Nitric oxide as a regulator of inflammatory processes

Nitric oxide (NO) plays an important role in mediating many aspects of inflammatory responses. NO is an effector molecule of cellular injury, and can act as an anti-oxidant. It can modulate the release of various inflammatory mediators from a wide range of cells participating in inflammatory responses (e.g., leukocytes, macrophages, mast cells, endothelial cells, and platelets). It can modulate blood flow, adhesion of leukocytes to the vascular endothelium and the activity of numerous enzymes, all of which can have an impact on inflammatory responses. In recent years, NO-releasing drugs have been developed, usually as derivatives of other drugs, which exhibit very powerful anti-inflammatory effects.     

Nitric oxide is an activity-dependent regulator of target neuron intrinsic excitability

Activity-dependent changes in synaptic strength are well established as mediating long-term plasticity underlying learning and memory, but modulation of?target neuron excitability could complement changes in synaptic strength and regulate network activity. It is thought that homeostatic mechanisms match intrinsic excitability to the incoming synaptic drive, but evidence for involvement of voltage-gated conductances is sparse. Here, we show that glutamatergic synaptic activity modulates target neuron excitability and switches the basis of action potential repolarization from Kv3 to Kv2 potassium channel dominance, thereby adjusting neuronal signaling between low and high activity states, respectively. This nitric oxide-mediated signaling dramatically increases Kv2 currents in both the auditory brain stem and hippocampus (>3-fold) transforming synaptic integration and information transmission but with only modest changes in action potential waveform. We conclude that nitric oxide is a homeostatic regulator, tuning neuronal excitability to the recent history of excitatory synaptic inputs over intervals of minutes to hours.     

Nitric oxide and cell death in liver cancer cells

Nitric oxide (NO) is a lipophillic, highly diffusible, and short-lived physiological messenger which regulates a variety of physiopathological responses. NO may exert its cellular action through cGMP-dependent and cGMP-independent pathways which includes different postranslational modifications. The effect of NO in cancer depends on the activity and localization of NOS isoforms, concentration and duration of NO exposure, cellular sensitivity, and hypoxia/re-oxygenation process. NO regulates critical factors such as the hypoxia inducible factor-1 (HIF-1) and p53 generally leading to growth arrest, apoptosis or adaptation. NO sensitizes hepatoma cells to chemotherapeutic compounds probably through increased p53 and cell death receptor expressions.     

Nitric oxide: a key regulator of myeloid inflammatory cell apoptosis

Apoptosis of inflammatory cells is a critical event in the resolution of inflammation, as failure to undergo this form of cell death leads to increased tissue damage and exacerbation of the inflammatory response. Many factors are able to influence the rate of apoptosis in neutrophils, eosinophils, monocytes and macrophages. Among these is the signalling molecule nitric oxide (NO), which possesses both anti- and proapoptotic properties, depending on the concentration and flux of NO, and also the source from which NO is derived. This review summarises the differential effects of NO on inflammatory cell apoptosis and outlines potential mechanisms that have been proposed to explain such actions.     

Nitric oxide: a regulator of eukaryotic initiation factor 2 kinases

Generation of nitric oxide (NO^?) can upstream induce and downstream mediate the kinases that phosphorylate the α subunit of eukaryotic initiation factor 2 (eIF2α), which plays a critical role in regulating gene expression. There are four known eIF2α kinases (EIF2AKs), and NO^? affects each one uniquely. Whereas NO^? directly activates EIF2AK1 (HRI), it indirectly activates EIF2AK3 (PERK). EIF2AK4 (GCN2) is activated by depletion of l-arginine, which is used by nitric oxide synthase (NOS) during the production of NO^?. Finally EIF2AK2 (PKR), which can mediate inducible NOS expression and therefore NO^? production, can also be activated by NO^?. The production of NO^? and activation of EIF2AKs coordinately regulate physiological and pathological events such as innate immune response and cell apoptosis.     

