Atherosclerotic cardiovascular disease (ACD) is the leading cause of mortality worldwide. The objective of this paper is to provide an overview of the global burden of ACD and its risk factors and to discuss the main challenges and opportunities for prevention. Publicly available data from the Global Burden of Disease Study were analyzed for ischemic heart disease (IHD), ischemic stroke and ACD risk factors. Data from the WHO Global Health Observatory were used to describe prevalence of diverse cardiometabolic risk factors. World Bank Gross Domestic Product per capita (GDPc) information was used to categorize countries according to income level. Cardiovascular mortality decreased globally from 1990–2010 with important differences by GDPc; during 1990 there was a positive association between IHD mortality and GDPc. Higher-income countries had higher rates compared to those of lower-income countries. High levels of body mass index (BMI), blood pressure, glucose and cholesterol have a differential contribution to mortality by income group over time; high-income countries have been able to reduce the contribution from these risk factors in the last 20 years, whereas lower/middle income countries show an increasing trend in mortality attributable to high BMI and glucose. Although age-adjusted ACD mortality rate trends decreased globally, the absolute number of ACD deaths is increasing in part due to the growth of the population and aging, as well as to important lifestyle and food-system changes that likely attenuate gains in prevention. Population and individual level preventable causes of ACD must be aggressively and efficiently targeted in countries of lower economic development in order to reduce the growing burden of disease due to ACD.
In this review we summarize the epidemiological, cross-sectional, and interventional studies examining the association between physical activity and brain volume, function, and risk for Alzheimer's disease. The epidemiological literature provides compelling evidence that greater amounts of physical activity are associated with a reduced risk of dementia in late life. In addition, randomized interventions using neuroimaging tools have reported that participation in physical activity increases the size of prefrontal and hippocampal brain areas, which may lead to a reduction in memory impairments. Consistent with these findings, longitudinal studies using neuroimaging tools also find that the volume of prefrontal and hippocampal brain areas are larger in individuals who engaged in more physical activity earlier in life. We conclude from this review that there is convincing evidence that physical activity has a consistent and robust association with brain regions implicated in age-related cognitive decline and Alzheimer's disease. In addition to summarizing this literature we provide recommendations for future research on physical activity and brain health.
Serious infections caused by bacteria that have become resistant to commonly used antibiotics have become a major global healthcare problem in the 21st century. They not only are more severe and require longer and more complex treatments, but they are also significantly more expensive to diagnose and to treat. Antibiotic resistance, initially a problem of the hospital setting associated with an increased number of hospital-acquired infections usually in critically ill and immunosuppressed patients, has now extended into the community causing severe infections difficult to diagnose and treat. The molecular mechanisms by which bacteria have become resistant to antibiotics are diverse and complex. Bacteria have developed resistance to all different classes of antibiotics discovered to date. The most frequent type of resistance is acquired and transmitted horizontally via the conjugation of a plasmid. In recent times new mechanisms of resistance have resulted in the simultaneous development of resistance to several antibiotic classes creating very dangerous multidrug-resistant (MDR) bacterial strains, some also known as “superbugs”. The indiscriminate and inappropriate use of antibiotics in outpatient clinics, hospitalized patients and in the food industry is the single largest factor leading to antibiotic resistance. In recent years, the number of new antibiotics licensed for human use in different parts of the world has been lower than in the recent past. In addition, there has been less innovation in the field of antimicrobial discovery research and development. The pharmaceutical industry, large academic institutions or the government are not investing the necessary resources to produce the next generation of newer safe and effective antimicrobial drugs. In many cases, large pharmaceutical companies have terminated their anti-infective research programs altogether due to economic reasons. The potential negative consequences of all these events are relevant because they put society at risk for the spread of potentially serious MDR bacterial infections.
