Alteration of leptin-induced STAT3 activation in the brain of senescence-accelerated mouse (SAM) P8

We used senescence-accelerated mouse prone 8 (SAMP8), a useful model of accelerated aging, to investigate the responsiveness to leptin with aging. The state of leptin-induced STAT3 phosphorylation in the hypothalamus was found to be higher in SAMP8 than in SAMR1, a control mouse showing normal aging, at 14-18 months of age but not at 2 months of age. Moreover, leptin receptor Ob-Rb expression in the hypothalamus was up-regulated in SAMP8. The results indicate that leptin sensitivity increases with aging in the SAM mouse brain.     

Effects of neopterin on the hematopoietic microenvironment of senescence-accelerated mice (SAM)

The pteridine neopterin (NP) is produced by monocytes and is known to be a useful marker of immunological activation, although, it remains elusive whether neopterin itself exhibits biological functions. Recently, we found that NP stimulates hematopoietic cell proliferation and differentiation by activating bone marrow stromal cell function. In order to elucidate the biological effect of NP on stromal cells, its effects on hematopoiesis was determined in the mouse model of age-related stromal impairment, senescence-accelerated mice (SAMs). An intraperitoneal administration of NP increased the number of peripheral leukocytes and CFU-GM in the bone marrow and spleen of young SAMs, however, no increase of CFU-GM in old SAMs (stromal impairment) was observed when compared with young SAMs. NP also increased the CFU-GM colony formation of bone marrow and spleen cells from young SAMs in a soft agar culture system, but it did not enhance CFU-GM colony formation of cells from old SAMs cultured in this system. Treatment with NP induced the production of hematopoietic stimulating factors, including IL-6 and GM-CSF, by bone marrow stromal cells from young SAMs but stromal cells from old SAMs did not respond to NP stimulation. Further studies will be required to clarify the mechanism by which NP stimulates the production of hematopoietic growth factors from stromal cells, the results of this study indicate that NP is a potent hematopoietic regulatory factor by activating stromal cell function(s).     

快速老化痴呆模型小鼠海马细胞凋亡检测及金属硫蛋白3对其的影响

目的：研究快速老化痴呆模型小鼠（SAMP8）海马CA1区神经元细胞凋亡的变化及不同浓度的金属硫蛋白3（MT3）对其的影响．并且与金属硫蛋白1（MT1）作用相比较。方法：给予7月龄SAMP8小鼠腹腔注射age浓度的MT3及MT1,28d后灌注取脑。进行海马CA1区Tunel试剂盒染色。结果：8月龄的SAMP8小鼠海马区神经元细胞凋亡指数明显高于对照组SAMR1小鼠。高浓度MT3组凋亡指数最低,差异有统计学意义。相同浓度MT3组和MT1对照组间差异无统计学意义。结论：SAMP8小鼠海马结构存在大量的神经元细胞凋亡;MT3有抑制细胞凋亡的作用,并有浓度依赖关系;MT3和MT1对细胞凋亡的影响无差异。     

G蛋白在快速老化痴呆小鼠SAMP8脑组织中的异常表达

摘要 目的：探索在不同月龄小鼠SAMP8皮层和海马中G蛋白的异常表达情况。方法：以正常老化小鼠SAMR1为对照,利用Western-blot方法检测Gαq/11、Gαi和GαS蛋白在8月龄和18月龄小鼠SAMP8的异常表达。结果：与同月龄SAMR1相比,GαS、Gαi和Gαq蛋白在8月龄小鼠SAMP8皮层和海马组织中的表达无明显异常（p﹥0.05）,而到18月龄时,SAMP8皮层部位Gαq表达量明显低于SAMR1（p﹤0.05）,海马部位Gαq和 Gαi的表达量也明显低于SAMR1（p﹤0.05）。结论：18月龄SAMP8脑组织中Gαq和 Gαi的异常表达参与了阿尔海默病（Alzheimer’s, AD）的病理进展,并有望作为AD治疗的一个靶点。     

