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Part 1: Kev Tiv Thaiv Qhov Zoo Ntawm Hydrogen Sulfide Ntawm Lub raum (Tshuaj Xyuas)

May 19, 2022

Yog xav paub ntxiv. tiv taujtina.xiang@wecistanche.com

Abstract. Hydrogen sulfide (H2S) yog ib qho tseem ceeb ntawm lub cev xa tawm roj uas ua haujlwm rau ntau yam kev ua haujlwm lom neeg hauv lub cev, zoo ib yam li cov pa roj carbon monoxide thiab nitric oxide. Cystathionine- -synthase, cystathionine-y-lyase, thiab cysteine ​​transaminase/3-mercaptopyruvate sulphotransferase yog cov enzymes tseem ceeb koom nrog hauv H2S ntau lawm hauv vivo, thiab mitochondria yog thawj qhov chaw ntawm cov metabolism. Nws tau raug tshaj tawm tias H thiab S ua haujlwm tseem ceeb hauv lub cevraum. Nyob rau hauv cov kab mob, xws li ischemia-reperfusion raug mob, tshuaj nephrotoxicity, thiab mob ntshav qab zib nephropathy, H2S ua haujlwm tseem ceeb hauv ob qho tib si tshwm sim thiab kev loj hlob ntawm tus kab mob. Qhov kev tshuaj xyuas tam sim no yog tsom los piav qhia txog kev tsim khoom, cov metabolism, thiab kev ua haujlwm ntawm lub cev ntawm H2S, thiab kev nce qib hauv kev tshawb fawb txog nws lub luag haujlwm hauvmob raumthiab lub raum fibrosis nyob rau hauv xyoo tas los.

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1. Taw qhia

Hydrogen sulfide (H2S) yog thawj zaug suav tias yog cov pa phem; Txawm li cas los xij, nrog rau kev tshawb fawb txuas ntxiv, nws tau raug nthuav tawm los ua lub luag haujlwm tseem ceeb hauv cov kab mob muaj sia, dhau los ua lwm qhov tseem ceeb roj xa tawm, nrog rau carbon monoxide (CO) thiab nitric oxide (NO) (1,2). Txij li thaum H2S tau raug lees paub tias muaj nyob rau hauv cov ntaub so ntswg mammalian, ntau cov kev tshawb fawb tau qhia tias H2S tuaj yeem siv zog.anti-inflammatory, tshuaj tiv thaiv oxidativekev ntxhov siab, thiab kev tiv thaiv fibrotic hauv lub cev (3,4). Cov kev tshawb fawb yav dhau los tau lees paub tias H, S ua haujlwm rau lub cev thiab kev ua haujlwm ntawm lub cevmob plawvlub cev, lub hlwb, thiab lub paj hlwb (5-7). Txawm li cas los xij, vim qhov tsis sib xws ntawm H2S-tsim enzymes nyob rau hauv ntau yam kabmob thiab cov ntaub so ntswg, qhov concentration ntawm H,2S sib txawv hauv cov kabmob sib txawv (8). Kev kawm txog cov txheej txheem hauv qab ntawm H2S hauv cov txheej txheem physiological thiab pathological hauv lub raum tuaj yeem pab ua kom nkag siab txog nws cov molecular biological mechanisms, tshwj xeeb tshaj yog hais txog nws lub luag haujlwm renoprotective.

