Geochemistry, soils and cardiovascular diseases

The hypothesis is presented that deficiencies or excesses in the content or availability of trace elements in rocks and soils, or in water flowing through them, may be a possible cause of certain chronic diseases, including cardiovascular ones. The geographic distribution of cardiovascular diseases is often associated with geochemical differences. This trend is particularly evident in the United States and in Europe, with higher rates for cardiovascular mortality in areas underlain by soils that are poor in most essential trace elements. Confirmation of this trend is found in connection with the degree of mineralization of local water supplies. Areas that are served by soft waters usually show higher rates of cardiovascular mortality and other forms of cardiovascular pathology, compared with the areas that are served by hard waters. Such a negative association between water hardness and cardiovascular pathology is evident in many countries, both industrialized and developing ones.     

Geochemistry,soils and cardiovascular diseases

Summary The hypothesis is presented that deficiencies or excesses in the content or availability of trace elements in rocks and soils, or in water flowing through them, may be a possible cause of certain chronic diseases, including cardiovascular ones. The geographic distribution of cardiovascular diseases is often associated with geochemical differences. This trend is particulalry evident in the United States and in Europe, with higher rates for cardiovascular mortality in areas underlain by soils that are poor in most essential trace elements. Confirmation of this trends is found in connection with the degree of mineralization of local water supplies. Areas that are served by soft waters usually show higher rates of cardiovascular mortality and other forms of cardiovascular pathology, compared with the areas that are served by hard waters. Such a negative association between water hardness and cardiovascular pathology is evident in many countries, both industrialized and developing ones.     

Implication of gut microbiota metabolites in cardiovascular and metabolic diseases

Evidence from the literature keeps highlighting the impact of mutualistic bacterial communities of the gut microbiota on human health. The gut microbita is a complex ecosystem of symbiotic bacteria which contributes to mammalian host biology by processing, otherwise, indigestible nutrients, supplying essential metabolites, and contributing to modulate its immune system. Advances in sequencing technologies have enabled structural analysis of the human gut microbiota and allowed detection of changes in gut bacterial composition in several common diseases, including cardiometabolic disorders. Biological signals sent by the gut microbiota to the host, including microbial metabolites and pro-inflammatory molecules, mediate microbiome–host genome cross-talk. This rapidly expanding line of research can identify disease-causing and disease-predictive microbial metabolite biomarkers, which can be translated into novel biodiagnostic tests, dietary supplements, and nutritional interventions for personalized therapeutic developments in common diseases. Here, we review results from the most significant studies dealing with the association of products from the gut microbial metabolism with cardiometabolic disorders. We underline the importance of these postbiotic biomarkers in the diagnosis and treatment of human disorders.     

Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases

Kynurenine pathway (KP) is the primary path of tryptophan (Trp) catabolism in most mammalian cells. The KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), and 3-hydroxyanthranilic acid (3-HAA). Increased catabolite concentrations in serum are associated with several cardiovascular diseases (CVD), including heart disease, atherosclerosis, and endothelial dysfunction, as well as their risk factors, including hypertension, diabetes, obesity, and aging. The first catabolic step in KP is primarily controlled by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Following this first step, the KP has two major branches, one branch is mediated by kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU) and is responsible for the formation of 3-HK, 3-HAA, and quinolinic acid (QA); and another branch is controlled by kynurenine amino-transferase (KAT), which generates KA. Uncontrolled Trp catabolism has been demonstrated in distinct CVD, thus, understanding the underlying mechanisms by which regulates KP enzyme expression and activity is paramount. This review highlights the recent advances on the effect of KP enzyme expression and activity in different tissues on the pathological mechanisms of specific CVD, KP is an inflammatory sensor and modulator in the cardiovascular system, and KP catabolites act as the potential biomarkers for CVD initiation and progression. Moreover, the biochemical features of critical KP enzymes and principles of enzyme inhibitor development are briefly summarized, as well as the therapeutic potential of KP enzyme inhibitors against CVD is briefly discussed.     

Mitochondrial dynamics in cell death and neurodegeneration

Mitochondria are highly dynamic organelles that continuously undergo two opposite processes, fission and fusion. Mitochondrial dynamics influence not only mitochondrial morphology, but also mitochondrial biogenesis, mitochondrial distribution within the cell, cell bioenergetics, and cell injury or death. Drp1 mediates mitochondrial fission, whereas Mfn1/2 and Opa1 control mitochondrial fusion. Neurons require large amounts of energy to carry out their highly specialized functions. Thus, mitochondrial dysfunction is a prominent feature in a variety of neurodegenerative diseases. Mutations of Mfn2 and Opa1 lead to neuropathies such as Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. Moreover, both Aβ peptide and mutant huntingtin protein induce mitochondrial fragmentation and neuronal cell death. In addition, mutants of Parkinson’s disease-related genes also show abnormal mitochondrial morphology. This review highlights our current understanding of abnormal mitochondrial dynamics relevant to neuronal synaptic loss and cell death in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.     

