Lub luag haujlwm ntawm PPAR Alpha hauv Kev Hloov Kho Ntawm Innate Immunity Part 2

5. PPAR lub luag haujlwm hauv Innate Immunity Effector Txheej Txheem: ROS/RNS Production

Ib qho tseem ceeb ntawm lub cev tiv thaiv kab mob hauv cov tsiaj yog tsim cov qauv ntawm cov pa oxygen (tsuas yog superoxide) thiab cov ntaub ntawv nquag ntawm nitrogen, feem ntau yog nitric oxide thiab nws cov derivatives [102]. Daim ntawv ntawm nitric oxide synthase (NOS) ib txwm cuam tshuam nrog kev mob yog qhov hu ua inducible nitric oxide synthase (iNOS lossis NOS 2). NOS 2 belongs rau tsev neeg enzymatic ntawm nitric oxide synthases (NOS), yog cov evolutionarily feem ntau nyob deb ntawm tsev neeg. NOS 2 tuaj yeem nthuav tawm hauv ntau hom hlwb thiab cov ntaub so ntswg [103].

Lwm qhov ob, NOS 1 thiab NOS 3, tseem hu ua 'constitutive' lossis Ca2 ntxiv - nyob ntawm cov enzymes, muaj nyob rau hauv ntau cov ntaub so ntswg thiab hlwb ntawm lub cev, feem ntau tab sis tsis yog nyob rau hauv qee cov neurons (NOS 1), nrog rau endothelial. cells (NOS 3) [104]. Lawv tsim kom muaj qis dua NO dua li NOS 2, txawm hais tias lawv cov kev ua haujlwm enzymatic sib piv hauv vitro [102]. Qhov tseem ceeb, nyob rau hauv ntau yam mob, tag nrho NOS enzymes yog ib qho ntawm cov ntaub ntawv nquag ntawm nitrogen thiab oxygen; Thaum tsis muaj L-arginine, lawv tsuas tsim superoxide thiab tej zaum yuav yog ib qho tseem ceeb ntawm oxidative/nitrosative stress [105].

Muaj kev sib raug zoo ntawm kev ua haujlwm enzyme thiab kev tiv thaiv kab mob. Enzymes yog cov protein molecules tseem ceeb hauv cov tsiaj muaj sia. Lawv tuaj yeem ua kom nrawm nrawm ntawm cov tshuaj tiv thaiv thiab ua lub luag haujlwm tseem ceeb hauv cov txheej txheem physiological. Ntau cov molecules hauv lub cev tiv thaiv kab mob, suav nrog cov tshuaj tiv thaiv kab mob, cytokines, thiab enzymes, ua lub luag haujlwm hauv kev hloov kho lub cev tiv thaiv kab mob. Peb kuj yuav tsum tau xyuam xim rau peb txoj kev tiv thaiv hauv lub neej txhua hnub. Cistanche tuaj yeem txhim kho kev tiv thaiv. Cistanche muaj ntau yam antioxidants, xws li vitamin C, vitamin C, carotenoids, thiab lwm yam. Cov khoom xyaw no tuaj yeem tshem tawm cov dawb radicals, txo oxidative kev nyuaj siab, thiab txhim kho kev tiv thaiv. qhov system tsis kam.

Nyem kom paub meej cistanche

PPAR agonists tuaj yeem txo qis NOS 2 [106,107], thaum lawv txhawb nqa ob leeg NOS 3 [108], uas ua lub luag haujlwm tiv thaiv kab mob plawv thiab NOS 1 (saib [109,110]). NOS 2 tau hais tawm de novo nyob rau hauv kev cuam tshuam ntawm proinflammatory yam [102], thiab, raws li nws tsis yog nyob ntawm calcium, nws tsuas yog downregulated los ntawm inhibition ntawm lub enzymatic kev ua si los yog proteolytic degradation ntawm lub enzyme. NOS kev ua haujlwm kuj yog nyob ntawm kev sib tw nrog lwm cov khoom siv substrate arginase, uas tsim cov urea thiab L-ornithine es tsis txhob L-citrulline thiab nitric oxide [111,112].

Qhov ua tau ntawm kev hloov txoj hauv kev tseem ceeb ntawm L-arginine metabolism los ntawm tiam NO thiab citrulline mus rau tiam ntawm urea thiab ornithine yog lub hauv paus rau kev ua haujlwm sib txawv ntawm M1 thiab M2 macrophages. M1 macrophages, tsis zoo li M2 macrophages, tsim cov dawb radicals thiab yog hom proinflammatory ntawm cov hlwb (raws li tau hais hauv Tshooj 3). Lawv pab txhawb txoj kev loj hlob ntawm cov qog nqaij hlav o [107]. PPAR, raws li ib qho kev txo qis ntawm qhov mob thiab kev tsim tawm dawb-radical, ua qhov no ua tus neeg sawv cev tiv thaiv kab mob. Thaum sib npaug rau cov qog nqaij hlav thiab muaj ntau haiv neeg ntawm cov qog macrophage phenotype mus rau M2, qhov xwm txheej dhau los ua qhov tsis meej thiab tsis paub tseeb. Qhov tshwm sim tiag tiag ntawm kev ua kom PPAR nyob ntawm seb hom qog thiab nws cov theem ntawm kev loj hlob [108]. Tseeb, fenofibrate inhibited kev loj hlob ntawm micrometastases ntawm melanoma BHM hauv Syrian hamster ntsws, tab sis tsis cuam tshuam rau kinetics ntawm thawj qog loj hlob, los yog kev loj hlob ntawm macro-metastases [113]. Nws yuav tsum tau hais ntxiv tias, tsis ntev los no, kev saib xyuas tshwj xeeb tau them rau qhov muaj peev xwm ntawm kev tswj hwm ntawm NOS 2 kev ua haujlwm los ntawm nws cov kev xaiv inhibitors kom ua tiav qib siab ntawm tib neeg monocyte physiological teb [114].

Qhov thib ob txheej txheem ntawm kev tiv thaiv innate uas cuam tshuam nrog kev tsim cov tshuaj me me uas muaj zog heev yog ua pa (los yog oxidative) tawg ua los ntawm phagocytes. PPAR agonists tau pom tias yuav ua rau kom macrophage microbicidal kev ua si los ntawm kev siv zog ntawm ROS ntau lawm thaum ua pa tawg. Qhov no yog tshwm sim los ntawm PPAR -dependent elevated qhia ntawm tseem ceeb heev transmembrane (gp91phox) thiab cytosolic (p47phox thiab p67phox) Cheebtsam ntawm NADPH oxidase [115]. Interestingly, nce ROS ntau lawm coj mus rau tiam ntawm oxidized low-density lipoproteins (ox-LDL), uas ntxiv txhawb PPAR ua kom. Activated PPAR downregulated TSIS MUAJ ntau lawm ntawm transrepression ntawm iNOS [115]. Qhov no yog ib qho piv txwv ntawm PPAR sib txawv tswj ntau yam kev tiv thaiv kab mob hauv nruab nrog cev, hauv qhov no, ROS thiab RNS. Ib qho kev nthuav qhia tsis txaus ntseeg tau tshwm sim hauv kev txhawb nqa ntawm lwm cov noob tseem ceeb rau tiam ntawm cov kab mob reactive thaum lub sij hawm ua pa tawg, uas yog, myeloperoxidase (MPO). Tus neeg txhawb nqa ntawm cov noob no muaj cov ntsiab lus tshwj xeeb Alu uas rov ua dua DNA cov xov tooj ntawm tes kis thoob plaws tib neeg cov genome hauv txog 1 lab luam [116]. Alu fragment nyob rau hauv MPO gene txhawb nqa muaj plaub hexamer sequences zoo ib yam li los yog zoo li canonical PPAR teb cov ntsiab lus (PPREs): AGGTCA, nrog 2 los yog 4 bp sib nrug ntawm lawv [117].

Qhov thib peb thiab thib plaub hexamers ua haujlwm raws li PPREs thiab haum PPAR / RXR lossis PPAR / RXR heterodimers, uas ua rau kev tswj hwm kev hloov pauv los ntawm PPAR ligands. Kuj ceeb tias, MPO kev qhia yog tswj hwm los ntawm PPAR agonist GW9578 thiab PPAR agonist MCC-555 nyob rau hauv cov lus qhia ntawm tib neeg macrophages, nyob ntawm txoj kev sib txawv; MPO yog qhov txo qis hauv macrophages tau los ntawm MG-CSF-kho monocytes thiab upregulated hauv M-CSF txawv hlwb [117]. Qhov sib txawv tuaj yeem raug ntaus nqi los ntawm kev siv sib txawv ntawm kev siv nuclear co-repressors, xws li NCoR los yog ntsiag to mediator ntawm retinoid thiab thyroid receptors (SMRT), hauv macrophages sib txawv nrog GM- vs. M-DAMP [117]. Qhov tseem ceeb, hom kev cai no yog tib neeg nkaus xwb, vim tias nas tsis muaj Alu cov ntsiab lus hauv lawv cov genome.

6. PPAR ua Immunomodulator thaum kis kab mob

Tiag tiag immunomodulatory kev txiav txim tsis yog dag nyob rau hauv unilateral inhibition los yog ua kom tag nrho cov txheej txheem inflammatory tab sis nyob rau hauv kev xaiv ntawm cov xaiv yam ntawm innate kev tiv thaiv. Xws li kev ua immunomodulatory ntawm PPAR tau pom nyob rau hauv cov kab mob parasitic lossis microbial. Ib qho piv txwv ntawm cov haujlwm no cuam tshuam txog kev cuam tshuam ntawm M2 polarization hauv macrophages ntawm cov neeg mob uas muaj Trypanosoma cruzi, parasitic euglenoid, uas yog lub luag haujlwm rau Chagas kab mob. Qhov kev sim ua rau cov nas kis tau pom tias PPAR agonist Wy-14643 nce qhov kev qhia ntawm M2 macrophage markers, arginase{3}}, mannose receptor (CD206), Ym1, thiab TGF , thiab txo qis kev tsim cov proinflammatory. molecules yam ntxwv ntawm M1 phenotype, xws li iNOS, NO, IL-1, IL-6 thiab TNF [118]. Txawm li cas los xij, qhov hloov pauv phenotypic no tau nrog PPAR (tab sis tsis yog PPAR) - nyob ntawm qhov nce ntawm phagocytic muaj peev xwm thiab kev ua haujlwm ntawm cov kab mob phagocytosis [118]. Cov txiaj ntsig no qhia tau hais tias kev ua kom PPAR tuaj yeem muaj qhov tseem ceeb hauv kev kho mob, vim tias nws cov tshuaj tiv thaiv immunomodulatory, ntawm ib sab, ntxiv dag zog rau macrophage effector muaj peev xwm, tab sis, ntawm qhov tod tes, pab daws qhov mob hnyav uas cuam tshuam nrog Chagas kab mob, uas ua rau muaj kev puas tsuaj rau ntau yam kabmob. .

Ib yam li immunomodulatory kev ua si ntawm PPAR nyob rau hauv cov ntsiab lus ntawm phagocytosis tau piav nyob rau hauv thawj peritoneal macrophage thiab microglia kab lis kev cai kho nrog ob peb PPAR agonists: endogenous cannabinomimetic (saib hauv qab), PEA, fenofibrate, los yog palmitic acid [119]. Cov tebchaw no, tshwj xeeb tshaj yog PEA, txhim kho phagocytosis thiab intracellular tua ntawm E. coli los ntawm macrophages thiab microglial hlwb. Txawm hais tias PEA pretreatment txo qis cov qib ntawm proinflammatory cytokines (IL-1 , IL-6, thiab TNF ) thiab chemokines (CXCL1) hauv cov ntaub so ntswg ntawm nas raug mob intracerebellar lossis intraperitoneal E. coli kab mob, Cov kab mob zoo heev tshem tawm ntawm cov ntshav, spleens, thiab cerebellum, uas txhais ua kom muaj sia nyob ntawm cov tsiaj no [119]. Cov txiaj ntsig no qhia txog qhov muaj peev xwm tiv thaiv tau ntawm PPAR ua kom muaj kab mob hauv cov kab mob.

Lwm qhov piv txwv qhia tau hais tias qhov exaggerated inflammatory teb tsis zoo rau tus tswv yog tuberculosis kab mob. Hauv qhov no, PPAR's immunomodulatory thiab metabolic lub luag haujlwm txuas nrog, ua rau muaj txiaj ntsig zoo rau cov nas uas muaj kab mob mycobacteria (Bacillus Calmette-Guerin lossis M. tuberculosis) piv nrog PPAR KO nas [120].

Qhov tsis muaj PPAR ua rau muaj cov kab mob hauv lub cev ntau zuj zus hauv macrophages, hnyav dua bacteremia hauv lub ntsws, tus po, thiab daim siab, thiab qib siab dua ntawm cov kab mob cytokines TNF thiab IL-6 hauv lub ntsws, piv rau wt. PPAR nas. Qhov exaggerated inflammatory teb yog txuam nrog ntau dua ntawm cov kab mob granuloma nyob rau hauv lub ntsws ntawm PPAR KO nas. Granuloma lesions yog qhov tshwm sim ntawm kev ua tsis tau zoo ntawm tus tswv tsev tiv thaiv mycobacteria vim tias lawv muaj cov leukocytes tuag, cov ntaub so ntswg puas hlwb multinucleated loj, thiab macrophages hloov mus rau cov hlwb ua npuas ncauj, uas muaj cov lipid-muaj vesicles, uas tsim kom muaj lub zog zoo rau kev muaj sia nyob thiab kev loj hlob. mycobacteria [121]. Pharmacological PPAR agonists, GW7647 thiab Wy-14643 induced phagosomal maturation los ntawm activation ntawm transcription factor EB (TFEB) thiab txo cov ciaj sia taus ntawm cov kab mob intracellular, uas tshwm sim los ntawm muaj zog fatty acid -oxidation thiab tshem tawm ntawm lipid-nplua nuj lub cev [ 120] ib. Qhov no yog ib qho piv txwv ntawm kev sib txuas ntawm PPAR -mediated lipid catabolism thiab nws cov tshuaj tiv thaiv kab mob, uas txhawb kev tiv thaiv kab mob hauv lub cev.

