Osteocalcin ameliorates cognitive dysfunctions in a mouse model of Alzheimer's Disease by reducing amyloid ß burden and upregulating glycolysis in neuroglia.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by the accumulation of amyloid ß peptides (Aß) and impaired glucose metabolism in the brain. Osteocalcin (OCN), an osteoblast-derived protein, has been shown to modulate brain functions but whether it has any effect on AD is undetermined. In this study, daily intraperitoneal injection of OCN for 4 weeks ameliorated the anxiety-like behaviors and cognitive dysfunctions in the APP/PS1 transgenic AD mice model, as shown in the increased entries into the central area in open field test, the increased time and entries into open arms in elevated plus maze test, the increased time spent in the light chamber in light-dark transition test, as well as the reduced escape latency and the increased preference for target quadrant in Morris water maze test. Aß burden in the hippocampus and cortex of AD mice was ameliorated by OCN. Besides, OCN improved the neural network function of the brain, mainly in the enhanced power of high gamma band in the medial prefrontal cortex of AD mice. The proliferation of astrocytes in the hippocampus in AD mice was also inhibited by OCN as demonstrated by immunofluorescence. Furthermore, OCN enhanced glycolysis in astrocytes and microglia, as evidenced by elevated glucose consumption, lactate production, and increased extracellular acidification rate. Such an effect was abolished when the receptor of OCN - Gpr158 was knockdown in astrocytes. Our study revealed OCN as a novel therapeutic factor for AD potentially through reducing Aß burden and upregulation of glycolysis in neuroglia.

Association of famine exposure and the serum calcium level in healthy Chinese adults.

Objective: Famine exposure and higher serum calcium levels are related with increased risk of many disorders, including Alzheimer's disease, atherosclerosis, diabetes, and osteoporosis. Whether famine exposure has any effect on serum calcium level is unclear. Besides, the normal reference range of serum calcium is variable among different populations. Our aims are 1) determining the reference interval of calcium in Chinese adults; 2) exploring its relationship with famine exposure. Methods: Data in this study was from a cross-sectional study of the epidemiologic investigation carried out during March-August 2010 in Jiading district, Shanghai, China. Nine thousand and two hundred eleven participants with estimated glomerular filtration rate (eGFR) ≥60ml/min/1.73m2 were involved to calculate reference interval of total calcium from 10569 participants aged 40 years or older. The analysis of famine exposure was conducted in 9315 participants with complete serum biochemical data and birth year information. Results: After rejecting outliers, the 95% reference interval of total serum calcium was 2.122~2.518 mmol/L. The equation of albumin-adjusted calcium was: Total calcium + 0.019* (49-Albumin), with a 95% reference interval of 2.151~2.500 mmol/L. Compared to the age-balanced control group, there was an increased risk of being at the upper quartile of total serum calcium (OR=1.350, 95%CI=1.199-1.521) and albumin-adjusted calcium (OR=1.381, 95%CI=1.234-1.544) in subjects experienced famine exposure in childhood. Females were more vulnerable to this impact (OR= 1.621, 95%CI= 1.396-1.883 for total serum calcium; OR=1.722, 95%CI= 1.497-1.980 for albumin-adjusted calcium). Conclusions: Famine exposure is an important environmental factor associated with the changes in circulating calcium concentrations, the newly established serum calcium normal range and albumin-adjusted calcium equation, together with the history of childhood famine exposure, might be useful in identifying subjects with abnormal calcium homeostasis and related diseases, especially in females.

