Insights into mechanisms behind arteriogenesis: what does the future hold?

Arteriogenesis, the enlargement of collateral vessels, seems a promising new target to improve blood flow to ischemic regions in patients suffering from cardiovascular conditions. With the growing knowledge of the mechanisms involved in arteriogenesis and the factors that influence the process, an increasing number of clinical trials are being performed to stimulate arteriogenesis, providing more insight in therapeutic opportunities for arteriogenesis. The expression of growth factors and the cooperation of surrounding and infiltrating cells seem to be essential in orchestrating the complex processes during arteriogenesis. In this review, we will discuss the regulating mechanisms of arteriogenesis, including the role of growth factors and different cell types and their implementation in a clinical setting. Furthermore, individual differences in the arteriogenic response will be considered, in light of the effect this will have on the success of therapeutic strategies to improve blood flow to ischemic tissue.     

Inhibitory machinery for the TGF-β family signaling pathway

Transforming growth factor-β (TGF-β) family signaling regulates cell growth and differentiation of many different cell types and is widely involved in the regulation of homeostasis during both embryogenesis and adult life. Therefore, aberrant TGF-β family signal transduction is linked to congenital disorders, tumorigenicity, and fibrosis, which can be life-threatening. A specific receptor-ligand complex initiates transduction of TGF-β family signaling to the nucleus via intracellular signal molecules, mainly Smads, whereby a number of bioactivities such as wound healing, immunomodulation, apoptosis, and angiogenesis are controlled. To avoid an excess of TGF-β family signaling in cells, the duration and intensity of the TGF-β family signal appear to be subject to elaborate regulation. In this paper, we describe recent advances in the understanding of how TGF-β family signals are perturbed and terminated to maintain homeostasis in cells.     

Inhibitory machinery for the TGF-β family signaling pathway

Transforming growth factor-β (TGF-β) family signaling regulates cell growth and differentiation of many different cell types and is widely involved in the regulation of homeostasis during both embryogenesis and adult life. Therefore, aberrant TGF-β family signal transduction is linked to congenital disorders, tumorigenicity, and fibrosis, which can be life-threatening. A specific receptor–ligand complex initiates transduction of TGF-β family signaling to the nucleus via intracellular signal molecules, mainly Smads, whereby a number of bioactivities such as wound healing, immunomodulation, apoptosis, and angiogenesis are controlled. To avoid an excess of TGF-β family signaling in cells, the duration and intensity of the TGF-β family signal appear to be subject to elaborate regulation. In this paper, we describe recent advances in the understanding of how TGF-β family signals are perturbed and terminated to maintain homeostasis in cells.     

Insights into mitochondrial quality control pathways and Parkinson’s disease

The brain uses more energy than any other human organ, accounting for 20 % of the body’s total demand. Mitochondria are energy-converting organelles with a pivotal role in meeting the energetic needs of the human brain. Therefore, the decline of these cellular powerhouses can have a negative impact on the function and plasticity of neurons and is believed to have a prominent role in ageing and in the occurrence of several neurological disorders, such as Parkinson’s disease (PD). As a consequence of their physiological roles, mitochondria are subjected to high levels of stress and have therefore developed several stress-protective mitochondrial quality control mechanisms that ensure the optimal activity of their molecular machinery. Here, we review some of the most recent advances in our understanding of the regulation of mitochondrial stress pathways with particular emphasis on how defective mitochondrial quality control might contribute to PD.     

Wnt signaling and human diseases: what are the therapeutic implications?

Wnt signaling plays an important role in regulating cell proliferation and differentiation. De-regulation of these signaling pathways has been implicated in many human diseases, ranging from cancers to skeletal disorders. Wnt proteins are a large family of secreted factors that bind to the Frizzled receptors and LRP5/6 co-receptors and initiate complex signaling cascades. Over the past two decades, our understanding of Wnt signaling has been significantly improved due to the identification of many key regulators and mediators of these pathways. Given that Wnt signaling is tightly regulated at multiple cellular levels, these pathways themselves offer ample nodal points for targeted therapeutics. Here, we focus on our current understanding of these pathways, the associations of Wnt signaling with human disorders, and the opportunities to target key components of Wnt signaling for rational drug discovery.     