Txawm hais tias lub cev loj ntawm cov pov thawj sau tseg cov txiaj ntsig tau txais txiaj ntsig ntawm PPAR ua kom muaj ntau yam kab mob nrog cov keeb kwm inflammatory, kuj tseem muaj qee yam mob uas PPAR -mediated immunomodulation yog qhov txaus ntshai. Cov piv txwv piv txwv yog qhov xwm txheej uas, tom qab kis tus kab mob khaub thuas, cov kab mob tom ntej (xws li, staphylococcal) superinfection tshwm sim. Cov tshuaj tua kab mob-resistant Staphylococci yog ib qho ua rau muaj kev phom sij rau lub neej nosocomial kab mob hauv cov neeg mob hauv tsev kho mob vim muaj kab mob pulmonary. Tam thiab cov npoj yaig [122] pom tias qhov muaj PPAR yog lub luag haujlwm rau kev mob hnyav dua thiab kev tuag ntau dua hauv wt nas piv rau PPAR KO nas. Tus kab mob kis tau tus kab mob uas tau tshwm sim ua ntej kev sib tw nrog S. aureus ua rau muaj kev nthuav qhia PPAR hauv lub ntsws. Ntxiv mus, kev soj ntsuam lipidomic ntawm bronchoalveolar lavage kua los ntawm cov nas muaj kab mob tau qhia tias superinfection ua rau muaj txiaj ntsig zoo ntawm ntau yam lipid mediators, xws li LOX khoom LTE4 thiab CYP450 cov khoom 11,12-dihydroxyeicosatrienoic acid (11,{9} }diHETrE) thiab 14,15-diHETrE, piv rau ib leeg kab mob, txawm yog kab mob los yog kab mob. 14,15-diHETre yog tus muaj zog PPAR agonist [123].

Qhov inhibition ntawm NF-κB signaling mediated los ntawm activated PPAR ua rau ib tug blunted proinflammatory teb rau cov kab mob thiab tsis muaj kev tswj ntawm cov kab mob loj hlob, uas inflicted ntau dua tuag [122]. Superinfection ua rau txo qis kev qhia ntawm macrophage inflammatory genes IL-1 , IL-6, CXCL5, thiab MMP-9, nrog rau cov scavenger receptor Marco, uas ua rau cov phagocytosis tsawg dua thiab cov kab mob hnyav dua. lub nra. Ntxiv mus, PPAR ua kom ua rau muaj zog necroptosis (ib qho programmed RIPK3 kinase-dependent lytic cell tuag), uas yog lub luag haujlwm rau kev puas tsuaj rau lub ntsws thiab ua rau cov tsiaj muaj kab mob hnyav heev [122].

Qhov tseem tsis tshua muaj, tab sis maj mam nthuav tawm cov ntaub ntawv sim qhia tias PPAR cuam tshuam rau tus tswv tsev teb rau cov kab mob kis. Kev koom tes zoo li no muaj txiaj ntsig zoo hauv qee qhov xwm txheej tab sis tuaj yeem ua rau muaj kev puas tsuaj rau lwm yam xwm txheej. Lub overexpression ntawm PPAR homolog nyob rau hauv ib tug grouper ntses (Epinephelus coioides, EcPPAR) thaiv interferon- thiab NF-κBinduced cytokine qhia thaum kis kab mob, uas ua rau mob cytopathic raug mob thiab hnyav multiplicity ntawm tus kab mob [124]. Lub ntsiab lus ntawm qhov pib kis tus kab mob yog qhov tseem ceeb heev vim nws txoj kev sib raug zoo nrog tus kab mob COVID-19 tsis tu ncua. Ib txoj kev tshawb fawb tau ua nyob rau hauv thawj tib neeg bronchial epithelial hlwb kis tus kab mob SARS-CoV-2 qhia kev hloov loj heev nyob rau hauv cov noob transcription qauv uas manifested endoplasmic reticular thiab mitochondrial kev nyuaj siab, metabolic reprogramming mus rau intensive lipid synthesis thiab tsub zuj zuj, impaired fatty acid oxidation, thiab upregulated aerobic glycolysis ntawm kev ua haujlwm ntawm NF-κB txoj hauv kev [125].

Xws li daim ntawv kos npe metabolic qhia tias kev kis kab mob ua rau PPAR signaling. Yog li, kev kho dua tshiab ntawm PPAR kev ua haujlwm tuaj yeem tau txais txiaj ntsig los ntawm kev thim rov qab ntawm cov kev hloov pauv no thiab kev kho cov metabolic 'kho'. Tseeb, kev kho mob ntawm cov kab mob ntawm tes kab mob nrog PPAR ligand fenofibrate alleviated lub dysregulation ntawm lipid metabolism, thaiv kab mob-induced phospholipid tsub zuj zuj, thiab remarkably txo tus kab mob load los ntawm 100- quav hauv 3 hnub thiab 1000- quav hauv 5 hnub [125]. Cov txiaj ntsig no zoo li txhawb qhov kev xav tias kev kho mob fenofibrate tuaj yeem txo cov tsos mob ntawm tus kab mob thaum lub sij hawm COVID-19 los ntawm kev txhawb cov fatty acid metabolism hauv alveolar epithelial hlwb, txhim kho pulmonary endothelial cell muaj nuj nqi, thiab calming down cytokine cua daj cua dub, ua rau ib tug Cov txiaj ntsig zoo rau cov neeg mob [126].

7. Kev sib cuam tshuam ntawm PPAR thiab Endocannabinoid System: Qhov cuam tshuam rau Inflamma-Tion, Neuroprotection, thiab Analgesia

7.1. Analgesic Lipid Mediators li PPAR Agonists

Kev puas tsuaj rau cov ntaub so ntswg, hypersensitivity rhiab heev, los yog cov kab mob hauv zos ua rau mob, uas ua rau cov lus teb nociceptive thiab mob. Cov tsos mob tshwm sim los ntawm proalgesic lipid mediators, xws li lysophospholipids thiab PDE2, los yog hydroxylated derivatives ntawm linoleic acid (piv txwv li, 13-hydroxy octadecanoic acid, 13-HODE), uas ua rau kom cov excitability ntawm nociceptive neurons [12] ].

Txawm li cas los xij, lwm pab pawg ntawm endogenous lipid mediators muaj qhov tsis sib xws, kev ua kom muaj zog. Ua los ntawm cannabinoid receptors CB1 thiab / los yog CB2, lawv txo qhov excitability ntawm sensory nociceptive neurons. Qhov no yog ib feem ntawm cov kab ke hu ua endocannabinoid, uas suav nrog ligands N-arachidonoylethanolamine (AEA, anandamide) thiab 2-arachidonoyl-glycerol (2-AG), uas tau pom thawj zaug, thiab lawv cov receptors. , cannabinoid receptors CB1 thiab CB2 qhia nyob rau hauv CNS thiab immunocompetent hlwb, feem, raws li zoo raws li TRPV1 thiab endocannabinoid-synthesizing thiab -degrading enzymes [128,129]. Tom qab ntawd, lwm cov fatty-acid ethanolamides (FAEs), xws li N-palmitoylethanolamide (PEA) thiab N-oleoyl ethanolamide (OEA), tau kuaj pom nyob rau hauv cov ntaub so ntswg mammalian thiab invertebrate [130–132]. OEA thiab PEA yog cov tshuaj lom neeg muaj txiaj ntsig thiab muaj zog PPAR agonists, nrog EC50 qhov tseem ceeb ntawm 0.12 µM thiab 3 µM, raws li [44,133], uas txuas PPAR nrog cov kab ke endocannabinoid. Ntau yam tshuaj lom neeg zoo li kev ua haujlwm ntawm OEA thiab PEA tau paub dav, suav nrog kev ua kom tsis haum tshuaj thiab tiv thaiv kev ua haujlwm cannabinomimetic, txawm hais tias lawv tsis yog bona fide CB1 lossis CB2 agonists [134]. Endocannabinoids thiab cannabimimetic yog tsim los ntawm kev thov los ntawm daim nyias nyias phospholipids, tab sis kuj tuaj yeem khaws cia hauv cov cellularly hauv lipid droplets [135,136]. Lawv muaj ntau nyob rau hauv lub hlwb, leukocytes, kab mob plab, thiab lwm yam ntaub so ntswg [137-139].

Txoj kev FAE biosynthesis feem ntau suav nrog kev tsim N-acylphosphatidylethanolamine los ntawm phosphatidylethanolamine los ntawm calcium-dependentN-acyl-transferase thiab tom qab hloov mus rau N-acyl-ethanolamine los ntawm N-acyl-phosphatidylethanolamine hydrolyzing [NAPE-10PLase] D. Ob peb lwm txoj hauv kev biosynthesis uas koom nrog lwm cov phospholipases thiab glycerophosphodiesterases kuj ua tau (rau kev tshuaj xyuas, saib [128]). Endocannabinoids yog nqus los ntawm cov hlwb thiab metabolized los ntawm intracellular fatty-acid amide hydrolase (FAAH) los yog N-acylethanolamine-hydrolyzing acid amidase (NAAA) [141].

OEA thiab PEA siv tshuaj tua kab mob thiab txo cov nociception nyob rau hauv ntau yam tsiaj qauv ntawm inflammatory mob [142,143]. PEA thiab hluavtaws PPAR ligands (GW7647, Wy-14634, perfluorooctanoic acid) tsim cov teebmeem analgesic thiab txo qis edema nyob rau hauv cov tshuaj induced qauv ntawm o [142,144–146]. Txawm hais tias, nyob rau qee kis, OEA tau ua ntawm nws tus kheej ntawm PPAR muaj [143], PEA-induced nociception thiab anti-inflammatory activated los ntawm PPAR [142,145].

Qhov tseem ceeb, PEA-mediated activation ntawm PPAR hauv CNS los ntawm intracerebroventricular PEA daim ntawv thov tuaj yeem txo cov kab mob peripheral (paw edema tom qab txhaj tshuaj carrageenan) [146]. Qhov no tau ua pov thawj qhov kev txiav txim ntawm cov endocrine nyob deb ntawm PEA, txawm hais tias cov txheej txheem molecular cuam tshuam nrog inhibition ntawm NF-κB txoj hauv kev hauv CNS cov ntaub so ntswg [146]. Ib qho kev koom tes PPAR kuj tau pom nyob rau hauv qhov kev sim nrog ib tug hluavtaws PPAR agonist GW7647, uas induced synergistic li ntawm AEA analgesic zog nyob rau hauv ib tug chemically induced inflammatory mob qauv [145,147]. Qhov kev txiav txim antinociceptive ntawm GW7647 yog nyob ntawm kev ua haujlwm ntawm cov kab hluav taws xob loj loj, uas txhawb ntxiv kev koom tes ntawm endocannabinoid system [145,147]. Lub zog ntawm endocannabinoid khi rau CB1 thiab CB2 receptors los ntawm cognate molecules, uas tsis yog agonists lawv tus kheej, tau pom thiab hu ua 'cov nyhuv entourage' [148].

Nyob rau hauv rooj plaub ntawm AEA, PEA, thiab OEA, cov txiaj ntsig zoo li no tuaj yeem piav qhia los ntawm FAAH kev koom tes hauv PEA thiab OEA hydrolysis, sparing lub pas dej loj ntawm AEA los ntawm kev degradation thiab tso cai rau nws qhib CB receptors. Qhov tseeb, cov nyhuv entourage tau piav qhia tias yog kev txhim kho vasodilation ntawm AEA los ntawm TRPV1 los ntawm PEA thiab OEA hauv endothelium [149]. Hauv cov ntsiab lus, tag nrho cov txiaj ntsig no qhia tau hais tias PPAR signaling pab txhawb kev mob inflammatory los ntawm cannabinomimetics OEA thiab PEA (Daim duab 3) [127].

7.2. PPAR Kev koom tes hauv kev daws teeb meem ntawm Neuroinflamation

Lub xub ntiag ntawm OEA thiab PEA hauv CNS cuam tshuam lawv cov haujlwm hauv lub cev ntawm cov neurons thiab glial hlwb. Ob lub tebchaw tau pom tias muaj txiaj ntsig zoo los ntawm kev tawm tsam cov lus teb glial inflammatory thiab los ntawm kev muab cytoprotection tshaj cov hlwb neuronal thiab lawv cov dej num hauv ntau lub xeev neuropathic. Neuroinflammation thiab exaggerated glial reactivity yog txuam nrog ntau cov kab mob neurodegenerative, raug mob, ischemia / reperfusion stress, thiab neuropathic mob [150-152]. Lub hlwb raug suav hais tias yog 'ib lub cev tsis muaj zog tiv thaiv kab mob, tiv thaiv los ntawm peripheral proinflammatory stimuli los ntawm cov ntshav-hlwb barrier, tab sis microglia, astrocytes, thiab mast hlwb muaj peev xwm ua rau neuroinflammation [153]. Kev ua tsis zoo lossis kev ua haujlwm ntev ntev ntawm cov hlwb hauv CNS ua rau muaj kev qhia ntau ntxiv ntawm TLRs, cytokines (TNF, IL-6), chemokines (CXCL6) metalloproteinases, ROS, thiab RNS, uas ua rau poob ntawm calcium homeostasis, neuronal. kev puas tsuaj, lossis apoptosis [151–153]. Lub peev xwm ntawm lipid amides, hu ua ALIAmides (autacoid hauv zos raug mob antagonists) los tiv thaiv kev mob neurogenic thiab mast-cell degranulation, tau thov los ntawm Rita Levi-Montalcini, tus Nobel laureate (1988), rau nws qhov kev tshawb pom hauv thaj tsam ntawm neurobiology [154] .

