It has long been understood that many of the same manipulations that increase longevity in Caenorhabditis elegans also increase resistance to various acute stressors, and vice-versa; moreover these findings hold in more complex organisms as well. Nevertheless, the mechanistic relationship between these phenotypes remains unclear, and in many cases the overlap between stress resistance and longevity is inexact. Here we review the known connections between stress resistance and longevity, discuss instances in which these connections are absent, and summarize the theoretical explanations that have been posited for these phenomena. deletions in Caenorhabditis elegans alter the localization of intracellular reactive oxygen species and show molecular compensation. J Gerontol A Biol Sci Med Sci. 2009; 64:530-539. 30. McCord JM, Fridovich I. Superoxide dismutase. an enzymic function for erythrocuprein (hemocuprein). J Biol Chem. 1969; 244:6049-6055. 31. Walker TK, Tosic J. The ;catalase test', with special reference to acetobacter species. Biochem J. 1943; 37:10-12. 32. Mills GC. The purification and properties of glutathione peroxidase of erythrocytes. J Biol Chem. 1959; 234:502-506. 33. Brenot A, King KY, Janowiak B, Griffith O, Caparon MG. Contribution of glutathione peroxidase to the virulence of streptococcus pyogenes. Infect Immun. 2004; 72:408-413. 34. Larsen PL. Aging and resistance to oxidative damage in. A redox-sensitive peroxiredoxin that is important for longevity has tissue-and stress-specific roles in stress resistance.

In mammals, specific lipids and amino acids serve as crucial signaling molecules. In bacteria, conjugates of lipids and amino acids (referred to as lipoamino acids) have been identified and found to possess biological activity. Here, we report that mammals also produce lipoamino acids, specifically the arachidonyl amino acids. We show that the conjugate of arachidonic acid and glycine (N-arachidonylglycine (NAGly)) is present in bovine and rat brain as well as other tissues and that it suppresses tonic inflammatory pain. The biosynthesis of NAGly and its degradation by the enzyme fatty acid amide hydrolase can be observed in rat brain tissue. In addition to NAGly, bovine brain produces at least two other arachidonyl amino acids: N-arachidonyl ␥-aminobutyric acid (NAGABA) and N-arachidonylalanine. Like NAGly, NAGABA inhibits pain. These findings open the door to the identification of other members of this new class of biomolecules, which may be integral to pain regulation and a variety of functions in mammals.Molecules found in bacteria that consist of a lipid moiety conjugated to an amino acid have been termed lipoamino acids (1-3). Burstein et al. (4) found that the lipoamino acid Narachidonylglycine (NAGly) 1 causes hot plate analgesia in mice, indicating its possible biological relevance in mammals. NAGly was first synthesized (5) as a structural analog of the endogenous cannabinoid anandamide (6), and it was found to lack affinity for the cannabinoid CB1 receptor. We hypothesized that NAGly may be produced by mammalian tissues because it is composed of the naturally occurring compounds glycine and arachidonic acid. Herein we show that at least three arachidonyl amino acids are natural constituents in mammalian brain: NAGly, N-arachidonyl ␥-aminobutyric acid (NAGABA), and N-arachidonylalanine (NAAla). One member of this group, NAGly, is characterized in detail here. It is synthesized in situ in rat brain tissue from the precursors arachidonic acid and glycine, and it is hydrolyzed by the enzyme fatty acid amide hydrolase (FAAH). NAGly is widely distributed among mammalian tissues, implying multiple functions. One possible physiological function of NAGly is pain suppression, indicated by its marked suppression of formalininduced pain behavior in rats, confirming a previous report of analgesic activity in mice (4). EXPERIMENTAL PROCEDURESTissue Extraction and Purification-The procedure comprised a liquidliquid extraction modified from that described by Folch et al. (7) followed by a series of solid-phase separations. Fresh bovine brain and rat organs were homogenized in the methanol fraction of 20 volumes of 2:1 chloroform:methanol and centrifuged for 15 min at 31,000 ϫ g at 4°C. Chloroform was then added to the supernatant. NaCl (0.2 volume, 0.73%) was mixed with the crude homogenate, and the solution was allowed to separate overnight at 4°C or centrifuged at 1,000 ϫ g for 15 min. The upper phase was discarded and the interphase washed twice. The lower phase was then applied to diethylaminopropyl silica-based...