2. General physicochemical zog ntawm H2S.

H2S yog cov roj tsis muaj xim uas tsw tsw zoo li cov qe lwj; Cov ntxhiab tsw ntawm H2S tuaj yeem khaws los ntawm tib neeg olfactory system thaum lub siab nyob hauv huab cua mus txog 1/400 ntawm nws cov tshuaj lom (9). Raws li cov kua qaub tsis muaj zog, H2S dissociates hauv dej kom ncav cuag qhov sib npaug ntawm chav tsev kub (25 degree) nrog pKa, ntawm 6.97-7.06 thiab pKa, ntawm 12.35-15.0. Ntxiv mus, H2S nyob rau hauv ib tug aqueous tov yog volatile, thiab nws kev sib nrig sib hloov ntawm cov kua theem thiab cov roj theem mus txog equilibrium, raws li qhia nyob rau hauv Fig.1; Qhov kev sib npaug no cuam tshuam los ntawm qhov kub thiab txias, siab, thiab lwm yam kuab tshuaj hauv cov kua dej aqueous (10). Tsis tas li ntawd, H2S yog lipophilic heev, uas tsis tsuas yog tso cai rau nws kom muaj cov concentration ntau dua nyob rau hauv cov xwm txheej muaj roj ntau, tab sis kuj tso cai rau nws mus ywj pheej. nkag mus rau lipid biofilms yam tsis muaj kev vam khom rau cov channel membrane kom ua rau nws txoj haujlwm lom neeg (11). Txij li H2S thiab HS ua ke nyob rau hauv ib qho kev daws teeb meem, nws yog ib qho nyuaj rau kev ua kom pom tseeb qhov txawv ntawm lawv qhov twg muaj lub luag haujlwm hauv cov txheej txheem lom neeg lossis seb lawv ob leeg puas muaj cov teebmeem lom.

Dissociation equilibrium of H2S in aqueous solution (25˚C)

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3. tiam thiab metabolism ntawm H2S

Generation ntawm H2S.Qhov kev sib txuas ntawm H_S hauv cov tsiaj nyeg feem ntau yog nyob ntawm txoj hauv kev enzymatic. Peb cov txheej txheem enzyme uas ua rau H2S ntau lawm suav nrog kev sib koom ua ke ntawm cystathionine- -synthase (CBS), cystathionine-y-lyase (CSE), thiab cysteine ​​transaminase (CAT) nrog 3-mercaptopyruvate ({{7 }}MP) sulphotransferase (3-MST)(12,13). Nrog pyridoxal phosphate (tseem hu ua vitamin B6) ua ib cofactor, CSE thiab CBS yog lub luag hauj lwm rau feem ntau ntawm endogenous H2S generated, raws li qhia nyob rau hauv Fig.2.L-cysteine ​​yog catalyzed los ntawm CSE los yog CBS los tsim HS thiab L-serine. , los yog los ntawm CBS los tsim pyruvate, NH; thiab H2S.CSE tuaj yeem polymerize ob L-cysteine ​​residues rau hauv L-cystine, thiab tom qab ntawd CSE siv L-cystine ua substrate kom decompose nws mus rau hauv thiocysteine, pyruvate, thiab NH3. Lub generated thiocysteine ​​reacts nrog rau lwm yam thiols tsim H2S los ntawm ib tug nonenzymatic cov tshuaj tiv thaiv. Tsis tas li ntawd, L-cysteine ​​polymerizes nrog L-homocysteine ​​li substrates rau CSE los yog CBS los tsim L-cystathionine thiab H2S.L-cystathionine yog ntxiv decomposed los ntawm CSE rau hauv L-cysteine, a-ketobutyrate thiab NH thiab L-cysteine ​​ncig yog tiav. (12,13). Nws tau raug tshaj tawm tias nyob rau hauv cov tshuaj tiv thaiv uas L-cysteine ​​metabolized rau H2S ntawm CBS, tus nqi ntawm H2S tsim los ntawm -hloov yog 50X ntawm -elimination (14). Thaum lub sij hawm zus tau tej cov H2S los ntawm CSE, lub , -elimination ntawm cysteine ​​​​yog thawj qhov chaw ntawm HS, accounting rau 70 feem pua ​​​​ntawm H2S ntau lawm (15).