Atherosclerosis is a chronic disease hallmarked by chronic inflammation, endothelial dysfunction and lipid accumulation in the vasculature. Although lipid modification and deposition are thought to be a major source of the continuous inflammatory stimulus, a large body of evidence suggests that infectious agents may contribute to atherosclerotic processes. This could occur by either direct effects through infection of vascular cells and/or through indirect effects by induction of cytokine and acute phase reactant proteins by infection at other sites. Multiple bacterial and viral pathogens have been associated with atherosclerosis by seroepidemiological studies, identification of the infectious agent in human atherosclerotic tissue, and experimental studies demonstrating an acceleration of atherosclerosis following infection in animal models of atherosclerosis. This review will focus on those infectious agents for which biological plausibility has been demonstrated in animal models and on the challenges of proving a role of infection in human atherosclerotic disease.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system associated with demyelination and axonal loss eventually leading to neurodegeneration. MS exhibits many of the hallmarks of an inflammatory autoimmune disorder including breakdown of the blood–brain barrier (BBB). The BBB is a complex organization of cerebral endothelial cells, pericytes and their basal lamina, which are surrounded and supported by astrocytes and perivascular macrophages. In pathological conditions, lymphocytes activated in the periphery infiltrate the central nervous system to trigger a local immune response that ultimately damages myelin and axons. Cytotoxic factors including pro-inflammatory cytokines, proteases, and reactive oxygen and nitrogen species accumulate and may contribute to myelin destruction. Dysregulation of the BBB and transendothelial migration of activated leukocytes are among the earliest cerebrovascular abnormalities seen in MS brains and parallel the release of inflammatory cytokines. In this review we establish the importance of the role of the BBB in MS. Improvements in our understanding of molecular mechanism of BBB functioning in physiological and pathological conditions could lead to improvement in the quality of life of MS patients.
Due to the public health problem represented by obesity, the study of adipose tissue, particularly of the adipocyte, is central to the understanding of metabolic abnormalities associated with the development of obesity. The concept of adipocyte as endocrine and functional cell is not totally understood and can be currently defined as the capacity of the adipocyte to sense, manage, and send signals to maintain energy equilibrium in the body. Adipocyte functionality is lost during obesity and has been related to adipocyte hypertrophy, disequilibrium between lipogenesis and lipolysis, impaired transcriptional regulation of the key factors that control adipogenesis, and lack of sensitivity to external signals, as well as a failure in the signal transduction process. Thus, dysfunctional adipocytes contribute to abnormal utilization of fatty acids causing lipotoxicity in non-adipose tissue such as liver, pancreas and heart, among others. To understand the metabolism of the adipocyte it is necessary to have an overview of the developmental process of new adipocytes, regulation of adipogenesis, lipogenesis and lipolysis, endocrine function of adipocytes and metabolic consequences of its dysfunction. Finally, the key role of adipose tissue is shown by studies in transgenic animals or in animal models of diet-induced obesity that indicate the contribution of adipose tissue during the development of metabolic syndrome. Thus, understanding of the molecular process that occurs in the adipocyte will provide new tools for the treatment of metabolic abnormalities during obesity.
The blood–brain barrier (BBB) is a dynamic and complex interface between the blood and the central nervous system regulating brain homeostasis. Major functions of the BBB include the transport of nutrients and protection of the brain from toxic compounds. This review summarizes the most important transport pathways contributing to the nutrition of the brain. Carrier-mediated transport selectively delivers small molecules like sugars, amino acids, vitamins, and trace elements. Large biomolecules, lipoproteins, peptide and protein hormones cross the BBB by receptor-mediated transport. Active efflux transporters participate in the brain efflux of endogenous metabolites as well as toxins, xenobiotics and drugs. Dysfunction in the transport of nutrients at the BBB is described in several neurological disorders and diseases. The BBB penetration of neuroprotective nutrients, especially plant polyphenols and alkaloids, their potential protective effect on brain endothelium and the interaction of nutraceuticals with active efflux transporters at the BBB are discussed. In vitro BBB models to examine nutrient transport are also presented.
Background and Aims Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are nephro- and cardiovascular toxins, produced solely by the gut microbiota, which have pro-inflammatory and pro-oxidative properties in vitro . We undertook this study to investigate the associations between IS and PCS and both inflammation and oxidative stress in the chronic kidney disease (CKD) population. Methods In this cross-sectional observational cohort study, participants with stage 3–4 CKD who enrolled in a randomized controlled trial of cardiovascular risk modification underwent baseline measurements of serum total and free IS and PCS (measured by ultraperformance liquid chromotography), inflammatory markers (interferon gamma [IFN-γ], interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-α]), antioxidant and oxidative stress markers (plasma glutathione peroxidase [GPx] activity, total antioxidant capacity [TAC] and F2-isoprostanes) and pulse wave velocity (PWV), a marker of arterial stiffness. Results There were 149 CKD patients (59% male; age 60 ± 10 years; 44% diabetic) with a mean eGFR of 40 ± 9 mL/min/1.73 m2 (range 25–59). Serum free and total IS were independently associated with serum IL-6, TNF-α and IFN-γ, whereas serum free and total PCS were independently associated with serum IL-6 and PWV. Free IS and PCS were additionally independently associated with serum GPx but not with TAC or F2-isoprostanes. Conclusions IS and PCS were associated with elevated levels of selected inflammatory markers and an antioxidant in CKD patients. PCS was also associated with increased arterial stiffness. Inflammation and oxidative stress may contribute to the nephro- and cardiovascular toxicities of IS and PCS. Intervention studies targeting production of IS and PCS by dietary manipulation and the subsequent effect on cardiovascular-related outcomes are warranted in the CKD population.
