administration-9-tetrahydrocannabinol-thc-adolescent-adult

Administration of &#916;<sup>9</sup>-Tetrahydrocannabinol (THC) in Adolescent and Adult Mice

&#916;9-tetrahydrocannabinol (THC) is responsible for the intoxicating (psychotropic) effects of cannabis and cannabis-derived products currently ...

University of California, Irvine

Monoacylglycerol lipase (MGL) is a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Previous efforts to design MGL inhibitors have focused on chemical scaffolds that irreversibly block the activity of this enzyme. Here, we describe two naturally occurring terpenoids, pristimerin and euphol, which inhibit MGL activity with high potency (median effective concentration, IC(50) = 93 nM and 315 nM, respectively) through a reversible mechanism. Mutational and modeling studies suggest that the two agents occupy a common hydrophobic pocket located within the putative lid domain of MGL, and each reversibly interacts with one of two adjacent cysteine residues (Cys(201) and Cys(208)) flanking such pocket. This previously unrecognized regulatory region might offer a molecular target for potent and reversible inhibitors of MGL.

Discovery of potent and reversible monoacylglycerol lipase inhibitors.

&#x51CF;&#x5C11;&#x5927;&#x8111;&#x7684;&#x4E8C;&#x5341;&#x4E8C;&#x78B3;&#x516D;&#x70EF;&#x9178;&#x7684;&#x6C34;&#x5E73; (C22:6n-3)&#xFF0C;&#x795E;&#x7ECF;&#x8425;&#x517B;&#x548C;&#x795E;&#x7ECF;&#x4FDD;&#x62A4;&#x4F5C;&#x7528;&#x7684;&#x8102;&#x80AA;&#x9178;&#xFF0C;&#x53EF;&#x80FD;&#x6709;&#x52A9;&#x4E8E;&#x963F;&#x5C14;&#x8328;&#x6D77;&#x9ED8;&#x75C5;&#x60A3;&#x8005;&#x7684;&#x8BA4;&#x77E5;&#x80FD;&#x529B;&#x8870;&#x9000;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x8C03;&#x67E5;&#x662F;&#x5426;&#x63D0;&#x4F9B;&#x7ED9;&#x5927;&#x8111;&#x7684;&#x4E8C;&#x5341;&#x4E8C;&#x78B3;&#x516D;&#x70EF;&#x9178;&#x7684;&#x809D;&#x9176;&#x7CFB;&#x7EDF;&#x662F;&#x529F;&#x80FD;&#x5931;&#x8C03;&#x6B64;&#x75C5;&#x3002;&#x4E8C;&#x5341;&#x4E8C;&#x78B3;&#x516D;&#x70EF;&#x9178;&#x542B;&#x91CF;&#x964D;&#x4F4E;&#x4E86;&#x989E;&#x76AE;&#x5C42;&#x3001; mid-frontal &#x76AE;&#x8D28;&#x548C;&#x5C0F;&#x8111;&#x7684;&#x8001;&#x5E74;&#x75F4;&#x5446;&#x75C7;&#xFF0C;&#x60A3;&#x8005;&#x76F8;&#x6BD4;&#xFF0C;&#x63A7;&#x5236;&#x79D1;&#x76EE; (P = 0.007)&#x3002;&#x8FF7;&#x4F60;&#x7CBE;&#x795E;&#x72B6;&#x6001;&#x68C0;&#x67E5; (MMSE) &#x5F97;&#x5206;&#x4E0E;&#x989E;&#x76AE;&#x5C42;&#x7684;&#x4E8C;&#x5341;&#x4E8C;&#x78B3;&#x516D;&#x70EF;/&alpha;-&#x4E9A;&#x9EBB;&#x6BD4;&#x7387;&#x6B63;&#x76F8;&#x5173; &#xFF08;P = 0.005) &#x548C; mid-frontal &#x76AE;&#x8D28; &#xFF08;P = 0.018)&#xFF0C;&#x4F46;&#x6CA1;&#x6709;&#x5C0F;&#x8111;&#x3002;&#x540C;&#x6837;&#xFF0C;&#x809D;&#x4E8C;&#x5341;&#x4E8C;&#x78B3;&#x516D;&#x70EF;&#x9178;&#x7684;&#x542B;&#x91CF;&#x662F;&#x963F;&#x5C14;&#x8328;&#x6D77;&#x9ED8;&#x75C5;&#x60A3;&#x8005;&#x4F4E;&#x4E8E;&#x5BF9;&#x7167;&#x7EC4; (P = 0.011)&#x3002;&#x809D;&#x4E8C;&#x5341;&#x4E8C;&#x78B3;&#x516D;&#x70EF;/&alpha;-&#x4E9A;&#x9EBB;&#x6BD4;&#x7387;&#x4E0E; MMSE &#x5F97;&#x5206;&#x79EF;&#x6781;&#x76F8;&#x5173; (r = 0.78 &#xFF1B;P &lt; 0.0001&#xFF09;&#xFF0C;&#x548C;&#x6D88;&#x6781;&#x4E0E;&#x5168;&#x7403;&#x6076;&#x5316;&#x89C4;&#x6A21;&#x7B49;&#x7EA7; (P = 0.013)&#x3002;&#x4E8C;&#x5341;&#x4E8C;&#x78B3;&#x516D;&#x70EF;&#x9178;&#x7684;&#x524D;&#x4F53;&#xFF0C;&#x5305;&#x62EC; tetracosahexaenoic &#x9178; (C24:6n-3)&#xFF0C;&#x88AB;&#x9AD8;&#x67B6;&#x963F;&#x5C14;&#x8328;&#x6D77;&#x9ED8;&#x75C5;&#x60A3;&#x8005;&#x7684;&#x809D;&#x810F; (P = 0.041&#xFF09;&#xFF0C;&#x800C;&#x51CF;&#x5C11;&#x8FC7;&#x6C27;&#x5316;&#x7269;&#x7684; d-&#x53CC;&#x529F;&#x80FD;&#x86CB;&#x767D;&#xFF0C;&#x50AC;&#x5316; tetracosahexaenoic &#x9178;&#x8F6C;&#x5316;&#x4E8C;&#x5341;&#x4E8C;&#x78B3;&#x516D;&#x70EF;&#x9178;&#xFF0C;&#x8868;&#x8FBE; (P = 0.048&#xFF09;&#x3002;&#x5176;&#x4ED6;&#x53C2;&#x4E0E;&#x4E8C;&#x5341;&#x4E8C;&#x78B3;&#x516D;&#x70EF;&#x9178;&#x4EE3;&#x8C22;&#x7684;&#x57FA;&#x56E0;&#x662F;&#x4E0D;&#x53D7;&#x5F71;&#x54CD;&#x3002;&#x7ED3;&#x679C;&#x8868;&#x660E;&#xFF0C;d-&#x53CC;&#x529F;&#x80FD;&#x86CB;&#x767D;&#x6D3B;&#x6027;&#x7684;&#x8D64;&#x5B57;&#x635F;&#x5BB3;&#x809D;&#x810F;&#x7684;&#x963F;&#x5C14;&#x8328;&#x6D77;&#x9ED8;&#x75C5;&#x60A3;&#x8005;&#xFF0C;&#x51CF;&#x8F7B;&#x8FD9;&#x7ED9;&#x5927;&#x8111;&#x7684;&#x795E;&#x7ECF;&#x4FDD;&#x62A4;&#x4F5C;&#x7528;&#x8102;&#x80AA;&#x9178;&#x7684;&#x901A;&#x91CF;&#x4E8C;&#x5341;&#x4E8C;&#x78B3;&#x516D;&#x70EF;&#x9178;&#x7684;&#x751F;&#x7269;&#x5408;&#x6210;&#x3002;

&#x4E8C;&#x5341;&#x4E8C;&#x78B3;&#x516D;&#x70EF;&#x9178;&#x7684;&#x4E0D;&#x8DB3;&#x809D;&#x5408;&#x6210;&#x4E0E;&#x963F;&#x5C14;&#x8328;&#x6D77;&#x9ED8;&#x75C5;&#x60A3;&#x8005;&#x7684;&#x8BA4;&#x77E5;&#x529F;&#x80FD;&#x969C;&#x788D;&#x76F8;&#x5173;&#x3002;

Reduced brain levels of docosahexaenoic acid (C22:6n-3), a neurotrophic and neuroprotective fatty acid, may contribute to cognitive decline in Alzheimer's disease. Here, we investigated whether the liver enzyme system that provides docosahexaenoic acid to the brain is dysfunctional in this disease. Docosahexaenoic acid levels were reduced in temporal cortex, mid-frontal cortex and cerebellum of subjects with Alzheimer's disease, compared to control subjects (P â€Š=â€Š 0.007). Mini Mental State Examination (MMSE) scores positively correlated with docosahexaenoic/Î±-linolenic ratios in temporal cortex (P =â€Š 0.005) and mid-frontal cortex (P â€Š=â€Š 0.018), but not cerebellum. Similarly, liver docosahexaenoic acid content was lower in Alzheimer's disease patients than control subjects (P â€Š=â€Š 0.011). Liver docosahexaenoic/Î±-linolenic ratios correlated positively with MMSE scores (r â€Š=â€Š 0.78; P<0.0001), and negatively with global deterioration scale grades (P â€Š=â€Š 0.013). Docosahexaenoic acid precursors, including tetracosahexaenoic acid (C24:6n-3), were elevated in liver of Alzheimer's disease patients (P â€Š=â€Š 0.041), whereas expression of peroxisomal d-bifunctional protein, which catalyzes the conversion of tetracosahexaenoic acid into docosahexaenoic acid, was reduced (P â€Š= 0.048). Other genes involved in docosahexaenoic acid metabolism were not affected. The results indicate that a deficit in d-bifunctional protein activity impairs docosahexaenoic acid biosynthesis in liver of Alzheimer's disease patients, lessening the flux of this neuroprotective fatty acid to the brain.

