Mitochondrial quality control in AMD: does mitophagy play a pivotal role?

Age-related macular degeneration (AMD) is the predominant cause of visual loss in old people in the developed world, whose incidence is increasing. This disease is caused by the decrease in macular function, due to the degeneration of retinal pigment epithelium (RPE) cells. The aged retina is characterised by increased levels of reactive oxygen species (ROS), impaired autophagy, and DNA damage that are linked to AMD pathogenesis. Mitophagy, a mitochondria-specific type of autophagy, is an essential part of mitochondrial quality control, the collective mechanism responsible for this organelle’s homeostasis. The abundance of ROS, DNA damage, and the excessive energy consumption in the ageing retina all contribute to the degeneration of RPE cells and their mitochondria. We discuss the role of mitophagy in the cell and argue that its impairment may play a role in AMD pathogenesis. Thus, mitophagy as a potential therapeutic target in AMD and other degenerative diseases is as well explored.     

Mechanisms of cellular invasion by intracellular parasites

Numerous disease-causing parasites must invade host cells in order to prosper. Collectively, such pathogens are responsible for a staggering amount of human sickness and death throughout the world. Leishmaniasis, Chagas disease, toxoplasmosis, and malaria are neglected diseases and therefore are linked to socio-economical and geographical factors, affecting well-over half the world’s population. Such obligate intracellular parasites have co-evolved with humans to establish a complexity of specific molecular parasite–host cell interactions, forming the basis of the parasite’s cellular tropism. They make use of such interactions to invade host cells as a means to migrate through various tissues, to evade the host immune system, and to undergo intracellular replication. These cellular migration and invasion events are absolutely essential for the completion of the lifecycles of these parasites and lead to their for disease pathogenesis. This review is an overview of the molecular mechanisms of protozoan parasite invasion of host cells and discussion of therapeutic strategies, which could be developed by targeting these invasion pathways. Specifically, we focus on four species of protozoan parasites Leishmania, Trypanosoma cruzi, Plasmodium, and Toxoplasma, which are responsible for significant morbidity and mortality.     

The role of inflammation in sporadic and familial Parkinson’s disease

The etiology of Parkinson’s disease (PD) is complex and most likely involves numerous environmental and heritable risk factors. Interestingly, many genetic variants, which have been linked to familial forms of PD or identified as strong risk factors, also play a critical role in modulating inflammatory responses. There has been considerable debate in the field as to whether inflammation is a driving force in neurodegeneration or simply represents a response to neuronal death. One emerging hypothesis is that inflammation plays a critical role in the early phases of neurodegeneration. In this review, we will discuss emerging aspects of both innate and adaptive immunity in the context of the pathogenesis of PD. We will highlight recent data from genetic and functional studies that strongly support the theory that genetic susceptibility plays an important role in modulating immune pathways and inflammatory reactions, which may precede and initiate neuronal dysfunction and subsequent neurodegeneration. A detailed understanding of such cellular and molecular inflammatory pathways is crucial to uncover pathogenic mechanisms linking sporadic and hereditary PD and devise tailored neuroprotective interventions.     

An eicosanoid-centric view of atherothrombotic risk factors

Cardiovascular disease is the foremost cause of morbidity and mortality in the Western world. Atherosclerosis followed by thrombosis (atherothrombosis) is the pathological process underlying most myocardial, cerebral, and peripheral vascular events. Atherothrombosis is a complex and heterogeneous inflammatory process that involves interactions between many cell types (including vascular smooth muscle cells, endothelial cells, macrophages, and platelets) and processes (including migration, proliferation, and activation). Despite a wealth of knowledge from many recent studies using knockout mouse and human genetic studies (GWAS and candidate approach) identifying genes and proteins directly involved in these processes, traditional cardiovascular risk factors (hyperlipidemia, hypertension, smoking, diabetes mellitus, sex, and age) remain the most useful predictor of disease. Eicosanoids (20 carbon polyunsaturated fatty acid derivatives of arachidonic acid and other essential fatty acids) are emerging as important regulators of cardiovascular disease processes. Drugs indirectly modulating these signals, including COX-1/COX-2 inhibitors, have proven to play major roles in the atherothrombotic process. However, the complexity of their roles and regulation by opposing eicosanoid signaling, have contributed to the lack of therapies directed at the eicosanoid receptors themselves. This is likely to change, as our understanding of the structure, signaling, and function of the eicosanoid receptors improves. Indeed, a major advance is emerging from the characterization of dysfunctional naturally occurring mutations of the eicosanoid receptors. In light of the proven and continuing importance of risk factors, we have elected to focus on the relationship between eicosanoids and cardiovascular risk factors.     

