Inflammatory pain, such as arthritis pain, is a growing health problem 1 . Inflammatory pain is generally treated with opioids and cyclooxygenase (COX) inhibitors, but both are limited by side effects. Recently, resolvins, a novel family of lipid mediators including RvE1 and RvD1 derived from omega-3 polyunsaturated fatty acid, show remarkable potency in treating disease conditions associated with inflammation 2, 3 . Here we report that peripheral (intraplantar) or spinal (intrathecal) administration of RvE1 or RvD1 (0.3-20 ng) potently reduces inflammatory pain behaviors in mice induced by intraplantar injection of formalin, carrageenan or complete Freund's adjuvant, without affecting basal pain perception. Intrathecal RvE1 also inhibits spontaneous pain and heat and mechanical hypersensitivity evoked by intrathecal capsaicin and TNF-α. RvE1 plays anti-inflammatory roles via reducing neutrophil infiltration, paw edema, and proinflammatory cytokine expression. RvE1 also abolishes TRPV1-and TNF-α-induced excitatory postsynaptic current increase and TNF-α-evoked NMDA receptor hyperactivity in spinal dorsal horn neurons, via inhibition of ERK signaling pathway. Thus, we demonstrate a novel role of resolvins in normalizing spinal synaptic plasticity that has been implicated in generating pain hypersensitivity. Given the remarkable potency of resolvins and well known side effects of opioids and COX inhibitors, resolvins may represent novel analgesics for treating inflammatory pain.Resolution of acute inflammation, once thought to be a passive process, is now shown to involve active biochemical programs that enable inflamed tissues to return to homeostasis 2 . The actions of pro-resolution mediators are in sharp contrast to those of currently used antiinflammatory therapeutics. For example, inhibitors of COX and lipoxygenases disrupt resolution, because these enzymes are also required for the biosynthesis of pro-resolution mediators [4][5][6] . Resolvins, such as RvD1 and RvE1, are biosynthesized from omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), respectively, and show remarkable potency in resolving inflammation-related diseases such as periodontal diseases, asthma, and retinopathy 2, 3, 7 . Peripheral and central mechanisms of inflammatory pain are not fully understood [8][9][10][11] . Here, we examined whether peripheral and central resolvins can attenuate inflammatory pain, and further investigated how resolvins regulate synaptic plasticity in spinal cord dorsal horn neurons that has been strongly implicated in the generation of persistent pain 10, 11 .First, we examined the actions of RvE1 in an acute inflammatory pain condition induced by intraplantar injection of formalin. Formalin induced characteristic two-phase spontaneous pain behavior, and the second phase is likely mediated by spinal cord mechanisms 12, 13 . We delivered synthetic resolvins to the mouse spinal cord via intrathecal (i.t.) route using lumbar puncture 14,15 . Preemptive injection of RvE1 at very low ...
Copper is an essential element that becomes highly cytotoxic when concentrations exceed the capacity of cells to sequester the ion. Here, we identify a new copper-specific repressor (CsoR) of a copper-sensitive operon (cso) in Mycobacterium tuberculosis (Mtb) that is representative of a large, previously uncharacterized family of proteins (DUF156). Electronic and X-ray absorption spectroscopies reveal that CsoR binds a single-monomer mole equivalent of Cu(I) to form a trigonally coordinated (S(2)N) Cu(I) complex. The 2.6-A crystal structure of copper-loaded CsoR shows a homodimeric antiparallel four-helix bundle architecture that represents a novel DNA-binding fold. The Cu(I) is coordinated by Cys36, Cys65' and His61' in a subunit bridging site. Cu(I) binding negatively regulates the binding of CsoR to a DNA fragment encompassing the operator-promoter region of the Mtb cso operon; this results in derepression of the operon in Mtb and the heterologous host Mycobacterium smegmatis. Substitution of Cys36 or His61 with alanine abolishes Cu(I)- and CsoR-dependent regulation in vivo and in vitro. Potential roles of CsoR in Mtb pathogenesis are discussed.
Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid reactive oxygen species (ROS). Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. In this work, we show that the import of oxidized cysteine (cystine) via system xC– is a critical dependency of pancreatic ductal adenocarcinoma (PDAC), which is a leading cause of cancer mortality. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, down-regulated ferroptosis. Studying genetically engineered mice, we found that the deletion of a system xC– subunit, Slc7a11, induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.
