Regulated upon activation,normal T cell expressed and secreted(RANTES)levels in the peripheral blood of patients with Alzheimer’s disease

Alzheimer’s disease(AD)is the most common type of dementia,but it is very difficult to diagnose with certainty,so many AD studies have attempted to find early and relevant diagnostic markers.Regulated upon activation,normal T cell expressed and secreted(RANTES,also known as C-C chemokine ligand)is a chemokine involved in the migration of T cells and other lymphoid cells.Changes in RANTES levels and its expression in blood or in cerebrospinal fluid have been reported in some neurodegenerative diseases,such as Parkinson’s disease and multiple sclerosis,but also in metabolic diseases in which inflammation plays a role.The aim of this observational study was to assess RANTES levels in peripheral blood as clinical indicators of AD.Plasma levels of RANTES were investigated in 85 AD patients in a relatively early phase of AD(median 8.5 months after diagnosis;39 men and 46 women;average age 75.7 years),and in 78 control subjects(24 men and 54 women;average age 66 years).We found much higher plasma levels of RANTES in AD patients compared to controls.A negative correlation of RANTES levels with age,disease duration,Fazekas scale score,and the medial temporal lobe atrophy(MTA)score(Scheltens’s scale)was found in AD patients,i.e.,the higher levels corresponded to earlier stages of the disease.Plasma RANTES levels were not correlated with cognitive scores.In AD patients,RANTES levels were positively correlated with the levels of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-α,which is consistent with the wellknown fact that AD is associated with inflammatory processes.RANTES levels were also positively correlated with insulin levels in AD patients,with insulin resistance(HOMA-R)and pancreatic beta cell function(HOMA-F).This study evaluated several clinical and metabolic factors that may affect plasma levels of RANTES,but these factors could not explain the increases in RANTES levels observed in AD patients.Plasma levels of RANTES appear to be an interesting peripheral marker for early stages of AD.The study was approved by the Ethics Committee of Institute of Endocrinology,Prague,Czech Republic on July 22,2011.

A panel of monoclonal antibodies against the prion protein proves that there is no prion protein in human pancreatic ductal epithelial cells

Prion diseases are a group of neurodegenerative diseases that are fatal. The study of these unique diseases in China is hampered by a lack of resources. Amongst the most important resources for biological study are monoclonal antibodies. Here, we characterize a panel of monoclonal antibodies specific for cellular prion protein by enzyme-linked immunosorbent assay(ELISA), immunofluorescent staining, flow cytometry, and western blotting. We identify several antibodies that can be used for specific applications and we demonstrate that there is no prion protein expression in human pancreatic ductal epithelial cells(HPDC).

Metabolic programming determines the lineage-differentiation fate of murine bone marrow stromal progenitor cells

Enhanced bone marrow adipogenesis and impaired osteoblastogenesis have been observed in obesity,suggesting that the metabolic microenvironment regulates bone marrow adipocyte and osteoblast progenitor differentiation fate.To determine the molecular mechanisms,we studied two immortalized murine cell lines of adipocyte or osteoblast progenitors(BMSCs^adipo and BMSC^sosteo,respectively)under basal and adipogenic culture conditions.At baseline,BMSCs^adipo,and BMSCs^osteo exhibit a distinct metabolic program evidenced by the presence of specific global gene expression,cellular bioenergetics,and metabolomic signatures that are dependent on insulin signaling and glycolysis in BMSCs^osteo versus oxidative phosphorylation in BMSCs^adipo.To test the flexibility of the metabolic program,we treated BMSCsadipo with parathyroid hormone,S961(an inhibitor of insulin signaling)and oligomycin(an inhibitor of oxidative phosphorylation).The treatment induced significant changes in cellular bioenergetics that were associated with decreased adipocytic differentiation.Similarly,12 weeks of a high-fat diet in mice led to the expansion of adipocyte progenitors,enhanced adipocyte differentiation and insulin signaling in cultured BMSCs.Our data demonstrate that BMSC progenitors possess a distinct metabolic program and are poised to respond to exogenous metabolic cues that regulate their differentiation fate.