六味地黄汤对快速老化小鼠海马差异表达基因的影响

目的研究六味地黄汤(LW)对快速老化小鼠(senescenceacceleratedmouse,SAM)海马差异表达基因的影响,揭示LW增强认知功能的分子作用机制。方法应用快速老化小鼠亚系SAMP8和SAMR1海马差异表达cDNA芯片,比较SAMP8和SAMR1、SAMP8阴性对照和SAMR1阳性对照、石衫碱甲处理的SAMP8和SAMP8阴性对照以及LW处理的SAMP8和SAMP8阴性对照8个基因表达谱,并对LW的药物效应基因进行比较。结果给予SAMP8LW后,基因DUSP12、NSF、STUB1、CAMKⅡα、AMFR、UQCRFS1和11个新基因的表达出现显著差异,这些基因涉及蛋白酪氨酸磷酸酶家族、苏氨酸/丝氨酸蛋白激酶家族、泛素连接酶和线粒体功能等,LW对SAMP8海马的基因表达具有明显的调控作用。结论提示LW作用于认知功能也许是通过维持正常的细胞增殖和分化、保护正常的突触传递、调节Ca2+信号转导、改善线粒体的功能等途径实现的,基因DUSP12、NSF、STUB1、CAMKⅡα、AMFR、UQCRFS1和11个新基因可能是LW改善学习记忆功能的潜在作用靶标。     

Effects of long-term ethanol consumption on GABAergic neurons in the mouse hippocampus: a quantitative immunocytochemical study

The effects of 6 months' ethanol consumption by mice on hippocampal GABAergic neurons were investigated by means of an immunocytochemical method using GABA antibodies. Although ethanol treatment did not modify body or brain weights in our experimental conditions, two differences were observed in ethanol-treated mice, as compared to controls: a decrease in the labelling intensity of immunopositive neurons and fibers in the dorsal and the ventral parts of the hippocampus; and a decrease in the number of immunopositive neurons. This neuronal loss was statistically significant in the ventral hippocampus only, where it reached about 25% in the stratum radiatum. It is concluded that chronic ethanol consumption leads to a decrease in GABA content of hippocampal neurons and to a loss of GABAergic neurons, mostly in the ventral part of the hippocampus. These alterations in GABAergic transmission could be related to the well known functional deficits observed in chronic alcoholism.     

Effects of repeated administrations of facteur thymique sérique (FTS) on biochemical changes related to aging in senescence-accelerated mouse (SAM).

Superoxide dismutase (SOD) activity,malondialdehyde (MDA) content and monoamine oxidase B (MAO-B) activity were measured in the brain, liver and kidney of a normal aging strain (R/1) and an accelerating aging strain (P/8) senescence-accelerated mice (SAM) at 9-10 months of age, and the effects of facteur thymique sérique (FTS) were examined. The activity of Cu,Zn-SOD in the kidney and MAO-B in the liver was significantly low and high in SAM-P/8 compared to SAM-R/1. FTS enhanced the activity of Mn-SOD and Cu,Zn-SOD in the kidney of SAM-P/8 and Cu,Zn-SOD activity in the brain of both SAM-P/8 and SAM-R/1. It decreased the activity of MAO-B in the liver and the contents of malondialdehyde (MDA) in the brain and kidney of SAM-P/8. Thus, FTS affects the biochemical factors related to senescence in SAM-P/8, a particular senescent animal model, and may thus possibly be effective as an anti-senescent medicine.     

Bevacizumab for neovascular age-related macular degeneration (ABC trial): multicenter randomized double-masked study

Evaluation of: Tufail A, Patel PJ, Egan C et al.; ABC Trial Investigators. Bevacizumab for neovascular age related macular degeneration (ABC trial): multicentre randomised double masked study. BMJ 340, c2459 (2010). The ABC trial is the first multicenter, randomized clinical trial that addresses the safety and efficacy of bevacizumab (Avastin(?), Genentech, Inc., CA, USA) in the treatment of neovascular age-related macular degeneration. The trial showed that an initial loading dose of three intravitreal injections of Avastin 1.25 mg at 6-week intervals, followed by a 6-weekly variable retreatment regimen, according to strict functional and anatomic criteria for up to 1 year, is safe and effective. The results are in line with those reported previously in the pivotal ranibizumab (Lucentis(?), Genentech, Inc.) trials following monthly intravitreal injections. The trial also exemplifies the paradigm shift in primary end point selection and patient expectation that the arrival of anti-VEGF agents, such as Lucentis and Avastin, has allowed for. Instead of visual stabilization and retardation of visual loss, patients and physicians now expect visual improvement following treatment. Such expectation was almost unrealistic prior to the availability of these agents.     