N-Arachidonoyldopamine (NADA) was recently identified as an endogenous ligand for the vanilloid type 1 receptor (VR1). Further analysis of the bovine striatal extract from which NADA was isolated indicated the existence of substances corresponding in molecular mass to N-oleoyldopamine (OLDA), N-palmitoyldopamine (PALDA), and N-stearoyldopamine (STEARDA). Quadrupole time-of-flight mass spectrometric analysis of bovine striatal extracts revealed the existence of OLDA, PALDA, and STEARDA as endogenous compounds in the mammalian brain. PALDA and STEARDA failed to affect calcium influx in VR1-transfected human embryonic kidney (HEK) 293 cells or paw withdrawal latencies from a radiant heat source, and there was no evidence of spontaneous pain behavior. By contrast, OLDA induced calcium influx (EC 50 ‫؍‬ 36 nM), reduced the latency of paw withdrawal from a radiant heat source in a dose-dependent manner (EC 50 ‫؍‬ 0.72 g), and produced nocifensive behavior. These effects were blocked by co-administration of the VR1 antagonist iodo-resiniferatoxin (10 nM for HEK cells and 1 g/50 l for pain behavior). These findings demonstrate the existence of an endogenous compound in the brain that is similar to capsaicin and NADA in its chemical structure and activity on VR1. Unlike NADA, OLDA was only a weak ligand for rat CB1 receptors; but like NADA, it was recognized by the anandamide membrane transporter while being a poor substrate for fatty-acid amide hydrolase. Analysis of the activity of six additional synthetic and potentially endogenous N-acyldopamine indicated the requirement of a long unsaturated fatty acid chain for an optimal functional interaction with VR1 receptors.We recently identified N-arachidonoyldopamine (NADA) 1 as an endogenous compound that possesses nanomolar potency for vanilloid type 1 (VR1) and cannabinoid CB1 receptors (1-3). Following injection into skin, NADA produces VR1-mediated thermal hyperalgesia, with an EC 50 of 1.5 g. Previous studies indicated that anandamide and the lipoxygenase product 12(S)-hydroperoxyeicosatetraenoic acid also possess affinity for VR1 (4, 5). However, whereas NADA is similar in potency to capsaicin in a variety of assays of VR1 activity, anandamide and 12(S)-hydroperoxyeicosatetraenoic acid are at least 20-fold less potent than capsaicin (4).All of the putative endovanilloids identified to date are products of arachidonic acid, an unsaturated long chain fatty acid with a primary role in inflammation and pain. Research on the structure-activity relationship for VR1 has shown that a vanillylamine moiety and a long unsaturated acyl chain are required for optimal interaction with the receptor (6, 7). Although anandamide and lipoxygenase products contain the long unsaturated acyl chain, they lack the vanillyl group, which probably accounts for their decreased affinity for and efficacy on VR1 compared with NADA. Because dopamine is a naturally occurring aromatic amine structurally similar to vanillylamine, it was hypothesized that certain unsaturated N-acyldopamines may exist i...

The potent bioactive sphingolipid mediator, sphingosine-1-phosphate (S1P), is produced by 2 sphingosine kinase isoenzymes, SphK1 and SphK2. Expression of SphK1 is up-regulated in cancers, including leukemia, and associated with cancer progression. A screen of sphingosine analogs identified (2R,3S,4E)-N-methyl-5-(4-pentylphenyl)-2-aminopent-4-ene-1,3-diol, designated SK1-I (BML-258), as a potent, water-soluble, isoenzymespecific inhibitor of SphK1. In contrast to pan-SphK inhibitors, SK1-I did not inhibit SphK2, PKC, or numerous other protein kinases. SK1-I decreased growth and survival of human leukemia U937 and Jurkat cells, and enhanced apoptosis and cleavage of Bcl-2. Lethality of SK1-I was reversed by caspase inhibitors and by expression of Bcl-2. SK1-I not only decreased S1P levels but concomitantly increased levels of its proapoptotic precursor ceramide. Conversely, S1P protected against SK1-I-induced apoptosis. SK1-I also induced multiple perturbations in activation of signaling and survival-related proteins, including diminished phosphorylation of ERK1/2 and IntroductionSphingosine-1-phosphate (S1P), a potent lipid mediator produced from sphingosine by sphingosine kinases (SphKs), regulates many processes important for cancer progression, including cell growth and survival. 1 In contrast to S1P, its precursors, sphingosine and ceramide, are associated with growth arrest and induction of apoptosis. 2 Thus, the balance between these interconvertible sphingolipid metabolites has been viewed as a cellular rheostat determining cell fate. 3 Numerous studies have shown that perturbations in the S1P/ceramide rheostat are involved in the regulation of resistance to chemotherapy and radiation therapy of neoplastic cells, including those of hematopoietic origin. 2,4,5 Two SphK isoenzymes, SphK1 and SphK2, have been described that, although sharing many features, 6,7 exhibit distinct functions. SphK1 promotes cell growth and survival, [8][9][10][11] whereas SphK2, when overexpressed, has opposite effects. 12,13 SphK1 is a key enzyme that regulates the S1P/ceramide rheostat. 12,14,15 Indeed, S1P and SphK1 have long been implicated in resistance of both primary leukemic cells and leukemia cell lines to apoptosis induced by commonly used cytotoxic agents. 3,[16][17][18] Non-isoenzyme-specific inhibitors of SphKs, such as L-threo-dihydrosphingosine (safingol) and N,N-dimethylsphingosine (DMS), are cytotoxic to leukemia cells. 18,19 Interestingly, multidrugresistant HL-60 myelogenous leukemia cells were more sensitive to DMS than the parental cells. 18 Moreover, SphK1 activity was lower in HL-60 cells sensitive to doxorubicin or etoposide than in MDR (multidrug resistance protein)-1-or MRP1 (multidrug resistance protein 1)-positive HL-60 cells. Enforced expression of SphK1 in sensitive HL-60 cells blocked apoptosis, whereas down-regulation of SphK1 overcame chemoresistance by inducing mitochondria-dependent apoptosis. 10 These observations take on added significance in light of evidence that MDR expression is a strong p...

Sphingosine-1-phosphate is a potent sphingolipid mediator of diverse processes important for brain tumors, including cell growth, survival, migration, invasion, and angiogenesis. Sphingosine kinase 1 (SphK1