Insect hemolymph clotting

The clot’s appearance in different large-bodied insects has been described, but until recently, little was known about any insect clot’s molecular makeup, and few experiments could directly test its function. Techniques have been developed in Drosophila (fruit fly) larvae to identify clotting factors that can then be tested for effects on hemostasis, healing, and immunity. This has revealed unanticipated complexity in the hemostatic mechanisms in these larvae. While the clot’s molecular structure is not yet fully understood, progress is being made, and the loss of clotting factors has been shown to cause subtle immune defects. The few similarities between coagulation in different insect species and life stages, and the current state of knowledge about coagulation in insects are discussed.     

Metabolic syndrome as a risk factor for neurological disorders

The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. At the molecular level, metabolic syndrome is accompanied not only by dysregulation in the expression of adipokines (cytokines and chemokines), but also by alterations in levels of leptin, a peptide hormone released by white adipose tissue. These changes modulate immune response and inflammation that lead to alterations in the hypothalamic ‘bodyweight/appetite/satiety set point,’ resulting in the initiation and development of metabolic syndrome. Metabolic syndrome is a risk factor for neurological disorders such as stroke, depression and Alzheimer’s disease. The molecular mechanism underlying the mirror relationship between metabolic syndrome and neurological disorders is not fully understood. However, it is becoming increasingly evident that all cellular and biochemical alterations observed in metabolic syndrome like impairment of endothelial cell function, abnormality in essential fatty acid metabolism and alterations in lipid mediators along with abnormal insulin/leptin signaling may represent a pathological bridge between metabolic syndrome and neurological disorders such as stroke, Alzheimer’s disease and depression. The purpose of this review is not only to describe the involvement of brain in the pathogenesis of metabolic syndrome, but also to link the pathogenesis of metabolic syndrome with neurochemical changes in stroke, Alzheimer’s disease and depression to a wider audience of neuroscientists with the hope that this discussion will initiate more studies on the relationship between metabolic syndrome and neurological disorders.     

Targeting NADPH oxidases for the treatment of cancer and inflammation

NADPH oxidases are a family of oxidases that utilize molecular oxygen to generate hydrogen peroxide and superoxide, thus indicating physiological functions of these highly reactive and short-lived species. The regulation of these NADPH oxidases (nox) enzymes is complex, with many members of this family exhibiting complexity in terms of subunit composition, cellular location, and tissue-specific expression. While the complexity of the nox family (Nox1-5, Duox1, 2) is daunting, the complexity also allows for targeting of NADPH oxidases in disease states. In this review, we discuss which inflammatory and malignant disorders can be targeted by nox inhibitors, as well as clinical experience in the use of such inhibitors.     

Is the ubiquitin-proteasome system impaired in Huntington’s disease?

