SciCombinator

Discover the most talked about and latest scientific content & concepts.

Journal: Current opinion in pharmacology

27

Systemic glucocorticoid excess causes osteoporosis, insulin resistance and central obesity. Recently it has been recognized that tissue glucocorticoid levels can increase independently of circulating levels. This occurs through increased activity of the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme which is expressed in bone, synovium, liver and adipose tissue. Mice with global 11β-HSD1 deletion exhibit increased severity of experimental arthritis. However, selective disruption of glucocorticoid signalling in osteoblasts and osteocytes attenuates murine experimental arthritis. In addition, such mice are protected against the adverse metabolic features caused by glucocorticoid excess. Taken together, these results indicate that bone cells, through local glucocorticoid signalling, are involved in the regulation of joint inflammation as well as systemic fuel metabolism. Clinical studies have demonstrated that specific inhibitors of 11β-HSD1 improve insulin sensitivity and reduce weight, suggesting that inhibition of this glucocorticoid-activating enzyme may have applications for treating the adverse metabolic features associated with rheumatic disease.

Concepts: Insulin, Obesity, Rheumatoid arthritis, Insulin resistance, Adipose tissue, Glucocorticoid, Metabolic syndrome, Enzyme inhibitor

27

Omega-3 polyunsaturated fatty acids (PUFAs) are known to alleviate joint stiffness and pain in rheumatoid arthritis patients. However, the mechanisms by which omega-3s exert their beneficial effects has not been fully explored. Herein we discuss a novel class of bioactive lipid mediators, which are enzymatically biosynthesized in vivo from omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), termed resolvins. These lipid mediators exert anti-inflammatory and pro-resolving properties and are log-orders more potent than their precursors. We also highlight that formation of pro-resolving mediators can be enhanced by widely used anti-inflammatory and cardioprotective drugs (aspirin and statins) via the modification of cyclooxygenase-2 enzymatic activity. These bioactive pro-resolving lipid mediators provide further rationale for the beneficial effects of dietary supplementation with fish oils, and offer new avenues for developing therapeutics for inflammatory conditions such as rheumatoid arthritis.

Concepts: Inflammation, Nutrition, Fatty acid, Fatty acids, Essential fatty acid, Omega-3 fatty acid, Eicosapentaenoic acid, Docosahexaenoic acid

27

It is now widely accepted that the development of atherosclerotic lesions involves a chronic inflammatory response that includes both innate and adaptive immune mechanisms. However, it is still unclear precisely what induces the inflammatory response. Furthermore, inflammation within the blood vessel can be divided into direct mechanisms where the primary inflammatory events occur within the intima of the blood vessel and contribute to both the initiation and progression of the plaques and indirect mechanisms where inflammation at nonvascular sites can contribute to the progression of the lesions. The direct mechanisms include lipid deposition and modification, influx of lipoprotein associated factors and microparticles derived from many different cell types, and possibly bacterial and viral infection of vascular cells. Indirect mechanisms derive from inflammation related to autoimmune diseases, smoking, respiratory infection, and pollution exposure, and possibly periodontal disease and gastric infection. The mechanisms include secretion of cytokines and other inflammatory factors into the circulation with subsequent uptake into the plaques, egress and recruitment of activated inflammatory cells, formation of dysfunctional HDL and crossreactive autoantibodies.

Concepts: Immune system, Inflammation, Disease, Atherosclerosis, Infection, Blood vessel, Artery, Endothelium

24

Obesity is a growing public health problem and affects 35% US adults. Obesity increases the risk of many cancer types and is associated with poor outcomes. Clinical management of cancer patients has been essentially the same between normal weight and obese individuals. Understanding causal mechanisms by which obesity drives cancer initiation and progression is essential for the development of novel precision therapy for obese cancer patients. One caveat is that various mechanisms have been proposed for different cancer types for their progression under obesity. Since obesity is known to have global impact on inflammation, here we will summarize recent literature and discuss the potential of inflammation being the common causal mechanism to promote cancer promotion across cancer types.

Concepts: Cancer, Oncology, Causality, Obesity, Overweight, Weight loss, Malnutrition, Childhood obesity

5

Neural stem cells exist in specialized regions of the brain and have the capacity to give rise to neurons and glia over the lifespan. The process of giving rise to new neurons, also known as neurogenesis, is thought to be important in cognition and certain types of brain repair. However, during aging, neural stem cell number and function is reduced resulting in fewer new neurons and declines in learning, memory and repair. Recently, research has approached this problem through the lens of rejuvenation that now has produced several strategies, from dietary to pharmacological interventions, to restore functional neurogenesis that resembles the youthful brain. Here, we outline aging in the subventricular zone neurogenic niche, review the multiple modalities of rejuvenation strategies, and propose next steps for future studies to approach translational outcomes.

4

Aging is the prime risk factor for the broad-based development of diseases. Frailty is a phenotypical hallmark of aging and is often used to assess whether the predicted benefits of a therapy outweigh the risks for older patients. Senescent cells form as a consequence of unresolved molecular damage and persistently secrete molecules that can impair tissue function. Recent evidence shows senescent cells can chronically interfere with stem cell function and drive aging of the musculoskeletal system. In addition, targeted apoptosis of senescent cells can restore tissue homeostasis in aged animals. Thus, targeting cellular senescence provides new therapeutic opportunities for the intervention of frailty-associated pathologies and could have pleiotropic health benefits.

