Not just angiotensinases: new roles for the angiotensin-converting enzymes

The renin-angiotensin system (RAS) is a critical regulator of blood pressure and fluid homeostasis. Angiotensin II, the primary bioactive peptide of the RAS, is generated from angiotensin I by angiotensin-converting enzyme (ACE). A homologue of ACE, ACE2, is able to convert angiotensin II to a peptide with opposing effects, angiotensin-(1-7). It is proposed that disturbance of the balance of ACE and ACE2 expression and/or function is important in pathologies in which angiotensin II plays a role. These include cardiovascular and renal disease, lung injury and liver fibrosis. The critical roles of ACE and ACE2 in regulating angiotensin II levels have traditionally focussed attention on their activities as angiotensinases. Recent discoveries, however, have illuminated the roles of these enzymes and of the ACE2 homologue, collectrin, in intracellular trafficking and signalling. This paper reviews the key literature regarding both the catalytic and non-catalytic roles of the angiotensin-converting enzyme gene family.     

Modulation of Kv7 channels and excitability in the brain

Neuronal Kv7 channels underlie a voltage-gated non-inactivating potassium current known as the M-current. Due to its particular characteristics, Kv7 channels show pronounced control over the excitability of neurons. We will discuss various factors that have been shown to drastically alter the activity of this channel such as protein and phospholipid interactions, phosphorylation, calcium, and numerous neurotransmitters. Kv7 channels locate to key areas for the control of action potential initiation and propagation. Moreover, we will explore the dynamic surface expression of the channel modulated by neurotransmitters and neural activity. We will also focus on known principle functions of neural Kv7 channels: control of resting membrane potential and spiking threshold, setting the firing frequency, afterhyperpolarization after burst firing, theta resonance, and transient hyperexcitability from neurotransmitter-induced suppression of the M-current. Finally, we will discuss the contribution of altered Kv7 activity to pathologies such as epilepsy and cognitive deficits.     

Multidrug-resistant cancer cells and cancer stem cells hijack cellular systems to circumvent systemic therapies,can natural products reverse this?

Chemotherapy is one of the most effective and broadly used approaches for cancer management and many modern regimes can eliminate the bulk of the cancer cells. However, recurrence and metastasis still remain a major obstacle leading to the failure of systemic cancer treatments. Therefore, to improve the long-term eradication of cancer, the cellular and molecular pathways that provide targets which play crucial roles in drug resistance should be identified and characterised. Multidrug resistance (MDR) and the existence of tumor-initiating cells, also referred to as cancer stem cells (CSCs), are two major contributors to the failure of chemotherapy. MDR describes cancer cells that become resistant to structurally and functionally unrelated anti-cancer agents. CSCs are a small population of cells within cancer cells with the capacity of self-renewal, tumor metastasis, and cell differentiation. CSCs are also believed to be associated with chemoresistance. Thus, MDR and CSCs are the greatest challenges for cancer chemotherapy. A significant effort has been made to identify agents that specifically target MDR cells and CSCs. Consequently, some agents derived from nature have been developed with a view that they may overcome MDR and/or target CSCs. In this review, natural products-targeting MDR cancer cells and CSCs are summarized and clustered by their targets in different signaling pathways.     

Fishes of Bly Tunnel, Lassen County, California

Leon Bly Tunnel, which connects Eagle Lake to Willow Creek, was investigated to see if the water issuing from the tunnel was lake water or spring water and to check reports of its being inhabited by fish. We found that the water was similar to that of highly alkaline Eagle Lake, despite a block placed in the tunnel in 1986. Five species of fish were found in the tunnel, the same species inhabiting both Willow Creek and Eagle Lake, although the creek was much warmer and less alkaline than the lake. The fish originated from the creek. Fish in the tunnel were either not feeding or were consuming snails ( Vorticifex sp.), the principal invertebrate present. The largest fish (35 cm SL) captured were rainbow trout ( Oncorhynchus mykiss ).     

The in vitro effect of aprotinin upon spleen cells from normal and tumour-bearing mice exposed to PPD and tumour cells

Summary A protinin (Trasylol) is shown to enhance the response of spleen cells from normal and tumour bearing mice to PPD and tumour cells. This enhancement is greater in the tumour-bearing mice.Acknowledgments. We are grateful to Bayer (U.K.) Limited for generous supplies of aprotinin. The PPD was supplied by the Ministry of Agriculture. The work was supported by a grant from the North of England Cancer Research Campaign.     

Newly identified genetic risk variants for celiac disease related to the immune response

Our genome-wide association study of celiac disease previously identified risk variants in the IL2-IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 x 10(-7)). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2-IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways.     

Silencing of unsynapsed meiotic chromosomes in the mouse

In Neurospora, DNA unpaired in meiosis both is silenced and induces silencing of all DNA homologous to it. This process, called meiotic silencing by unpaired DNA, is thought to protect the host genome from invasion by transposable elements. We now show that silencing of unpaired (unsynapsed) chromosome regions also takes place in the mouse during both male and female meiosis. The tumor suppressor protein BRCA1 is implicated in this silencing, mirroring its role in the meiotic silencing of the X and Y chromosomes in normal male meiosis. These findings impact on the interpretation of the relationship between synaptic errors and sterility in mammals and extend our understanding of the biology of Brca1.     

Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy

Mental retardation and epilepsy often occur together. They are both heterogeneous conditions with acquired and genetic causes. Where causes are primarily genetic, major advances have been made in unraveling their molecular basis. The human X chromosome alone is estimated to harbor more than 100 genes that, when mutated, cause mental retardation. At least eight autosomal genes involved in idiopathic epilepsy have been identified, and many more have been implicated in conditions where epilepsy is a feature. We have identified mutations in an X chromosome-linked, Aristaless-related, homeobox gene (ARX), in nine families with mental retardation (syndromic and nonspecific), various forms of epilepsy, including infantile spasms and myoclonic seizures, and dystonia. Two recurrent mutations, present in seven families, result in expansion of polyalanine tracts of the ARX protein. These probably cause protein aggregation, similar to other polyalanine and polyglutamine disorders. In addition, we have identified a missense mutation within the ARX homeodomain and a truncation mutation. Thus, it would seem that mutation of ARX is a major contributor to X-linked mental retardation and epilepsy.