Abstract: The role of epigenetics in human disease has become an area of increased research interest. Collaborative efforts from scientists and clinicians have led to a better understanding of the molecular mechanisms by which epigenetic regulation is involved in the pathogenesis of many human diseases. Several neurological and non-neurological disorders are associated with mutations in genes that encode for epigenetic factors. One of the most studied proteins that impacts human disease and is associated with deregulation of epigenetic processes is Methyl CpG binding protein 2 (MeCP2). MeCP2 is an epigenetic regulator that modulates gene expression by translating epigenetic DNA methylation marks into appropriate cellular responses. In order to highlight the importance of epigenetics to development and disease, we will discuss how MeCP2 emerges as a key epigenetic player in human neurodevelopmental, neurological, and non-neurological disorders. We will review our current knowledge on MeCP2-related diseases, including Rett Syndrome, Angelman Syndrome, Fetal Alcohol Spectrum Disorder, Hirschsprung disease, and Cancer. Additionally, we will briefly discuss about the existing MeCP2 animal models that have been generated for a better understanding of how MeCP2 impacts certain human diseases.
Abstract: Mitochondrial diseases, which altogether represent not so rare diseases, can be due to mutations either in the nuclear or mitochondrial genomes. Several model organisms or cell lines are usually employed to understand the mechanisms underlying diseases, yeast being one of them. However, in the case of mutations within the mitochondrial genome, yeast is a major model because it is a facultative aerobe and its mitochondrial genome can be genetically engineered and reintroduced in vivo. In this short review, I will describe how these properties can be exploited to mimic mitochondrial pathogenic mutations, as well as their limits. In particular; pathological mutations of tRNA, cytb, and ATPase genes have been successfully modeled. It is essential to stress that what has been discovered with yeast (molecular mechanisms underlying the diseases, nuclear correcting genes, import of tRNA into mitochondria or compounds from drug screening) has been successfully transferred to human patient lines, paving the way for future therapies.
Abstract: In the class Kinetoplastida, we find an order of parasitic protozoans classified as Trypanosomatids. Three major pathogens form part of this order, Trypanosoma cruzi, Trypanosoma brucei, and Leishmania, which are responsible for disease and fatalities in millions of humans worldwide, especially in non-industrialized countries in tropical and sub-tropical regions. In order to develop new drugs and treatments, the physiology of these pathogenic protozoans has been studied in detail, specifically the significance of membrane transporters in host parasites interactions. Aquaporins and Aquaglyceroporins (AQPs) are a part of the major intrinsic proteins (MIPs) super-family. AQPs are characterized for their ability to facilitate the diffusion of water (aquaporin), glycerol (aquaglyceroporin), and other small-uncharged solutes. Furthermore, AQPs have been shown to allow the ubiquitous passage of some metalloids, such as trivalent arsenic and antimony. These trivalent metalloids are the active ingredient of a number of chemotherapeutic agents used against certain cancers and protozoan parasitic infections. Recently, the importance of the AQPs not only in osmotic adaptations but also as a factor in drug resistance of the trypanosomatid parasites has been reported. In this review, we will describe the physiological functions of aquaporins and their effect in drug response across the different trypanosomatids.
Abstract: The clustering of cardio-metabolic risk factors, either when called metabolic syndrome (MetS) or not, substantially increases the risk of cardiovascular disease (CVD) and causes mortality. One of the possible mechanisms for this clustering's adverse effect is an increase in arterial stiffness (AS), and in high central aortic blood pressure (CABP), which are significant and independent CVD risk factors. Arterial hypertension was connected to AS long ago; however, other MetS components (obesity, dyslipidaemia, dysglycaemia) or MetS associated abnormalities not included in MetS diagnostic criteria (renal dysfunction, hyperuricaemia, hypercoaglutability, menopause, non alcoholic fatty liver disease, and obstructive sleep apnea) have been implicated too. We discuss the evidence connecting these cardio-metabolic risk factors, which negatively affect AS and finally increase CVD risk. Furthermore, we discuss the impact of possible lifestyle and pharmacological interventions on all these cardio-metabolic risk factors, in an effort to reduce CVD risk and identify features that should be taken into consideration when treating MetS patients with or without arterial hypertension.
Abstract: Oxidative stress is a key mechanism causing protein aggregation, cell death and neurodegeneration in the nervous system. The neuronal cytoskeleton, that is, microtubules, actin filaments and neurofilaments, plays a key role in defending the nervous system against oxidative stress-induced damage and is also a target for this damage itself. Microtubules appear particularly susceptible to damage, with oxidative stress downregulating key microtubule-associated proteins [MAPs] and affecting tubulin through aberrant post-translational modifications. Actin filaments utilise oxidative stress for their reorganisation and thus may be less susceptible to deleterious effects. However, because cytoskeletal components are interconnected through crosslinking proteins, damage to one component affects the entire cytoskeletal network. Neurofilaments are phosphorylated under oxidative stress, leading to the formation of protein aggregates reminiscent of those seen in neurodegenerative diseases. Drugs that target the cytoskeleton may thus be of great use in treating various neurodegenerative diseases caused by oxidative stress.