Effects of Liu-Wei-Di-Huang decoction, a typical traditional Chinese medicinal prescription, on learning and memory in senescence-accelerated mouse ( SAM) and hippocampal synaptic plasticity in rats

AIM: To investigate the effect of Lu-Wei-Di--Huang decoction(LW) on learning and memory in SAM and the hippocampalsynaptic plasticity in rats. METHODS: The behavioralexperiments including passive avoidance performance, shuttle boxand water maze tests wer conducted to assess the learning andmemory of mice and long-term potentiation (LTP) experimentwas employed as a model to examine the hippocampal synapticplasticity by recording the evoked potentials extracellularly inhippocampal dentate gyrus with tetanic stimulation to perforantpathway in anesthetized rats. RESULTS: Memory registrationand retention capacity, spatial memory as well as conditioned     

The burden of age-related macular degeneration: results of a cohort study in two French referral centres

OBJECTIVE: To describe the economic impact of age-related macular degeneration (AMD) and to assess its medical and non-medical costs. DESIGN AND SETTINGS: An observational study was carried out in 105 patients in two French centres in a sample of 105 French patients. All consecutive patients, consulting during a 3-week period, were included provided they were 60 years of age or older and they presented an exudative form of AMD with a distant visual acuity in the best eye < or = 20/40. Data collected included clinical items, treatment modalities, medical follow-up, transport costs, impact of AMD on living conditions and welfare payments related to visual impairment. Costs were presented in 2000 values. PERSPECTIVE: General payer perspective (Social Security, private health insurance and patient). RESULTS: Mean age was 79.3 years and ranged from 62.8-95 years. Average length of disease evolution was 3.5 years. During a 3-month period, patients had a mean of 2.6 visits to the ophthalmologist. Thirty percent of the patients used vascular medications and 72.4% had been previously treated by laser photocoagulation. Only 10% had benefited from visual rehabilitation. Annual AMD cost per patient was 3660.29 euros (EUR) [95% CI: 2881.92-4438.62]. Half of these annual costs were medical costs. Other major cost components were home help costs EUR904.91 [95% CI: 478.88-1330.94] and transport costs for care EUR542.73 [95% CI: 146.31-939.14]. Non-medical costs were significantly higher for patients with more severe disease. CONCLUSIONS: The economic argument that costs are higher in patients with the lowest visual acuity emphasises the necessity of early detection and treatment of patients with AMD.     

Aflibercept (VEGF Trap-Eye) for the treatment of exudative age-related macular degeneration

Aflibercept, a soluble receptor molecule that binds VEGF, has been recently approved for the treatment of exudative age-related macular degeneration. This fusion protein with binding sequences from VEGF receptors 1 and 2 possesses high binding affinity for isomers of VEGF-A, VEGF-B and PlGF, and prevents VEGF from initiating proliferation and migration of vascular endothelial cells. Phase III trials showed that intravitreal aflibercept given monthly or every 2 months produces visual improvement and decrease in macular thickness comparable with monthly ranibizumab. The second year of the trials demonstrated that as-needed aflibercept maintained vision with few required injections. Aflibercept promises to decrease the treatment burden faced by patients with exudative age-related macular degeneration.     

Anti-platelet effects of vitamin supplements in age-related macular degeneration: an in vitro study

Objective: The purpose of this experimental study was to investigate the role of vitamin supplements (Ocuvite, Vitalux Omega, and Nutrof Total) as possible inhibitors of the onset of age-related macular degeneration (AMD).

Materials and methods: The anti-aggregating effect of each vitamin was determined against four accumulative factors namely, platelet activating factor (PAF), adenosine diphosphate (ADP), thrombin receptor-activating peptide (TRAP), and arachidonic acid (AA) in the platelet rich plasma (PRP) of healthy volunteers.

Results: Ocuvite, Vitalux Omega, and Nutrof Total were more potent inhibitors against PAF and ADP compared to TRAP and AA. Among the three vitamins, Nutrof Total displayed more potent inhibitions against TRAP and AA, while against PAF and ADP all the three vitamins revealed similar IC₅₀ values.

Conclusions: The vitamins Ocuvite, Vitalux Omega, and Nutrof Total have anti-aggregating effects and therefore can be used against AMD in healthy volunteers.     

姜黄素对痴呆模型小鼠学习记忆能力的改善作用及对细胞凋亡的影响

目的探讨姜黄素对痴呆模型小鼠学习记忆能力的改善作用和对脑细胞凋亡及凋亡相关蛋白的影响。方法选用自然快速脑老化小鼠为研究对象,随机将SAMP8脑老化小鼠分为模型组、姜黄素治疗组和盐酸多奈哌齐对照组,将SAMR1小鼠作为正常对照组。采用行为学方法评价各组小鼠治疗前后的学习记忆能力变化,TUNEL法检测海马与皮层的细胞凋亡率,免疫细胞化学法测定细胞凋亡相关蛋白bcl-2和bax的表达情况。结果姜黄素能够明显改善自然快速脑老化小鼠的学习记忆能力,与模型组比较差异有统计学意义(P<0.05);姜黄素治疗组小鼠海马和皮层的细胞凋亡数减少,与模型组比较差异有统计学意义(P<0.05);凋亡相关蛋白bcl-2表达升高,bax表达降低,并且bcl-2/bax比值升高,差异具有统计学意义(P<0.05)。结论姜黄素对痴呆模型小鼠的学习记忆能力具有一定的改善作用,其作用机制可能与其调节凋亡相关蛋白bcl-2与bax的表达有关。     

