In certain aspects, the invention relates to methods for identifying compounds which modulate Akt activity mediated by the rictor-mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activity.

http://science.sciencemag.org/content/sci/307/5712/1098.full.pdf

Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex

Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB.

http://wealthandhealth.ltd.uk/over100/origins%20of%20western%20diet.pdf

Origins and evolution of the Western diet: health implications for the 21st century

In both type 1 and type 2 diabetes, the late diabetic complications in nerve, vascular endothelium, and kidney arise from chronic elevations of glucose and possibly other metabolites including free fatty acids (FFA). Recent evidence suggests that common stress-activated signaling pathways such as nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases underlie the development of these late diabetic complications. In addition, in type 2 diabetes, there is evidence that the activation of these same stress pathways by glucose and possibly FFA leads to both insulin resistance and impaired insulin secretion. Thus, we propose a unifying hypothesis whereby hyperglycemia and FFA-induced activation of the nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases stress pathways, along with the activation of the advanced glycosylation end-products/receptor for advanced glycosylation end-products, protein kinase C, and sorbitol stress pathways, plays a key role in causing late complications in type 1 and type 2 diabetes, along with insulin resistance and impaired insulin secretion in type 2 diabetes. Studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine suggest that new strategies may become available to treat these conditions.

/pdf/oxidative-stress-and-stress-activated-signaling-pathways-a-3134ynljka.pdf

Oxidative Stress and Stress-Activated Signaling Pathways: A Unifying Hypothesis of Type 2 Diabetes

Transcription in eukaryotic cells has been described as quantal, with pulses of messenger RNA produced in a probabilistic manner. This description reflects the inherently stochastic nature of gene expression, known to be a major factor in the heterogeneous response of individual cells within a clonal population to an inducing stimulus. Here we show in Saccharomyces cerevisiae that stochasticity (noise) arising from transcription contributes significantly to the level of heterogeneity within a eukaryotic clonal population, in contrast to observations in prokaryotes, and that such noise can be modulated at the translational level. We use a stochastic model of transcription initiation specific to eukaryotes to show that pulsatile mRNA production, through reinitiation, is crucial for the dependence of noise on transcriptional efficiency, highlighting a key difference between eukaryotic and prokaryotic sources of noise. Furthermore, we explore the propagation of noise in a gene cascade network and demonstrate experimentally that increased noise in the transcription of a regulatory protein leads to increased cell-cell variability in the target gene output, resulting in prolonged bistable expression states. This result has implications for the role of noise in phenotypic variation and cellular differentiation.

Noise in eukaryotic gene expression

Evidence for the involvement of vicinal sulfhydryl groups in insulin-activated hexose transport by 3T3-L1 adipocytes.

Development of Insulin Resistance in 3T3-L1 Adipocytes

The pH of the tumor microenvironment drives the metastatic phenotype and chemotherapeutic resistance of tumors. Understanding the mechanisms underlying this pH-dependent phenomenon will lead to improved drug delivery and allow the identification of new therapeutic targets. This includes an understanding of the role pH plays in primary tumor cells, and the regulatory factors that permit cancer cells to thrive. Over the last decade, carbonic anhydrases (CAs) have been shown to be important mediators of tumor cell pH by modulating the bicarbonate and proton concentrations for cell survival and proliferation. This has prompted an effort to inhibit specific CA isoforms, as an anti-cancer therapeutic strategy. Of the 12 active CA isoforms, two, CA IX and XII, have been considered anti-cancer targets. However, other CA isoforms also show similar activity and tissue distribution in cancers and have not been considered as therapeutic targets for cancer treatment. In this review, we consider all the CA isoforms and their possible role in tumors and their potential as targets for cancer therapy.

Carbonic Anhydrases: Role in pH Control and Cancer.

Preface. Part I Introduction. 1 Overview of the Carbonic Anhydrase Field. Part II Carbonic Anhydrases: Ancient but Relevant. Physiological Functions of the Alpha Class of Carbonic Anhydrases. 3 Catalytic Mechanism of alpha-Class Carbonic Anhydrases: CO2 Hydration and Proton Transfer. 4 Structure and Catalytic Mechanism of b-Carbonic Anhydrases. 5 Prokaryotic Carbonic Anhydrases of Earth's Environment. 6 Carboxysomal Carbonic Anhydrases. 7 Carbonic Anhydrases and their Interplay with Acid/base-coupled Membrane Transporters. 8 Carbonic Anhydrase Related Proteins: Molecular Biology and Evolution. 9 Membrane Associated Carbonic Anhydrase IV (CA IV): A Personal and Historical Perspective. 10 Carbonic Anhydrase Expression in Kidney and Renal Cancer: Implications for Diagnosis and Treatment. 11 Carbonic Anhydrase IX: Regulation and Role in Cancer. 12 Carbonic Anhydrase IX as an Imaging and Therapeutic Target for Tumors and Metastases. 13 Carbonic Anhydrase IX (CAIX) as a Mediator of Hypoxia-induced Stress Response in Cancer Cells. 14 Carbonic Anhydrases and Brain pH in the Control of Neruronal Excitability. 15 Carbonic Anhydrase Inhibitors: Drug Design. 16 Natural Products that Inhibit Carbonic Anhydrases. 17 Glaucoma and the Application of Carbonic Anhydrase Inhibitors. 18 Carbonic Anhydrase Inhibitors and High Altitude Illnesses. 19 Thermal-Stable Carbonic Anhydrases: A Structural Overview. 20 Carbonic Anhydrases in Industrial Applications. Index.

Carbonic anhydrase: mechanism, regulation, links to disease, and industrial applications

It has recently been known that berberine, an alkaloid of medicinal plants, has anti-hyperglycemic effects. To explore the mechanism underlying this effect, we used 3T3-L1 adipocytes for analyzing the signaling pathways that contribute to glucose transport. Treatment of berberine to 3T3-L1 adipocytes for 6 h enhanced basal glucose uptake both in normal and in insulin-resistant state, but the insulin-stimulated glucose uptake was not augmented significantly. Inhibition of phosphatidylinositol 3-kinase (PI 3-K) by wortmannin did not affect the berberine effect on basal glucose uptake. Berberine did not augment tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate (IRS)-1. Further, berberine had no effect on the activity of the insulin-sensitive downstream kinase, atypical protein kinase C (PKCζ/λ). However, interestingly, extracellular signal-regulated kinases (ERKs), which have been known to be responsible for the expression of glucose transporter (GLUT)1, were significantly activated in berberine-treated 3T3-L1 cells. As expected, the level of GLUT1 protein was increased both in normal and insulin-resistant cells in response to berberine. But berberine affected the expression of GLUT4 neither in normal nor in insulin-resistant cells. In addition, berberine treatment increased AMP-activated protein kinase (AMPK) activity in 3T3-L1 cells, which has been reported to be associated with GLUT1-mediated glucose uptake. Together, we concluded that berberine increases glucose transport activity of 3T3-L1 adipocytes by enhancing GLUT1 expression and also stimulates the GLUT1-mediated glucose uptake by activating GLUT1, a result of AMPK stimulation.

Susan C. Frost

Papers

Evidence for the involvement of vicinal sulfhydryl groups in insulin-activated hexose transport by 3T3-L1 adipocytes.

Development of Insulin Resistance in 3T3-L1 Adipocytes

Carbonic Anhydrases: Role in pH Control and Cancer.

Carbonic anhydrase: mechanism, regulation, links to disease, and industrial applications

Berberine activates GLUT1-mediated glucose uptake in 3T3-L1 adipocytes.