Tseeb, ntau cov kev tshawb fawb pom tau hais tias OEA thiab PEA, cais raws li ALIAmides, tuaj yeem muab kev tiv thaiv neuroprotection los ntawm kev txo qis ntawm cov lus teb rau hauv lub hlwb los ntawm kev hloov kho ntawm glial cell functions. Benito thiab cov npoj yaig tau tshawb pom tias N-fatty acyl ethanolamines (OEA, PEA, AEA) thiab hluavtaws agonists ntawm PPAR (Wy-14643) thiab PPAR (troglitazone) alleviate inflammatory teb induced los ntawm kev kho mob ntawm astrocytes nrog -amyloid peptide fragments. [155]. Cov tshuaj tiv thaiv kab mob tau kho los ntawm PPAR , PPAR , thiab TRPV1 kev ua, tab sis tsis yog los ntawm CB1 lossis CB2 [155]. Cov tshuaj tiv thaiv neuroprotective ntawm PEA thiab ib qho endocannabinoid 2-AG tau pom nyob rau hauv tus qauv excitatory ntawm neuronal puas nyob rau hauv organotypic hippocampal daim kab lis kev cai [156]. PEA thiab 2-AG tau cawm txog 50 feem pua ​​​​ntawm cov neurons los ntawm NMDA-induced cell tuag, ua rau cov hlwb microglial, txawm tias los ntawm kev sib txawv thiab kev sib koom ua ke. PEA thaiv microglial inflammatory kev ua ub no, xws li TSIS MUAJ ntau lawm thiab nrhiav tau ntawm ameboid morphology, yam ntxwv ntawm ib tug activated mob [156]. Cov teebmeem no tau cuam tshuam nrog PPAR nuclear translocation, uas qhia txog nws txoj kev koom tes hauv cov txheej txheem.

7.3. PPAR -Mediated Regulation of Microglia thiab Macrophage Functions

Glia-qhia kev ua ntawm PEA tau kawm los ntawm Scuderi thiab coauthors, uas, nyob rau hauv ib tug series ntawm cov ntaub ntawv, qhia tau hais tias PEA los yog hluavtaws PPAR agonists, nyob rau hauv ib tug PPAR-dependent yam, txo cov cim ntawm glial o thiab txhim kho neuronal nyob rau hauv cov tsiaj qauv ntawm Alzheimer's kab mob, nrog rau hauv kev sib xyaw glial-neuronal cell kab lis kev cai thiab organotypic neural kab lis kev cai [157-159]. Kev ua haujlwm immunomodulatory ntawm PEA thiab kev sib cuam tshuam ntawm PPAR thiab endocannabinoid system kuj tau txheeb xyuas hauv thawj microglial thiab macrophage kab lis kev cai [160]. Txoj kev tshawb no tau nthuav tawm tias CB2 mRNA thiab qib protein tau nce ntxiv los ntawm kev kho mob nrog PEA thiab cov hluavtaws PPAR agonist GW7647, thiab cov nyhuv no tau tshwm sim los ntawm PPAR / RXR heterodimer khi rau kev txhawb nqa thiab kev hloov pauv ntawm cov noob encoding CB2 [160]. PEA-induced microglial effector ua haujlwm hauv PPAR-dependent yam thiab txhim kho phagocytosis thiab tua ntawm Porphyromonas gingivalis los ntawm microglia thiab chemotaxis rau 2-AG [160].

Ntxiv rau qhov kev hloov kho ntawm cov tshuaj tiv thaiv kab mob phagocytosis, PEA tuaj yeem hloov kho cov haujlwm ntawm cov macrophages, xws li efferocytosis (piv txwv li, phagocytosis thiab tshem tawm ntawm cov hlwb apoptotic) [161]. PEA yog tsim endogenously los ntawm M2c-polarized tab sis tsis M1-polarized macrophages [161]. Exogenous chronic tswj ntawm PEA txwv kev tsim cov quav hniav thaum ntxov, tiv thaiv los ntawm kev sib sau ntawm proinflammatory M1 macrophage nyob rau hauv cov quav hniav, thiab txhawb nqa efferocytosis los ntawm M2a- thiab M2c-polarized macrophages, uas ncua qhov pib ntawm arteriosclerosis [161]. Cov txiaj ntsig no qhia tau tias endogenous PPAR ligand PEA muaj peev xwm hloov kho microglia thiab macrophage lom ua haujlwm.

7.4 ib. PPAR lub luag haujlwm hauv Kev Txhim Kho Kev Ua Haujlwm ntawm Neural Tom Qab Raug Mob lossis Kab Mob

Neuroprotective OEA kev ua haujlwm kuj tau pom tias yog kev txwv tsis pub hu ua glial caws pliav (piv txwv li, thaj chaw uas muaj cov kab mob reactive astrocytes, microglia, fibroblasts, thiab cov khoom sib txuas ntxiv ntawm cov matrix) tsim, tom qab focal cerebral ischemia raug mob [162]. Glial caws pliav yog cov tshuaj tiv thaiv lub cev rau kev raug mob, tab sis nws impedes neurite tsim, axon regrowth, thiab rov qab los tom qab lub hlwb stroke. OEA nce PPAR qhia nyob rau hauv lub hlwb cortex thiab downregulated glial caws pliav cim (S100B, glial fibrillary acidic protein GFAP, metalloproteinases MMP-2, MMP-9, thiab neurocan) nyob rau hauv cheeb tsam ischemic los ntawm ib tug PPAR-dependent mechanism. [162]. Qhov tseem ceeb, cov txheej txheem lom neeg tau muab txhais ua qhov zoo dua ntawm lub cev muaj zog hauv cov nas tom qab mob stroke [162]. OEA kuj txo qis cov lus teb ntawm cov kab mob endothelial (xws li IL-6, IL-8, ICAM-1, thiab VCAM qhia) evoked los ntawm TNF , hauv PPAR - thiab CB{{12 }}dependent yam [163].

Cov dej num lom neeg ntawm OEA thiab PEA zoo li zoo sib xws thiab qee zaum sib tshooj, tab sis tsis yog ib txwm zoo ib yam, raws li qhia hauv cov chaw sim sib txawv. Qhov sib txawv ntawm OEA thiab PEA qhov kev ua tau pom nyob rau hauv ib txoj kev tshawb fawb uas soj ntsuam kev ua haujlwm tsis zoo ntawm lub paj hlwb hauv cov qauv tsiaj ntawm neonatal anoxia / ischemia-induced hlwb raug mob [164]. PEA, tab sis tsis yog OEA kev kho mob muaj peev xwm txwv tsis pub hippocampal astrogliosis cov cim (xws li, ionized calcium-binding adapter protein Iba-1, GFAP) thiab rov kho PPAR protein qhia hauv anoxia / ischemia- cuam tshuam lub hlwb thaj tsam [164]. Cov teebmeem no tau cuam tshuam nrog kev paub txog kev txawj ntse thiab kev rov zoo dua ntawm qhov chaw thiab kev nco, piv rau cov tsiaj uas raug anoxia / ischemia [164]. Txawm li cas los xij, OEA tau ua pov thawj tias muaj txiaj ntsig zoo hauv ameliorating kev paub tsis txaus ntseeg thiab txhawb nqa neurogenesis hauv ischemia- cuam tshuam lub hlwb thaj tsam ntawm cov nas raug rau nruab nrab cerebral artery occlusion [165].

Ib qho tseem ceeb immunomodulatory kev txiav txim ntawm OEA thiab PEA koom nrog TLR3 teeb liab thaum lub sij hawm innate teb rau cov kab mob kis. Ib tsab ntawv ceeb toom tsis ntev los no los ntawm Flannery et al. [166] pom tau tias intracerebroventricular kev tswj hwm ntawm TLR3 ligand, kab mob mimetic polyinosinic-polycytidylic acid (poly I: C), coj mus rau induction ntawm hypothalamic interferon thiab NF-κB- tswj txoj hauv kev ntawm proinflammatory noob qhia thiab hyperthermia. Kev kho mob nrog ob qho tib si OEA thiab PEA attenuated TLR3-kev kho mob hyperthermia, tab sis tsuas yog OEA (tsis yog PEA) tau txais txiaj ntsig hauv kev txo qis ntawm poly I: C-induced inflammatory gene qhia, suav nrog TNF , iNOS, IL{{7} } , COX-2, interferon gamma-induced protein 10 (IP{11}}), thiab interferon-regulated factor IRF7. Qhov tseeb tias PPAR antagonist GW6471 txo qis cov teebmeem no qhia txog PPAR kev koom tes hauv cov cai no [166]. Cov txiaj ntsig no muaj qhov cuam tshuam tseem ceeb rau kev kis tus kab mob SARS-CoV{17}} tam sim no, uas feem ntau ua rau muaj teeb meem hauv CNS, tshwm sim los ntawm kev puas hlwb thiab kev puas siab puas ntsws, xws li kev tsis nco qab, kev xav, kev ntxhov siab, kev nyuaj siab, thiab dementia [167 ].

7.5. PPAR thiab Endocannabinoid kev koom tes hauv kev tswj hwm ntawm Mast-Cell Functions

Mast hlwb yog ib qho tseem ceeb hauv lub cev tiv thaiv kab mob uas, vim yog lawv cov degranulation sai, tuaj yeem tswj tau qhov pib ntawm o ntawm ntau cov ntaub so ntswg. PEA tau pom tias txo qis hauv zos tsub zuj zuj zuj zus thiab ua kom cov kab mob mast hauv ntau cov qauv inflammatory: (i) tom qab tshuaj P txhaj rau pob ntseg pinna [154], (ii) thaum lub sij hawm chemically induced allergic dermatitis hauv nas [168], (iii) hauv myelin basic protein (MBP)-induced neuronal raug mob nyob rau hauv ib tug neuron-glia- mast cell coculture qauv ntawm ntau yam sclerosis [169], (iv) nyob rau hauv nas mast cell kab RBL-2H3 [170], (v) tom qab ischemia/reperfusion inflammatory raug mob ntawm txoj hnyuv tom qab splanchnic artery occlusion nyob rau hauv nas [171], thiab (vi) thaum lub sij hawm chemically induced colitis uas ua hauj lwm raws li ib tug tsiaj qauv ntawm inflammatory plob tsis so tswj kab mob [172].

Nyob rau hauv tag nrho cov qauv kev sim no, PEA suppressed ntau yam ntawm cov tshuaj tiv thaiv uas tsim los ntawm mast hlwb los yog lwm yam leukocytes, xws li chemotaxis, degranulation, enzyme tso tawm, thiab induction ntawm proinflammatory cytokines. Qhov kev tawm tsam ntawm mast-cell kev ua haujlwm tau ua rau txo qis ntawm cov ntaub so ntswg puas tsuaj thiab txhim kho lub cev nqaij daim tawv ua haujlwm. Ib qho kev siv tshuaj molecular tuaj yeem koom nrog cov teebmeem no, vim hais tias, tsis hais tus qauv siv, lawv tau kho kom haum xeeb, tsawg kawg yog ib feem, los ntawm PPAR thiab CB2 ua kom [168–170], nrog rau, qee zaum, los ntawm GPR55 thiab TRPV1. [172], uas ntxiv txhawb nqa lub luag haujlwm ntawm PPAR hauv kev hloov pauv ntawm kev tiv thaiv kab mob hauv lub cev thiab nws cov kev sib txuas nrog endocannabinoid system.

Txawm li cas los xij, qhov kev tshawb pom tsis ntev los no tau nthuav tawm lub teeb tshiab ntawm kev sib txuas ntawm cannobinomimetics, mast cells, thiab metabolism, uas yog, ketogenesis. Cov ntawv tshaj tawm los ntawm Daniele Piomelli pawg tau qhia txog lub luag haujlwm tsis txaus ntseeg ntawm histamine secreted los ntawm mast hlwb raws li tus neeg nruab nrab tsim nyog los ua kom muaj ketogenesis hauv daim siab hauv lub xeev ntawm kev noj zaub mov tsis txaus [173]. Hom kev tswj hwm metabolic cuam tshuam nrog OEA-kev txiav txim siab ntawm hepatocytes. Txhua zaus, tom qab pub mis, OEA yog tsim nyob rau hauv cov hnyuv me los ntawm kev noj cov lipids thiab koom nrog hauv kev tswj cov zaub mov raws li tus neeg sawv cev satiety ntawm PPAR ua kom [133,174]. Txawm li cas los xij, thaum lub sijhawm noj zaub mov tsis txaus, ketogenesis nyob ntawm daim siab-derived OEA. Lub luag haujlwm tseem ceeb hauv cov txheej txheem no yog ua los ntawm cov pej xeem ntawm cov hlwb mast uas nyob hauv lub plab hnyuv thiab tso tawm histamine hauv lub xeev yoo mov. Histamine nkag mus rau hauv lub siab los ntawm portal ncig thiab nkoos hepatocytes rau OEA secretion ntawm activation ntawm histamine H1 receptors [173]. Tsis tas li ntawd, OEA khi rau PPAR hauv hepatocytes ua rau kev hloov pauv ntawm PPAR -target noob uas tswj ketogenesis, suav nrog ACAT1, HMGSC2, thiab Fgf21 [173]. Cov txiaj ntsig no muab cov kev sib txuas tshiab ntawm mast hlwb ua cov tshuaj tiv thaiv kab mob hauv lub cev, cannabinomimetic PPAR ligand OEA, thiab PPAR -dependent ketogenesis ua cov lus teb rau kev yoo mov.

8. Evolutionary Aspects ntawm PPAR -Mediated Immunomodulation

Ib qho ntawm cov yam ntxwv tseem ceeb ntawm cov lus teb innate yog qhov ceev thiab tam sim ntawd ntawm cov tshuaj tiv thaiv rau menacing invaders. Nyob rau hauv cov vertebrates siab dua, qhov tseeb thiab sai launching ntawm lub innate mechanisms yuav lub sij hawm rau kev npaj ntawm systemic adaptive tiv thaiv. Hauv invertebrates, qhov ua tau zoo ntawm kev tiv thaiv kab mob hauv lub cev yog qhov teeb meem ntawm txoj sia thiab kev tuag. Cov kev cai meej ntawm cov lus teb innate yog ib txoj kev sib txuas lus uas koom nrog ntau txoj hauv kev qhia, suav nrog kev ua haujlwm ntawm cov receptors nuclear, xws li PPARs. Cov kev cai lij choj no txiav txim siab txog kev ua tiav ntawm kev tiv thaiv kab mob parasitic, kab mob, thiab kab mob, ntxiv rau kev muab ib puag ncig zoo rau microbiota commensal thiab txwv tsis pub muaj mob ntsig txog cov ntaub so ntswg puas thiab raug mob.