Deficient liver biosynthesis of docosahexaenoic acid correlates with cognitive impairment in Alzheimer's disease.

Niveaux r&#xE9;duite du cerveau de l&#x26;#39;acide docosahexa&#xE9;no&#xEF;que (C22: 6n-3), un acide gras neurotrophique et neuroprotecteur, peut contribuer au d&#xE9;clin cognitif dans la maladie d&#x26;#39;Alzheimer. Ici, nous avons cherch&#xE9; &#xE0; savoir si le syst&#xE8;me enzymatique du foie qui fournit l&#x26;#39;acide docosahexa&#xE9;no&#xEF;que au cerveau est dysfonctionnel dans cette maladie. Niveaux acide docosahexa&#xE9;no&#xEF;que ont &#xE9;t&#xE9; r&#xE9;duites dans le cortex temporal, mi-cortex frontal et le cervelet de sujets atteints de la maladie d&#x26;#39;Alzheimer, comparativement aux sujets t&#xE9;moins (P = 0,007). Mini Mental State Examination (MMSE) scores positivement corr&#xE9;l&#xE9;e avec les ratios docosahexa&#xE9;no&#xEF;que / &#x3B1;-linol&#xE9;nique dans cortex temporal (P = 0,005) et la mi-frontale du cortex (P = 0,018), mais pas le cervelet. De m&#xEA;me, la teneur en acide docosahexa&#xE9;no&#xEF;que foie &#xE9;tait plus faible chez les patients la maladie d&#x26;#39;Alzheimer que les sujets t&#xE9;moins (P = 0,011). Foie docosahexa&#xE9;no&#xEF;que / &#x3B1;-linol&#xE9;nique ratios corr&#xE9;l&#xE9;e positivement avec les scores MMSE (r = 0,78, P &#x26;lt;0,0001), et n&#xE9;gativement avec mondiaux grades &#xE9;chelle de d&#xE9;t&#xE9;rioration (p = 0,013). Pr&#xE9;curseurs de l&#x26;#39;acide docosahexa&#xE9;no&#xEF;que, y compris l&#x26;#39;acide tetracosahexaenoic (C24: 6n-3), ont &#xE9;t&#xE9; &#xE9;lev&#xE9;s dans le foie de patients atteints de maladies d&#x26;#39;Alzheimer (P = 0,041), alors que l&#x26;#39;expression de peroxysomes d-bifonctionnel prot&#xE9;ines, qui catalyse la conversion de l&#x26;#39;acide tetracosahexaenoic en acide docosahexa&#xE9;no&#xEF;que, &#xE9;tait r&#xE9;duite (P = 0,048). D&#x26;#39;autres g&#xE8;nes impliqu&#xE9;s dans le m&#xE9;tabolisme acide docosahexa&#xE9;no&#xEF;que n&#x26;#39;ont pas &#xE9;t&#xE9; touch&#xE9;s. Les r&#xE9;sultats indiquent que le d&#xE9;ficit en activit&#xE9; de la prot&#xE9;ine d-bifonctionnel alt&#xE8;re la biosynth&#xE8;se des acides docosahexa&#xE9;no&#xEF;que dans le foie de patients atteints de maladies d&#x26;#39;Alzheimer, ce qui r&#xE9;duit le flux de cet acide gras neuroprotecteur dans le cerveau.

Biosynth&#xE8;se foie d&#xE9;ficient en acide docosahexa&#xE9;no&#xEF;que en corr&#xE9;lation avec les troubles cognitifs dans la maladie d&#x26;#39;Alzheimer

Reduziert Gehirn Ebenen der Docosahexaens&auml;ure (C22:6n-3), eine Fetts&auml;ure Neurotrophic und neuroprotektive kann dazu beitragen, kognitive R&uuml;ckgang der Alzheimer-Krankheit. Hier wir untersucht, ob das Leber-Enzym-System, das Docosahexaens&auml;ure zum Gehirn bietet bei dieser Krankheit eine gest&ouml;rte ist. Docosahexaens&auml;ure S&auml;ure in temporalen Kortex, mid-frontal Cortex und Kleinhirn von Patienten mit Alzheimer-Krankheit, reduziert wurden im Vergleich zu den Themen Steuern (P = 0,007). Mini Mental State Pr&uuml;fung (MMSE) Resultate positiv korreliert mit Docosahexaens&auml;ure/&alpha;-Linolens&auml;ure-Verh&auml;ltnissen im temporalen Kortex (P = 0,005) und mid-frontal Kortex (P = 0,018), aber nicht des Kleinhirns. Auch die Leber Docosahexaens&auml;ure S&auml;urengehalt war in der Alzheimer-Krankheit Patienten niedriger als Kontrollpersonen (P = 0,011). Leber Docosahexaens&auml;ure/&alpha;-Linolens&auml;ure Verh&auml;ltnisse korreliert positiv mit MMSE Scores (R = 0,78; P &lt; 0,0001), und negativ mit Verschlechterung der globalen Skala Noten (P = 0,013). Saure Vorl&auml;ufer Docosahexaens&auml;ure, einschlie&szlig;lich Tetracosahexaenoic S&auml;ure (C24:6n-3), wurden erh&ouml;hte in der Leber von Alzheimer-Patienten (P = 0.041), w&auml;hrend der Ausdruck des Peroxisomale d-Bifunktionelles Protein, das die Umwandlung von Tetracosahexaenoic S&auml;ure in Docosahexaens&auml;ure katalysiert, reduziert wurde (P = 0,048). Andere Gene Docosahexaens&auml;ure sauren Stoffwechsel beteiligt waren nicht betroffen. Die Ergebnisse zeigen, dass ein Defizit an d-Bifunktionelles Protein Aktivit&auml;t Docosahexaens&auml;ure S&auml;ure-Biosynthese in der Leber von Alzheimer-Patienten, Verminderung des Fluss diese neuroprotektive Fetts&auml;ure zum Gehirn beeintr&auml;chtigt.

Mangelhafte Leber Biosynthese von Docosahexaens&auml;ure korreliert mit kognitiver Beeintr&auml;chtigung bei Alzheimer-Krankheit.

Ha ridotto i livelli cerebrali di acido docosaesaenoico (C22:6n-3), un acido grasso neurotrofici e neuroprotective, pu&ograve; contribuire al declino cognitivo nella malattia di Alzheimer. Qui, abbiamo indagato se il sistema degli enzimi epatici che fornisce acido docosaesaenoico al cervello &egrave; disfunzionale in questa malattia. Docosaesaenoico sono stati ridotti livelli di acidi nella corteccia temporale, corteccia opistosoma e cervelletto di soggetti con malattia di Alzheimer, rispetto ai soggetti di controllo (P = 0.007). Gol di esame dello stato mentale (MMSE) mini correlato positivamente con rapporti docosaesaenoico/&alpha;-linolenico nella corteccia temporale (P = 0,005) e corteccia opistosoma (P = 0,018), ma non il cervelletto. Allo stesso modo, tenore di acido docosaesanoico fegato era inferiore nei pazienti con malattia di Alzheimer a soggetti di controllo (P = 0,011). Fegato docosaesaenoico/&alpha;-linolenico rapporti correlato positivamente con punteggi MMSE (r = 0.78; P &lt; 0,0001) e negativamente con gradi scala deterioramento globale (P = 0,013). Precursori acidi docosaesaenoico, tra cui l&#39;acido tetracosahexaenoic (C24:6n-3), sono stati elevati nel fegato di pazienti con malattia di Alzheimer (P = 0.041), mentre &egrave; stata ridotta espressione della proteina bifunzionale d perossisomiale, che catalizza la conversione dell&#39;acido tetracosahexaenoic in acido docosaesaenoico, (P = 0,048). Non sono stati colpiti altri geni coinvolti nel metabolismo acido docosaesaenoico. I risultati indicano che un deficit di attivit&agrave; della proteina bifunzionale d altera la biosintesi di acido docosaesaenoico nel fegato di pazienti con malattia di Alzheimer, diminuendo il flusso di questo acido grasso neuroprotective al cervello.

Biosintesi epatica carenza di acido docosaesaenoico correla con deterioramento cognitivo nella malattia di Alzheimer.