ARB affects nicotine-induced gene expression profile in human coronary artery endothelial cells

AIM: To investigate the effects of nicotine and nicotine plus angiotensin Ⅱ receptor blocker(ARB) on the gene expression profile of human coronary artery endothelial cells(HCAECs).METHODS: The changes in gene expression profiles in HCAECs treated with nicotine and nicotine plus ARB olmesartan were analyzed by DNA microarray. In nicotine-treated HCAECs, 432 genes selected by P < 0.01 were greater than 1.5-fold compared with the untreated cells. Data were analyzed using IPA(Ingenuity? Systems, www.ingenuity.com).RESULTS: The gene expression levels of tumor necrosis factor-α, collagen type 1, matrix metalloproteinase-10, and disintegrin and metalloprotease domain 8, which are related to "cardiovascular function and disease", were significantly increased. In canonical pathway analyses using IPA, "atherosclerosis signaling" was strongly affected by nicotine treatment and this effect was reduced by co-incubation with ARB olmesartan. These data indicate that the deleterious cardiovascular consequences of cigarette smoking may, at least in part, be due to the nicotine-induced gene expression profile related to "atherosclerosis signaling".CONCLUSION: The inhibitory effect of ARB against the nicotine-induced gene expression profile may possibly induce anti-atherosclerotic effects that are independent of those from lowering the blood pressure.

Human fetal mesenchymal stem cells differentiate into brown and white adipocytes： a role for ERRα in human UCP1 expression

We investigated the ability of fetal mesenchymal stem cells （fMSCs） to differentiate into brown and white adi- pocytes and compared the expression of a number of marker genes and key regulatory factors. We showed that the expression of key adipocyte regulators and markers during differentiation is similar to that in other human and mu- rine adipocyte models, including induction of PPARy2 and FABP4. Notably, we found that the preadipocyte marker, Pref-1, is induced early in differentiation and then declines markedly as the process continues, suggesting that fMSCs first acquire preadipocyte characteristics as they commit to the adipogenic lineage, prior to their differentiation into mature adipocytes. After adipogenic induction, some stem cell isolates differentiated into cells resembling brown adi- pocytes and others into white adipocytes. Detailed investigation of one isolate showed that the novel brown fat-deter- mining factor PRDM16 is expressed both before and after differentiation. Importantly, these cells exhibited elevated basal UCP-1 expression, which was dependent on the activity of the orphan nuclear receptor ERRa, highlighting a novel role for ERRa in human brown fat. Thus fMSCs represent a useful in vitro model for human adipogenesis, and provide opportunities to study the stages prior to commitment to the adipocyte lineage. They also offer invaluable in- sights into the characteristics of human brown fat.

同时患家族性甲状腺髓样癌及先天性巨结肠的一个罕见的捷克家族

Purpose: The RET proto-oncogene is involved in neural crest disorders. Activa ting germline mutations in the RET protooncogene cause the development of famili al medullary thyroid carcinoma (FMTC) or medullary thyroid carcinoma (MTC) as a part of multiple endocrine neoplasia type 2 (MEN2) syndrome. Inactivating germli nemutations in the RET proto-oncogene are detected in Hirschsprung’s disease ( HSCR). Only in a very small number of families are these 2 diseases expressed to gether. Methods: This study presents a novel Czech kindred with FMTC-HSCR pheno type. Two family members (mother and daughter) were tested for RET germline muta tions in exons 10, 11, 13, 14, 15, and 16. Results: Direct fluorescent sequencin g of genomic DNA revealed a heterozygous mutation in the RET proto-oncogene in exon 10 at codon C609Y in both persons tested. This family was reclassified, tha nks to genetic screening from the apparently sporadic MTC-HSCR to FMTC-HSCR. C onclusion: The germline mutation was detected because of the systematic genetic screening of the RET proto-oncogene, which is useful for genetic counseling of potential risk of HSCR and MTC in other family members. This family could be add ed to the small worldwide cohort of families with MEN2A/FMTC-HSCR.

GATA4 mutations are uncommon in patients with 46,XY disorders of sex development without heart anomaly

Dear Editor, Disorders of sex development （DSDs） are a group of conditions in which chromosomal, gonadal, or anatomical sex is atypical.1 DSD in genetic males （46,XY DSD） primarily results from impaired androgen production or action or perturbed genital morphogenesis？ The current understanding of the genetic basis of 46,XY DSD remains fragmentary. For example, although more than 15 genes have been implicated in the development ofnonsyndromic hypospadias,2 one of the most common forms of 46,XY DSD,~ mutations in these genes account for 〈20% of the cases.3