PPARs thiab NOS ua piv txwv piv txwv ntawm yuav ua li cas cov ntsiab lus ntawm kev tiv thaiv kab mob hauv lub cev thiab lawv cov txheej txheem tswj kev sib koom ua ke hauv lub nceeg vaj tsiaj. Ntawm ib sab, NOS belongs rau tsev neeg loj ntawm evolutionarily ancient enzymes uas suav nrog ntau pro- thiab eukaryotic flavodoxins [175,176]. Muaj ntau qhov kev xav ntawm lawv txoj kev sib raug zoo hauv cov neeg tsis muaj zog hauv kev ua haujlwm ntawm hemolymph homeostasis kev saib xyuas thiab kev puas tsuaj ntawm cov kab mob, piv txwv li, tej zaum sib koom ua ke hauv hemocyte NOS, zoo li cov ntaub ntawv rau horseshoe crabs [175,177].

Ntawm qhov tod tes, PPARs, txawm tias lawv lub hauv paus chiv keeb hauv tsev neeg nuclear uas tshwm sim hauv metazoans, hloov zuj zus hauv cov tsiaj tsuas yog lig raws li cov ceg ntawm Deuterostomata, whereas, nyob rau hauv chordates, lawv muaj hnub los ntawm evolution ntawm Branchiostomata [178]. Yog li ntawd, lawv muaj nyob rau hauv tag nrho cov vertebrates, tab sis (tshwj tsis yog Branchiostomata) tsis muaj nyob rau hauv invertebrates [178]. Lawv lub xub ntiag zoo li cuam tshuam nrog kev hloov pauv ntawm lub cev tiv thaiv kab mob thiab cov ntaub so ntswg adipose, tab sis lawv cov ntaub so ntswg tshwj xeeb tsis sib tshooj nrog lawv cov kev ua haujlwm sib txawv. Cov ceg tseem ceeb tshaj plaws ntawm tsev neeg no zoo li tau sawv cev los ntawm PPAR , thiab kev hloov pauv ntawm tag nrho tsev neeg muaj ob qhov kev hloov pauv ntawm cov noob, thawj qhov txav PPAR sib nrug, thiab lwm qhov muab faib rau lwm pab pawg hauv PPAR thiab subfamilies [179]. Qhov no yuav tsum tau muaj nyob rau theem ntawm ancient, primitive Teleostei [178,179].

Lub caij no, cov ntoo muaj ntau yam NOS tsev neeg yuav tsum tau hauv paus kom tob li hauv qee qhov Protista, raws li tam sim no nyob rau hauv ib qho kev sib txawv sab ceg hauv slime pwm, fungi, thiab siv tau tag nrho Eukaryota suav nrog (ib qho kev sib txawv ntawm qhov sib txawv) siab cov nroj tsuag (Arabidopsis thaliana [180]) . Qhov no tuaj yeem piav qhia txog kev koom tes ntawm PPARs hauv kev ua haujlwm ntawm ntau yam NOS hauv cov vertebrates. Raws li kev hloov pauv, kev sib txawv ntawm NOS tsev neeg tau txais txiaj ntsig zoo ib yam, qhov kev koom tes ntawm PPARs hauv ntau yam ntawm NOS kev ua haujlwm yuav muaj ntau dua lossis tsawg dua (Daim duab 4).

9. Cov lus xaus thiab kev xav

PPAR raws li ib qho kev hloov pauv tau ua rau muaj kev cuam tshuam rau cov cellular metabolism thiab intracellular teeb liab transduction cov xwm txheej, uas hloov lub physiology thiab tus cwj pwm ntawm PPAR - nthuav tawm cov hlwb ntawm ob lub cev tiv thaiv kab mob thiab nonimmune provenance. Cov kev hloov pauv ntawm lub cev no yog ua raws li kev ua haujlwm ntawm immunomodulatory ntawm PPAR hais hauv tshooj dhau los. Qhov dav dav ntawm kev ua ntawm endogenous thiab pharmacological PPAR agonists qhia rau lub cev tiv thaiv kab mob txhawb txoj kev loj hlob ntawm kev siv tshuaj kho mob ntau dua ntawm PPAR-targeted kev daws teeb meem hauv ntau yam kab mob sib kis thiab kab mob ntawm kev tiv thaiv keeb kwm yav dhau. Tam sim no tus kab mob SARS-CoV-2 muaj thoob qhov txhia chaw tau tsim ib qho kev xav tau los hloov kho cov txheej txheem canonical rau kev kho tus kab mob kis kab mob thiab tau qhib qhov kev xav tsis thoob rau cov kev sim tshiab, xws li siv PPAR agonists los ua kom muaj kev puas tsuaj cytokine cua daj cua dub. nyob rau hauv cov mob hnyav COVID-19.

Tus sau kev koom tes:

Conceptualization, MG; Cov ntaub ntawv tshawb fawb thiab kev sib tham txog lub ntsiab lus, MG, MP, PMP, thiab PP; kev sau ntawv—kev npaj ua ntej, MG, MP, PMP, thiab PP; sau ntawv- tshuaj xyuas thiab kho, MG, MP, PMP, thiab PP; Daim duab npaj, MG Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.

Nyiaj txiag:

Qhov kev tshawb fawb no tau nyiaj los ntawm N43 / DBS / 000158 rau PP

Kev tsis sib haum xeeb ntawm kev txaus siab:

Cov kws sau ntawv tshaj tawm tsis muaj kev sib cav txog kev txaus siab.

Cov ntawv luv

2-AG, 2-arachidonoyl-glycerol; ACAT1, acetoacetyl-CoA thiolase 1; AEA, N-arachidonoylethanolamine; AMPs, antimicrobial peptides; AP-1, activation protein 1; CB, cannabinoid receptors; CLRs, C-hom lectin receptors; COX, cyclooxygenase; CSF, colony-stimulating factor; DAMPs, kev puas tsuaj cuam tshuam nrog cov qauv molecular; DOPA, dihydroxyphenylalanine; FAAH, fatty-acid amide hydrolase; FAEs, fatty-acid ethanolamides; FAO, fatty acid oxidation; FGF21, fibroblast kev loj hlob 21; FREPs, fibrinogen-related proteins; HETE, hydroxy eicosatetraenoic acid; HMGCS2, 3-hydroxy-3-methylglytaryl-CoA synthetase 2; HPETE, hydroperoxy eicosatetraenoic acid; IDO, indoleamine-2, 3-dioxygenase; IL, interleukin; ILCs, innate lymphoid hlwb; IRF, interferon-regulated yam; JAK, Janus activated kinase; JNK, c-Jun N-terminal kinase; KO, khob; LOX, lipoxygenase; LPS, lipopolysaccharide; LT, leukotriene; MAMPs, microbial-associated molecular qauv; MBP, myelin yooj yim protein; MCP1, monocyte chemoattractant protein 1; MDSCs, myeloid-derived suppressor hlwb; MMP-9, matrix metalloproteinase 9; NAAA, N-acylethanolaminehydrolyzing acid amidase; NAPE-PLD, N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D; NCOR, nuclear receptor co-repressor; NF-κB, nuclear factor κB; NLR, nucleotide-binding oligomerization domain (NOD)-leucin-rich repeat (LRR)-muaj cov receptors; Tsis yog, nitric oxide; NOD, nucleotide-binding oligomerization domain; NOS, nitric oxide synthase; OEA, oleylethanolamide; PAMPs, cov kab mob cuam tshuam nrog cov qauv molecular; PEA, palmitoylethanolamide; PG, prostaglandin; PPAR, peroxisome proliferator-activated receptor; PPRE, peroxisome proliferator teb cov ntsiab lus; PRRs, qauv-pom zoo receptors; RIG1, retinoic acid inducible noob 1; RLR, retinoic acid inducible gene 1 (RIG1)-zoo li receptors; RNS, reactive nitrogen hom; ROR, retinoid orphan receptor; ROS, reactive oxygen hom; RXR, retinoid X receptor; SAPK, kev ntxhov siab-activated protein kinase; SMRT, silence mediator ntawm retinoid thiab thyroid receptors; STAT, teeb liab transducer thiab activator ntawm transcription; TF, ntaub so ntswg; TFEB, transcription factor EB; TGF, kev hloov pauv kev loj hlob; TLR, Tus Xov Tooj Zoo li receptors; TNF, qog necrosis yam; TRPV1, ib ntus receptor muaj peev xwm cation channel vanilloid subfamily tus tswv cuab 1; TXNIP, thioredoxin-interacting protein.

Cov ntaub ntawv

1. Boraschi, D.; Italiani, P. Innate immune memory: Lub sij hawm rau kev siv cov lus tseeb. Pem hauv ntej. Immunol. 2018, 9, 799. [CrossRef]

2. Netea, MG; Quintin, J.; van der Meer, JW Kev Tiv Thaiv Kev Tiv Thaiv: Lub cim xeeb rau kev tiv thaiv tus tswv tsev. Cell Host Microbe 2011, 9, 355–361. [CrossRef]

3. Mas, Y.; Siva-Jothy, MT Adaptive innate tiv thaiv? Responsive-mode prophylaxis in the mealworm beetle, Tenebrio molitor. Proc. Biol. Sci. 2003, 270, 2475–2480. [CrossRef]

4. Torre, C.; Abnawb, P.; Tsoumtsa, LL. Mottola, G.; Lepolard, C.; Trouplin, V.; Gimenez, G.; Desrousseaux, J.; Gempp, S.; Levasseur, UA; ua al. Staphylococcus aureus txhawb nqa Smed-PGRP-2/Smed-setd8-1 methyltransferase signaling hauv planarian neoblasts kom hnov ​​​​cov tshuaj tiv thaiv kab mob hauv lub sijhawm rov kis mob. EBioMedicine 2017, 20, 150–160. [CrossRef] [PubMed]

5. Zhang, T.; Qias, L.; Sun, Z.; Vaj, L.; Zhou, Z.; Liu, R.; Yees, F.; Sun, R.; Nkauj, L. Qhov tshwj xeeb txhawb kev tiv thaiv kab mob hauv Pacific oysters (Crassostrea gigas) tiv thaiv kev sib tw thib ob nrog Vibrio splendidus. Dev. Comp. Immunol. 2014, 45, 141–150. [CrossRef]

6. Wang, X.; Zhao, Q.; Christensen, BM Identification and characterization of the fibrinogen-like domain of fibrinogen-related proteins in the yoov, Anopheles gambiae, and the fruitfly, Drosophila melanogaster, genomes. BMC Genom. 2005, 6, 114. [CrossRef] [PubMed]

7. Mello, D.; Marino, R.; Italiani, P.; Boraschi, D. Innate tiv thaiv kab mob hauv lub cev tsis muaj zog metazoans: Kev ntsuam xyuas tseem ceeb. Pem hauv ntej. Immunol. 2018, 9, 1915. [CrossRef]

8. Cerenius, L.; Soderhall, K. Kev tiv thaiv kab mob ntawm invertebrate phenoloxidases. Dev. Comp. Immunol. 2021, 122, 104098. [CrossRef]

9. Coates, CJ; Nairn, J. Ntau hom kev tiv thaiv kab mob ntawm hemocyanins. Dev. Comp. Immunol. Xyoo 2014, 45, 43–55. [CrossRef] [PubMed]

10. Yaj, D.; Han, Z.; Oppenheim, JJ Alarmins thiab kev tiv thaiv. Immunol. Rev. 2017, 280, 41–56. [CrossRef]

11. Amarante-Mendes, GP; Adjemian, S.; Branco, LWM; Zanetti, LC; Weinlich, R. Bortoluci, KR Pattern Recognition Receptors, thiab Tus Tswv Tsev Cell Tuag Molecular Machinery. Pem hauv ntej. Immunol. 2018, 9, 2379. [CrossRef] [PubMed]

12. Olive, C. Pattern recognition receptors: Sentinels innate immunity and targets of new vaccine adjuvants. Kws Tshuaj Tiv Thaiv Kab Mob 2012, 11, 237–256. [CrossRef]

13. Rabinovitch, M. Professional, thiab tsis yog tus kws tshaj lij phagocytes: Kev taw qhia. Trends Cell Biol. Xyoo 1995, 5, 85–87. [CrossRef]

14. Lim, JJ; Grinstein, S.; Roth, Z. Diversity and versatility of phagocytosis: Lub luag hauj lwm hauv lub cev tiv thaiv kab mob, kho cov ntaub so ntswg, thiab homeostasis. Pem hauv ntej. Kab mob Cell. Microbiol. 2017, 7, 191. [CrossRef]

15. Witko-Sarsat, V.; Descamps-Latscha, B. Neutrophil-derived Oxidants thiab proteinases li immunomodulatory mediators hauv o. Mediat. Mob. 1994, 3, 257–273. [CrossRef] [PubMed]

16. Nguyen, GT; Ntsuab, ER; Mecsas, J. Neutrophils rau ROScue: Mechanisms of NADPH oxidase activation and bacterial resistance. Pem hauv ntej. Kab mob Cell. Microbiol. 2017, 7, 373. [CrossRef] [PubMed]

17. Kettle, AJ; Winterbourn, CC Myeloperoxidase: Ib qho tseem ceeb regulator ntawm neutrophil oxidant ntau lawm. Redox Rep. 1997, 3, 3–15. [CrossRef]

18. Prolo, C.; Alvarez, MN; Radi, R. Peroxynitrite, muaj zog macrophage-derived oxidizing cytotoxin los tawm tsam cov kab mob invading. Biofactors 2014, 40, 215–225. [CrossRef]

19. Yamasaki, R.; Lu, H.; Butovsky, UA; Aw, N.; Rietsch, AM; Cialic, R.; Wu, PM; Doykan, CE; Lin, J.; Cotleur, AC; ua al. Lub luag haujlwm sib txawv ntawm microglia thiab monocytes hauv cov hlab ntsha hauv nruab nrab ntawm lub paj hlwb. J. Exp. Med. 2014, 211, 1533–1549. [CrossRef]