&#x30C9;&#x30B3;&#x30B5;&#x30D8;&#x30AD;&#x30B5;&#x30A8;&#x30F3;&#x9178;&#xFF08;C22&#xFF1A;6N-3&#xFF09;&#x306E;&#x6E1B;&#x5C11;&#x3001;&#x8133;&#x306E;&#x30EC;&#x30D9;&#x30EB;&#x3001;&#x795E;&#x7D4C;&#x3068;&#x795E;&#x7D4C;&#x8102;&#x80AA;&#x9178;&#x306F;&#x3001;&#x30A2;&#x30EB;&#x30C4;&#x30CF;&#x30A4;&#x30DE;&#x30FC;&#x75C5;&#x306B;&#x304A;&#x3051;&#x308B;&#x8A8D;&#x77E5;&#x6A5F;&#x80FD;&#x306E;&#x4F4E;&#x4E0B;&#x306B;&#x8CA2;&#x732E;&#x3059;&#x308B;&#x304B;&#x3082;&#x3057;&#x308C;&#x306A;&#x3044;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x8133;&#x3078;&#x306E;&#x30C9;&#x30B3;&#x30B5;&#x30D8;&#x30AD;&#x30B5;&#x30A8;&#x30F3;&#x9178;&#x3092;&#x63D0;&#x4F9B;&#x3059;&#x308B;&#x809D;&#x81D3;&#x306E;&#x9175;&#x7D20;&#x30B7;&#x30B9;&#x30C6;&#x30E0;&#x306F;&#x3001;&#x3053;&#x306E;&#x75C5;&#x6C17;&#x3067;&#x6A5F;&#x80FD;&#x4E0D;&#x5168;&#x306B;&#x9665;&#x3063;&#x3066;&#x3044;&#x308B;&#x304B;&#x3069;&#x3046;&#x304B;&#x3092;&#x691C;&#x8A0E;&#x3057;&#x305F;&#x3002;&#x30C9;&#x30B3;&#x30B5;&#x30D8;&#x30AD;&#x30B5;&#x30A8;&#x30F3;&#x9178;&#x30EC;&#x30D9;&#x30EB;&#x306F;&#x3001;&#x5BFE;&#x7167;&#x7FA4;&#xFF08;P = 0.007&#xFF09;&#x306B;&#x6BD4;&#x3079;&#x3066;&#x3001;&#x30A2;&#x30EB;&#x30C4;&#x30CF;&#x30A4;&#x30DE;&#x30FC;&#x75C5;&#x88AB;&#x9A13;&#x8005;&#x306E;&#x5074;&#x982D;&#x8449;&#x76AE;&#x8CEA;&#x3001;&#x4E2D;&#x524D;&#x982D;&#x76AE;&#x8CEA;&#x3068;&#x5C0F;&#x8133;&#x3067;&#x6E1B;&#x5C11;&#x3057;&#x305F;&#x3002;&#x30DF;&#x30CB;&#x30E1;&#x30F3;&#x30BF;&#x30EB;&#x30B9;&#x30C6;&#x30FC;&#x30C8;&#x691C;&#x67FB;&#xFF08;MMSE&#xFF09;&#x30B9;&#x30B3;&#x30A2;&#x306F;&#x3001;&#x7A4D;&#x6975;&#x7684;&#x306B;&#x30C9;&#x30B3;&#x30B5;&#x30D8;&#x30AD;&#x30B5;&#x30A8;&#x30F3;/&#x3B1;-&#x30EA;&#x30CE;&#x30EC;&#x30F3;&#x5074;&#x982D;&#x8449;&#x76AE;&#x8CEA;&#x306E;&#x6BD4;&#xFF08;P = 0.005&#xFF09;&#x3068;&#x534A;&#x3070;&#x524D;&#x982D;&#x76AE;&#x8CEA;&#xFF08;P =&#x200B;&#x200B; 0.018&#xFF09;&#x3067;&#x306F;&#x306A;&#x304F;&#x3001;&#x5C0F;&#x8133;&#x3068;&#x76F8;&#x95A2;&#x3057;&#x3066;&#x3044;&#x305F;&#x3002;&#x540C;&#x69D8;&#x306B;&#x3001;&#x809D;&#x81D3;&#x30C9;&#x30B3;&#x30B5;&#x30D8;&#x30AD;&#x30B5;&#x30A8;&#x30F3;&#x9178;&#x542B;&#x6709;&#x91CF;&#x304C;&#x5BFE;&#x7167;&#x7FA4;&#xFF08;P = 0.011&#xFF09;&#x3088;&#x308A;&#x3082;&#x30A2;&#x30EB;&#x30C4;&#x30CF;&#x30A4;&#x30DE;&#x30FC;&#x75C5;&#x60A3;&#x8005;&#x3067;&#x4F4E;&#x304B;&#x3063;&#x305F;&#x3002;&#x809D;&#x81D3;&#x30C9;&#x30B3;&#x30B5;&#x30D8;&#x30AD;&#x30B5;&#x30A8;&#x30F3;/ MMSE&#x30B9;&#x30B3;&#x30A2;&#xFF08;R = 0.78&#x3001;P &#x26;lt;0.0001&#xFF09;&#x3068;&#x6B63;&#x306E;&#x76F8;&#x95A2;&#x3092;&#x793A;&#x3057;&#x3001;&#x3B1;-&#x30EA;&#x30CE;&#x30EC;&#x30F3;&#x9178;&#x306E;&#x6BD4;&#x7387;&#x30B0;&#x30ED;&#x30FC;&#x30D0;&#x30EB;&#x52A3;&#x5316;&#x30B9;&#x30B1;&#x30FC;&#x30EB;&#x306E;&#x30B0;&#x30EC;&#x30FC;&#x30C9;&#xFF08;P = 0.013&#xFF09;&#x3068;&#x3057;&#x3001;&#x5426;&#x5B9A;&#x7684;&#x306B;&#x3002;&#x30C6;&#x30C8;&#x30E9;&#x30B3;&#x30B5;&#x30D8;&#x30AD;&#x30B5;&#x30A8;&#x30F3;&#x9178;&#xFF08;C24&#xFF1A;6N-3&#xFF09;&#x3092;&#x542B;&#x3080;&#x30C9;&#x30B3;&#x30B5;&#x30D8;&#x30AD;&#x30B5;&#x30A8;&#x30F3;&#x9178;&#x306E;&#x524D;&#x99C6;&#x4F53;&#x306F;&#x3001;&#x3001;&#x3001;&#x30C9;&#x30B3;&#x30B5;&#x30D8;&#x30AD;&#x30B5;&#x30A8;&#x30F3;&#x9178;&#x306B;&#x30C6;&#x30C8;&#x30E9;&#x30B3;&#x30B5;&#x30D8;&#x30AD;&#x30B5;&#x30A8;&#x30F3;&#x9178;&#x306E;&#x5909;&#x63DB;&#x3092;&#x89E6;&#x5A92;&#x3059;&#x308B;&#x30DA;&#x30EB;&#x30AA;&#x30AD;&#x30B7;&#x30BD;&#x30FC;&#x30E0;&#x306E;D-&#x4E8C;&#x5B98;&#x80FD;&#x6027;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x306E;&#x767A;&#x73FE;&#x306F;&#x3001;&#x30A2;&#x30EB;&#x30C4;&#x30CF;&#x30A4;&#x30DE;&#x30FC;&#x75C5;&#x60A3;&#x8005;&#xFF08;P = 0.041&#xFF09;&#x306E;&#x809D;&#x81D3;&#x306B;&#x3055;&#x308C;&#x305F;&#x4E0A;&#x6607;&#x3057;&#x305F;&#xFF08;P = 0.048&#xFF09;&#x6E1B;&#x5C11;&#x3057;&#x305F;&#x3002;&#x30C9;&#x30B3;&#x30B5;&#x30D8;&#x30AD;&#x30B5;&#x30A8;&#x30F3;&#x9178;&#x306E;&#x4EE3;&#x8B1D;&#x306B;&#x95A2;&#x4E0E;&#x3059;&#x308B;&#x4ED6;&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x306B;&#x306F;&#x5F71;&#x97FF;&#x3057;&#x307E;&#x305B;&#x3093;&#x3067;&#x3057;&#x305F;&#x3002;&#x7D50;&#x679C;&#x306F;&#x3001;d-&#x4E8C;&#x5B98;&#x80FD;&#x6027;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x6D3B;&#x6027;&#x306E;&#x6B20;&#x640D;&#x306F;&#x3001;&#x8133;&#x306B;&#x3001;&#x3053;&#x306E;&#x795E;&#x7D4C;&#x8102;&#x80AA;&#x9178;&#x306E;&#x30D5;&#x30E9;&#x30C3;&#x30AF;&#x30B9;&#x3092;&#x5C11;&#x306A;&#x304F;&#x3001;&#x30A2;&#x30EB;&#x30C4;&#x30CF;&#x30A4;&#x30DE;&#x30FC;&#x75C5;&#x60A3;&#x8005;&#x306E;&#x809D;&#x81D3;&#x3067;&#x306E;&#x30C9;&#x30B3;&#x30B5;&#x30D8;&#x30AD;&#x30B5;&#x30A8;&#x30F3;&#x9178;&#x306E;&#x751F;&#x5408;&#x6210;&#x3092;&#x963B;&#x5BB3;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;

&#x30C9;&#x30B3;&#x30B5;&#x30D8;&#x30AD;&#x30B5;&#x30A8;&#x30F3;&#x9178;&#x306E;&#x6B20;&#x4E4F;&#x306E;&#x809D;&#x751F;&#x5408;&#x6210;&#x306F;&#x3001;&#x30A2;&#x30EB;&#x30C4;&#x30CF;&#x30A4;&#x30DE;&#x30FC;&#x75C5;&#x306B;&#x304A;&#x3051;&#x308B;&#x8A8D;&#x77E5;&#x6A5F;&#x80FD;&#x969C;&#x5BB3;&#x3068;&#x76F8;&#x95A2;&#x3059;&#x308B;