Tsis zoo li CSE thiab CBS, 3-MST siv hlau zinc ua cofactor(14). Ntxiv mus, L-cysteine ​​yuav tsum tau hloov mus rau hauv 3-MP thiab L-glutamic acid los ntawm cov tshuaj tiv thaiv ntawm CAT nrog -ketoglutarate, thiab 3-MP yog ces desulfurized los ntawm 3-MST raws li ib tug ncaj substrate. los tsim HS thiab pyruvate(16,17).In peroxisomes, D-amino acid oxidase catalyzes D-cysteine, es tsis txhob L-cysteine, los tsim 3-MP, NH3 thiab H2O, nyob rau hauv muaj dej thiab oxygen, thiab qhov tshwm sim 3-MP yog pauv mus rau mitochondria rau 3-MST siv los tsim H2S(18). Kev nkag ntawm 3-MP hauv peroxidase rau hauv mitochondria feem ntau yog nyob rau hauv daim ntawv ntawm vesicles, raws li qhia hauv Fig.2. Cov kev soj ntsuam soj ntsuam tau tshaj tawm tias cov synthesis ntawm CSE thiab CBS hauv cov neeg mob uas muaj kab mob hauv lub raum tau txo qis, qhov kev qhia ntawm 3-MST thiab hemorrhagic homocysteine ​​​​nce (19). Qhov no tuaj yeem piav qhia los ntawm cov txheej txheem tshwj xeeb ntawm kev ua haujlwm siv los ntawm cov lus hais saum toj no los tsim H2S. Thaum kev tsim cov H2S los ntawm CBS thiab CSE ntawm txoj kev L-homocysteine ​​/ L-cystathionine raug txo, kev siv L-homocysteine ​​raug txwv, thiab tus neeg mob tuaj yeem nrog hyperhomocysteine ​​​​emia.

Figure 2. In the cytoplasm, 1‑3: CSE or CBS catalyzes the β‑replacement reaction of L‑cysteine and L‑homocysteine to polymerize and form L‑cystathionine and H2S. L‑cystathionine is decomposed by CSE into L‑cysteine, α‑ketobutyrate and NH3 by means of α, γ‑elimination. L‑cysteine continues to participate in the reaction. 4 and 5: L‑cysteine is catalyzed to produce L‑serine and H2S via CBS β‑elimination or CSE α, β‑elimination. 7: CBS catalyzes L‑cysteine to produce pyruvate, NH3 and H2S through α, β‑elimination. 6 and 9: CSE first polymerizes two L‑cysteines into L‑cystine, then CSE uses L‑cystine as a substrate to decompose it into thiocysteine (mercaptocysteine, Cyc‑SSH), pyruvate and NH3, resulting in thiocysteine generating H2S via nonenzymatic reactions with other thiols. 8: L‑homocysteine generates α‑ketobutyrate, NH3 and H2S through CSE α, γ‑elimination. In the mitochondria, CAT catalyzes L‑cysteine and α‑ketoglutarate to produce 3‑MP, which is then catalyzed by 3‑MST to produce pyruvate and H2S. In peroxisomes, 3‑MP produced by DAO and catalyzed by D‑cysteine is transported to the mitochondria in vesicles. H2S, hydrogen sulfide; CBS, cystathionine‑β‑synthase; CSE, cystathionine‑γ‑lyase; 3‑MP, 3‑mercap‑ topyruvate; CAT, cysteine transaminase; 3‑MST, 3‑MP sulphotransferase; DAO, D‑amino acid oxidase.