20. Schulz, D.; Severin, Y.; ib. Zanotelli, VRT; Bodenmiller, B. In-depth characterization ntawm monocyte-derived macrophages siv ib pawg cytometry-based phagocytosis assay. Sci. Rep. 2019, 9, 1925. [CrossRef]

21. Gerner, EW; Meyskens, FL, Jr. Polyamines, thiab mob qog noj ntshav: qub molecules, kev nkag siab tshiab. Nat. Rev. Cancer 2004, 4, 781–792. [CrossRef] [PubMed]

22. Luk, GD Lub luag haujlwm tseem ceeb ntawm polyamine metabolism hauv kev tsim cov kab mob siab. Inhibition ntawm deoxyribonucleic acid thiab protein synthesis thiab cov ntaub so ntswg regeneration los ntawm difluoromethylornithine nyob rau hauv nas. Gastroenterology 1986, 90, 1261–1267. [CrossRef]

23. Murray, PJ Macrophage polarization. Annu. Rev. Physiol. 2017, 79, 541–566. [CrossRef]

24. Locati, M.; Curtale, G.; Mantovani, A. Diversity, Mechanisms, thiab qhov tseem ceeb ntawm macrophage plasticity. Annu. Rev. Pathol. 2020, 15, 123–147. [CrossRef] [PubMed]

25. Gasteiger, G.; D'Osualdo, A.; Schubert, DA; Weber, UA; Bruscia, EM; Hartl, D. Cellular innate tiv thaiv: Ib qho kev ua si qub nrog cov neeg tshiab. J. Innate. Immun. 2017, 9, 111–125. [CrossRef]

26. Erb, KJ; Holloway, JW; Le Gros, G. Mast cells nyob rau hauv pem hauv ntej kab. Innate tiv thaiv kab mob. Curr. Biol. Xyoo 1996, 6, 941–942. [CrossRef]

27. Sendo, S.; Saegusa, J.; Morinobu, A. Myeloid-derived suppressor hlwb nyob rau hauv cov kab mob uas tsis yog-neoplastic inflamed. Mob. Regen. 2018, 38, 19. [CrossRef]

28. Killig, M.; Glatzer, T.; Romagnani, C. Paub cov tswv yim ntawm pawg 3 innate lymphoid hlwb. Pem hauv ntej. Immunol. 2014, 5, 142. [CrossRef]

29. Trabanelli, S.; Gomez-Cadena, A.; Salome, IB; Michaud, K.; Mavilio, D.; Landis, BN; Janus, P.; Jandus, C. Human innate lymphoid cells (ILCs): Mus rau lub cev tsis muaj zog-phenotyping. Cytom. B Clin. Cytom. 2018, 94, 392–399. [CrossRef]

30. Manoharan, I.; Suryawanshi, A.; Hong, Y.; Ranganathan, P.; Shanmugam, A.; Ahmad, S.; Swafford, D.; Manicassamy, IB; Ramesh, G.; Koni, PA; ua al. Homeostatic PPARalpha signaling txwv cov lus teb rau commensal microbiota hauv txoj hnyuv. J. Immunol. Xyoo 2016, 196, 4739–4749. [CrossRef]

31. Sagebiel, AF; Steinert, F.; Lunemann, S.; Korner, C.; Schreurs, R.; Altfeld, M.; ib. Perez, D.; Reinshagen, K.; Bunders, MJ cov ntaub so ntswg-nyob Eomes (ntxiv rau) NK hlwb yog cov neeg nyob hauv lub cev lymphoid loj hauv tib neeg cov hnyuv. Nat. Pawg. 2019, 10, 975. [CrossRef]

32. Gordon, SM; Chaix, J.; Roob, LJ; Wu, J.; Madera, S.; Sun, JC; Lindsten, T.; Reiner, SL Cov ntaub ntawv hloov pauv T-thawj koom ruam thiab Eomes tswj cov chaw kuaj xyuas tseem ceeb ntawm cov neeg tua neeg ntawm tes kom loj hlob. Kev tiv thaiv 2012, 36, 55–67. [CrossRef] [PubMed]

33. Herbert, DR; Douglas, IB; Zullo, K. Group 2 innate lymphoid cells (ILC2): Hom 2 kev tiv thaiv kab mob thiab kev tiv thaiv kab mob helminth. Int. J. Mol. Sci. 2019, 20, 2276. [CrossRef]

34. Hepworth, MR; Fung, TC; Masur, SH; Kelsen, JR; McConnell, FM; Dubrot, J.; DR, DR; Hugues, S.; Farrar, MA; Reith, W.; ua al. Kev tiv thaiv kab mob. Pab pawg 3 innate lymphoid hlwb kho cov hnyuv xaiv ntawm cov kab mob commensal-specific CD4 (plus) T hlwb. Science 2015, 348, 1031–1035. [CrossRef] [PubMed]

35. Nr., DR; Hepworth, MR Group 3 innate lymphoid cells: Kev sib txuas lus ntawm cov kab mob hauv plab hnyuv. Pem hauv ntej. Immunol. 2017, 8, 1298. [CrossRef]

36. Celsus, AC De Medicina, 1st ed.; Nicolaus Laurentii: Florence, Ltalis, 1478.

37. Frias, B.; Merighi, A. Capsaicin, nociception thiab mob. Molecules 2016, 21, 797. [CrossRef]

38. Nilius, B.; Owsianik, G. Lub sijhawm hloov receptor muaj peev xwm tsev neeg ntawm ion raws. Genome Bio. 2011, 12, 218. [CrossRef] [PubMed]

39. Desvergne, B.; Wahli, W. Peroxisome proliferator-activated receptors: Nuclear tswj cov metabolism. Endocrinol. Rev. 1999, 20, 649–688. [CrossRef]

40. Sertznig, P.; Seifert, M.; Tilgen, W. Reichrath, J. Cov ntsiab lus tam sim no thiab kev pom yav tom ntej: Kev ua haujlwm ntawm peroxisome proliferator-activated receptors (PPARs) rau cov kab mob, kev loj hlob, thiab kev kho mob qog noj ntshav. J. Cell Physiol. 2007, 212, 1–12. [CrossRef]

41. Kamata, S.; Oyama, T.; Saib, K.; Honda, A.; Yamamoto, Y.; Suda, K.; Ishikawa, R.; Ib, T.; Watanabe, Y.; Shibata, T.; ua al. PPARalpha ligand-binding domain qauv nrog endogenous fatty acids thiab fibrates. iScience 2020, 23, 101727. [CrossRef]

42. Wahli, W.; Michalik, L. PPARs ntawm kev sib tshuam ntawm lipid signaling thiab o. Trends Endocrinol. Metab. 2012, 23, 351–363. [CrossRef]

43. Lo Verme, J.; Fu, J.; Astarita, G.; La Rana, G.; Rau, R.; Calignano, A.; Piomelli, D. Lub nuclear receptor peroxisome proliferator-activated receptor-alpha mediates lub anti-inflammatory kev ua ntawm palmitoylethanolamide. Mol. Pharmacol. 2005, 67, 15–19. [CrossRef]

44. LoVerme, J.; La Rana, G.; Rau, R.; Calignano, A.; Piomelli, D. Kev tshawb nrhiav cov tshuaj palmitoylethanolamide receptor. Lub neej Sci. 2005, 77, 1685–1698. [CrossRef]

45. de Lera, AR; Krezel, W. Ruhl, R. Ib qho endogenous mammalian retinoid X receptor ligand, thaum kawg! ChemMedChem 2016, 11, 1027–1037. [CrossRef]

46. ​​Ruhl, R.; Krzyzosiak, A.; Niewiadomska-Cimicka, A.; Rochel, N.; Tsaus, L.; Vas, B.; Wietrzych-Schindler, M.; Alvarez, S.; Szklenar, M.; Neeb, L.; ua al. 9-cis-13,14-dihydro retinoic acid yog endogenous retinoid ua raws li RXR ligand hauv cov nas. PLoS Genet. Xyoo 2015, 11, e1005213. [CrossRef] [PubMed]

47. Najib, J. Fenofibrate nyob rau hauv kev kho mob ntawm dyslipidemia: Kev tshuaj xyuas cov ntaub ntawv raws li lawv muaj feem xyuam rau cov tshiab supra bioavailable ntsiav tshuaj formulation. Clin. Ther. 2002, 24, 2022–2050. [CrossRef]

48. Blais, JE; Tong, GKY; Pathadka, S.; Moog, M.; Wong, ICK; Chan, EW Kev sib piv kev ua tau zoo thiab kev nyab xeeb ntawm statin thiab fibrate monotherapy: Kev tshuaj xyuas cov txheej txheem thiab kev tshuaj ntsuam xyuas ntawm lub taub hau-rau-lub taub hau randomized tswj kev sim. PLoS ONE 2021, 16, e0246480. [CrossRef] [PubMed]

49. Alsheikh-Ali, AA; Kuvin, JT; Karas, RH Risk ntawm cov xwm txheej tsis zoo nrog fibrates. Am. J. Cardiol. 2004, 94, 935–938. [CrossRef] [PubMed]

50. Caipainen, A.; Kieran, MW; Huang, S.; Butterfield, C.; Bielenberg, D.; Mostoslavsky, G.; Mulligan, R.; Folkman, J.; Panigrahy, D. PPARalpha deficiency nyob rau hauv inflammatory cells suppresses qog loj hlob. PLoS IB 2007, 2, e260. [CrossRef] [PubMed]

51. Fujimura, Y.; Tachibana, H.; Yamada, K. Peroxisome proliferator-activated receptor ligands tsis zoo tswj cov kev qhia ntawm high-affinity IgE receptor Fc epsilon RI nyob rau hauv tib neeg basophilic KU812 hlwb. Biochem. Biophys. Res. Pawg. 2002, 297, 193–201. [CrossRef]

52. Wb, G.; Honda, K.; Loeyens, M.; Papin, JP; Auwerx, J.; Staels, IB; Capron, M.; ib. Dombrowicz, D. Peroxisome proliferator-activated receptors alpha thiab gamma down-regulate allergic inflammatory and eosinophil activation. J. Exp. Med. 2003, 198, 411–421. [CrossRef] [PubMed]

53. Chinetti, G.; Fruchart, JC; Staels, B. Peroxisome proliferator-activated receptors: Lub hom phiaj tshiab rau kev hloov kho tshuaj ntawm macrophage noob qhia thiab kev ua haujlwm. Curr. Opin. Lipidol. 2003, 14, 459–468. [CrossRef]

54. Babaev, VR; Kev, H.; Ding, L.; Yancey, PG; Daws, DE; Kovacs, WJ; Semenkovich, CF; Fazio, S.; Linton, MF Macrophage qhia ntawm peroxisome proliferator-activated receptor-alpha txo atherosclerosis hauv low-density lipoprotein receptor-deficient nas. Xyoo 2007, 116, 1404–1412. [CrossRef] [PubMed]

55. Wu, L.; Zhang, X.; Zheng, L.; Zhao, H.; Yog, G.; Zhang, Q.; Zhou, Y.; Li, J.; Zhang, J. Wang, J.; ua al. RIPK3 orchestrates fatty acid metabolism hauv cov qog nqaij hlav macrophages thiab hepatocarcinogenesis. Cancer Immunol. Res. Xyoo 2020, 8, 710–721. [CrossRef] [PubMed]

56. Brocker, CN; Yog, J.; Kim, D.; Qu, A.; Bonzo, JA; Gonzalez, FJ Hepatocyte-specific PPARA qhia tshwj xeeb tshaj yog txhawb nqa agonist-induced cell proliferation yam tsis muaj kev cuam tshuam los ntawm nonparenchymal hlwb. Am. J. Physiol. Mob plab. Lub siab Physiol. 2017, 312, G283–G299. [CrossRef]

57. Dubrac, S.; Stoitzner, P.; Pirkebner, D.; Elentner, UA; Schoonjans, K.; Auwerx, J.; Saib, S.; Hengster, P. Fritsch, P. Romani, N.; ua al. Peroxisome proliferator-activated receptor-alpha activation inhibits Langerhans cell function. J. Immunol. Xyoo 2007, 178, 4362–4372. [CrossRef]

58. Poulsen, RC; Mughan, PJ; Kruger, MC Long-chain polyunsaturated fatty acids thiab kev tswj cov pob txha metabolism. Exp. Biol. Med. 2007, 232, 1275–1288. [CrossRef]

59. Tus Thawj Coj, A.; Truitt, J.; Merriman, M.; Ponomareva, O.; Jameson, K.; Ferguson, LB; Mayfield, RD; Harris, RA Localization ntawm PPAR isotypes nyob rau hauv cov laus nas thiab tib neeg lub hlwb. Sci. Rep. 2016, 6, 27618. [CrossRef]

60. Kroetz, DL; Yog, P.; Koste, P.; Bianchi, P.; Pineau, T. Peroxisome proliferator-activated receptor alpha tswj lub siab CYP4A induction adaptive teb rau kev tshaib plab thiab ntshav qab zib. J. Biol. Chem. Xyoo 1998, 273, 31581–31589. [CrossRef]

61. Hashimoto, T.; Fujita, T.; Usuda, N.; Cook, W.; Qi, C.; Peters, JM; Gonzalez, FJ; Yeldandi, AV; Rau, MS; Reddy, JK Peroxisomal thiab mitochondrial fatty acid beta-oxidation hauv nas nullizygous rau ob qho tib si peroxisome proliferator-activated receptor alpha thiab peroxisomal fatty acyl-CoA oxidase. Genotype correlation nrog fatty siab phenotype. J. Biol. Chem. 1999, 274, 19228–19236. [CrossRef]

62. Vila-Brau, A.; De Sousa-Coelho, AL; Mayordomo, C.; Hlo, D.; Marrero, PF Tib Neeg HMGCS2 tswj mitochondrial fatty acid oxidation thiab FGF21 qhia hauv HepG2 cell kab. J. Biol. Chem. 2011, 286, 20423–20430. [CrossRef]