HOOKLESS1 is a positive regulator in Arabidopsis thermomorphogenesis

<正>Dear Editor,With the inevitable trend of global warming, it is urgent to understand how plants sense and respond to temperature increases for designing new crop varieties that can tolerate high ambient temperature. In Arabidopsis thaliana, high ambient temperature promotes hypocotyl elongation in seedlings and stimulates petiole elongation and hyponasty in rosette leaves. These changes in architecture are collectively     

Nitric oxide as a regulator of neuronal motility and regeneration in the locust embryo

Nitric oxide (NO) is known as a gaseous messenger in the nervous system. It plays a role in synaptic plasticity, but also in development and regeneration of nervous systems. We have studied the function of NO and its signaling cascade via cyclic GMP in the locust embryo. Its developing nervous system is well suited for pharmacological manipulations in tissue culture. The components of this signaling pathway are localized by histochemical and immunofluorescence techniques. We have analyzed cellular mechanisms of NO action in three examples: 1. in the peripheral nervous system during antennal pioneer axon outgrowth, 2. in the enteric nervous system during migration of neurons forming the midgut nerve plexus, and 3. in the central nervous system during axonal regeneration of serotonergic neurons after axotomy. In each case, internally released NO or NO-induced cGMP synthesis act as permissive signals for the developmental process. Carbon monoxide (CO), as a second gaseous messenger, modulates enteric neuron migration antagonistic to NO.     

Nitric oxide as the regulator of intracellular homeostasis in the uterus myocytes

The published data on the mechanisms and regulation of active and passive Ca2+ transport in the myometrium have been analyzed. Particular attention is paid to the cGMP-dependent and independent pathways of action of nitric oxide or its derivatives on intracellular Ca2+ homeostasis of uterine smooth muscle and its contractile activity. Information on the effect of nitric oxide on Ca2+ -transport systems of other types of smooth muscles is provided in a comparative aspect. Based on own experimental results and literature data a scheme of NO action in the myometrium is suggested in which nitric oxide or its derivatives cause Ca2+ -dependent polarization of the sarcolemma. In accordance with our results, this effect may be based on the increase of sarcolemma Ca2+ permeability under the influence of NO or its derivatives and the stimulation of at least the initial passive transport of the cation in the myocytes mediated by dihydropyridine-sensitive channels. Additional factors that contribute to the polarization of the membrane are the increase of protons transport from the muscle cells and stimulation of Na+, K+ -ATPase. Acting on the sarcoplasmic reticulum, nitrosactive compounds activate the inclusion of calcium in this compartment and inhibit Ca2+ -induced release of the cation. The latter effects are able to provide compensation for NO-induced Ca2+ increase in myocytes and supress the electromechanical coupling at Ca2+ release from the reticulum. NO-derivates also inhibit a key link in the smooth muscle contractile act--the formation of the Ca2+ -calmodulin complex.     