&#xAC10;&#xC18C; &#xB1CC; &#xC218;&#xC900;&#xC758; docosahexaenoic &#xC0B0; &#xC131; (C22:6n-3), &#x79D1; &#xBC0F; &#xC2E0;&#xACBD; &#xBCF4;&#xD638; &#xC9C0;&#xBC29;&#xC0B0; &#xC54C; &#xCE20; &#xD558;&#xC774; &#xBA38; &#xBCD1;&#xC5D0;&#xC11C; &#xC778;&#xC9C0; &#xAC10;&#xC18C;&#xC5D0; &#xAE30;&#xC5EC;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC5EC;&#xAE30;, &#xC6B0;&#xB9AC;&#xAC00; docosahexaenoic &#xC0B0;&#xC774; &#xB1CC;&#xB97C; &#xC81C;&#xACF5; &#xD558;&#xB294; &#xAC04; &#xD6A8;&#xC18C; &#xC2DC;&#xC2A4;&#xD15C;&#xC774;&#xC774; &#xC9C8;&#xBCD1;&#xC5D0;&#xC11C; &#xBD88;&#xD589; &#xC778;&#xC9C0; &#xC870;&#xC0AC; &#xD588;&#xB2E4;. &#xC81C;&#xC5B4; &#xACFC;&#xBAA9;&#xC5D0; &#xBE44;&#xD574; Docosahexaenoic &#xC0B0; &#xC131; &#xC218;&#xC900;&#xC744; &#xCE21; &#xB450; &#xC5FD; &#xD53C; &#xC9C8;, mid-frontal &#xD53C; &#xC9C8;&#xACFC; &#xC18C; &#xB1CC; &#xC54C; &#xCE20; &#xD558;&#xC774; &#xBA38; &#xBCD1;&#xC73C;&#xB85C; &#xACFC;&#xBAA9;&#xC758; &#xAC10;&#xC18C; &#xD588;&#xB2E4; (P = 0.007). &#xBBF8;&#xB2C8; &#xC815;&#xC2E0; &#xC0C1;&#xD0DC; &#xAC80;&#xC0AC; (MMSE) &#xC810;&#xC218; &#xCE21; &#xB450; &#xC5FD; &#xD53C; &#xC9C8;&#xC5D0;&#xC11C; docosahexaenoic/&alpha;-linolenic &#xBE44;&#xC728;&#xC640; &#xAE0D;&#xC815;&#xC801;&#xC73C;&#xB85C; &#xC0C1;&#xAD00; (P = 0.005)&#xACFC; mid-frontal &#xD53C; &#xC9C8; (P = 0.018), &#xC18C; &#xB1CC; &#xD558;&#xC9C0; &#xD558;&#xC9C0;&#xB9CC;. &#xB9C8;&#xCC2C;&#xAC00;&#xC9C0;&#xB85C;, &#xAC04; docosahexaenoic &#xC0B0; &#xC131; &#xCF58;&#xD150;&#xCE20; &#xC81C;&#xC5B4; &#xACFC;&#xBAA9; &#xBCF4;&#xB2E4; &#xC54C; &#xCE20; &#xD558;&#xC774; &#xBA38; &#xBCD1; &#xD658;&#xC790;&#xC5D0;&#xC11C; &#xB0AE; &#xC558;&#xB2E4; (P = 0.011). &#xAC04; docosahexaenoic/&alpha;-linolenic &#xBE44;&#xC728; MMSE &#xC810;&#xC218;&#xC640; &#xAE0D;&#xC815;&#xC801;&#xC73C;&#xB85C; &#xC0C1;&#xAD00; (r = 0.78; P &lt; 0.0001), &#xADF8;&#xB9AC;&#xACE0; &#xBD80;&#xC815;&#xC801;&#xC778; &#xAE00;&#xB85C;&#xBC8C; &#xC545;&#xD654; &#xADDC;&#xBAA8; &#xC131;&#xC801; (P = 0.013). Docosahexaenoic &#xC0B0; &#xC720;&#xB3C4;&#xCCB4;, tetracosahexaenoic &#xC0B0;&#xC744; &#xD3EC;&#xD568; &#xD558; &#xC5EC; (C24:6n-3), &#xC54C; &#xCE20; &#xD558;&#xC774; &#xBA38; &#xBCD1; &#xD658;&#xC790;&#xC758; &#xAC04; &#xC0C1;&#xC2B9; &#xD588;&#xB2E4; (P = 0.041) &#xC2DD; catalyzes docosahexaenoic &#xC0B0;&#xC5D0; tetracosahexaenoic &#xC0B0;&#xC758; &#xBCC0;&#xD658;, peroxisomal d bifunctional &#xB2E8;&#xBC31;&#xC9C8;&#xC758; &#xAC10;&#xC18C; &#xD558;&#xB294; &#xBC18;&#xBA74;, (P = 0.048). &#xB2E4;&#xB978; &#xC720;&#xC804;&#xC790; docosahexaenoic &#xC0B0; &#xC131; &#xB300;&#xC0AC;&#xC5D0; &#xAD00;&#xB828; &#xB41C; &#xC601;&#xD5A5;&#xC744; &#xC8FC;&#xC9C0;. &#xACB0;&#xACFC; d bifunctional &#xB2E8;&#xBC31;&#xC9C8; &#xD65C;&#xB3D9;&#xC5D0;&#xC11C; &#xC801;&#xC790; &#xAC04; &#xB1CC;&#xC5D0;&#xC774; &#xC2E0;&#xACBD; &#xBCF4;&#xD638; &#xC9C0;&#xBC29;&#xC0B0;&#xC758; &#xC720;&#xB7C9;&#xC744; &#xC904;&#xC774;&#xB294; &#xC54C; &#xCE20; &#xD558;&#xC774; &#xBA38; &#xBCD1; &#xD658;&#xC790;&#xC758; docosahexaenoic &#xC0B0; &#xC0DD; &#xD569;&#xC131; &#xC190;&#xC0C1; &#xB098;&#xD0C0;&#xB0C5;&#xB2C8;&#xB2E4;.

Docosahexaenoic &#xC0B0;&#xC758; &#xBD80;&#xC871; &#xAC04; &#xC0DD; &#xD569;&#xC131; &#xC54C; &#xCE20; &#xD558;&#xC774; &#xBA38; &#xBCD1; &#xC778;&#xC9C0; &#xC7A5;&#xC560;&#xC640; &#xC5F0;&#xAD00; &#xC2DC;&#xD0B5;&#xB2C8;&#xB2E4;.

Reducci&#xF3;n de los niveles cerebrales de &#xE1;cido docosahexaenoico (C22: 6n-3), un &#xE1;cido graso neurotr&#xF3;fico y neuroprotector, puede contribuir al deterioro cognitivo en la enfermedad de Alzheimer. En este caso, se investig&#xF3; si el sistema de enzima del h&#xED;gado que proporciona el &#xE1;cido docosahexaenoico en el cerebro es disfuncional en esta enfermedad. Los niveles de &#xE1;cido docosahexaenoico se redujeron en la corteza temporal, la corteza media-frontal y el cerebelo de los sujetos con enfermedad de Alzheimer, en comparaci&#xF3;n con los sujetos de control (P = 0,007). Mini Examen del Estado Mental (MMSE) resultados de una correlaci&#xF3;n positiva con relaci&#xF3;n docosahexaenoico / &#x3B1;-linol&#xE9;nico en la corteza temporal (p = 0,005) y mediados de la corteza frontal (P = 0,018), pero no cerebelo. Del mismo modo, el contenido de &#xE1;cido docosahexaenoico del h&#xED;gado fue menor en los pacientes con enfermedad de Alzheimer que los sujetos de control (P = 0,011). H&#xED;gado docosahexaenoico / ratios de &#x3B1;-linol&#xE9;nico se correlacion&#xF3; positivamente con puntuaciones en el MMSE (r = 0,78, p &#x26;lt;0,0001), y negativamente con las calificaciones globales de deterioro escala (p = 0,013). Precursores de &#xE1;cido docosahexaenoico, incluyendo el &#xE1;cido tetracosahexaenoic (C24: 6n-3), fueron elevados en el h&#xED;gado de pacientes con enfermedad de Alzheimer (p = 0,041), mientras que la expresi&#xF3;n de la peroxisomal D-bifuncional prote&#xED;na que cataliza la conversi&#xF3;n de &#xE1;cido tetracosahexaenoic en &#xE1;cido docosahexaenoico, fue redujo (P = 0,048). Otros genes implicados en el metabolismo del &#xE1;cido docosahexaenoico no se vieron afectadas. Los resultados indican que un d&#xE9;ficit en actividad de la prote&#xED;na D-bifuncional deteriora la bios&#xED;ntesis de &#xE1;cido docosahexaenoico en el h&#xED;gado de pacientes con enfermedad de Alzheimer, disminuyendo el flujo de este &#xE1;cido graso neuroprotector al cerebro.

La bios&#xED;ntesis hep&#xE1;tica deficiente de &#xE1;cido docosahexaenoico se correlaciona con el deterioro cognitivo en la enfermedad de Alzheimer

The molecular bases of Alzheimer's disease (AD) remain unclear. We used a lipidomic approach to identify lipid abnormalities in the brains of subjects with AD (N = 37) compared to age-matched controls (N = 17). The analyses revealed statistically detectable elevations in levels of non-esterified monounsaturated fatty acids (MUFAs) and mead acid (20:3n-9) in mid-frontal cortex, temporal cortex and hippocampus of AD patients. Further studies showed that brain mRNAs encoding for isoforms of the rate-limiting enzyme in MUFAs biosynthesis, stearoyl-CoA desaturase (SCD-1, SCD-5a and SCD-5b), were elevated in subjects with AD. The monounsaturated/saturated fatty acid ratio ('desaturation index')--displayed a strong negative correlation with measures of cognition: the Mini Mental State Examination test (r = -0.80; P = 0.0001) and the Boston Naming test (r = -0.57; P = 0.0071). Our results reveal a previously unrecognized role for the lipogenic enzyme SCD in AD.