63. Daynes, RA; Jones, DC Emerging lub luag haujlwm ntawm PPARs hauv kev mob thiab tiv thaiv kab mob. Nat. Rev. Immunol. 2002, 2, 748–759. [CrossRef]

64. Ammazzalorso, A.; Bruno, ib.; Florio, R. De Lelis, L.; Laghezza, A.; Cerchia, C.; De Filipis, B.; Fantacuzzi, M.; Giampietro, L.; ib. Maccallini, C.; ib. ua al. Sulfonimide thiab amide derivatives li tshiab PPARalpha antagonists: Synthesis, antiproliferative kev ua si, thiab docking kev tshawb fawb. ACS Med. Chem. Lett. 2020, 11, 624–632. [CrossRef]

65. Kev, P.; De Bosscher, K.; Besnard, S.; ib. Vanden Berghe, W. Peters, JM; Gonzalez, FJ; Fruchart, JC; Tedgui, A.; Haegman, G.; Staels, B. Peroxisome proliferator-activated receptor alpha tsis zoo tswj cov vascular inflammatory gene teb los ntawm kev sib tham tsis zoo nrog cov ntsiab lus ntawm NF-kappaB thiab AP-1. J. Biol. Chem. Xyoo 1999, 274, 32048–32054. [CrossRef] [PubMed]

66. Planavila, A.; Iglesias, R.; Giralt, M.; ib. Villarroya, F. Sirt1 ua haujlwm nrog PPARalpha los tiv thaiv lub plawv ntawm hypertrophy, metabolic dysregulation, thiab o. Cardiovasc. Res. 2011, 90, 276–284. [CrossRef]

67. Rothgiesser, KM; Feem, M.; Hottiger, MO Acetylation ntawm p65 ntawm lysine 314 yog ib qho tseem ceeb rau lig NF-kappaB-dependent gene qhia. BMC Genom. 2010, 11, 22. [CrossRef] [PubMed]

68. Zhang, N.; Chu, ES; Zhang, J. Li, X.; Liang, Q.; Chen, J.; Chen, M.; ib. Thib, N.; Farrell, G.; Sung, JJ; ua al. Peroxisome proliferator-activated receptor alpha inhibits hepatocarcinogenesis los ntawm kev sib kho ntawm NF-kappaB txoj kev taw qhia. Oncotarget 2014, 5, 8330–8340. [CrossRef] [PubMed]

69. Yakhauj, MD; Harrison, SC Structure ntawm IkappaBalpha/NF-kappaB complex. Cell 1998, 95, 749–758. [CrossRef]

70. Chen, LF; Greene, WC Shaping the nuclear action of NF-kappaB. Nat. Rev. Mol. Cell Bio. 2004, 5, 392–401. [CrossRef]

71. Murakami, K.; Booj, H.; Unoki, H.; Saito, Y. Cov nyhuv ntawm PPARalpha ua kom cov macrophages ntawm qhov tso tawm ntawm inflammatory cytokines hauv kab lis kev cai adipocytes. Eur. J. Pharmacol. 2007, 561, 206–213. [CrossRef]

72. Marx, N.; Mackman, N.; Schonbeck, UA; Yilmaz, N.; Hombach, V.; Libby, P.; Plutzky, J. PPARalpha activators inhibit cov ntaub so ntswg qhia thiab kev ua haujlwm hauv tib neeg monocytes. Xyoo 2001, 103, 213–219. [CrossRef]

73. Neeb, BP; Corseaux, D.; Chinetti, G.; Zawadzki, C.; Fruchart, JC; Duriez, P.; Staels, IB; Jude, B. PPARalpha agonists inhibit cov ntaub so ntswg qhia hauv tib neeg monocytes thiab macrophages. Xyoo 2001, 103, 207–212. [CrossRef] 74. Haque, SJ; Sharma, P. Interleukins thiab STAT signaling. Vitam. Horm. Xyoo 2006,

74, 165–206. [CrossRef]

75. Shipley, JM; Waxman, DJ Down-txoj cai ntawm STAT5b transcriptional kev ua los ntawm ligand-activated peroxisome proliferator-activated receptor (PPAR) alpha thiab PPARgamma. Mol. Pharmacol. 2003, 64, 355–364. [CrossRef] [PubMed]

76. Shipley, JM; Waxman, DJ Simultaneous, bidirectional inhibitory crosstalk ntawm PPAR thiab STAT5b. Toxicol. Appl. Pharmacol. 2004, 199, 275–284. [CrossRef] [PubMed]

77. Zhou, YC; Waxman, DJ STAT5b down-regulates peroxisome proliferator-activated receptor alpha transcription by inhibition of ligand-independent activation function region-1 trans-activation domain. J. Biol. Chem. Xyoo 1999, 274, 29874–29882. [CrossRef] [PubMed]

78. Lin, JX; Leonard, WJ Lub luag haujlwm ntawm Stat5a thiab Stat5b hauv kev taw qhia los ntawm IL-2 tsev neeg cytokines. Oncogene 2000, 19, 2566–2576. [CrossRef] [PubMed]

79. Bendickova, K.; Fric, J. Lub luag haujlwm ntawm IL-2 hauv kev sib txuas ntawm kev yoog raws thiab kev tiv thaiv hauv lub cev, thiab ua ib qho cuab yeej rau kev kho mob ntawm tes. J. Leukoc. Biol. Xyoo 2020, 108, 427–437. [CrossRef] 80. Devchand, PR; Keller, H.; Peters, JM; Vazquez, M.; Gonzalez, FJ; Wahli, W. PPARalpha-leukotriene B4 txoj hauv kev los tswj kev mob. Xwm Txheej 1996, 384, 39–43. [CrossRef]

81. Dahlen, SE; Ib, J.; Hedqvist, P.; Arfors, KE; Hammarstrom, S.; Lindgren, JA; Samuelsson, B. Leukotrienes txhawb plasma to thiab leukocyte adhesion nyob rau hauv postcapillary venules: Nyob rau hauv vivo cuam tshuam nrog rau qhov mob inflammatory teb. Proc. Natl. Acad. Sci. USA 1981, 78, 3887–3891. [CrossRef]

82. Lindbom, L.; Hedqvist, P.; Dahlen, SE; Lindgren, JA; Arfors, KE Leukotriene B4 induces extravasation thiab migration ntawm polymorphonuclear leukocytes hauv vivo. Acta Physiol. Luam theej duab. 1982, 116, 105–108. [CrossRef] [PubMed]

83. Marleau, S.; Fruteau de Laclos, B. Sanchez, AB; Poubelle, PE; Borgeat, P. Lub luag hauj lwm ntawm 5-lipoxygenase cov khoom nyob rau hauv lub zos tsub zuj zuj ntawm neutrophils nyob rau hauv dermal o ntawm luav. J. Immunol. 1999, 163, 3449–3458.

84. Yus, K. Bayona, W.; Kallen, IB; Harding, HP; Ravera, CP; McMahon, G.; Brown, M.; Lazar, MA Differential activation ntawm peroxisome proliferator-activated receptors los ntawm eicosanoids. J. Biol. Chem. 1995, 270, 23975–23983. [CrossRef] [PubMed]

85. Christofides, A.; Konstantinidou, E.; Jani, C.; Boussiotis, VA Lub luag haujlwm ntawm peroxisome proliferator-activated receptors (PPAR) hauv kev tiv thaiv kab mob. Metabolism 2021, 114, 154338. [CrossRef]

86. Wolf, AJ; Reyes, CN; Liang, W. Becker, C.; Shimada, K.; Wheeler, ML; Cho, HC; Popescu, NI; Coggeshal, KM; Arditi, M.; ib. ua al. Hexokinase yog ib qho kev tiv thaiv kab mob hauv lub cev rau kev kuaj xyuas cov kab mob peptidoglycan. Cell 2016, 166, 624–636. [CrossRef]

87. Frosali, S.; Pagliari, D.; Gambassi, G.; Landolfi, R.; Pandolfi, F.; Cianci, R. Yuav ua li cas kev sib cuam tshuam ntawm cov neeg hu xov tooj zoo li receptors, microbiota, thiab kev tiv thaiv kab mob hauv plab tuaj yeem cuam tshuam rau kev mob plab. J. Immunol. Res. 2015, 2015, 489821. [CrossRef]

88. Vaj, Y.; Yim, Y.; Chen, X.; Zhao, Y.; Wu, Y.; Li, Y.; Wang, X.; Chen, H.; Xiang, C. Induction ntawm plab hnyuv Th17 hlwb los ntawm flagellins los ntawm segmented filamentous kab mob. Pem hauv ntej. Immunol. 2019, 10, 2750. [CrossRef] [PubMed]

89. Park, JH; Jeong, SY; Choi, AJ; Kim, SJ Lipopolysaccharide ncaj qha txhawb nqa Th17 qhov sib txawv hauv vitro modulating phosphorylation ntawm RelB thiab NF-kappaB1. Immunol. Lett. 2015, 165, 10–19. [CrossRef]

90. Silveira, LS; Pimentel, GD; Souza, CO; Biondo, LA; Teixeira, AAS; Lima, UA; Batatinha, HAP; Rosa Neto, JC; Lira, FS Cov nyhuv ntawm qhov mob nruab nrab-qib kev sib tham ntawm cov metabolic thiab inflammatory profile ntawm PPAR-alpha knockout nas. Cell Biochem. Ua haujlwm. 2017, 35, 510–517. [CrossRef]

91. Becker, J.; ib. Delayre-Orthez, C.; Frossard, N.; Pons, F. Kev cai ntawm peroxisome proliferator-activated receptor-alpha qhia thaum lub ntsws mob. Pum. Pharmacol. Ther. 2008, 21, 324–330. [CrossRef]

92. Chistyakov, DV; Aleshin, SE; Astakhov, AA; Sergeeva, MG; Reiser, G. Kev tswj hwm ntawm peroxisome proliferator-activated receptors (PPAR) alpha thiab -gamma ntawm nas hlwb astrocytes nyob rau hauv chav kawm ntawm kev ua kom los ntawm tus xov tooj zoo li receptor agonists. J. Neeb. 2015, 134, 113–124. [CrossRef]

93. Dana, N.; Javanmard, HS; Vaseghi, G. Cov nyhuv ntawm fenofibrate, PPARalpha activator ntawm tus xov tooj hu ua receptor-4 teeb liab hloov hauv melanoma ob leeg hauv vitro thiab hauv vivo. Clin. Txhais lus. Oncol. Xyoo 2020, 22, 486–494. [CrossRef]

94. Shen, W.; Gao, Y.; Lu, B.; Zhang, Q.; Hu, Y.; Chen, Y. Negatively tswj TLR4/NF-kappaB signaling ntawm PPARalpha hauv endotoxin-induced uveitis. Biochim. Biophys. Xyoo 2014, 1842, 1109–1120. [CrossRef] [PubMed]

95. Lamkanfi, M.; Dixit, VM Mechanisms thiab functions of inflammasomes. Cell 2014, 157, 1013–1022. [CrossRef] [PubMed]

96. Zheng, D.; Liwinski, T.; Elinav, E. Inflammasome activation thiab kev cai: Mus rau kev nkag siab zoo ntawm cov txheej txheem nyuaj. Cell Discov. 2020, 6, 36. [CrossRef] [PubMed]

97. Seok, JK; Kang, HC; Cho, YY; Li, HS; Lee, JY Txoj Cai ntawm NLRP3 inflammasome los ntawm kev hloov kho tom qab kev txhais lus thiab cov khoom me me. Pem hauv ntej. Immunol. 2020, 11, 618231. [CrossRef]

98. Gugliandolo, E.; Fusco, R.; Ginestra, G.; D'Amico, R.; Bisignano, C.; Mandalari, G.; Cuzzocrea, S.; Di Paola, R. Kev koom tes ntawm TLR4 thiab PPAR-alpha receptors hauv tus tswv teb thiab NLRP3 Inflammasome activation, tiv thaiv kab mob ntsws nrog Pseudomonas aeruginosa. Xyoo 2019, 51, 221–227. [CrossRef] [PubMed]

99. Brocker, CN; Kim, D.; Melia, T.; Kev, K.; Velenosi, TJ; Takahashi, S.; Aibara, D.; Bonzo, JA; Levi, M.; Waxman, DJ; ua al. Ntev tsis-coding RNA Gm15441 attenuates hepatic inflammasome activation nyob rau hauv teb rau PPARA agonism thiab yoo mov. Nat. Pawg. 2020, 11, 5847. [CrossRef]

100. Hu, J.; Zhu, Z.; Yim, H.; Yaj, J.; Ma, H.; Li, L.; Zhao, Y. Oleoylethanolamide tiv thaiv kev mob siab rau lub siab los ntawm kev tswj Nrf-2/HO-1 thiab NLRP3 txoj hauv kev hauv nas. Pem hauv ntej. Pharmacol. 2020, 11, 605065. [CrossRef]

101. Lama, A.; Provensi, G.; Amoriello, R. Pirozzi, C.; Rani, IB; Mollica, MP; Rau, GM; Ballerini, C.; ib. Meli, R.; Passani, MB Cov tshuaj tiv thaiv kab mob thiab tiv thaiv kab mob ntawm OEA txwv DSS-induced colitis hauv nas. Biomed. Kws tshuaj. 2020, 129, 110368. [CrossRef]

102. Alderton, WK; Cooper, CE; Knowles, RG Nitric oxide synthases: Cov qauv, kev ua haujlwm, thiab inhibition. Biochem. J. 2001, 357, 593–615. [CrossRef]

103. Kleinert, H.; Schwarz, PM; Forstermann, U. Kev cai ntawm kev qhia ntawm inducible nitric oxide synthase. Biol. Chem. 2003, 384, 1343–1364. [CrossRef] [PubMed] 104. Forstermann, U.; Boissel, JP; Kleinert, H. Kev nthuav qhia kev tswj hwm ntawm 'constitutive' isoforms ntawm nitric oxide synthase (NOS I thiab NOS III). FASEB J. 1998, 12, 773–790. [CrossRef] [PubMed]

