Decrease of miR-146b-5p in Monocytes during Obesity Is Associated with Loss of the Anti-Inflammatory but Not Insulin Signaling Action of Adiponectin

Background: Low adiponectin, a well-recognized antidiabetic adipokine, has been associated with obesity-related inflammation, oxidative stress and insulin resistance. Globular adiponectin is an important regulator of the interleukin-1 receptor-associated kinase (IRAK)/NFkB pathway in monocytes of obese subjects. It protects against inflammation and oxidative stress by inducing IRAK3. microRNA (miR)-146b-5p inhibits NFkB-mediated inflammation by targeted repression of IRAK1 and TNF receptor-associated factor-6 (TRAF6). Therefore, we measured the expression of miR-146b-5p in monocytes of obese subjects. Because it was low we determined the involvement of this miR in the anti-inflammatory, antioxidative and insulin signaling action of globular adiponectin. Methods: miR-146b-5p expression in monocytes of obese subjects was determined by qRT-PCR. The effect of miR-146b-5p silencing on molecular markers of inflammation, oxidative stress and insulin signaling and the association with globular adiponectin was assessed in human THP-1 monocytes. Results: miR-146b-5p was downregulated in monocytes of obese persons. Low globular adiponectin decreased miR-146b-5p and IRAK3 in THP-1 monocytes, associated with increased mitochondrial reactive oxygen species (ROS). Intracellular ROS and insulin receptor substrate-1 (IRS1) protein were unchanged. Silencing of miR-146b-5p with an antisense inhibitor resulted in increased expression of IRAK1 and TRAF6 leading to more NFkB p65 DNA binding activity and TNFa. As

Neuropathic Pain Phenotype Does Not Involve the NLRP3 Inflammasome and Its End Product Interleukin-1β in the Mice Spared Nerve Injury Model.

The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is one of the main sources of interleukin-1β (IL-1β) and is involved in several inflammatory-related pathologies. To date, its relationship with pain has not been studied in depth. The aim of our study was to elucidate the role of NLRP3 inflammasome and IL-1β production on neuropathic pain. Results showed that basal pain sensitivity is unaltered in NLRP3-/- mice as well as responses to formalin test. Spared nerve injury (SNI) surgery induced the development of mechanical allodynia and thermal hyperalgesia in a similar way in both genotypes and did not modify mRNA levels of the NLRP3 inflammasome components in the spinal cord. Intrathecal lipopolysaccharide (LPS) injection increases apoptosis-associated speck like protein (ASC), caspase-1 and IL-1β expression in both wildtype and NLRP3-/- mice. Those data suggest that NLRP3 is not involved in neuropathic pain and also that other sources of IL-1β are implicated in neuroinflammatory responses induced by LPS

Monoaminergic and histaminergic strategies and treatments in brain diseases

The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson's disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable strategies for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity), the identification of monoamines in the diseases processes (Parkinson's disease, addiction) and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer's disease, stroke). In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review.peer-reviewe

A single migrant enhances the genetic diversity of an inbred puma population

Migration is essential for maintaining genetic diversity among populations, and pumas (Puma concolor) provide an excellent model for studying the genetic impacts of migrants on populations isolated by increasing human development. In densely populated southern California, USA, puma populations on the east and west side of interstate highway 15 (I-15) have become fragmented into a small inbred population on the west side (Santa Ana Mountains) and a relatively larger, more diverse population on the east side (Eastern Peninsular Range). From 146 sampled pumas, genetic analyses indicate seven pumas crossed I-15 over the last 15 years, including four males from west to east, and three males from east to west. However, only a single migrant (named M86) was detected to have produced offspring and contribute to gene flow across the I-15 barrier. Prior to the M86 migration, the Santa Ana population exhibited inbreeding and had significantly lower genetic diversity than the Eastern Peninsular Range population. After M86 emigrated, he sired 11 offspring with Santa Ana females, decreasing inbreeding measures and raising heterozygosity to levels similar to pumas in the Eastern Peninsular Range. The emigration of M86 also introduced new alleles into the Santa Ana population, although allelic richness still remained significantly lower than the Eastern Peninsular population. Our results clearly show the benefit of a single migrant to the genetics of a small, isolated population. However, ongoing development and habitat loss on both sides of I-15 will increasingly strengthen the barrier to successful migration. Further monitoring, and potential human intervention, including minimizing development effects on connectivity, adding or improving freeway crossing structures, or animal translocation, may be needed to ensure adequate gene flow and long-term persistence of the Santa Ana puma population

A single migrant enhances the genetic diversity of an inbred puma population.