Gut microbiota-derived propionate mediates the neuroprotective effect of osteocalcin in a mouse model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to identify certain molecule(s) derived from the gut microbiota, which has the potential to manage PD. Osteocalcin (OCN), an osteoblast-secreted protein, has been shown to modulate brain function. Thus, it is of interest to investigate whether OCN could exert protective effect on PD and, if yes, whether the underlying mechanism lies in the subsequent changes in gut microbiota. RESULTS: The intraperitoneal injection of OCN can effectively ameliorate the motor deficits and dopaminergic neuronal loss in a 6-hydroxydopamine-induced PD mouse model. The further antibiotics treatment and fecal microbiota transplantation experiments confirmed that the gut microbiota was required for OCN-induced protection in PD mice. OCN elevated Bacteroidetes and depleted Firmicutes phyla in the gut microbiota of PD mice with elevated potential of microbial propionate production and was confirmed by fecal propionate levels. Two months of orally administered propionate successfully rescued motor deficits and dopaminergic neuronal loss in PD mice. Furthermore, AR420626, the agonist of FFAR3, which is the receptor of propionate, mimicked the neuroprotective effects of propionate and the ablation of enteric neurons blocked the prevention of dopaminergic neuronal loss by propionate in PD mice. CONCLUSIONS: Together, our results demonstrate that OCN ameliorates motor deficits and dopaminergic neuronal loss in PD mice, modulating gut microbiome and increasing propionate level might be an underlying mechanism responsible for the neuroprotective effects of OCN on PD, and the FFAR3, expressed in enteric nervous system, might be the main action site of propionate. Video abstract.

Protective effects of ß- nicotinamide adenine dinucleotide against motor deficits and dopaminergic neuronal damage in a mouse model of Parkinson's disease.

The level of nicotinamide adenine dinucleotide (NAD) decreases in Parkinson's disease (PD), and its reduction has been reported to be involved in many age-associated neurodegenerative pathologies. Thus, we investigated whether NAD replenishment is beneficial in a 6-hydroxydopamine (6-OHDA)-induced mouse model of PD. Preinjection with NAD in the striatum ameliorated motor deficits and dopaminergic neuronal damage in the substantia nigra and striatum of a mouse model of PD. Moreover, preincubation with NAD protected PC12 cells against the loss of cell viability, morphological damage, oxidative stress and mitochondrial dysfunction caused by 6-OHDA. These results add credence to the beneficial role of NAD against parkinsonian neurodegeneration in mouse models of PD, provide evidence for the potential of NAD for the prevention of PD, and suggest that NAD prevents pathological changes in PD via decreasing mitochondrial dysfunctions.

Roles for osteocalcin in brain signalling: implications in cognition- and motor-related disorders.

It is now generally accepted that the extra-skeleton functionalities of bone are multifaceted. Its endocrine functions came first to light when it was realized that osteoblasts, the bone forming cells, maintain energy homeostasis by improving glucose metabolism, insulin sensitivity and energy expenditure through osteocalcin, a multipurpose osteokine secreted by osteoblasts. Recently, the emerging knowledge on the functional aspects of this osteokine expanded to properties including adult and maternal regulation of cognitive functions. Therapeutic potential of this osteokine has also been recently reported in experimental Parkinson's disease models. This review highlights such findings on the functions of osteocalcin in the brain and emphasizes on exploring and analyzing much more in-depth basic and clinical studies.

Osteocalcin Ameliorates Motor Dysfunction in a 6-Hydroxydopamine-Induced Parkinson's Disease Rat Model Through AKT/GSK3ß Signaling.

Osteoblasts derived osteocalcin (OCN) is recently reported to be involved in dopaminergic neuronal development. As dopaminergic neuronal injury in the substantia nigra (SN) is a pathological hallmark of Parkinson's disease (PD), we investigated whether OCN could exert protective effects on 6-hydroxydopamine (6-OHDA)-induced PD rat model. Our data showed that the OCN level in the cerebrospinal fluid (CSF) in PD rat models was significantly lower than that in controls. Intervention with OCN could improve the behavioral dysfunction in PD rat models and reduce the tyrosine hydroxylase (TH) loss in the nigrostriatal system. In addition, OCN could inhibit the astrocyte and microglia proliferation in the SN of PD rats. In vitro studies showed that OCN significantly ameliorated the neurotoxicity of 6-OHDA through the AKT/GSK3ß signaling pathway. In summary, OCN plays a protective role against parkinsonian neurodegeneration in the PD rat model, suggesting a potential therapeutic use of OCN in PD.