105. Pou, S.; Kev, L.; Surichamorn, W.; Rosen, GM Mechanism ntawm superoxide tiam los ntawm neuronal nitric-oxide synthase. J. Biol. Chem. 1999, 274, 9573–9580. [CrossRef] [PubMed]

106. Paukkeri, EL; Leppanen, T.; Sareila, UA; Vuolteenaho, K.; Kankaanranta, H.; Moilanen, E. PPARalpha agonists inhibit nitric oxide ntau lawm los ntawm kev txhim kho iNOS degradation hauv LPS-kho macrophages. Br. J. Pharmacol. 2007, 152, 1081–1091. [CrossRef] [PubMed]

107. Van Ginderachter, JA; Movahedi, K.; Van den Bossche, J.; De Baetselier, P. Macrophages, PPARs, thiab mob qog noj ntshav. PPAR Res. 2008, 2008, 169414. [CrossRef]

108. Maccallini, C.; ib. Mollica, UA; Amoroso, R. Txoj cai zoo ntawm eNOS signaling los ntawm PPAR agonists nyob rau hauv cov kab mob plawv. Am. J. Cardiovasc. Tshuaj 2017, 17, 273–281. [CrossRef]

109. Tanaka, S.; Hosogi, S.; Saib, Y.; Shimamoto, C.; Matsumura, H.; Inui, T.; Marunaka, Y.; Nakahari, T. PPARalpha induced NOS1 phosphorylation ntawm PI3K/Akt nyob rau hauv guinea npua antral mucous hlwb: NO-enhancement hauv Ca(2 ntxiv)-regulated exocytosis. Biomed. Res. 2016, 37, 167–178. [CrossRef]

110. Tanaka, S.; Sugiyama, N.; Takahashi, Y.; Mantoku, D.; Saib, Y.; Kev, H.; Nakano, T.; Shimamoto, C.; Matsumura, H.; Marunaka, Y.; ua al. PPARalpha autocrine regulation ntawm Ca(2)(ntxiv)-tswj exocytosis hauv guinea npua antral mucous hlwb: TSIS TAU thiab cGMP tsub zuj zuj. Am. J. Physiol. Mob plab. Lub siab Physiol. 2014, 307, G1169–G1179. [CrossRef]

111. Bune, AJ; Shergill, JK; Cammac, R.; Ua noj, HT L-arginine depletion los ntawm arginase txo cov nitric oxide ntau lawm hauv endotoxic shock: Kev tshawb fawb electron paramagnetic resonance. PEB Lett. 1995, 366, 127–130. [CrossRef]

112. Mills, CD; Kincaid, K.; Alt, JM; Heilman, MJ; Hill, AM M-1/M-2 macrophages thiab Th1/Th2 paradigm. J. Immunol. 2000, 164, 6166–6173. [CrossRef] [PubMed] 113. Grabacka, M.; Placha, W.; Plonka, PM; Paj, S.; Urbanska, K.; Laidler, P.; Slominski, A. Inhibition ntawm melanoma metastases los ntawm fenofibrate. Arch. Dermatol. Res. 2004, 296, 54–58. [CrossRef]

114. Gallorini, M.; Rapino, M.; Schweikl, H.; Cataldi, UA; Amoroso, R.; Maccallini, C. Selective inhibitors ntawm inducible nitric oxide synthase ua modulators ntawm tes teb nyob rau hauv LPS-stimulated human monocytes. Molecules 2021, 26, 4419. [CrossRef]

115. Teissier, E.; Nohara, A.; Chinetti, G.; Paumelle, R.; Cariou, IB; Fruchart, JC; Brandes, RP; Shah, A.; Staels, B. Peroxisome proliferator-activated receptor alpha induces NADPH oxidase act in macrophages, ua rau tiam LDL nrog PPAR-alpha activation zog. Circ. Res. 2004, 95, 1174–1182. [CrossRef]

116. Deininger, P. Alu ntsiab: Paub SINEs. Genome Bio. 2011, 12, 236. [CrossRef] [PubMed]

117. Reynolds, WF; Kumar, AP; Piedrafita, FJ Tib neeg myeloperoxidase noob yog tswj los ntawm LXR thiab PPARalpha ligands. Biochem. Biophys. Res. Pawg. Xyoo 2006, 349, 846–854. [CrossRef]

118. Penas, F.; Mirkin, UA; Vera, M.; Cev, A.; Gonzalez, CD; Gomez, MI; Kev muag khoom, ME; Goren, NB Kev Kho Mob hauv vitro nrog PPARalpha thiab PPARgamma ligands tsav M1-to-M2 polarization ntawm macrophages los ntawm T. cruzi-mob nas. Biochim. Biophys. Xyoo 2015, 1852, 893–904. [CrossRef] [PubMed]

119. Redlich, S.; Rib, S.; Schutze, S.; Nau, R. Palmitoylethanolamide txhawb nqa phagocytosis ntawm Escherichia coli K1 los ntawm macrophages thiab ua kom cov nas tiv thaiv kab mob. J. Neuroinflamm. 2014, 11, 108. [CrossRef]

120. Kim, YS; Li, HM; Kim, JK; Yang, CS; Kim, TS; Jung, M.; Jin, HS; Kim, S.; Yaj, J.; Aw, GT; ua al. PPAR-alpha activation mediates innate party tiv thaiv los ntawm induction ntawm TFEB thiab lipid catabolism. J. Immunol. 2017, 198, 3283–3295. [CrossRef]

121. Peyron, P.; Vaubourgeix, J.; Poquet, Y.; Levillain, F.; Botanch, C.; Bardou, F.; Daws, M.; Emile, JF; Marchou, IB; Cardona, PJ; ua al. Foamy macrophages los ntawm cov neeg mob tuberculous 'granulomas ua ib lub chaw muaj zaub mov zoo rau M. tuberculosis persistence. PLoS Pathog. Xyoo 2008, 4, e1000204. [CrossRef]

122. Tam, VC; Suen, R.; Ua tsaug, PM; Armando, UA; Lucarelli, R. Gorrochotegui-Escalante, N.; Diercks, AH; Quhenberger, O.; Dennis, EA; Aderem, UA; ua al. PPARalpha exacerbates necroptosis, ua rau muaj kev tuag ntau ntxiv hauv cov kab mob khaub thuas tom qab mob khaub thuas. Proc. Natl. Acad. Sci. USA 2020, 117, 15789–15798. [CrossRef] [PubMed]

123. Ng, VY; Huang, Y.; Reddy, LM; Falck, JR; Lin, ET; Kroetz, DL Cytochrome P450 eicosanoids yog activators ntawm peroxisome proliferator-activated receptor alpha. Drug Metab. Dispos. 2007, 35, 1126–1134. [CrossRef]

124. Yaj, M.; Wang, Y.; Chen, J.; Wang, Q.; Wei, S.; Vang, S.; Qin, Q. Kev soj ntsuam ua haujlwm ntawm Epinephelus coioides peroxisome proliferative-activated receptor alpha (PPARalpha): Kev koom tes hauv kev teb rau cov kab mob kis. Ntses. Plhaub Immunol. 2020, 102, 257–266. [CrossRef]

125. Ehrlich, A.; lwj, S.; Ioannidis, K.; Hofree, M.; tenOever, BR; Nahmias, Y. The SARS-CoV-2 Transcriptional Metabolic Signature in Lung Epithelium. Muaj nyob online: https://ssrn.com/abstract=3650499 ( nkag mus rau 28 Cuaj hlis 2021).

126. Heffernan, KS; Ranadive, SM; Jae, SY Exercise as drug for COVID-19: On PPAR with emerging pharmacotherapy. Med. 2020, 143, 110197. [CrossRef]

127. Piomelli, D.; Hohmann, AG; Seybold, V.; Hammock, BD A lipid rooj vag rau peripheral tswj qhov mob. J. Neeb. 2014, 34, 15184–15191. [CrossRef]

128. Chiurchiu, V.; Battistini, L. Maccarrone, M. Endocannabinoid signaling nyob rau hauv innate thiab adaptive tiv thaiv. Immunology 2015, 144, 352–364. [CrossRef]

129. Guindon, J.; Hohmann, AG Lub endocannabinoid system thiab mob. CNS Neurol. Teeb meem. Drug Targets 2009, 8, 403–421. [CrossRef] [PubMed]

130. Bisogno, T.; Ventriglia, M.; Milone, UA; Mosca, M.; Cimino, G.; Di Marzo, V. Kev tshwm sim thiab cov metabolism ntawm anandamide thiab lwm yam acyl-ethanolamides nyob rau hauv zes qe menyuam ntawm hiav txwv urchin Paracentrotus lividus. Biochim. Biophys. Xyoo 1997, 1345, 338–348. [CrossRef]

131. Sib, N.; De Petrocellis, L.; Montanaro, F.; ib. Cimino, G.; Di Marzo, V. Bioactive ntev saw N-acyl ethanolamines nyob rau hauv tsib hom edible bivalve mollusks. Muaj feem cuam tshuam rau mollusk physiology thiab seafood kev lag luam. Biochim. Biophys. Acta 1998, 1389, 101–111. [CrossRef]

132. Matias, I.; Bisogno, T.; Melck, D.; Vandenbulcke, F.; Verger-Bocquet, M.; De Petrocellis, L.; Sergheraert, C.; Breton, C.; ib. Di Marzo, V.; Salzet, M. Cov pov thawj rau ib qho endocannabinoid system nyob rau hauv lub hauv paus paj hlwb ntawm leech Hirudo medicinalis. Lub hlwb Res. Mol. Lub hlwb Res. 2001, 87, 145–159. [CrossRef]

133. Fu, J.; Gaetani, S.; Kev, F.; Lo Verme, J.; Serrano, UA; Rodriguez De Fonseca, F.; Rosengarth, UA; Lus, H.; Di Giacomo, B.; Tarzia, G.; ua al. Oleylethanolamide tswj kev noj zaub mov thiab lub cev hnyav los ntawm kev ua kom lub zog ntawm cov receptor PPAR-alpha. Xwm Txheej 2003, 425, 90–93. [CrossRef]

134. Bradshaw, HB; Walker, JM Kev nthuav dav ntawm cannabimimetic thiab lwm yam lipid mediators. Br. J. Pharmacol. 2005, 144, 459–465. [CrossRef]

135. Oddi, S.; ib. Fezza, F.; Pasquariello, N.; De Simone, C.; Rapino, C.; Dainese, E.; Finazzi-Agro, UA; Maccarrone, M. Cov ntaub ntawv pov thawj rau kev sib txuam ntawm cov tshuaj anandamide hauv adiposomes. Cell Mol. Lub neej Sci. Xyoo 2008, 65, 840–850. [CrossRef]

136. Kaczocha, M.; Glaser, ST; Chaw, J.; Brown, DA; Deutsch, DG Lipid droplets yog qhov chaw tshiab ntawm N-acylethanolamine inactivation los ntawm fatty acid amide hydrolase -2. J. Biol. Chem. 2010, 285, 2796–2806. [CrossRef] [PubMed]

137. Bisogno, T.; Maurelli, S.; Melck, D.; De Petrocellis, L.; Di Marzo, V. Biosynthesis, uptake, thiab degradation ntawm anandamide thiab palmitoylethanolamide hauv leukocytes. J. Biol. Chem. Xyoo 1997, 272, 3315–3323. [CrossRef] [PubMed]

138. Tsoo, K.; Ikematsu, N.; Uyam, T.; Deutsch, DG; Tokumura, A.; Ueda, N. Biosynthetic pathways ntawm bioactive Nacylethanolamines nyob rau hauv lub hlwb. CNS Neurol. Teeb meem. Drug Targets 2013, 12, 7–16. [CrossRef]

139. Fegley, D.; Gaetani, S.; Duranti, UA; Tontini, A.; Mas, M.; Tarzia, G.; Piomelli, D. Cwj pwm ntawm fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 30 -carbamoyl-biphenyl-3-yl ester (URB597): Cov teebmeem ntawm anandamide thiab oleoylethanolamide deactivation. J. Pharmacol. Exp. Ther. 2005, 313, 352–358. [CrossRef]

140. Ogura, Y.; Parsons, WH; Kamat, SS; Cravatt, BF A calcium-dependent acyltransferase uas tsim N-acyl phosphatidylethanolamines. Nat. Chem. Biol. 2016, 12, 669–671. [CrossRef]

141. Ueda, N.; Tsob, K.; Uyama, T. Metabolism ntawm endocannabinoids thiab lwm yam N-acyl ethanolamines: Canonical thiab lwm txoj hauv kev. FEBS J. 2013, 280, 1874–1894. [CrossRef] [PubMed]

142. LoVerme, J.; Rau, R.; La Rana, G.; Fu, J.; Farthing, J.; Mattace-Raso, G.; Meli, R.; Hohmann, UA; Calignano, A.; Piomelli, D. Rapid broad-spectrum analgesia los ntawm kev ua kom cov peroxisome proliferator-activated receptor-alpha. J. Pharmacol. Exp. Ther. 2006, 319, 1051–1061. [CrossRef]

143. Suardiaz, M.; Estivill-Torrus, G.; Goicoechea, C.; Bilbao, UA; de Fonseca, RF Analgesic zog ntawm oleoyl ethanolamide (OEA) nyob rau hauv visceral thiab inflammatory mob. Mob 2007, 133, 99–110. [CrossRef] [PubMed]

144. Taylor, BK; Dadia, N.; Yang, CB; Krishnan, S.; Badr, M. Peroxisome proliferator-activated receptor agonists inhibit inflammatory edema thiab hyperalgesia. Inflamation 2002, 26, 121–127. [CrossRef]

145. Russo, R.; LoVerme, J.; La Rana, G.; D'Agostino, G.; Saib, O.; Calignano, A.; Piomelli, D. Synergistic antinociception los ntawm cannabinoid receptor agonist anandamide thiab PPAR-alpha receptor agonist GW7647. Eur. J. Pharmacol. 2007, 566, 117–119. [CrossRef]