During the past few years, an increasing set of evidence has supported the major role of deregulation of the interaction patterns between glial cells and neurons in the pathway toward neuronal degeneration. Neurons and glial cells, together with brain vessels, constitute an integrated system for brain function. Inflammation is a process related with the onset of several neurodegenerative disorders, including Alzheimer's disease (AD). Several hypotheses have been postulated to explain the pathogenesis of AD, but none provides insight into the early events that trigger metabolic and cellular alterations in neuronal degeneration. The amyloid hypothesis was sustained on the basis that Aβ-peptide deposition into senile plaques is responsible for neurodegeneration. However, recent findings point to Aβ oligomers as responsible for synaptic impairment in neuronal degeneration. Amyloid is only one among many other major factors affecting the quality of neuronal cells. Another explanation derives from the tau hypothesis, supported by the observations that tau hyperphosphorylations constitute a common feature of most of the altered signaling pathways in degenerating neurons. Altered tau patterns have been detected in the cerebrospinal fluids of AD patients, and a close correlation was observed between the levels of hyperphosphorylated tau isoforms and the degree of cognitive impairment. On the other hand, the anomalous effects of cytokines and trophic factors share in common the activation of tau hyperphosphorylation patterns. In this context, a neuroimmunological approach to AD becomes relevant. When glial cells that normally provide neurotrophic factors essential for neurogenesis are activated by a set of stressing events, they overproduce cytokines and NGF, thus triggering altered signaling patterns in the etiopathogenesis of AD. A solid set of discoveries has strengthened the idea that altered patterns in the glia-neuron interactions constitute early molecular events within the cascade of cellular signals that lead to neurodegeneration in AD. A direct correlation has been established between the Aβ-induced neurodegeneration and cytokine production and its subsequent release. In effect, neuroinflammation is responsible for an abnormal secretion of proinflammatory cytokines that trigger signaling pathways that activate brain tau hyperphosphorylation in residues that are not modified under normal physiological conditions. Other cytokines such as IL-3 and TNF-α seem to display neuroprotective activities. Elucidation of the events that control the transitions from neuroprotection to neurodegeneration should be a critical point toward elucidation of AD pathogenesis.
Background and Aims Many studies show that fish oil with high content of n-3 polyunsaturated fatty acids (PUFAs) plays an important role in human health and disease. But the effects of fish oil with high content of PUFAs on gut microbiota, which are also known play a significant role in several human diseases, is not clear. In the present study we evaluated the effects of fish oil with high content of n-3 PUFAs on gut microbiota. Methods Changes in gut microbiota in ICR mice after supplementation of fish oil (containing eicosapentaenoic acid and docosahexaenoic acid: ∼40 and 27% respectively) for 15 days was characterized using the hypervariable V3 region of the 16 rRNA gene-based polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) profiling, DNA sequencing, and phylogenetic analysis techniques. Results Fish oil treatment resulted in a decrease in Helicobacter, Uncultured bacterium clone WD2_aaf07d12 (GenBank: EU511712.1), Clostridiales bacterium, Sphingomonadales bacterium and Pseudomonas species Firmicutes , and several uncultured bacteria. Conclusions Fish oil with a high content of n-3 PUFAs are capable of producing significant changes in the gut microbiota that may, at least in part, explain the health benefits or injury induced by fish oil use.
