Elevated expression levels of miR-143/5 in saphenous vein smooth muscle cells from patients with Type 2 diabetes drive persistent changes in phenotype and function

Type 2 diabetes (T2DM) promotes premature atherosclerosis and inferior prognosis after arterial reconstruction. Vascular smooth muscle cells (SMC) respond to patho/physiological stimuli, switching between quiescent contractile and activated synthetic phenotypes under the control of microRNAs (miRs) that regulate multiple genes critical to SMC plasticity. The importance of miRs to SMC function specifically in T2DM is unknown. This study was performed to evaluate phenotype and function in SMC cultured from non-diabetic and T2DM patients, to explore any aberrancies and investigate underlying mechanisms. Saphenous vein SMC cultured from T2DM patients (T2DM-SMC) exhibited increased spread cell area, disorganised cytoskeleton and impaired proliferation relative to cells from non-diabetic patients (ND-SMC), accompanied by a persistent, selective up-regulation of miR-143 and miR-145. Transfection of premiR-143/145 into ND-SMC induced morphological and functional characteristics similar to native T2DM-SMC; modulating miR-143/145 targets Kruppel-like factor 4, alpha smooth muscle actin and myosin VI. Conversely, transfection of antimiR-143/145 into T2DM-SMC conferred characteristics of the ND phenotype. Exposure of ND-SMC to transforming growth factor beta (TGFβ) induced a diabetes-like phenotype; elevated miR-143/145, increased cell area and reduced proliferation. Furthermore, these effects were dependent on miR-143/145. In conclusion, aberrant expression of miR-143/145 induces a distinct saphenous vein SMC phenotype that may contribute to vascular complications in patients with T2DM, and is potentially amenable to therapeutic manipulation

Whispered Art History : Twenty Years at the Western Front

Wallace introduces this account of the Western Front with a brief history, followed by an extended chronology since 1973. Five essays treat the development of different arms of the centre's activities: the history of video activity; funding, administration, and equipment; literary readings and the place of performed text; the New Music programme and its position; and performance art, through a sampling of its history at the Front. Biographical notes on authors. 32 bibl. ref

Whispered Art History : Twenty Years at the Western Front

Wallace introduces this account of the Western Front with a brief history, followed by an extended chronology since 1973. Five essays treat the development of different arms of the centre's activities: the history of video activity; funding, administration, and equipment; literary readings and the place of performed text; the New Music programme and its position; and performance art, through a sampling of its history at the Front. Biographical notes on authors. 32 bibl. ref

Neuropeptides : Active neuromodulators involved in the pathophysiology of suicidal behavior and major affective disorders

Neuropeptides, protein-like molecules used for direct communication between neurons, may play a critical role in the pathophysiology of mood disorders and suicidal behavior. This chapter aims to critically review the current literature on associations between neuropeptides, major affective disorders, and suicidal behavior. Most studies included in this overview reported an association between suicidality and corticotropin-releasing factor (CRF), VGF nerve growth factor inducible (VGF), cholecystokinin (CCK), orexin, substance P, and neuropeptide Y (NPY). It has been suggested that these molecules play a key role in many biological functions and act as important neuromodulators of emotional processing. The majority of the studies reviewed in this chapter found that suicidal subjects display higher mean concentrations of various neuropeptides compared to control subjects although depressed patients and suicide completers may also display lower NPY levels throughout the brain compared to healthy controls or individuals deceased from causes other than suicide. In addition, some studies have reported that orexin and corticotropin-releasing hormone (CRH) levels are lower in suicidal patients. In spite of these cross-sectional reports, a causal link between neuropeptide dysregulation and suicidality cannot be determined. The main implications of the studies that are included in the present chapter are critically analyzed and discussed

Developmental vitamin D deficiency alters MK-801-induced behaviours in adult offspring

Stress is known to modulate sensitisation to repeated psychostimulant exposure. However, there is no direct evidence linking glucocorticoids and sensitisation achieved by repeated administration of the NMDA receptor antagonist MK-801. We tested the hypothesis that co-administration of RU486, a glucocorticoid receptor (GR) antagonist, prior to repeated daily MK-801 injections would block the expression of locomotor sensitisation due to its dual effects on corticosterone and dopamine. We employed a repeated MK-801 administration locomotor sensitisation paradigm in male Sprague Dawley rats. RU486 or a dimethyl sulfoxide (DMSO) vehicle was co-administered with MK-801 or saline during the induction phase. Subsequent to withdrawal, rats were challenged with MK-801 alone to test for the expression of sensitisation. In a separate cohort of rats, plasma corticosterone levels were quantified from blood samples taken on the 1st, 4th and 7th day of induction and at expression. One day after challenge, nucleus accumbens tissue levels of dopamine and its metabolites DOPAC and HVA were measured. During the induction phase, RU486 progressively enhanced locomotor sensitisation to MK-801. RU486 and MK-801 both showed stimulatory effects on corticosterone levels and this was further augmented when given in combination. Contrary to our hypothesis, RU486 did not block the expression of locomotor sensitisation to MK-801 and actually increased levels of dopamine, DOPAC and HVA in nucleus accumbens tissue. Our results showed that RU486 has augmentative rather than inhibitory effects on MK-801-induced sensitisation. This study indicates a divergent role for glucocorticoids in sensitisation to MK-801 compared to sensitisation with other psychostimulants