The porphyrin pathway: the final common pathway?

When I was learning pathology a wise and knowledgeable mentor described a final common pathway that allows many diseases to overlap in their presentation. This pathway was never identified for it was unknown. Recent books by physicians have suggested that maintaining body balance and/or treatment by a substance could halt or repair damage caused by a wide array of diseases, once again suggesting a common thread amongst diseases. Again no mention was made regarding what was this common denominator. I have been interested in people who have more than one disease, feeling that there must be a link. My interest in the porphyrin pathway has strengthened that impression. Since finding Doss's list of diseases having porphyrin abnormalities unrelated to a porphyria, I have worked on models that would allow me to show a way where porphyrin abnormalities may be a part of the final common pathway for all disease. I have finally decided that a spider's web is that model. The following discussion will attempt to demonstrate that this hypothesis could be true.     

Type 1 diabetes: lessons for other autoimmune diseases?

Type 1 diabetes (T1D) satisfies many of the criteria for an autoimmune disease. The impact of the environment to promote the development of T1D and the ability to identify individuals at risk for T1D years before clinical presentation afford lessons for other autoimmune diseases, in regard to gene-environment interactions and the potential for rational approaches to pre-clinical diagnosis and prevention. Public health measures aimed at the modern pro-inflammatory environment are required to stem the rising tide not only of T1D but other autoimmune and chronic inflammatory disorders. In the non-obese diabetic (NOD) model of spontaneous autoimmune diabetes, compelling evidence indicates that adaptive autoimmunity to the pancreatic beta cell is initially targeted against proinsulin. Proof-of-principle studies in the NOD mouse, which established that insulin and proinsulin peptides could be applied as tools to induce immune tolerance and protect against diabetes development, await successful translation to at-risk humans. Initial trials of insulin-specific immunotherapy in humans show promise and reveal ways of optimising this approach that are also applicable to other autoimmune diseases.     

“Old drugs” for the treatment of rheumatoid arthritis: will the cholinergic anti-inflammatory pathway and anti-nociceptive pathway work?

Based on the newly discovered cholinergic anti-inflammatory pathway, on the anti-nociceptive pathway and on our preliminary research, we raise a new strategy for the treatment of rheumatoid arthritis (RA) which mainly focuses on the application of old drugs that can activate both of the above mentioned pathways. It has been reported that nicotinic receptor agonists used for the treatment of neurological diseases were expected to be applied to the therapy of inflammatory diseases (RA). Therefore, it is promising that old drugs available in clinics may exert new functions for the treatment of RA, which may greatly reduce the expense of such treatment, once applied. These currently-used old drugs should be considered as another new resource in exploring anti-rheumatic agents under the guidance of the newly discovered cholinergic anti-inflammatory pathway and the anti-nociceptive pathway.     

Same or different? Insights into the etiology of phonological awareness and rapid naming

This work’s objective was to offer additional insights into the psychological and genetic bases of reading ability and disability, and to evaluate the plausibility of a variety of psychological models of reading involving phonological awareness (PA) and rapid naming (RN), both hypothesized to be principal components in such models. In Study 1, 488 unselected families were assessed with measures of PA and RN to investigate familial aggregation and to obtain estimates of both the number and effect-magnitude of genetic loci involved in these traits’ transmission. The results of the analyses from Study 1 indicated the presence of genetic effects in the etiology of individual differences for PA and RN and pointed to both the shared and unique sources of this genetic variance, which appeared to be exerted by multiple (3–6 for PA and 3–5 for RN) genes. These results were used in Study 2 to parameterize a simulation of 3000 families with quantitatively distributed PA and RN, so that the robustness and generalizability of the Study 1 findings could be evaluated. The findings of both studies were interpreted according to established theories of reading and our own understanding of the etiology of complex developmental disorders.