Elevated stearoyl-CoA desaturase in brains of patients with Alzheimer's disease.

&#x963F;&#x5C14;&#x8328;&#x6D77;&#x9ED8;&#x75C5; (AD) &#x7684;&#x5206;&#x5B50;&#x57FA;&#x7840;&#x4ECD;&#x4E0D;&#x6E05;&#x695A;&#x3002;&#x6211;&#x4EEC;&#x4F7F;&#x7528; lipidomic &#x65B9;&#x6CD5;&#x6765;&#x6807;&#x8BC6; AD &#x60A3;&#x8005;&#x8111;&#x5185;&#x7684;&#x8840;&#x8102;&#x5F02;&#x5E38; &#xFF08;N = 37) &#x76F8;&#x6BD4;&#xFF0C;&#x5E74;&#x9F84;&#x5339;&#x914D;&#x7684;&#x63A7;&#x4EF6; &#xFF08;N = 17)&#x3002;&#x5206;&#x6790;&#x663E;&#x793A;&#x7EDF;&#x8BA1;&#x4E0A;&#x63A2;&#x6D4B;&#x6D77;&#x62D4;&#x6C34;&#x5E73;&#x975E;&#x916F;&#x5316;&#x7684;&#x5355;&#x4E0D;&#x9971;&#x548C;&#x8102;&#x80AA;&#x9178; (MUFAs) &#x548C;&#x8702;&#x871C;&#x9152;&#x9178; (20:3n-9&#xFF09; mid-frontal &#x76AE;&#x8D28;&#x3001; &#x989E;&#x76AE;&#x5C42;&#x548C;&#x6D77;&#x9A6C;&#x7684; AD &#x60A3;&#x8005;&#x3002;&#x8FDB;&#x4E00;&#x6B65;&#x7684;&#x7814;&#x7A76;&#x8868;&#x660E;&#x5927;&#x8111;&#x5206;&#x6CCC;&#x901F;&#x7387;&#x9650;&#x5236;&#x9176;&#x5728; MUFAs &#x751F;&#x7269;&#x5408;&#x6210;&#x7684;&#x9176;&#x7684;&#x7F16;&#x7801;&#xFF0C;&#x786C;&#x8102;&#x9170; CoA &#x53BB;&#x9971;&#x548C;&#x9176; (SCD 1&#x3001; SCD-5a &#x548C; SCD-5b&#xFF09;&#xFF0C;&#x88AB;&#x63D0;&#x5347;&#x4E0E; AD &#x7684;&#x79D1;&#x76EE;&#x3002;&#x5355;&#x4E0D;&#x9971;&#x548C;/&#x9971;&#x548C;&#x8102;&#x80AA;&#x9178;&#x6BD4;&#x4F8B; (&#39;&#x51CF;&#x9971;&#x548C;&#x5EA6;&#x6307;&#x6570;&#xFF09; &mdash; &mdash; &#x663E;&#x793A;&#x5F3A;&#x5927;&#x7684;&#x8D1F;&#x76F8;&#x5173;&#x6027;&#x4E0E;&#x8BA4;&#x77E5;&#x7684;&#x63AA;&#x65BD;&#xFF1A; &#x8FF7;&#x4F60;&#x5FC3;&#x7406;&#x72B6;&#x6001;&#x68C0;&#x67E5;&#x6D4B;&#x8BD5; (r =-0.80 &#xFF1B;P = 0.0001&#xFF09; &#x548C;&#x6CE2;&#x58EB;&#x987F;&#x547D;&#x540D;&#x6D4B;&#x8BD5; (r =-0.57 &#xFF1B;P = 0.0071&#xFF09;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x7814;&#x7A76;&#x7ED3;&#x679C;&#x63ED;&#x793A;&#x5728; AD &#x4E2D;&#x7684;&#x8102;&#x6E90;&#x9176; SCD &#x4EE5;&#x524D;&#x65E0;&#x6CD5;&#x8BC6;&#x522B;&#x7684;&#x4F5C;&#x7528;&#x3002;

&#x9AD8;&#x67B6;&#x786C;&#x8102;&#x9170; CoA &#x53BB;&#x9971;&#x548C;&#x9176;&#x5728;&#x963F;&#x5C14;&#x8328;&#x6D77;&#x9ED8;&#x75C5;&#x60A3;&#x8005;&#x7684;&#x5927;&#x8111;&#x4E2D;&#x3002;

Les bases mol&#xE9;culaires de la maladie d&#x26;#39;Alzheimer (AD) restent floues. Nous avons utilis&#xE9; une approche lipodimique d&#x26;#39;identifier des anomalies lipidiques dans les cerveaux de sujets atteints de MA (N = 37) par rapport &#xE0; l&#x26;#39;&#xE2;ge des t&#xE9;moins appari&#xE9;s (N = 17). Les analyses ont r&#xE9;v&#xE9;l&#xE9; une &#xE9;l&#xE9;vation statistiquement d&#xE9;tectables dans les niveaux de non-est&#xE9;rifi&#xE9;s acides gras monoinsatur&#xE9;s (AGMI) et l&#x26;#39;hydromel acide (20:3 n-9) &#xE0; la mi-cortex frontal, le cortex temporal et l&#x26;#39;hippocampe des patients atteints de MA. D&#x26;#39;autres &#xE9;tudes ont montr&#xE9; que les ARNm codant pour des isoformes c&#xE9;r&#xE9;brales de la enzyme limitante de la biosynth&#xE8;se des AGMI, st&#xE9;aroyl-CoA d&#xE9;saturase (SCD-1, SCD-5a et SCD-5b), ont &#xE9;t&#xE9; &#xE9;lev&#xE9;s chez les sujets atteints de MA. Le ratio d&#x26;#39;acides mono-insatur&#xE9;s / gras satur&#xE9; (&#xAB;indice de d&#xE9;saturation&#xBB;) - appara&#xEE;t une forte corr&#xE9;lation n&#xE9;gative avec les mesures de la cognition: le Mini Mental State Examination de test (r = -0,80, p = 0,0001) et le Boston Naming test (r = - 0,57; P = 0,0071). Nos r&#xE9;sultats r&#xE9;v&#xE8;lent un r&#xF4;le non comptabilis&#xE9; ant&#xE9;rieurement pour le SCD lipog&#xE9;nique enzyme dans AD.

Elevated st&#xE9;aroyl-CoA d&#xE9;saturase dans les cerveaux des patients atteints de la maladie d&#x26;#39;Alzheimer

Die molekularen Grundlagen der Alzheimer-Krankheit (AD) sind noch unklar. Wir verwendet einen Lipidomic Ansatz zur Identifizierung von Lipid-Anomalien im Gehirn von Patienten mit AD (N = 37) im Vergleich zu altersbezogenen Kontrollen (N = 17). Die Analyse ergab statistisch nachweisbare Erhebungen nicht verestert einfach unges&auml;ttigte Fetts&auml;uren (MUFAs) und Mead&#39;sche S&auml;ure (20:3n-9) in mid-frontal Kortex, temporalen Kortex und Hippocampus AD-Patienten. Weitere Studien zeigten, dass Gehirn mRNAs Codierung f&uuml;r Isoformen geschwindigkeitsbestimmende Enzym MUFAs Biosynthese, Stearoyl-CoA-Desaturase (SCD-1, SCD-5a und SCD-5b), wurden bei Patienten mit AD erhoben. Das einfach unges&auml;ttigten/ges&auml;ttigt Fetts&auml;ure-Verh&auml;ltnis (Entf&auml;rben-Index)--angezeigt eine starke negative Korrelation mit Ma&szlig;nahmen der Erkenntnis: das Staatsexamen der Mini-Mental-Test (R = 0,63; P = 0,0001) und der Benennung von Boston-Test (R = 0.89; P = 0.0071). Unsere Ergebnisse zeigen eine zuvor unbekannte Rolle f&uuml;r das Lipogenic Enzym SCD in AD.

Erh&ouml;hten Stearoyl-CoA Desaturase in Gehirnen von Patienten mit Alzheimer-Krankheit.

Le basi molecolari della malattia di Alzheimer (AD) rimangono poco chiare. Abbiamo usato un approccio lipidomica per identificare anomalie dei lipidi nel cervello dei soggetti con AD (N = 37) rispetto ai controlli corrispondenti et&agrave; (N = 17). Le analisi hanno rivelato statisticamente rilevabile elevazioni nei livelli di acidi grassi non esterificati monoinsaturi (MUFAs) e acido eicosatrienoico (20:3n-9) nell&#39;opistosoma corteccia, corteccia temporale e ippocampo dei pazienti AD. Ulteriori studi hanno mostrato che cervello mRNA codifica per isoforme dell&#39;enzima di limitazione della velocit&agrave; nella biosintesi MUFAs, stearoil-CoA desaturasi (SCD-1, SCD-5a e 5b-SCD), sono stati elevati nei soggetti con AD. Il rapporto di acidi grassi monoinsaturi/saturi &#39;(indice di desaturazione del)-- visualizzato una forte correlazione negativa con misure della cognizione: il test Mini mentali dichiarano l&#39;esame (r =-0.80; P = 0.0001) e il Boston Naming test (r =-0.57; P = 0.0071). I nostri risultati rivelano un ruolo precedentemente non riconosciuto per l&#39;enzima lipogenici SCD nell&#39;annuncio.