Role of host-defence peptides in eye diseases

The eye and its associated tissues including the lacrimal system and lids have evolved several defence mechanisms to prevent microbial invasion. Included among this armory are several host-defence peptides. These multifunctional molecules are being studied not only for their endogenous antimicrobial properties but also for their potential therapeutic effects. Here the current knowledge of host-defence peptide expression in the eye will be summarised. The role of these peptides in eye disease will be discussed with the primary focus being on infectious keratitis, inflammatory conditions including dry eye and wound healing. Finally the potential of using host-defence peptides and their mimetics/derivatives for the treatment and prevention of eye diseases is addressed.     

Apoptotic and necrotic cell death induced by death domain receptors

Apoptosis and necrosis are two distinct forms of cell death. Caspases are indispensable as initiators and effectors of apoptotic cell death and are involved in many of the morphological and biochemical features of apoptosis. Major changes in mitochondrial membrane integrity and release of proapoptotic factors, such as cytochrome c from the mitochondrial intermembrane space, play an important sensor and amplifying role during apoptotic cell death. In vitro studies of cell death in cell lines have revealed that inhibition of the classical caspase-dependent apoptotic pathway leads in several cases to necrotic cell death. Thus, the same cell death stimulus can result either in apoptotic or necrotic cell death, depending on the availability of activated caspase. Therefore, death domain receptors may initiate an active caspase-independent necrotic signaling pathway. In this review, we describe what is known about the apoptotic and necrotic cell death pathways. Principal elements of necrosis include mitochondrial oxidative phosphorylation, reactive oxygen production, and non-caspase proteolytic cascades depending on serine proteases, calpains, or cathepsins.     

Role of p21-activated kinases in cardiovascular development and function

p21-activated kinases (Paks) are a group of six serine/threonine kinases (Pak1-6) that are involved in a variety of biological processes. Recently, Paks, more specifically Pak1, -2, and -4, have been shown to play important roles in cardiovascular development and function in a range of model organisms including zebrafish and mice. These functions include proper morphogenesis and conductance of the heart, cardiac contractility, and development and integrity of the vasculature. The mechanisms underlying these effects are not fully known, but they likely differ among the various Pak isoforms and include both kinase-dependent and -independent functions. In this review, we discuss aspects of Pak function relevant to cardiovascular biology as well as potential therapeutic implications of small-molecule Pak inhibitors in cardiovascular disease.     

Immunogenicity of necrotic cell death

The mode of tumor cell death has significant effects on anti-tumor immunity. Although, previously it was thought that cell death is an inert effect, different investigators have clearly shown that dying tumors can attract, activate and mature professional antigen presenting cells and dendritic cells. In addition, others and we have shown that the type of tumor cell death not only controls the presence or absence of specific tumor antigens, but also can result in immunological responses ranging from immunosuppression to anti-tumor immunity. More importantly, it is possible to enhance anti-tumor immunity both in vitro and in vivo by targeting specific molecular mechanisms such as oligopeptidases and the proteasome. These studies not only extend our knowledge on basic immunological questions and the induction of anti-tumor immunity, but also have implications for all types of cancer treatments, in which rapid tumor cell death is induced. This review is a comprehensive summary of cell death and particularly necrosis and the pivotal role it plays in anti-tumor immunity.     

Serotonin reuptake inhibitors and cardiovascular diseases: a platelet connection

Selective serotonin reuptake inhibitors (SSRIs) are a heterogeneous group of new antidepressants that cause a well documented acquired but reversible serotonin deficiency in blood platelets. Platelets are small, anucleate cells and are the only blood cells specialized in storing peripheral serotonin. Platelets are also an integral part of the hemostatic process that is initiated during pathologic thrombus formation in cardiovascular diseases. Serotonin release from platelets is important for functional hemostasis as indicated by congenital diseases with serotonin-deficient platelets that can lead to life-threatening bleeding problems. The postulate that SSRIs should have an impact on cardiovascular diseases is therefore well founded. Cardiovascular effects of SSRIs have indeed been shown in a number of studies investigating the effect of SSRIs in patients with psychosomatic comorbidity. SSRIs reduce the incidence of recurrent myocardial infarction (MI) in patients suffering from post-MI depression. In addition, SSRIs inhibit tight clot formation of platelets in vitro, which points to a direct anti-thrombotic or pro-fibrinolytic effect of SSRIs.Received 16 June 2004; received after revision 9 September 2004; accepted 23 September 2004