Nurses' knowledge and attitudes on comfort nursing care for hospitalized patients.

To investigate the knowledge and attitudes of practicing nurses on comfort care for hospitalized patients, a survey was conducted in 311 registered nurses from a major teaching hospital. A total of 212 (68.1%) of the participants showed an adequate knowledge of comfort care. Participants who had 6 years or more working experience returned a higher mean scores on physiological and psychological aspects of comfort care (P < 0.05). The total scores were the highest among participants from intensive care unit and the lowest among participants from the oncology department. Although 282 (90.7%) participants were involved in comfort care, only 210 (67.5%) received formal hospital-based training in this practice. We conclude that there was a large difference in the knowledge between nurses from different departments on comfort care. Continuing education programmes are required to improve the knowledge and skills in comfort care.

Comparison of oral and intravenous hydration strategies for the prevention of contrast-induced nephropathy in patients undergoing coronary angiography or angioplasty: a randomized clinical trial.

OBJECTIVE: The efficacy of oral hydration in the prevention of contrast-induced nephropathy in patients undergoing elective coronary intervention is unclear. METHODS: A total of 120 patients were randomly assigned to three groups. Group A (n = 40) received intravenous hydration before and after coronary angiography or angioplasty. Group B (n = 40) received oral tap water before and after the procedures, whereas group C (n = 40) received only postprocedural drinking water. Levels of serum creatinine and urea nitrogen were measured before, 12 hours after, 2 and 3 days after the coronary angiography or angioplasty. RESULTS: : There was no statistically significant difference in the age, sex, baseline renal function and the volume of contrast medium used during the coronary procedures among the three groups (P > 0.05).There was no statistically significant difference in the mean serum creatinine or urea nitrogen among the three groups 12 hours, and 3 days after the coronary procedures ( P > 0.05).The incidence of contrast-induced nephropathy in group A, B and C was 5.0% (2/40), 7.5% (3/40) and 5.0% (2/40), respectively (P = 0.86). Renal function in the seven patients who experienced contrast-induced nephropathy recovered within a week following rehydration treatment. CONCLUSIONS: Pre- and post-procedural oral hydration was as effective as intravenous rehydration in the prevention of contrast-induced nephropathy in patients undergoing coronary angiography or angioplasty.

[Differential proteins in esophageal squamous cell line EC9706/CDDP identified by SILAC quantitative proteomic approach].

Multidrug resistance (MDR) is one of the main causes leading to the failure in cancer treatment. Differential proteins between esophageal squamous cell carcinoma (ESCC) cell line EC9706 and its cisdiamminedichloroplatinum (CDDP)-resistant subline EC9706/CDDP revealed by quantitative analysis may provide deeper insights into the molecular mechanisms of MDR implicated in ESCC. EC9706/CDDP was generated by exposure of its parental sensitive EC9706 to a step-wise increase of CDDP concentration during EC9706 cultivation. The stable isotope labeling with amino acids in cell culture (SILAC) was used to label EC9706 and EC9706/CDDP with heavy and light medium, separately. Mixed peptides derived from EC9706 and EC9706/CDDP were analyzed by high performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS/MS) and subsequently subjected to bioinformatics analysis to identify differential proteins between EC9706 and EC9706/CDDP. Compared to parental EC9706, EC9706/CDDP manifested phenotypes of slow proliferation, cell pleomorphology, atypia and increased resistant-index 3.23. Seventy-four differential proteins identified in the present study belongs to various families with multiple functions, such as cytoskeleton (20%), energy metabolism (11%), transcription regulation and DNA repair (11%), redox homeostasis (9.5%), protein biosynthesis and mRNA processing (12%), ribosome constituent (8.1%), molecular chaperone (8.1%), immunity/inflammation (5.4%), intracellular transport (5.4%) and nucleosome assembly (2.7%), which indicated that development of MDR is a complicated process involving dysregulation of multiple molecules and pathways. The data is of great value for in-depth elucidation of molecular mechanisms of the MDR implicated in ESCC and may represent potential molecular targets for future therapeutic development.