Mcl-1 is a key regulator of the ovarian reserve

A majority of ovarian follicles are lost to natural death, but the disruption of factors involved in maintenance of the oocyte pool results in a further untimely follicular depletion known as premature ovarian failure. The anti-apoptotic B-cell lymphoma 2 (Bcl-2) family member myeloid cell leukemia-1 (MCL-1) has a pro-survival role in various cell types; however, its contribution to oocyte survival is unconfirmed. We present a phenotypic characterization of oocytes deficient in Mcl-1, and establish its role in maintenance of the primordial follicle (PMF) pool, growing oocyte survival and oocyte quality. Mcl-1 depletion resulted in the premature exhaustion of the ovarian reserve, characterized by early PMF loss because of activation of apoptosis. The increasingly diminished surviving cohort of growing oocytes displayed elevated markers of autophagy and mitochondrial dysfunction. Mcl-1-deficient ovulated oocytes demonstrated an increased susceptibility to cellular fragmentation with activation of the apoptotic cascade. Concomitant deletion of the pro-apoptotic Bcl-2 member Bcl-2-associated X protein (Bax) rescued the PMF phenotype and ovulated oocyte death, but did not prevent the mitochondrial dysfunction associated with Mcl-1 deficiency and could not rescue long-term breeding performance. We thus recognize MCL-1 as the essential survival factor required for conservation of the postnatal PMF pool, growing follicle survival and effective oocyte mitochondrial function.Estimates of the human primordial follicle (PMF) reservoir, the size of which dictates the extent of the ovarian reserve, indicates the presence of at least half a million oocytes per ovary at birth.^{1, 2} The essential decision that PMFs face is either long-term arrest with a possibility of recruitment toward the growing pool, or death. Even upon recruitment to the growing pool, intricately orchestrated crosstalk of survival signals between ovarian somatic cells and oocytes facilitate the ovulation of a single oocyte in human in each cycle. Hence, the default fate for millions of ovarian germ cells is death, as only a small fraction survive till ovulation.³ Insufficient endowment during fetal development or excessive oocyte loss during postnatal life further limits the ovarian reserve and can result in an untimely exhaustion of the follicle pool leading to premature ovarian failure (POF); a syndrome that affects around 1% of all women, with a higher prevalence (up to 30%) in families with heritable traits of this condition.^{4, 5} Mechanisms responsible for maintenance of the follicular reserve are poorly understood, however, biological assessments and mathematical modeling reveal that progressive loss of follicles with age is non-linear and accelerates, especially after 38 years.^{6, 7} With a declining ovarian reserve, poor oocyte quality is an additional factor that contributes to the reduced fertility associated with increased maternal age. Oocytes and resulting embryos of older mothers have increased rates of aneuploidies likely due to defects in chromosomal cohesion and meiotic spindle stability, decreased DNA repair capacity, altered gene expression, impaired mitochondrial function and elevated cellular redox, all contributing to increased rates of cell death.^{8, 9, 10}The marked decline of oocyte number in mammalian ovaries has been attributed to oocyte loss via stage-specific modes of death. As yet, perinatal PMF loss in mice most frequently engages apoptotic cell death,^{11, 12} whereas within the postnatal ovary, oocytes in growing follicles undergo atresia, a less ''molecularly'' defined death, carrying hallmarks of both apoptosis and autophagy.^{13, 14, 15} It is thus surprising that no member of the anti-apoptotic B-cell lymphoma 2 (Bcl-2) family has been identified with a definitive role in governing oocyte survival and the maintenance of the ovarian reserve. Bcl-2l2/Bcl-w and Bcl-2-l10/Diva deficiency had no apparent impact on the ovarian reserve, and although ablation of Bcl-2 led to a loss of one-third of the adult PMF pool, the growing follicle pool was not significantly impacted and these animals did not undergo POF.^{16, 17, 18, 19} Conditional Bcl-x (Bcl-2l1) inactivation led to increased primordial germ cell apoptosis in the embryo,²⁰ but postnatal inactivation of Bcl-x in oocytes did not compromise the ovarian reserve in young females.²¹ Bcl2a1a/Bfl-1/A1 was low to undetectable in fully grown germinal vesicle (GV) or ovulated murine oocytes,²² however, the impact of Bfl-1 deficiency on the ovarian reserve has not yet been analyzed to the best of our knowledge. Consequently, either various anti-apoptotic Bcl-2 members have overlapping roles in governing postnatal oocyte survival and maintenance of the adult ovarian reserve in mice, or the anti-apoptotic Bcl-2 member that regulates this decision has yet to be identified.     

RANKL-induced schlafen2 is a positive regulator of osteoclastogenesis

Osteoclasts are hematopoietic lineage derived-multinucleated cells that resorb bone. Their activity in balance with that of osteoblast is essential for bone homeostasis. Receptor activator of NF-κB ligand (RANKL) is known as an essential cytokine for the osteoclastogenesis, and c-Jun signaling in cooperation with NFAT family is crucial for RANKL-regulated osteoclastogenesis. We show here that schlafen2 (Slfn2), a member of a new family of growth regulatory genes involved in thymocyte development, is critical for osteoclastogenesis. RANKL selectively induces Slfn2 expression in osteoclast precursors via Rac1 signaling pathway. Targeted inhibition of Slfn2 by small interfering RNAs (siRNAs) markedly inhibits the formation of osteoclasts by diminishing the activation of c-Jun and the expression of c-Jun and NFATc1. In contrast, the overexpression of Slfn2 markedly increased phosphorylation and transactivation of c-Jun by RANKL. Together, these results indicate that Slfn2 has an essential role in osteoclastogenesis, functioning upstream of c-Jun and NFATc1.     

New aspects of the Warburg effect in cancer cell biology

Altered cellular metabolism is a defining feature of cancer [1]. The best studied metabolic phenotype of cancer is aerobic glycolysis--also known as the Warburg effect--characterized by increased metabolism of glucose to lactate in the presence of sufficient oxygen. Interest in the Warburg effect has escalated in recent years due to the proven utility of FDG-PET for imaging tumors in cancer patients and growing evidence that mutations in oncogenes and tumor suppressor genes directly impact metabolism. The goals of this review are to provide an organized snapshot of the current understanding of regulatory mechanisms important for Warburg effect and its role in tumor biology. Since several reviews have covered aspects of this topic in recent years, we focus on newest contributions to the field and reference other reviews where appropriate.