Summary G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors1 that instigate signaling through nucleotide exchange on heterotrimeric G proteins. Nucleotide exchange, or more precisely GDP dissociation from the G protein α-subunit, is the key step toward G protein activation and initiation of downstream signaling cascades. Despite a wealth of biochemical and biophysical studies on inactive and active conformations of several heterotrimeric G proteins, the molecular underpinnings of G protein activation remain elusive. To characterize this mechanism we applied peptide amide hydrogen-deuterium exchange mass spectrometry (DXMS) to probe changes in the structure of the heterotrimeric G protein Gs (the stimulatory G protein for adenylyl cyclase) upon formation of a complex with agonist-bound β2 adrenergic receptor (β2AR). Our studies reveal structural links between the receptor binding surface and the nucleotide-binding pocket of Gs that undergo higher levels of hydrogen-deuterium exchange (HX) than would be predicted from the crystal structure of the β2AR-Gs complex. Together with x-ray crystallographic and electron microscopic data of the β2AR-Gs complex (ref 2 and Westfield et al, manuscript submitted), we provide a rationale for a mechanism of nucleotide exchange whereby the receptor perturbs the structure of the amino-terminal region of α-subunit of Gs and consequently alters the ‘P-loop’ that binds the β-phosphate in GDP. As with the ras-family of small molecular weight G proteins, P-loop stabilization and β-phosphate coordination are key determinants of GDP (and GTP) binding affinity.
Thioredoxin 1 (Trx1) facilitates the reduction of signaling molecules and transcription factors by cysteine thiol-disulfide exchange, thereby regulating cell growth and death. Here we studied the molecular mechanism by which Trx1 attenuates cardiac hypertrophy. Trx1 upregulates DnaJb5, a heat shock protein 40, and forms a multiple-protein complex with DnaJb5 and class II histone deacetylases (HDACs), master negative regulators of cardiac hypertrophy. Both Cys-274/Cys-276 in DnaJb5 and Cys-667/Cys-669 in HDAC4 are oxidized and form intramolecular disulfide bonds in response to reactive oxygen species (ROS)-generating hypertrophic stimuli, such as phenylephrine, whereas they are reduced by Trx1. Whereas reduction of Cys-274/Cys-276 in DnaJb5 is essential for interaction between DnaJb5 and HDAC4, reduction of Cys-667/Cys-669 in HDAC4 inhibits its nuclear export, independently of its phosphorylation status. Our study reveals a novel regulatory mechanism of cardiac hypertrophy through which the nucleocytoplasmic shuttling of class II HDACs is modulated by their redox modification in a Trx1-sensitive manner.
Neutrino-cooled hyperaccretion disks around stellar mass black holes are plausible candidates for the central engine of gamma-ray bursts. We calculate the one-dimensional structure and the annihilation luminosity of such disks. The neutrino optical depth is of crucial importance in determining the neutrino cooling rate and is in turn dependent on the electron fraction, the free nucleon fraction, and the electron degeneracy, with given density and temperature of the disk matter. We construct a bridging formula for the electron fraction that works for various neutrino optical depths, and give exact definitions for the free proton fraction and free neutron fraction. We show that the electron degeneracy has important effects in the sense that it enlarges the absorption optical depth for neutrinos, and it along with the neutronization processes favored by high temperature cause the electron fraction to drop to be below 0.1 in the inner region of the disk. The resulting neutrino annihilation luminosity is considerably reduced comparing with that obtained in previous works where the electron degeneracy was not considered and the electron fraction was simply taken to be 0.5, but it is still likely to be adequate for gamma-ray bursts, and it is ejected mainly from the inner region of the disk and has an anisotropic distribution.
Toll-like receptors (TLRs) are germline-encoded pattern-recognition receptors (PRRs) to initiate innate immune responses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associated molecular patterns (PAMPs). After tissue injury or cellular stress, TLRs can also detect endogenous ligands known as danger-associated molecular patterns (DAMPs). TLRs are expressed in various cell types in the central nervous system (CNS), including non-neuronal and neuronal cells, and contribute to both infectious and non-infectious disorders in the CNS. Following tissue insult and nerve injury, TLRs (such as TLR2, 3, and 4) induce the activation of microglia and astrocytes and the production of the proinflammatory cytokines in the spinal cord, leading to the development and maintenance of inflammatory pain and neuropathic pain. In particular, primary sensory neurons, such as nociceptors express TLRs (e.g., TLR4 and TLR7) to sense exogenous PAMPs and endogenous DAMPs released after tissue injury and cellular stress. These neuronal TLRs are new players in the processing of pain and itch by increasing the excitability of primary sensory neurons. Given the prevalence of chronic pain and itch and the suffering of the affected people, insights into TLR signaling in nervous system will open a new avenue for the management of clinical pain and itch.
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