Background and Aims Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease in which reducing pro-inflammatory and/or increasing anti-inflammatory molecules is the mainstay of treatment. The aim of this study was to evaluate the effects of supplementation with resveratrol as an antiinflammatory and antioxidant agent on inflammation and quality of life in patients with active UC. Methods and Results In this randomized, double-blind, placebo-controlled study, 50 eligible patients with active mild to moderate UC were supplemented with either a 500-mg resveratrol or placebo capsule for 6 weeks. Serum inflammatory markers, activity of NF-κB in peripheral blood mononuclear cells (PBMC) and quality of life were assessed at baseline and at the end of the study. Resveratrol supplementation led to a significant reduction in plasma levels of TNF-α (19.70 ± 12.80 to 17.20 ± 10.09 pg/mL) and hs-CRP (4764.25 ± 2260.48 to 2584.50 ± 1792.80 ng/mL) and activity of NF-κB in PBMCs (0.19 ± 0.05 to 0.10 ± 0.04 OD) ( p <0.001), whereas there were no significant changes of these factors in placebo group. Also, the score of inflammatory bowel disease questionnaire -9 (IBDQ-9) increased, whereas the clinical colitis activity index score decreased significantly in the resveratrol group (32.72 ± 7.52 to 47.64 ± 8.59) ( p <0.001) and when compared with the placebo group (35.54 ± 9.50 to 41.08 ± 6.59) ( p <0.001). Conclusion Our results indicate that 6 weeks supplementation with 500 mg resveratrol can improve quality of life and disease clinical colitis activity at least partially through inflammation reduction in patients with UC. Whether these effects will be continued in longer duration of treatment remains to be determined.
Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by innate and adaptive immune system involvement. A key component of atherosclerotic plaque inflammation is the persistence of different innate immune cell types including mast cells, neutrophils, natural killer cells, monocytes, macrophages and dendritic cells. Several endogenous signals such as oxidized low-density lipoproteins, and exogenous signals such as lipopolysaccharides, trigger the activation of these cells. In particular, these signals orchestrate the early and late inflammatory responses through the secretion of pro-inflammatory cytokines and contribute to plaque evolution through the formation of foam cells, among other events. In this review we discuss how innate immune system cells affect atherosclerosis pathogenesis.
Traumatic brain injury (TBI) is one of the most frequent causes of death in the young population. Several clinical trials have unsuccessfully focused on direct neuroprotective therapies. Recently immunotherapeutic strategies shifted into focus of translational research in acute CNS diseases. Cross-talk between activated microglia and blood–brain barrier (BBB) could initiate opening of the BBB and subsequent recruitment of systemic immune cells and mediators into the brain. Stabilization of the BBB after TBI could be a promising strategy to limit neuronal inflammation, secondary brain damage and acute neurodegeneration. This review provides an overview on the pathophysiology of TBI and brain edema formation including definitions and classification of TBI, current clinical treatment strategies, as well as current understanding on the underlying cellular processes. A summary of in vivo and in vitro models to study different aspects of TBI is presented. Three mechanisms proposed for stabilization of the BBB, myosin light chain kinases, glucocorticoid receptors and peroxisome proliferator-activated receptors are reviewed for their influence on barrier-integrity and outcome after TBI. In conclusion, the BBB is recommended as a promising target for the treatment of traumatic brain injury, and it is suggested that a combination of BBB stabilization and neuroprotectants may improve therapeutic success.
Metabolic syndrome (MetS) should be considered a clinical entity when its different symptoms share a common etiology: obesity/insulin resistance as a result of a multi-organ dysfunction. The main interest in treating MetS as a clinical entity is that the addition of its components drastically increases the risk of atherosclerosis. In MetS, the adipose tissue plays a central role along with an unbalanced gut microbiome, which has become relevant in recent years. Once visceral adipose tissue (VAT) increases, dyslipidemia and endothelial dysfunction follow as additive risk factors. However, when the nonalcoholic fatty liver is present, risk of a cardiovascular event is highly augmented. Epicardial adipose tissue (EAT) seems to increase simultaneously with the VAT. In this context, the former may play a more important role in the development of the atherosclerotic plaque than the latter. Hence, EAT may act as a paracrine tissue vis-à-vis the coronary arteries favoring the local inflammation and the atheroma calcification.