Ubiquitylated inclusion bodies (IBs) found in Huntington’s disease (HD) postulate an impaired ubiquitin-proteasome system. However, this hypothesis remains controversial. In vitro-generated polyglutamine aggregates failed to inhibit purified proteasomes, while filamentous huntingtin aggregates isolated from mice resulted in inhibition. However, similarly isolated IBs did not, thus suggesting that IB formation is protective by sequestering smaller inhibitory aggregates. Accordingly, proteasome-activity assays in IB-containing mouse brain homogenates did not show decreased activity. On the contrary, some of the endoproteolytic proteasome activities increased, probably due to altered subunit composition. However, activity was found decreased in postmortem human HD tissue. Finally, evidence supporting the hypothesis was found in HD cell models expressing fluorescent ubiquitin-proteasome system reporters but not in retina of SCA-7 mice with similar reporters. In summary, it seems that mutant huntingtin, probably in intermediate aggregate forms, has the potential to inhibit proteasome activity, but the global status of the system in HD brain tissue is not yet fully elucidated.     

CD11b-bearing mononuclear leucocytes and IgA levels in the staging of human immunodeficiency virus infection

Certain immunological parameters (i.e. low CD4+ T cell numbers, high serum soluble CD8) have been described as prognostic factors for the progression of human immunodeficiency virus (HIV) infection to later clinical stages. In the present study we have found in one hundred HIV-infected Spanish patients (81% drug abusers, 7% homosexuals, 6% heterosexuals, and 6% other or unknown risk groups) that CD11b+ peripheral blood mononuclear cells are increased in those with persistent lymphadenopathy as compared to other clinical stages (asymptomatic, AIDS-related complex and AIDS). Serum IgA was significantly increased in AIDS patients, and in patients at any other clinical stage who had concomitant infections (mainly mycobacterial and fungal). CD11b (an integrin with complement receptor functions) may thus be of clinical interest for the staging of HIV-infected patients, and reflect stage-selective immunological changes in mononuclear cell biology during HIV infection. High IgA on the other hand, would be a marker of concomitant infection as well as of disease progression. The results concern mostly drug addicts (the main risk group in Spain), but may apply to the other risk groups because no significant differences were detected between drug addicts (n=81) and non-drug addicts (n=19) for the studied variables (p>0.05).     

Chitotriosidase: the yin and yang

The enzyme chitotriosidase (ChT), the human analogue of chitinases from non-vertebrate species, is one of the most abundant and indicative proteins secreted by activated macrophages. Its enzymatic activity is elevated in serum of patients suffering from Gaucher’s disease type 1 and in some other inherited lysosomal storage disorders, as well as in diseases in which macrophages are activated. The last decade has witnessed the appearance of a substantial number of studies attempting to unravel its cellular functions, which have yet not been fully defined. A great deal of progress has been made in the study of the physiological roles of ChT. This review is looks at the key areas of investigations addressed to further illuminate whether ChT activation might have different functional meanings in various diseases. Received 7 June 2006; received after revision 24 July 2006; accepted 21 September 2006     

Experimentelle Untersuchungen zum Wirkungsmechanismus der beiden entwicklungsphysiologisch aktiven Fraktionen des «Gehirnhormons» der Insekten (Aktivationsfaktor I und II) auf die Prothoracaldrüse

Summary 2 prothoracotropical factors (activation factor I and II) have been obtained by gel filtration techniques from brains and corpora cardiaca of the cockroachPeriplaneta americana. In contrast to activation factor II, activation factor I caused significant influence of RNA synthesis. The RNA pattern of prothoracic glands stimulated by activation factor I as demonstrated by polyacrylamide gel electrophoresis consists of different kinds of RNA. Short time incubation revealed effects on sRNA synthesis, while long time incubation demonstrated predominantly increase of ribosomal RNA synthesis. Measurements of the membrane potential of the prothoracic gland cells of the wax mothGalleria mellonella indicated an increase by activation factor II; activation factor I was without any visible effect. Our results demonstrate for the first time that the two activation factors induce different effects at cellular level.

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Für technische Unterstützung danken wir FräuleinA. Zinsser und FrauR. Meissner.

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Durchgeführt mit Mitteln des Ministeriums für Wissenschaft und Technik und mit Unterstützung durch die Sächsische Akademie der Wissenschaften zu Leipzig.     