Inflammatory biomarker, neopterin, enlarges splenic mast-cell-progenitor pool: prominent impairment of responses in age-related stromal cell-impairment mouse SCI/SAM

Neopterin is produced by monocytes and is a useful biomarker of inflammatory responses. We found that neopterin enhances granulopoiesis, but suppresses B-lymphopoiesis triggered by the positive and negative regulations of cytokines produced by stromal cells in mice. In this study, neopterin was found to regulate mast cell development, which was confirmed in the mouse model of senescent stromal-cell impairment (SCI). In non-SCI mice (=less senescent stage of SCI mice), neopterin decreased the number of colonies of IL-3-dependent mast-cell progenitor cells (CFU-mast) from unfractionated bone-marrow cells, but not that from the lineage-negative bone-marrow cell population without stromal cells in a semisolid in vitro system. Neopterin increased the gene expression and protein production of TGF-beta, a negative regulator of CFU-mast, in cultured stromal cells, indicating that neopterin suppressed CFU-mast colony formation by inducing TGF-beta in stromal cells. In contrast to this in vitro study, in vivo treatment with neopterin did not significantly up-regulate TGF-beta. The intravenous injection of neopterin into mice decreased the number of femoral CFU-mast and the expression level of the gene for stem cell factor (SCF), a positive regulator of CFU-mast, whereas the number of splenic CFU-mast and SCF gene expression level increased. In SCI mice, the in vivo and in vitro responses of mast cell development and cytokine gene expression level to neopterin treatment were less marked than those in non-SCI mice. These results suggest that, firstly, neopterin augments the splenic pool of CFU-mast by the production of SCF, and secondly, such neopterin function becomes impaired during senescence because of an impaired stromal-cell function, resulting in the down-modulation of host-defense mechanisms.     

The influence of S-adenosylmethionine (SAM) on prolactin in depressed patients

Twenty subjects entered a double-blind placebo-controlled trial of SAM in depression. Prolactin concentrations were measured before and after 14 days' treatment. There was a highly significant fall in prolactin concentrations in the SAM-treated group.     

单侧湿性年龄相关性黄斑变性患者患眼黄斑区GCIPL厚度变化及其与血清IL-8水平的关系

目的 探讨单侧湿性年龄相关性黄斑变性（wetAMD）患者患眼黄斑区神经节细胞-内丛状层（GCIPL）厚度变化及其与血清白细胞介素（IL）-8水平的关系。方法 选取单侧wetAMD患者（wetAMD组）120例,根据荧光素眼底血管造影和吲哚菁绿血管造影检查结果将其分为单侧典型脉络膜新生血管（tCNV）组（45例）以及单侧息肉样脉络膜血管病变（PCV）组（75例）。另选取门诊健康体检眼科检查正常者75例（75眼）作为正常对照组。收集3组受试者的一般资料,并检测研究眼GCIPL厚度参数和血清IL-8水平,比较3组间上述指标的差异。分析GCIPL厚度与血清IL-8水平和wetAMD的关系及其诊断价值。结果 wetAMD组的吸烟比例、伴糖尿病比例以及血清IL-8水平高于对照组,而wetAMD组GCIPL厚度的各测量值均小于正常对照组（均P<0.05）。tCNV组的年龄、吸烟比例、伴糖尿病比例以及血清IL-8水平高于PCV组,而tCNV组GCIPL厚度的各测量值均小于PCV组（均P<0.05）。wetAMD患者患眼GCIPL厚度的各测量值均与血清IL-8水平呈显著负相关（均P<0...     

Ranibizumab: the evidence of its therapeutic value in neovascular age-related macular degeneration

Introduction:

Neovascular age-related macular degeneration (AMD) is the leading cause of severe, irreversible visual impairment in people over 60 years of age. Neovascular AMD is characterized by abnormal growth of blood vessels under the retina, specifically the macula. These vessels leak blood and fluids, damaging the retina and its photoreceptors, resulting in permanent loss of central vision. Vascular endothelial growth factor-A (VEGF-A) has been shown to play a critical role in the pathogenesis of neovascular AMD. In the US, ranibizumab, a VEGF-A blocker, is approved and indicated for the treatment of patients with neovascular AMD.

Aims:

To review the clinical evidence for ranibizumab in the treatment of neovascular AMD.