Background and Aims We undertook this study to assess the effects of omega-3 polyunsaturated fatty acids (PUFAs) (administered at ≥2.7 g/day) for a minimum duration of 3 months on clinical outcomes in patients with rheumatoid arthritis (RA). Methods The authors surveyed randomized controlled trials (RCTs) that examined the effects of omega-3 PUFAs on clinical outcomes in RA patients using Medline and the Cochrane Controlled Trials Register and by performing manual searches. Meta-analysis of RCTs was performed using fixed and random effects models. Outcomes are presented as standardized mean differences (SMD). Results Ten RCTs involving 183 RA patients and 187 placebo-treated RA controls were included in this meta-analysis. The analysis showed that omega-3 PUFAs clearly reduced nonsteroidal anti-inflammatory drug (NSAID) consumption (SMD −0.518, 95% CI −0.915 to −0.121, p = 0.011) without between-study heterogeneity ( I 2 = 0%). Tender joint count (SMD −0.214, 95% CI−0.489–0.062, p = 0.128), swollen joint count (SMD −0.170, 95% CI−0.454–0.114, p = 0.241), morning stiffness (SMD −0.224, 95% CI−0.955–0.212, p = 0.221), and physical function (SMD 0.264, 95% CI−0.232–0.724, p = 0.314) showed a trend to improve more in patients treated with omega-3 PUFAs than in placebo-treated controls, but they did not reach statistical significance. Conclusions This meta-analysis suggests that the use of omega-3 PUFAs at dosages >2.7 g/day for >3 months reduces NSAID consumption by RA patients. Further studies are needed to explore the clinical and NSAID-sparing effects of omega-3 PUFAs in RA.
Mesenchymal stem cells (MSCs) play an important role in the physiology and homeostasis of the hematopoietic system. Because MSCs generate most of the stromal cells present in the bone marrow (BM), form part of the hematopoietic stem cell (HSC) niche, and produce various molecules regulating hematopoiesis, their hematopoiesis-supporting capacity has been demonstrated. In the last decade, BM-MSCs have been proposed to be useful in some ex vivo protocols for HSC expansion, with the aim of expanding their numbers for transplant purposes (HSC transplant, HSCT). Furthermore, application of MSCs has been proposed as an adjuvant cellular therapy for promoting rapid hematopoietic recovery in HSCT patients. Although the MSCs used in preliminary clinical trials have come from the BM, isolation of MSCs from far more accessible sources such as neonatal tissues has now been achieved, and these cells have been found to possess similar biological characteristics to those isolated from the BM. Therefore, such tissues are now considered as a potential alternative source of MSCs for clinical applications. In this review, we discuss current knowledge regarding the biological characteristics of MSCs as related to their capacity to support the formation of hematopoietic stem and progenitor cells. We also describe MSC manipulation for ex vivo HSC expansion protocols used for transplants and their clinical relevance for hematopoietic recovery in HSCT patients.
The human gut is a highly complex ecosystem with an extensive microbial community, and the influence of the intestinal microbiota reaches the entire host organism. For example, the microbiome regulates fat storage, stimulates or renews epithelial cells, and influences the development and maturation of the brain and the immune system. Intestinal microbes can protect against infection by pathogenic bacteria, viruses, fungi and parasites. Hence, the maintenance of homeostasis between the gut microbiota and the rest of the body is crucial for health, with dysbiosis affecting disease. This review focuses on intestinal protozoa, especially those still representing a public health problem in Mexico, and their interactions with the microbiome and the host. The decrease in prevalence of intestinal helminthes in humans left a vacant ecological niche that was quickly occupied by protozoa. Although the mechanisms governing the interaction between intestinal microbiota and protozoa are poorly understood, it is known that the composition of the intestinal bacterial populations modulates the progression of protozoan infection and the outcome of parasitic disease. Most reports on the complex interactions between intestinal bacteria, protozoa and the immune system emphasize the protective role of the microbiota against protozoan infection. Insights into such protection may facilitate the manipulation of microbiota components to prevent and treat intestinal protozoan infections. Here we discuss recent findings about the immunoregulatory effect of intestinal microbiota with regards to intestinal colonization by protozoa, focusing on infections by , spp, , and . The possible consequences of the microbiota on parasitic, allergic and autoimmune disorders are also considered.
Many hypotheses have been raised regarding the pathophysiology of Alzheimer's disease (AD). Because amyloid beta peptide (Aβ) deposition in senile plaques appears as a late, nonspecific event, recent evidence points to tau phosphorylation and aggregation as the final common pathway in this multifactorial disease. Current approaches that provide evidence in favor of neuroimmunomodulation in AD and the roles of tau pathological modifications and aggregation into oligomers and filamentous forms are presented. We propose an integrative model on the pathogenesis of AD that includes several damage signals such as Aβ oligomers, oxygen free radicals, iron overload, homocysteine, cholesterol and LDL species. These activate microglia cells, releasing proinflammatory cytokines and producing neuronal degeneration and tau pathological modifications. Altered and aggregated forms of tau appear to act as a toxic stimuli contributing to neurodegeneration. Recent findings provide further support to the central role of tau in the pathogenesis of AD, so this protein has turned into a diagnostic and therapeutic target for this disease.