Muramyl dipeptide responsive pathways in Crohn’s disease: from NOD2 and beyond

Crohn’s disease (CD) is one of main disease entities under the umbrella term chronic inflammatory bowel disease. The etiology of CD involves alterations in genetic, microbiological, and immunological factors. This review is devoted to the role of the bacterial wall compound muramyl dipeptide (MDP) for the activation of inflammatory pathways involved in the pathogenesis of CD. The importance of this molecule is underscored by the fact that (1) MDP, which is found in most Gram-negative and -positive bacteria, is able to trigger several immunological responses in the intestinal system, and (2) that alterations in several mediators of the MDP response including—but not restricted to—nucleotide oligomerization domain 2 (NOD2) are associated with CD. The normalization of MDP signaling is one of several important factors that influence the intestinal inflammatory response, a fact which emphasizes the pathogenic importance of MDP signaling for the pathogenesis of CD. The important aspects of NOD2 and non-NOD2 mediated effects of MDP for the development of CD are highlighted, as well as how alterations in these pathways might translate into the development of new therapeutic strategies.     

Genome-wide association study to identify SNPs conferring risk of myocardial infarction and their functional analyses

Myocardial infarction might result from the interactions of multiple genetic and environmental factors, none of which can cause disease solely by each of themselves. Although molecular biological studies revealed that a number of proteins are possibly involved in its pathogenesis, little, if any genetic findings have been reported so far. To reveal genetic backgrounds of myocardial infarction, we performed a large-scale, case-control association study using 92,788 gene-based single-nucleotide polymorphism (SNP) markers. We have identified functional SNPs within the lymphotoxin-α gene (LTA) located on chromosome 6p21 that conferred susceptibility to myocardial infarction. Furthermore, we could identify galectin-2 protein as a binding partner of LTA protein. The association study further revealed that a functional SNP in LGALS2 encoding galectin-2, which led to altered secretion of LTA, also indicated a risk of myocardial infarction. A combined strategy of genetic and molecularcellular biological approaches may be useful in clarifying pathogenesis of common diseases.Received 7 March 2005; received after revision 22 April 2005; accepted 25 April 2005     

Integration of syntactic and semantic properties of the DNA code reveals chromosomes as thermodynamic machines converting energy into information

Understanding genetic regulation is a problem of fundamental importance. Recent studies have made it increasingly evident that, whereas the cellular genetic regulation system embodies multiple disparate elements engaged in numerous interactions, the central issue is the genuine function of the DNA molecule as information carrier. Compelling evidence suggests that the DNA, in addition to the digital information of the linear genetic code (the semantics), encodes equally important continuous, or analog, information that specifies the structural dynamics and configuration (the syntax) of the polymer. These two DNA information types are intrinsically coupled in the primary sequence organisation, and this coupling is directly relevant to regulation of the genetic function. In this review, we emphasise the critical need of holistic integration of the DNA information as a prerequisite for understanding the organisational complexity of the genetic regulation system.     

Complement factor H in host defense and immune evasion

Complement is the major humoral component of the innate immune system. It recognizes pathogen- and damage-associated molecular patterns, and initiates the immune response in coordination with innate and adaptive immunity. When activated, the complement system unleashes powerful cytotoxic and inflammatory mechanisms, and thus its tight control is crucial to prevent damage to host tissues and allow restoration of immune homeostasis. Factor H is the major soluble inhibitor of complement, where its binding to self markers (i.e., particular glycan structures) prevents complement activation and amplification on host surfaces. Not surprisingly, mutations and polymorphisms that affect recognition of self by factor H are associated with diseases of complement dysregulation, such as age-related macular degeneration and atypical haemolytic uremic syndrome. In addition, pathogens (i.e., non-self) and cancer cells (i.e., altered-self) can hijack factor H to evade the immune response. Here we review recent (and not so recent) literature on the structure and function of factor H, including the emerging roles of this protein in the pathophysiology of infectious diseases and cancer.