Evidence review:

Phase III clinical trial data have established ranibizumab as a safe and well-tolerated treatment for neovascular AMD. Monthly intravitreal injections of ranibizumab result in a statistically significantly greater proportion of patients losing <15 letters of visual acuity (VA) and statistically significant increases in the mean number of letters gained compared with controls. Anatomically, ranibizumab results in stabilization in the mean area of choroidal neovascularization (CNV) and statistically significant reductions in the mean area of leakage compared with controls. Although there is limited economic evidence available, ranibizumab therapy for neovascular AMD appears to deliver a significant degree of value gain in terms of quality of life when compared with other neovascular AMD interventions.

Place in therapy:

Clinical evidence establishes ranibizumab as a first-line therapy option for virtually all treatable neovascular AMD patients. Updating neovascular AMD treatment guidelines to reflect the evidence base for ranibizumab as a preferred first-line therapy would be beneficial for physicians in making informed treatment choices and ultimately helping to ensure the best care for patients.     

Effects of LW-AFC,a new formula derived from Liuwei Dihuang decoction,on intestinal microbiome in senescence-accelerated mouse prone 8 strain,a mouse model of Alzheimer disease

OBJECTIVE To investigate the effects of LW-AFC,a new formula derived fromLiuwei Dihuang decoction,on gut microbiota and the behavior of learning and memory of SAMP8 mice,a mouse model of Alzheimer Disease(AD),and identify the specific intestinal microbiota correlating with cognitive ability.METHODS Morris-water maze test,novel object recognition test and shuttle-box test were conducted to observe the ability of learning and memory.16S rRNA amplicon sequencing(Illumina,San Diego,CA,USA)was employed to investigate gut microbiota.RESULTS The treatment of LW-AFC improved cognitive impairments of SAMP8 mice,including spatial learning and memory ability,active avoidance response,and object recognition memory capability.Our data indicated that there were significantly 8 increased and 12 decreased operational taxonomic units(OTUs)in the gut microbiota of SAMP8 mice compared with senescence accelerated mouse resistant 1(SAMR1) strains,the control of SAMP8 mice.The treatment of LW-AFC altered 22(16 increased and 6 decreased)OTUs in SAMP8 mice and among them,15 OTUs could be reversed by LW-AFC treatment resulting in a microbial composition similar to that of SAMR1 mice.We further showed that there were7(3 negative and 4 positive correlation)OTUs significantly correlated with all the three types of cognitive abilities,at the order level,including Bacteroidales,Clostridiales,Desulfovibrionales,CW040,and two unclassified orders.LW-AFC had influences on bacterial taxa correlated with the abilities of learning and memory in SAMP8 mice and restored them to SAMR1 mice.CONCLUSION The effects of LW-AFC on improving cognitive impairments of SAMP8 mice might be via modulating intestinal microbiome and LW-AFC could be used as a potential anti-AD agent.     

Ranibizumab: the evidence of its therapeutic value in neovascular age-related macular degeneration

INTRODUCTION: Neovascular age-related macular degeneration (AMD) is the leading cause of severe, irreversible visual impairment in people over 60 years of age. Neovascular AMD is characterized by abnormal growth of blood vessels under the retina, specifically the macula. These vessels leak blood and fluids, damaging the retina and its photoreceptors, resulting in permanent loss of central vision. Vascular endothelial growth factor-A (VEGF-A) has been shown to play a critical role in the pathogenesis of neovascular AMD. In the US, ranibizumab, a VEGF-A blocker, is approved and indicated for the treatment of patients with neovascular AMD. AIMS: To review the clinical evidence for ranibizumab in the treatment of neovascular AMD. EVIDENCE REVIEW: Phase III clinical trial data have established ranibizumab as a safe and well-tolerated treatment for neovascular AMD. Monthly intravitreal injections of ranibizumab result in a statistically significantly greater proportion of patients losing <15 letters of visual acuity (VA) and statistically significant increases in the mean number of letters gained compared with controls. Anatomically, ranibizumab results in stabilization in the mean area of choroidal neovascularization (CNV) and statistically significant reductions in the mean area of leakage compared with controls. Although there is limited economic evidence available, ranibizumab therapy for neovascular AMD appears to deliver a significant degree of value gain in terms of quality of life when compared with other neovascular AMD interventions. PLACE IN THERAPY: Clinical evidence establishes ranibizumab as a first-line therapy option for virtually all treatable neovascular AMD patients. Updating neovascular AMD treatment guidelines to reflect the evidence base for ranibizumab as a preferred first-line therapy would be beneficial for physicians in making informed treatment choices and ultimately helping to ensure the best care for patients.