Elevata stearoil-CoA desaturasi nel cervello dei pazienti con malattia di Alzheimer.

&#x30A2;&#x30EB;&#x30C4;&#x30CF;&#x30A4;&#x30DE;&#x30FC;&#x75C5;&#xFF08;AD&#xFF09;&#x306E;&#x5206;&#x5B50;&#x57FA;&#x76E4;&#x306F;&#x4E0D;&#x660E;&#x3067;&#x3042;&#x308B;&#x3002;&#x6211;&#x3005;&#x306F;&#x3001;&#x5E74;&#x9F62;&#x3092;&#x30DE;&#x30C3;&#x30C1;&#x3055;&#x305B;&#x305F;&#x30B3;&#x30F3;&#x30C8;&#x30ED;&#x30FC;&#x30EB;&#xFF08;N = 17&#xFF09;&#x306B;&#x6BD4;&#x3079;&#x3066;AD&#xFF08;N = 37&#xFF09;&#x3067;&#x88AB;&#x9A13;&#x8005;&#x306E;&#x8133;&#x5185;&#x306E;&#x8102;&#x8CEA;&#x7570;&#x5E38;&#x3092;&#x8B58;&#x5225;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;lipidomic&#x30A2;&#x30D7;&#x30ED;&#x30FC;&#x30C1;&#x3092;&#x4F7F;&#x7528;&#x3057;&#x3066;&#x3044;&#x307E;&#x3057;&#x305F;&#x3002;&#x5206;&#x6790;&#x306F;&#x3001;&#x975E;&#x30A8;&#x30B9;&#x30C6;&#x30EB;&#x5316;&#x4E0D;&#x98FD;&#x548C;&#x8102;&#x80AA;&#x9178;&#xFF08;MUFAs&#xFF09;&#x3068;&#x534A;&#x3070;&#x524D;&#x982D;&#x8449;&#x3001;&#x5074;&#x982D;&#x8449;&#x76AE;&#x8CEA;&#x304A;&#x3088;&#x3073;AD&#x60A3;&#x8005;&#x306E;&#x6D77;&#x99AC;&#x306B;&#x304A;&#x3051;&#x308B;&#x30DF;&#x30FC;&#x30C9;&#x9178;&#xFF08;20&#xFF1A;03&#x306E;n-9&#xFF09;&#x306E;&#x30EC;&#x30D9;&#x30EB;&#x3067;&#x7D71;&#x8A08;&#x7684;&#x306B;&#x691C;&#x51FA;&#x53EF;&#x80FD;&#x306A;&#x4E0A;&#x6607;&#x3092;&#x660E;&#x3089;&#x304B;&#x306B;&#x3057;&#x305F;&#x3002;&#x3055;&#x3089;&#x306A;&#x308B;&#x7814;&#x7A76;&#x304C;MUFAs&#x751F;&#x5408;&#x6210;&#x3001;&#x30B9;&#x30C6;&#x30A2;&#x30ED;&#x30A4;&#x30EB;-CoA&#x30C7;&#x30B5;&#x30C1;&#x30E5;&#x30E9;&#x30FC;&#x30BC;&#xFF08;SCD-1&#x3001;SCD-5a&#x3068;SCD-5B&#xFF09;&#x306B;&#x304A;&#x3051;&#x308B;&#x5F8B;&#x901F;&#x9175;&#x7D20;&#x306E;&#x30A2;&#x30A4;&#x30BD;&#x30D5;&#x30A9;&#x30FC;&#x30E0;&#x3092;&#x30B3;&#x30FC;&#x30C9;&#x3059;&#x308B;&#x8133;&#x306E;mRNA&#x304C;AD&#x3092;&#x6709;&#x3059;&#x308B;&#x88AB;&#x9A13;&#x8005;&#x3067;&#x4E0A;&#x6607;&#x3057;&#x3066;&#x3044;&#x305F;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x305F;&#x3002;&#x4E00;&#x4FA1;&#x4E0D;&#x98FD;&#x548C;/&#x98FD;&#x548C;&#x8102;&#x80AA;&#x9178;&#x6BD4;&#xFF08; &#x26;quot;&#x4E0D;&#x98FD;&#x548C;&#x5316;&#x30A4;&#x30F3;&#x30C7;&#x30C3;&#x30AF;&#x30B9; &#x26;#39;&#xFF09; - &#x8A8D;&#x77E5;&#x306E;&#x5C3A;&#x5EA6;&#x3068;&#x5F37;&#x3044;&#x8CA0;&#x306E;&#x76F8;&#x95A2;&#x95A2;&#x4FC2;&#x3092;&#x8868;&#x793A;&#xFF1A;&#x30DF;&#x30CB;&#x200B;&#x200B;&#x30E1;&#x30F3;&#x30BF;&#x30EB;&#x30B9;&#x30C6;&#x30FC;&#x30C8;&#x691C;&#x67FB;&#x8A66;&#x9A13;&#xFF08;R = -0.80&#x3001;P = 0.0001&#xFF09;&#x3001;&#x30DC;&#x30B9;&#x30C8;&#x30F3;&#xB7;&#x30CD;&#x30FC;&#x30DF;&#x30F3;&#x30B0;&#xB7;&#x30C6;&#x30B9;&#x30C8;&#xFF08;R =  - 0.57&#x3001;P = 0.0071&#xFF09;&#x3002;&#x6211;&#x3005;&#x306E;&#x7D50;&#x679C;&#x306F;&#x3001;AD&#x306B;&#x304A;&#x3051;&#x308B;&#x8102;&#x8CEA;&#x5408;&#x6210;&#x9175;&#x7D20;SCD&#x306E;&#x305F;&#x3081;&#x306B;&#x4EE5;&#x524D;&#x306B;&#x8A8D;&#x8B58;&#x3055;&#x308C;&#x3066;&#x3044;&#x306A;&#x3044;&#x5F79;&#x5272;&#x3092;&#x660E;&#x3089;&#x304B;&#x306B;&#x3057;&#x305F;&#x3002;

&#x30A2;&#x30EB;&#x30C4;&#x30CF;&#x30A4;&#x30DE;&#x30FC;&#x75C5;&#x60A3;&#x8005;&#x306E;&#x8133;&#x3067;&#x4E0A;&#x6607;&#x30B9;&#x30C6;&#x30A2;&#x30ED;&#x30A4;&#x30EB;-CoA&#x30C7;&#x30B5;&#x30C1;&#x30E5;&#x30E9;&#x30FC;&#x30BC;

&#xC54C; &#xCE20; &#xD558;&#xC774; &#xBA38; &#xBCD1; (AD)&#xC758; &#xBD84;&#xC790; &#xAE30;&#xC9C0; &#xBD88;&#xBD84;&#xBA85; &#xB0A8;&#xC544; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xB294; &#xAD11;&#xACE0;&#xC640; &#xACFC;&#xBAA9;&#xC758; &#xB450;&#xB1CC;&#xC5D0; &#xC788;&#xB294; &#xC9C0;&#xC9C8; &#xC774;&#xC0C1; &#xC2DD;&#xBCC4; lipidomic &#xC811;&#xADFC; &#xC0AC;&#xC6A9; (N = 37) &#xCEE8;&#xD2B8;&#xB864; &#xC77C;&#xCE58; &#xD558;&#xB294; &#xB098;&#xC774;&#xC5D0; &#xBE44;&#xD574; (N = 17). &#xBD84;&#xC11D; &#xBE44; esterified monounsaturated &#xC9C0;&#xBC29;&#xC0B0; (MUFAs) &#xBC0F; &#xBBF8;&#xB4DC; &#xC0B0;&#xC758; &#xC218;&#xC900;&#xC5D0;&#xC11C; &#xD1B5;&#xACC4;&#xC801;&#xC73C;&#xB85C; &#xAC10;&#xC9C0;&#xD560; &#xC218; &#xACE0;&#xB3C4; &#xACF5;&#xAC1C; (20:3n-9) mid-frontal &#xD53C; &#xC9C8;, &#xCE21; &#xB450; &#xC5FD; &#xD53C; &#xC9C8;&#xACFC; &#xD574; &#xB9C8;&#xC758; AD &#xD658;&#xC790;&#xC5D0;. &#xCD94;&#xAC00; &#xC5F0;&#xAD6C;&#xAC00; &#xB1CC; mRNAs isoforms MUFAs &#xC0DD; &#xD569;&#xC131;&#xC758; &#xC18D;&#xB3C4; &#xC81C;&#xD55C; &#xD6A8;&#xC18C;&#xC758; &#xC778;&#xCF54;&#xB529;, stearoyl CoA desaturase (SCD 1, SCD 5a &#xBC0F; 5b SCD) &#xD588;&#xB2E4;&#xC640; &#xAD11;&#xACE0; &#xACFC;&#xBAA9;&#xC5D0;&#xC11C; &#xB192;&#xC740; &#xBCF4;&#xC5EC;&#xC8FC;&#xC5C8;&#xB2E4;. &#xBD88;&#xD3EC;&#xD654;/&#xD3EC;&#xD654; &#xC9C0;&#xBC29;&#xC0B0; &#xBE44;&#xC728; (&#39;&#xBD88;&#xD3EC;&#xD654; &#xC9C0;&#39;)-&#xC778;&#xC2DD;&#xC758; &#xC870;&#xCE58;&#xC5D0; &#xAC15;&#xD55C; &#xBD80;&#xC815;&#xC801;&#xC778; &#xC0C1;&#xAD00; &#xAD00;&#xACC4; &#xD45C;&#xC2DC;: &#xBBF8;&#xB2C8; &#xC815;&#xC2E0; &#xC0C1;&#xD0DC; &#xAC80;&#xC0AC; &#xD14C;&#xC2A4;&#xD2B8; (r =-0.80; P = 0.0001)&#xC640; &#xBCF4;&#xC2A4;&#xD134; &#xBA85;&#xBA85; &#xD14C;&#xC2A4;&#xD2B8; (r =-0.57; P = 0.0071). &#xC6B0;&#xB9AC;&#xC758; &#xACB0;&#xACFC; &#xAD11;&#xACE0;&#xC5D0; lipogenic &#xD6A8;&#xC18C; SCD&#xC5D0; &#xB300; &#xD55C; &#xC774;&#xC804;&#xC5D0; &#xC778;&#xC2DD;&#xD560; &#xC218; &#xC5C6;&#xB294; &#xC5ED;&#xD560;&#xC744; &#xACF5;&#xAC1C;.