3

Obesity prevalence is increasing steadily throughout the world’s population in most countries and in parallel the prevalence of metabolic disorders including cardiovascular diseases and type 2 diabetes is also rising, but less is reported about excessive adiposity relationship with poorer cognitive performance, cognitive decline and dementia. Some human clinical studies have evidenced that obesity is related to the risk of the development of mild cognitive impairment, in the form of short-term memory and executive function deficits, as well as dementia and Alzheimer’s disease. The precise mechanisms that underlie the connections between obesity and the risk of cognitive impairment are still largely unknown but potential avenues of further research include insulin resistance, the gut-brain axis, and systemic mediators and central inflammation processes. A common feature of metabolic diseases is a chronic and low-grade activation of the inflammatory system. This inflammation may eventually spread from peripheral tissue to the brain, and recent reports suggest that neuroinflammation is an important causal mechanism in cognitive decline. This inflammatory status could be triggered by changes in the gut microbiota composition. Consumption of diets high in fat and sugar influences the microbiota composition, which may lead to an imbalanced microbial population in the gut. Thus, it has recently been hypothesized that the gut microbiota could be part of a mechanistic link between the consumption of high fat and other unbalanced diets and impaired cognition, termed ‘gut-brain axis’. The present review will aim at providing an integrative analysis of the effects of obesity and unbalanced diets on cognitive performance and discusses some of the potential mechanisms involved, namely inflammation and changes in gut-brain axis. Moreover, the review aims to analyze anti-inflammatory drugs that have been tested for the treatment of cognition and obesity, recently approved anti-obesity drugs that could also have an impact on central nervous system, and bioactive food compounds that modulate gut microbiota and could have an impact through the gut-brain axis. In this era of precision nutrition medicine, it is imperative to identify the various metabolic-neurocognitive phenotypes in order to understand the processes that drive these diseases so that targeted therapeutic strategies to prevent and successfully manage these complex, multifactorial diseases could be designed and developed.

Concepts: Alzheimer's disease, Inflammation, Nervous system, Brain, Gut flora, Metabolism, Obesity, Anti-inflammatory

3

Glaucoma is a progressive optic neuropathy of unknown origin. It has been hypothesized that a vascular component is involved in glaucoma pathophysiology. This hypothesis has gained support from studies showing that reduced ocular perfusion pressure is a risk factor for the disease. The exact nature of the involvement is, however, still a matter of debate. Based on recent evidence we propose a model including primary and secondary insults in glaucoma. The primary insult appears to happen at the optic nerve head. Increased intraocular pressure and ischemia at the post-laminar optic nerve head affects retinal ganglion cell axons. Modulating factors are the biomechanical properties of the tissues and cerebrospinal fluid pressure. After this primary insult retinal ganglion cells function at a reduced energy level and are sensitive to secondary insults. These secondary insults may happen if ocular perfusion pressure falls below the lower limit of autoregulation or if neurovascular coupling fails. Evidence for both faulty autoregulation and reduced hyperemic response to neuronal stimulation has been provided in glaucoma patients. The mechanisms appear to involve vascular endothelial dysfunction and impaired astrocyte-vessel signaling. A more detailed understanding of these pathways is required to direct neuroprotective strategies via the neurovascular pathway.

Concepts: Nervous system, Ganglion, Photon, Retina, Glaucoma, Ophthalmology, Retinal ganglion cell, Ganglion cell

2

Fibrosis can occur in most organs and is characterised by excessive and progressive extracellular matrix deposition and destruction of normal tissue architecture and function. In many cases treatment options are limited. Fibrotic diseases are therefore associated with high morbidity and mortality. Tissue biopsies remain a key part of diagnosing fibrosis; however, due to their invasive nature, tissue biopsies are unsuitable for monitoring disease progression. In some cases, tissue biopsies carry an unacceptable risk of mortality to the patient. Furthermore, assessing fibrosis via tissue biopsy is severely limited by the heterogenetic nature of fibrotic diseases and suffers from both sampling bias and observer variation/bias. The search for less invasive methods of diagnosing and monitoring fibrosis has led to the identification of many new biomarkers, many of which can be measured in serum in a so-called ‘liquid biopsy’ or can be imaged using state-of-the-art imaging modalities. These approaches have the potential to dramatically improve the diagnosis and monitoring of disease, and improve the design of clinical trials in to novel fibrotic therapies. This review summarises some of the recent advances in identifying novel biomarkers to diagnose and monitor fibrosis non-invasively.

2

The gut microbiome facilitates a consistent transfer of information between the gut and the brain and microRNAs may now represent a key signalling molecule that facilitates this relationship. This review will firstly examine how these small non-coding RNAs influence the gut microbiome, and secondly how the microbiome, when disturbed, may influence miRNA expression in the brain. In addition, we will examine the consequence that microbiome-related changes in miRNA expression have on neurodevelopment, behaviour and cognition. We will also discuss novel data that suggests miRNAs contained in our diet may influence our immune system in a positive manner, offering a further potential pathway for treatment of disorders of the gut-brain axis that are influenced by the microbiome.