146. D'Agostino, G.; La Rana, G.; Rau, R.; Saib, O.; Iacono, UA; Esposito, E.; Rau, GM; Cuzzocrea, S.; Lo Verme, J.; Piomelli, D.; ua al. Kev tswj hwm intracerebroventricular ntawm palmitoylethanolamide, ib qho endogenous peroxisome proliferator-activated receptor-alpha agonist, modulates carrageenan-induced paw edema hauv nas. J. Pharmacol. Exp. Ther. 2007, 322, 1137–1143. [CrossRef] [PubMed]

147. Russo, R.; Loverme, J.; La Rana, G.; Compton, TR; Parrott, J.; Duranti, UA; Tontini, A.; Mas, M.; Tarzia, G.; Calignano, A.; ua al. Cov fatty acid amide hydrolase inhibitor URB597 (cyclohexyl carbamic acid 30 -carbamoylbiphenyl-3-} yl ester) txo cov mob neuropathic tom qab kev tswj qhov ncauj hauv cov nas. J. Pharmacol. Exp. Ther. 2007, 322, 236–242. [CrossRef]

148. Ben-Shabat, S.; Fried, E.; Sheskin, T.; Tamiri, T.; Rhee, MH; Vogel, Z.; Bisogno, T.; De Petrocellis, L.; Di Marzo, V.; Mechoulam, R. Cov nyhuv entourage: Inactive endogenous fatty acid glycerol esters txhim khu 2-arachidonoyl-glycerol cannabinoid kev ua. Eur. J. Pharmacol. Xyoo 1998, 353, 23–31. [CrossRef]

149. Ho, WS; Barrett, DA; Randall, MD 'Entourage' cov teebmeem ntawm N-palmitoylethanolamide thiab N-oleoyl ethanolamide ntawm vasorelaxation rau anandamide tshwm sim los ntawm TRPV1 receptors. Br. J. Pharmacol. 2008, 155, 837–846. [CrossRef]

150. Steardo, L., Jr.; Bronzuoli, MR; Iacomino, ib.; Esposito, G.; Steardo, L.; ib. Scuderi, C. Puas yog neuroinflammation tig nplaim taws hauv Alzheimer tus kab mob? Tsom ntsoov rau astrocytes. Pem hauv ntej. Neurosci. 2015, 9, 259. [CrossRef]

151. Skaper, SD; Faci, L.; Giusti, P. Glia thiab mast hlwb raws li lub hom phiaj rau palmitoylethanolamide, anti-inflammatory thiab neuroprotective lipid mediator. Mol. Neurobiol. 2013, 48, 340–352. [CrossRef] [PubMed]

152. Amor, S.; Puentes, F.; Baker, D.; van der Valk, P. Inflamation in neurodegenerative kab mob. Immunology 2010, 129, 154–169. [CrossRef] [PubMed]

153. Colombo, E.; Farina, C. Astrocytes: Qhov tseem ceeb regulators ntawm neuroinflamation. Trends Immunol. 2016, 37, 608–620. [CrossRef] [PubMed]

154. Aloe, L.; Leon, UA; Levi-Montalcini, R. Ib lub tswv yim autacoid mechanism tswj tus cwj pwm mastocyte. Agents Actions 1993, 39, C145–C147. [CrossRef] 155. Benito, C.; Tolon, RM; Castillo, AI; Ruiz-Valdepenas, L.; Martinez-Orgado, JA; Fernandez-Sanchez, FJ; Vasquez, C.; Cravatt, BF; Romero, J. beta-Amyloid exacerbates o nyob rau hauv astrocytes tsis muaj fatty acid amide hydrolase los ntawm ib tug mechanism uas muaj PPAR-alpha, PPAR-gamma, thiab TRPV1, tab sis tsis CB(1) los yog CB(2) receptors. Br. J. Pharmacol. 2012, 166, 1474–1489. [CrossRef]

156. Hohmann, UA; Pluas, M.; Kleine, J. Hohmann, T.; Ghadban, C.; Dehghani, F. Cov teebmeem ntawm neuroprotective cannabinoids, palmitoylethanolamide, thiab 2-arachidonoylglycerol ntawm kev ua haujlwm thiab morphology ntawm microglia. Pem hauv ntej. Neurosci. 2019, 13, 1180. [CrossRef] [PubMed]

157. Bronzuoli, MR; Facchinetti, R. Steardo, L., Jr.; Romano, UA; Stecca, C.; Passarella, S.; Steardo, L.; ib. Cassano, T.; Scuderi, C. Palmitoylethanolamide dampens reactive astrogliosis thiab txhim kho neuronal trophic kev them nyiaj yug nyob rau hauv ib tug triple transgenic qauv ntawm Alzheimer tus kab mob: nyob rau hauv vitro thiab nyob rau hauv vivo pov thawj. Oxid. Med. Cell. Longev. 2018, 2018, 4720532. [CrossRef]

158. Scuderi, C.; Stecca, C.; Valenza, M.; ib. Ratano, P. Bronzuoli, MR; Bartoli, S.; Steardo, L.; ib. Pompili, E.; Fumagalli, L.; Campolongo, P.; ua al. Palmitoylethanolamide tswj reactive gliosis thiab ua haujlwm neuroprotective hauv cov qauv nas ntawm Alzheimer's kab mob. Cell Tuag Dis. Xyoo 2014, 5, e1419. [CrossRef] [PubMed]

159. Scuderi, C.; Valenza, M.; ib. Stecca, C.; Esposito, G.; Carratu, MR; Steardo, L. Palmitoylethanolamide exerts neuroprotective teebmeem nyob rau hauv mixed neuroglial kab lis kev cai thiab organotypic hippocampal slices ntawm peroxisome proliferator-activated receptor-alpha. J. Neuroinflamm. 2012, 9, 49. [CrossRef]

160. Guida, F.; Luongo, L.; Boccella, S.; Giordano, ME; Romano, R.; Bellini, G.; Manzo, ib.; Furiano, UA; Rizzo, A.; Imperatore, R.; ua al. Palmitoylethanolamide induces microglia kev hloov pauv cuam tshuam nrog nce kev tsiv teb tsaws thiab kev ua phagocytic: Kev koom tes ntawm CB2 receptor. Sci. Rep. 2017, 7, 375. [CrossRef]

161. Rinne, P.; Guillamat-Prats, R.; Rami, M.; Bindila, L.; ib. Nplhaib, L.; Lyytikainen, LP; Raitoharju, E.; Oksala, N.; Lehtimaki, T.; Weber, C.; ua al. Palmitoylethanolamide txhawb nqa kev daws teeb meem macrophage phenotype thiab txo qis kev tsim cov atherosclerotic plaque. Arterioscler. Thromb. Vasc. Biol. Xyoo 2018, 38, 2562–2575. [CrossRef]

162. Luo, D.; Zhang, YJ; Yuan, X.; Pan, Y.; Yaj, L.; Zhao, Y.; Zhou, R.; Chen, C.; Peng, L.; Li, W. ua al. Oleoylethanolamide inhibits glial activation ntawm modulating PPARalpha thiab txhawb lub cev muaj zog rov ua haujlwm tom qab lub hlwb ischemia. Pharmacol. Res. Xyoo 2019, 141, 530–540. [CrossRef]

163. Xu, X.; Guo, H.; Jing, Z.; Yaj, L.; Chen, C.; Peng, L.; Wang, X.; Yog, L.; Yog, R.; Jin, X.; ua al. N-oleoyl ethanolamine txo cov inflammatory cytokines thiab adhesion molecules hauv TNF-alpha-induced human umbilical vein endothelial cells los ntawm activating CB2 thiab PPAR-alpha. J. Cardiovasc. Pharmacol. 2016, 68, 280–291. [CrossRef]

164. Holubiec, MI; Romero, IB; Suarez, J.; Portavella, M.; Fernandez-Espejo, E.; Blancco, E.; Galeano, P.; de Fonseca, FR Palmitoylethanolamide tiv thaiv neuroinflammation, txo astrogliosis thiab khaws cia kev paub thiab spatial nco tom qab induction ntawm neonatal anoxia-ischemia. Psychopharmacology 2018, 235, 2929–2945. [CrossRef] [PubMed]

165. Yang, LC; Guo, H.; Zhou, H.; Suo, DQ; Li, WJ; Zhou, Y.; Zhao, Y.; Yang, WS; Jin, X. Kev kho mob ntev oleoyl ethanolamide txhim kho spatial cognitive deficits los ntawm kev txhim kho hippocampal neurogenesis tom qab transient focal cerebral ischemia. Biochem. Pharmacol. 2015, 94, 270–281. [CrossRef]

166. Flannery, LE; Kerr, DM; Hughes, EM; Kelly, C.; Costello, J. Thornton, AM; Humphrey, RM; Finn, DP; Roche, M. Nacylethanolamine regulation of TLR3-induced hyperthermia and neuroinflammatory gene expression: Lub luag hauj lwm rau PPARalpha. J. Neuroimmunol. 2021, 358, 577654. [CrossRef] [PubMed]

167. Taquet, M.; Geddes, JR; Husain, M.; ib. Luciano, S.; Harrison, PJ 6-hloov cov txiaj ntsig ntawm lub paj hlwb thiab kev puas siab puas ntsws hauv 236 379 cov neeg muaj txoj sia nyob ntawm COVID-19: Kev kawm rov qab los ntawm kev siv cov ntaub ntawv kho mob hauv hluav taws xob. Lancet Psychiatry 2021, 8, 416–427. [CrossRef]

168. Vaia, M.; Petrosino, S.; De Filipis, D.; Neeb, L.; Guarino, UA; Carnuccio, R. Di Marzo, V.; Iuvone, T. Palmitoylethanolamide txo qhov mob thiab khaus khaus hauv tus qauv nas ntawm kev sib cuag tsis haum dermatitis. Eur. J. Pharmacol. 2016, 791, 669–674. [CrossRef] [PubMed]

169. Skaper, SD; Faci, L.; Romanello, S.; Leon, A. Mast cell activation ua rau ncua neurodegeneration hauv kev sib xyaw hippocampal kab lis kev cai ntawm txoj kev nitric oxide. J. Neeb. 1996, 66, 1157–1166. [CrossRef]

170. Facci, L.; ib. Dal Tso, R.; Romanello, S.; Buriani, A.; Skaper, SD; Leon, A. Mast hlwb qhia ib qho peripheral cannabinoid receptor nrog qhov sib txawv rhiab heev rau anandamide thiab palmitoylethanolamide. Proc. Natl. Acad. Sci. USA 1995, 92, 3376–3380. [CrossRef]

171. Di Paola, R.; Impellizzeri, D.; Torre, UA; Masson, E.; Cappellani, A.; Faggio, C.; Esposito, E.; Trischitta, F.; Cuzzocrea, S. Cov teebmeem ntawm palmitoylethanolamide ntawm kev raug mob plab hnyuv thiab mob tshwm sim los ntawm ischemia-reperfusion hauv cov nas. J. Leukoc. Biol. 2012, 91, 911–920. [CrossRef] [PubMed]

172. Borrelli, F.; Romano, IB; Petrosino, S.; Pagano, E.; Kabasso, R.; Coppola, D.; ib. Batista, G.; Orlando, P. Di Marzo, V.; Izzo, AA Palmitoylethanolamide, ib txwm tshwm sim lipids, yog ib qho tshuaj tiv thaiv kab mob hauv qhov ncauj. Br. J. Pharmacol. 2015, 172, 142–158. [CrossRef]

173. Misto, A.; Provensi, G.; Vozella, V.; Passani, MB; Piomelli, D. Mast cell-derived histamine tswj lub siab ketogenesis ntawm oleoyl ethanolamide signaling. Cell Metab. 2019, 29, 91–102e5. [CrossRef] [PubMed]

174. Fu, J.; Kim, J.; Kev, F.; Astarita, G.; Piomelli, D. Lub hom phiaj kev txhim kho ntawm oleoylethanolamide ntau lawm nyob rau hauv proximal me txoj hnyuv induces thoob-plaub mov satiety nyob rau hauv nas. Am. J. Physiol. Kev cai. Integr. Comp. Physiol. Xyoo 2008, 295, R45–R50. [CrossRef]

175. Golderer, G.; Werner, ES; Leitner, S.; Grobner, P. Werner-Felmayer, G. Nitric oxide synthase yog induced nyob rau hauv sporulation ntawm Physarum polycephalum. Genes Dev. 2001, 15, 1299–1309. [CrossRef]

176. Hall, DA; Vander Kooi, CW; Stasik, CN; Stevens, SY; Zuiderweg, ER; Matthews, RG Mapping kev sib cuam tshuam ntawm flavodoxin thiab nws tus khub physiological flavodoxin reductase thiab cobalamin-dependent methionine synthase. Proc. Natl. Acad. Sci. USA 2001, 98, 9521–9526. [CrossRef] [PubMed]

177. Radomski, MW; Palmer, RM; Moncada, S. Modulation ntawm platelet aggregation los ntawm txoj kev L-arginine-nitric oxide. Trends Pharmacol. Sci. 1991, 12, 87–88. [CrossRef]

178. Escriva, H.; Saib, R.; Hnia, C.; Langlois, MC; Saumitou-Laprade, P.; Stehelin, D.; Capron, UA; Pierce, R.; Laudet, V. Ligand binding tau txais thaum lub sij hawm evolution ntawm nuclear receptors. Proc. Natl. Acad. Sci. USA 1997, 94, 6803–6808. [CrossRef]

179. Zhou, T.; Yan, X.; Wang, G.; Li, H.; Gan, X.; Zhang, T. Wang, J.; Li, L. Evolutionary qauv thiab kev soj ntsuam kev tswj xyuas los txhawb vim li cas muaj ntau haiv neeg muaj nyob rau hauv PPAR noob tsev neeg. Biomed. Res. Int. 2015, 2015, 613910. [CrossRef]

180. Crawford, NM Mechanisms for nitric oxide synthesis in nroj tsuag. J. Exp. Bot. 2006, 57, 471–478. [CrossRef] 181. Dohrmann, M.; Worheide, G. Sib ntsib thaum ntxov tsiaj evolution siv cov ntaub ntawv phylogenomic. Sci. Rep. 2017, 7, 3599. [CrossRef]

For more information:1950477648nn@gmail.com