&#xC54C; &#xCE20; &#xD558;&#xC774; &#xBA38; &#xBCD1; &#xD658;&#xC790;&#xC758; &#xB1CC;&#xC5D0;&#xC11C; &#xB192;&#xC740; stearoyl CoA desaturase.

Las bases moleculares de la enfermedad de Alzheimer (EA) siguen sin estar claros. Se utiliz&#xF3; un enfoque lipidomic para identificar anormalidades en los l&#xED;pidos en el cerebro de los sujetos con EA (N = 37) en comparaci&#xF3;n con controles pareados por edad (n = 17). Los an&#xE1;lisis revelaron elevaciones estad&#xED;sticamente detectables en los niveles de no esterificados &#xE1;cidos grasos monoinsaturados (MUFA) y &#xE1;cido Mead (20:3 n-9) a mediados de la corteza frontal, la corteza temporal y el hipocampo de pacientes con AD. Otros estudios demostraron que los ARNm del cerebro que codifican para las isoformas de la enzima limitante en la bios&#xED;ntesis de MUFA, estearoil-CoA desaturasa (SCD-1, SCD-5a y 5b-SCD), fueron elevados en los sujetos con EA. La proporci&#xF3;n de &#xE1;cidos grasos monoinsaturados / saturados (&#x26;quot;&#xED;ndice de desaturaci&#xF3;n&#x26;quot;) - muestra una fuerte correlaci&#xF3;n negativa con las medidas de la cognici&#xF3;n: la prueba de Mini Examen del Estado Mental (r = -0.80, p = 0,0001) y la prueba de denominaci&#xF3;n de Boston (r = - 0,57, p = 0,0071). Nuestros resultados revelan un papel previamente no reconocido por la enzima SCD lipog&#xE9;nica en el a&#xF1;o.

Elevado estearoil-CoA desaturasa en cerebros de pacientes con enfermedad de Alzheimer

Dietary fat exerts a potent stimulatory effect on feeding. This effect is mediated, at least in part, by a cephalic mechanism that involves recruitment of the vagus nerve and subsequent activation of endocannabinoid signaling in the gut. Here, we used a sham-feeding protocol in rats to identify fatty-acid constituents of dietary fat that might be responsible for triggering small-intestinal endocannabinoid signaling. Sham feeding rats with a corn oil emulsion increased endocannabinoid levels in jejunum, relative to animals that received either mineral oil (which contains no fatty acids) or no oil. Sham-feeding emulsions containing oleic acid (18:1) or linoleic acid (18:2) caused, on average, a nearly 2-fold accumulation of jejunal endocannabinoids, whereas emulsions containing stearic acid (18:0) or linolenic acid (18:3) had no such effect. In a 2-bottle-choice sham-feeding test, rats displayed strong preference for emulsions containing 18:2, which was blocked by pretreatment with the peripherally restricted CB1 cannabinoid receptor antagonists, AM6546 and URB447. Our results suggest that oral exposure to the monoenoic and dienoic fatty acid component of dietary fat selectively initiates endocannabinoid mobilization in the gut, and that this local signaling event is essential for fat preference.

Endocannabinoid signaling in the gut mediates preference for dietary unsaturated fats.

Monoacylglycerol lipase (MGL) is a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). 2-AG is one of the main endogenous lipid agonists for cannabinoid receptors in the brain and elsewhere in the body. In the central nervous system (CNS), MGL is localized to presynaptic nerve terminals of both excitatory and inhibitory synapses, where it helps control the regulatory actions of 2-AG on synaptic transmission and plasticity. In this chapter, we describe an in vitro method to assess MGL activity by liquid chromatography/mass spectrometry (LC/MS)-based quantitation of the reaction product. This method may be used to determine the basal or altered MGL activity in various cells or animal tissues after pharmacological, genetic, or biological manipulations. In addition, this assay can be used for MGL inhibitor screening using purified recombinant enzyme or MGL-overexpressing cells.

Assay of Monoacylglycerol Lipase Activity.

Knock-in homozygote VCPR155H/R155H mutant mice are a lethal model of valosin-containing protein (VCP)-associated inclusion body myopathy associated with Paget disease of bone, frontotemporal dementia and amyotrophic lateral sclerosis. Ceramide (d18:1/16:0) levels are elevated in skeletal muscle of the mutant mice, compared to wild-type controls. Moreover, exposure to a lipid-enriched diet reverses lethality, improves myopathy and normalizes ceramide levels in these mutant mice, suggesting that dysfunctions in lipid-derived signaling are critical to disease pathogenesis. Here, we investigated the potential role of ceramide in VCP disease using pharmacological agents that manipulate the ceramide levels in myoblast cultures from VCP mutant mice and VCP patients. Myoblasts from wild-type, VCPR155H/+ and VCPR155H/R155H mice, as well as patient-induced pluripotent stem cells (iPSCs), were treated with an inhibitor of ceramide degradation to increase ceramide via acid ceramidase (ARN082) for proof of principle. Three chemically distinct inhibitors of ceramide biosynthesis via serine palmitoyl-CoA transferase (L-cycloserine, myriocin or ARN14494) were used as a therapeutic strategy to reduce ceramide in myoblasts. Acid ceramidase inhibitor, ARN082, elevated cellular ceramide levels and concomitantly enhanced pathology. Conversely, inhibitors of ceramide biosynthesis L-cycloserine, myriocin and ARN14494 reduced ceramide production. The results point to ceramide-mediated signaling as a key contributor to pathogenesis in VCP disease and suggest that manipulating this pathway by blocking ceramide biosynthesis might exert beneficial effects in patients with this condition. The ceramide pathway appears to be critical in VCP pathogenesis, and small-molecule inhibitors of ceramide biosynthesis might provide therapeutic benefits in VCP and related neurodegenerative diseases.

Ceramide contributes to pathogenesis and may be targeted for therapy in VCP inclusion body myopathy.

Chronic pain affects 1.5 billion people worldwide but remains woefully undertreated. Understanding the molecular events leading to its emergence is necessary to discover disease-modifying therapies. Here we show that N-acylethanolamine acid amidase (NAAA) is a critical control point in the progression to pain chronicity, which can be effectively targeted by small-molecule therapeutics that inhibit this enzyme. NAAA catalyzes the deactivating hydrolysis of palmitoylethanolamide, a lipid-derived agonist of the transcriptional regulator of cellular metabolism, peroxisome proliferator-activated receptor-α (PPAR-α). Our results show that disabling NAAA in spinal cord during a 72-h time window following peripheral tissue injury halts chronic pain development in male and female mice by triggering a PPAR-α-dependent reprogramming of local core metabolism from aerobic glycolysis, which is transiently enhanced after end-organ damage, to mitochondrial respiration. The results identify NAAA as a crucial control node in the transition to chronic pain and a molecular target for disease-modifying medicines.

NAAA-regulated lipid signaling governs the transition from acute to chronic pain.

During adolescence, microglia are actively involved in neocortical maturation while concomitantly undergoing profound phenotypic changes. Because the teenage years are also a time of experimentation with cannabis, we evaluated whether adolescent exposure to the drug's psychotropic constituent, Δ-tetrahydrocannabinol (THC), might persistently alter microglia function.

Frequent Low-Dose Δ-Tetrahydrocannabinol in Adolescence Disrupts Microglia Homeostasis and Disables Responses to Microbial Infection and Social Stress in Young Adulthood.

The endocannabinoid system (ECS) is comprised of a set of lipid-derived messengers (the endocannabinoids, ECBs), proteins that control their production and degradation, and cell-surface cannabinoid (CB) receptors that transduce their actions. ECB molecules such as 2-arachidonoyl--glycerol (2-AG) and anandamide (arachidonoyl ethanolamide) are produced on demand and deactivated through enzymatic actions tightly regulated both temporally and spatially, serving homeostatic roles in order to respond to various challenges to the body. Key components of the ECS are present in the hypothalamus-pituitary-gonadal (HPG) axis, which plays critical roles in the development and regulation of the reproductive system in both males and females. ECB signaling controls the action at each stage of the HPG axis through CB receptors expressed in the hypothalamus, pituitary, and reproductive organs such as the testis and ovary. It regulates the secretion of hypothalamic gonadotropin-releasing hormone (GnRH), pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH), estrogen, testosterone, and affects spermatogenesis in males. Δ-tetrahydrocannabinol (THC) and other phytocannabinoids from  affect a variety of physiological processes by altering, or under certain conditions hijacking, the ECB system. Therefore, phytocannabinoids, in particular THC, may modify the homeostasis of the HPG axis by altering CB receptor signaling and cause deficits in reproductive function. While the ability of phytocannabinoids, THC and/or cannabidiol (CBD), to reduce pain and inflammation provides promising opportunities for therapeutic intervention for genitourinary and degenerative disorders, important questions remain regarding their unwanted long-term effects. It is nevertheless clear that the therapeutic potential of modulating the ECS calls for further scientific and clinical investigation.

