25, P75) of the TATs for POC tests was 47 min (39, 55.5 min) for cardiac troponin T, which was much longer than the international standard (30 min). The TATs of other cardiac biomarkers were also longer than 30 min. The low efficiency of TATs for POC tests was a common feature in both regional and national hospitals (p > 0.05). Myocardial infarction was diagnosed in 61% of investigated ED patients who visited national hospitals, which is more frequently than those diagnosed at regional hospitals (46%, p < 0.05). Chronic heart failure was less frequent at national hospitals (28%) than at regional hospitals (41%, p < 0.05). The patient distribution in this study indicates that patients have the tendency to choose hospitals when they are affected with chest pain. However, the POC panel is rarely used in the ED, which delayed the TAT level and affected laboratory efficiency. This finding indicates a severe problem in the administrative management of EDs. This issue should be addressed in the next version of the medical reform policy.

Pharmacological preconditioning with vitamin C attenuates intestinal injury via the induction of heme oxygenase-1 after hemorrhagic shock in rats.

Pre-induction of heme oxygenase (HO)-1, which is regarded as an effective method of "organ preconditioning", exerts beneficial effects during hemorrhagic shock (HS). However, the available HO-1 inducers exhibit disadvantages such as toxicity or complex technical requirements. Therefore, a safe and convenient HO-1 inducer would be promising and could be exploited in the treatment of foreseeable hemorrhaging, such as prior to major surgery. Here we investigated the effect of vitamin C (VitC), a common antioxidant, on intestinal HO-1 expression and examined whether VitC pretreatment prevented HS related intestinal tissue injuries after HO-1 induction. First, we conducted an in vitro study and found that HO-1 expression in rat intestinal epithelial cells (IEC-6) was induced by non-toxic VitC in a time and concentration dependent manner, and the mechanism was related to the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Next, we conducted an in vivo study and found that VitC induced intestinal HO-1 protein expression (mainly observed in the intestinal epithelial cells) and HO-1 activity in normal SD rats, and that these HO-1 levels were further enhanced by VitC in a rat model of HS. The HS related intestinal injuries, including histological damage, pro-inflammatory cytokine levels (tumor necrosis factor and interleukin-6), neutrophil infiltration and apoptosis decreased after VitC pretreatment, and this alleviating of organ injuries was abrogated after the inhibition of HO-1 activity by zinc protoporphyrin-IX. It was of note that VitC did little histological damage to the intestine of the sham rats. These data suggested that VitC might be applied as a safe inducer of intestinal HO-1 and that VitC pretreatment attenuated HS related intestinal injuries via the induction of HO-1.