Migration is essential for maintaining genetic diversity among populations, and pumas (Puma concolor) provide an excellent model for studying the genetic impacts of migrants on populations isolated by increasing human development. In densely populated southern California, USA, puma populations on the east and west side of interstate highway 15 (I-15) have become fragmented into a small inbred population on the west side (Santa Ana Mountains) and a relatively larger, more diverse population on the east side (Eastern Peninsular Range). From 146 sampled pumas, genetic analyses indicate seven pumas crossed I-15 over the last 15 years, including four males from west to east, and three males from east to west. However, only a single migrant (named M86) was detected to have produced offspring and contribute to gene flow across the I-15 barrier. Prior to the M86 migration, the Santa Ana population exhibited inbreeding and had significantly lower genetic diversity than the Eastern Peninsular Range population. After M86 emigrated, he sired 11 offspring with Santa Ana females, decreasing inbreeding measures and raising heterozygosity to levels similar to pumas in the Eastern Peninsular Range. The emigration of M86 also introduced new alleles into the Santa Ana population, although allelic richness still remained significantly lower than the Eastern Peninsular population. Our results clearly show the benefit of a single migrant to the genetics of a small, isolated population. However, ongoing development and habitat loss on both sides of I-15 will increasingly strengthen the barrier to successful migration. Further monitoring, and potential human intervention, including minimizing development effects on connectivity, adding or improving freeway crossing structures, or animal translocation, may be needed to ensure adequate gene flow and long-term persistence of the Santa Ana puma population

Long-term actions of interleukin-1β on delay and tonic firing neurons in rat superficial dorsal horn and their relevance to central sensitization

Background: Cytokines such as interleukin 1β (IL-1β) have been implicated in the development of central sensitization that is characteristic of neuropathic pain. To examine its long-term effect on nociceptive processing, defined medium organotypic cultures of rat spinal cord were exposed to 100 pM IL-1β for 6–8 d. Interleukin effects in the dorsal horn were examined by whole-cell patch-clamp recording and Ca²⁺ imaging techniques. Results Examination of the cultures with confocal Fluo-4 AM imaging showed that IL-1β increased the change in intracellular Ca²⁺ produced by exposure to 35–50 mM K⁺. This is consistent with a modest increase in overall dorsal horn excitability. Despite this, IL-1β did not have a direct effect on rheobase or resting membrane potential nor did it selectively destroy any specific neuronal population. All effects were instead confined to changes in synaptic transmission. A variety of pre- and postsynaptic actions of IL-1β were seen in five different electrophysiologically-defined neuronal phenotypes. In putative excitatory 'delay' neurons, cytokine treatment increased the amplitude of spontaneous EPSC's (sEPSC) and decreased the frequency of spontaneous IPSC's (sIPSC). These effects would be expected to increase dorsal horn excitability and to facilitate the transfer of nociceptive information. However, other actions of IL-1β included disinhibition of putative inhibitory 'tonic' neurons and an increase in the amplitude of sIPSC's in 'delay' neurons. Conclusion Since spinal microglial activation peaks between 3 and 7 days after the initiation of chronic peripheral nerve injury and these cells release IL-1β at this time, our findings define some of the neurophysiological mechanisms whereby nerve-injury induced release of IL-1β may contribute to the central sensitization associated with chronic neuropathic pain.Medicine, Faculty ofNon UBCReviewedFacult

Table S1 from A single migrant enhances the genetic diversity of an inbred puma population

Microsatellite locus-specific details.; Na: number of alleles; Ne: effective number of alleles; I: Shannon index; HO: observed heterozygosity; uHE: unbiased expected heterozygosity; F: fixation index

Long-term actions of interleukin-1β on delay and tonic firing neurons in rat superficial dorsal horn and their relevance to central sensitization

Abstract Background Cytokines such as interleukin 1β (IL-1β) have been implicated in the development of central sensitization that is characteristic of neuropathic pain. To examine its long-term effect on nociceptive processing, defined medium organotypic cultures of rat spinal cord were exposed to 100 pM IL-1β for 6–8 d. Interleukin effects in the dorsal horn were examined by whole-cell patch-clamp recording and Ca2+ imaging techniques. Results Examination of the cultures with confocal Fluo-4 AM imaging showed that IL-1β increased the change in intracellular Ca2+ produced by exposure to 35–50 mM K+. This is consistent with a modest increase in overall dorsal horn excitability. Despite this, IL-1β did not have a direct effect on rheobase or resting membrane potential nor did it selectively destroy any specific neuronal population. All effects were instead confined to changes in synaptic transmission. A variety of pre- and postsynaptic actions of IL-1β were seen in five different electrophysiologically-defined neuronal phenotypes. In putative excitatory 'delay' neurons, cytokine treatment increased the amplitude of spontaneous EPSC's (sEPSC) and decreased the frequency of spontaneous IPSC's (sIPSC). These effects would be expected to increase dorsal horn excitability and to facilitate the transfer of nociceptive information. However, other actions of IL-1β included disinhibition of putative inhibitory 'tonic' neurons and an increase in the amplitude of sIPSC's in 'delay' neurons. Conclusion Since spinal microglial activation peaks between 3 and 7 days after the initiation of chronic peripheral nerve injury and these cells release IL-1β at this time, our findings define some of the neurophysiological mechanisms whereby nerve-injury induced release of IL-1β may contribute to the central sensitization associated with chronic neuropathic pain.</p