Phytocannabinoids, the Endocannabinoid System and Male Reproduction.

Cannabis use by adolescents is widespread, but its effects on the ovaries remain largely unknown. Δ9-tetrahydrocannabinol (THC) exerts its pharmacological effects by activating, and in some conditions hijacking, cannabinoid receptors (CBRs). We hypothesized that adolescent exposure to THC affects ovarian function in adulthood. Peripubertal female C57BL/6N mice were given THC (5 mg/kg) or its vehicle, once daily by intraperitoneal injection. Some mice received THC from postnatal day (PND) 30-33 and their ovaries were harvested PND34; other mice received THC from PND30-43, and their ovaries were harvested PND70. Adolescent treatment with THC depleted ovarian primordial follicle numbers by 50% at PND70, 4 weeks after the last dose. The treatment produced primordial follicle activation, which persisted until PND70. THC administration also caused DNA damage in primary follicles and increased PUMA protein expression in oocytes of primordial and primary follicles. Both CB1R and CB2R were expressed in oocytes and theca cells of ovarian follicles. Enzymes involved in the formation (N-acylphosphatidylethanolamine phospholipase D) or deactivation (fatty acid amide hydrolase) of the endocannabinoid anandamide were expressed in granulosa cells of ovarian follicles and interstitial cells. Levels of mRNA for CBR1 were significantly increased in ovaries after adolescent THC exposure, and upregulation persisted for at least 4 weeks. Our results support that adolescent exposure to THC may cause aberrant activation of the ovarian endocannabinoid system in female mice, resulting in substantial loss of ovarian reserve in adulthood. Relevance of these findings to women who frequently used cannabis during adolescence warrants investigation.

Adolescent exposure to low-dose Δ9-tetrahydrocannabinol depletes the ovarian reserve in female mice.

New potent, selective monoacylglycerol lipase (MAGL) inhibitors based on the azetidin-2-one scaffold ((±)--, (±)--, and (±)--) were developed as irreversible ligands, as demonstrated by enzymatic and crystallographic studies for (±)-, (±)-, and (±)-. X-ray analyses combined with extensive computational studies allowed us to clarify the binding mode of the compounds.  was identified as selective for MAGL when compared with other serine hydrolases. Solubility,  metabolic stability, cytotoxicity, and absence of mutagenicity were determined for selected analogues. The most promising compounds ((±)-, (±)-, and (±)-) were used for  studies in mice, showing a decrease in MAGL activity and increased 2-arachidonoyl--glycerol levels in forebrain tissue. In particular,  is characterized by a high eudysmic ratio and (3,4)- is one of the most potent irreversible inhibitors of /MAGL identified thus far. These results suggest that the new MAGL inhibitors have therapeutic potential for different central and peripheral pathologies.

Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. SARs, Structural Analysis, and Biological Characterization.

Gulf War Illness (GWI) is a chronic disorder characterized by a heterogeneous set of symptoms that include pain, fatigue, anxiety, and cognitive impairment. These are thought to stem from damage caused by exposure under unpredictable stress to toxic Gulf War (GW) chemicals, which include pesticides, nerve agents, and prophylactic drugs. We hypothesized that GWI pathogenesis might be rooted in long-lasting disruption of the endocannabinoid (ECB) system, a signaling complex that serves important protective functions in the brain. Using a mouse model of GWI, we found that tissue levels of the ECB messenger, anandamide, were significantly reduced in the brain of diseased mice, compared to healthy controls. In addition, transcription of the Faah gene, which encodes for fatty acid amide hydrolase (FAAH), the enzyme that deactivates anandamide, was significant elevated in prefrontal cortex of GWI mice and brain microglia. Behavioral deficits exhibited by these animals, including heightened anxiety-like and depression-like behaviors, and defective extinction of fearful memories, were corrected by administration of the FAAH inhibitor, URB597, which normalized brain anandamide levels. Furthermore, GWI mice displayed unexpected changes in the microglial transcriptome, implying persistent dampening of homeostatic surveillance genes and abnormal expression of pro-inflammatory genes upon immune stimulation. Together, these results suggest that exposure to GW chemicals produce a deficit in brain ECB signaling which is associated with persistent alterations in microglial function. Pharmacological normalization of anandamide-mediated ECB signaling may offer an effective therapeutic strategy for ameliorating GWI symptomology.

Targeting dysfunctional endocannabinoid signaling in a mouse model of Gulf War illness.

Acute injuries can progress into painful states that endure long after healing. The mechanisms underlying this transition remain unclear, but metabolic adaptations to the bioenergy demands imposed by injury are plausible contributors. Here we show that peripheral injury activates AKT/mTORC1 in afferent segments of the mouse spinal cord, redirecting local core metabolism toward biomass production while simultaneously suppressing autophagy-mediated biomass reclamation. This metabolic shift supports neuroplasticity, but creates a resource bottleneck that depletes critical spinal cord nutrients. Preventing this depletion with a modified diet normalizes biomass generation and autophagy and halts the transition to chronic pain. This effect, observed across multiple pain models, requires activation of the nutrient sensors, sirtuin-1 and AMPK, as well as restoration of autophagy. The findings identify metabolic reprogramming and consequent autophagy suppression as key drivers of the progression to pain chronicity and highlight nutritional and pharmacological interventions that could prevent this progression after surgery or other physical traumas.

Metabolic reprogramming in the spinal cord drives the transition to pain chronicity.

Cannabis use typically starts in early to mid-adolescence. Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, targets cannabinoid receptors (CBRs) to exert its pharmacological effects. Expression of CBRs has been observed in human and rodent testes, but their potential role in the control of reproductive function remains unclear. We aimed to elucidate how THC exposure during adolescence or young adulthood affects the reproductive health of males. C57BL/6N male mice were given THC (5 mg/kg) or vehicle, once daily by intraperitoneal (ip) injection from postnatal day (PND) 30 to PND 43 (adolescent exposure) or PND 70 to PND 83 (adult exposure), and testes were harvested at PND 70 and PND 110, respectively. Results showed that CBRs (CB1R and CB2R) and enzymes that biosynthesize or inactivate the endocannabinoid anandamide (AEA) -N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) or fatty acid amide hydrolase (FAAH), respectively-are expressed in the mouse testis. THC exposure in adolescence decreased sperm numbers and increased seminiferous tubule degeneration in young adult testes, while adult exposure did not affect spermatogenesis and seminiferous tubule morphology. Both adolescent and adult THC exposure resulted in decreased plasma testosterone levels; however, only mice with adolescent THC exposure showed impaired steroidogenesis with dysregulated expression of steroidogenic acute regulatory protein (StAR) and steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). Our results support that adolescent THC exposure may cause testicular toxicity through direct and aberrant activation of CBRs in the testis. These studies show that the adolescent testis is more sensitive than the adult testis to THC-induced disruption of spermatogenesis.

Article	Year
Discovery of potent and reversible monoacylglycerol lipase inhibitors. Chemistry & biology\| PubMed ID: 19875078	2009
Deficient liver biosynthesis of docosahexaenoic acid correlates with cognitive impairment in Alzheimer's disease. PloS one\| PubMed ID: 20838618	2010
Elevated stearoyl-CoA desaturase in brains of patients with Alzheimer's disease. PloS one\| PubMed ID: 22046234	2011
Endocannabinoid signaling in the gut mediates preference for dietary unsaturated fats. FASEB journal : official publication of the Federation of American Societies for Experimental Biology\| PubMed ID: 23463697	2013
Assay of Monoacylglycerol Lipase Activity. Methods in molecular biology (Clifton, N.J.)\| PubMed ID: 27245902	2016
Ceramide contributes to pathogenesis and may be targeted for therapy in VCP inclusion body myopathy. Human molecular genetics\| PubMed ID: 33410456	2021
NAAA-regulated lipid signaling governs the transition from acute to chronic pain. Science advances\| PubMed ID: 34678057	2021
Frequent Low-Dose Δ-Tetrahydrocannabinol in Adolescence Disrupts Microglia Homeostasis and Disables Responses to Microbial Infection and Social Stress in Young Adulthood. Biological psychiatry\| PubMed ID: 35750512	2022
Phytocannabinoids, the Endocannabinoid System and Male Reproduction. The world journal of men's health\| PubMed ID: 36578200	2023
Adolescent exposure to low-dose Δ9-tetrahydrocannabinol depletes the ovarian reserve in female mice. Toxicological sciences : an official journal of the Society of Toxicology\| PubMed ID: 36912754	2023
Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. SARs, Structural Analysis, and Biological Characterization. Journal of medicinal chemistry\| PubMed ID: 38241614	2024
Targeting dysfunctional endocannabinoid signaling in a mouse model of Gulf War illness. Neuropharmacology\| PubMed ID: 39241906	2024
Metabolic reprogramming in the spinal cord drives the transition to pain chronicity. bioRxiv : the preprint server for biology\| PubMed ID: 39975205	2025
Adolescent exposure to Δ9-tetrahydrocannabinol (THC) impairs testicular function in young adult male mice. Toxicological sciences : an official journal of the Society of Toxicology\| PubMed ID: 40127192	2025

Kwang-Mook Jung

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