Metabolism ntawm H2S. H2S hauv lub cev feem ntau metabolized los ntawm mitochondria (20). Sulfoquinone oxidoreductase (SQOR) hauv mitochondria tuaj yeem siv H2S thiab metabolize nws mus rau hauv thiosulfate nrog kev pab ntawm thiosulfate sulfurtransferase (TST) thiab thiol dioxygenase (ETHEl). Thaum cov txheej txheem no, txo glutathione ua lub luag haujlwm tseem ceeb, thiab thiosulfate ntxiv oxidized nyob rau hauv qhov kev txiav txim ntawm thiosulfate reductase thiab sulfite oxidase (SUOX), thiab thaum kawg tawm hauv daim ntawv ntawm sulfate los ntawm ob lub raum, raws li qhia hauv Fig.3.Lub luag haujlwm ntawm O, nyob rau hauv cov txheej txheem no, yog irreplaceable (21,22). Qhov tseem ceeb, coenzyme Q (CoQ) muaj feem cuam tshuam nrog cov enzymes tau hais tseg. Ib txoj kev tshawb fawb yav dhau los tau qhia tias qhov tsis muaj CoQ tuaj yeem ua rau txo qis ntawm kev qhia theem ntawm thioquinone oxidoreductase, TST, ETHE1, thiab SUOX(23). Thaum lub sijhawm pib ntawm CoQ tsis txaus, SQOR qib tau txo qis, cuam tshuam rau H2S oxidation, thiab CoQ supplementation tuaj yeem txuag H2S metabolism tsis cuam tshuam rau nws cov khoom tsim (24). Thaum SQOR kev ua haujlwm thiab cov qib protein txo qis, cov protein ntau ntawm lwm cov mitochondrial enzymes (TST, ETHEl, thiab SUOX) hauv H2S oxidation txoj hauv kev nce hauv fibroblasts; Txawm li cas los xij, nws tsis paub meej tias qhov kev nce qib ntawm ntau cov enzymes yog qhov nce ib ntus ntawm cov nyiaj them poob haujlwm lossis qhov sib npaug ntawm qhov txo qis hauv SQOR qib (23). Yog li ntawd, nws yog ib qho tseem ceeb uas yuav tau tshawb xyuas cov txiaj ntsig ntawm CoQ deficiency ntawm H2S metabolic enzymes, uas yuav pab tau rau kev kawm txog kev tswj hwm ntawm H2S concentration los ntawm H2S metabolic txoj hauv kev los cuam tshuam ntau txoj hauv kev hauv lub cev.

Figure 3. Oxidative metabolism of H2S in the mitochondria. H2S in the mitochondria is activated by SQOR, which receives an‑SH group to form an‑SSH group. In the presence of O2 and H2O, ‑SSH is used by ETHE1 to generate H2SO3, which is further converted into thiosulfate by TST using the‑SSH group. Finally, thiosulfate is oxidized by TR and SUOX, and is eventually excreted in the kidney as sulfate. H2S, hydrogen sulfide; SQOR, sulfoquinone oxidoreductase; ETHE1, thiodioxygenase; TST, thiosulfate sulfur transferase; TR, thiosulfate reductase; SUOX, sulfite oxidase.

Raws li ib txwm muaj lub cev muaj zog, thaum H2S ntau lawm hauv cov ntaub so ntswg ntau tshaj li kev siv cov metabolism, lwm txoj hauv kev metabolic, cytoplasmic methyltransferase methylation, yuav tsum tau. Txog niaj hnub no, paub txog methyltransferases hauv tib neeg lub cev yog thiopurine methyltransferase (TPMT) thiab thiol methyltransferase (TMT). TPMT xaiv methylates thiopurine tebchaw, thaum TMT xaiv methylates aliphatic mercaptan substrates. Siv cov spectrometry loj los ntsuas qhov tsim ntawm methyl sulfide, cov methylation ntawm H2S thiab cov kinetic curves tau raug soj ntsuam yav tas los; Km ntawm methylation ntawm HS yog 146.2 ntxiv rau 29.2 μmol (25). Nws kuj tau pom tias tib neeg methyltransferase-zoo li cov protein 7B tuaj yeem ua rau kev hloov pauv ntawm pawg methyl los ntawm S-adenosine 1-methionine rau H2S thiab lwm yam exogenous mercaptan me me molecules, yog li metabolizing H2S (25). Tsis tas li ntawd, H2S tuaj yeem raug tshem tawm los ntawm methemoglobin lossis hlau / nonmetallic molecules, xws li oxidized glutathione (26).

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4. Lub luag haujlwm ntawm lub cev ntawm H2S hauv lub raum

Lub raum excretory muaj nuj nqi. Cov kev tshawb fawb soj ntsuam tau lees paub tias plasma H2S qib tau zoo cuam tshuam nrog glomerular filtration rate hauv cov neeg mob uas muaj kab mob raum ntev (CKD). Tsis tas li ntawd, cov ntsiab lus hauv cov ntshav homocysteine ​​​​hauv cov neeg mob uas muaj qib siab CKD (CKD3-5) tau raug tshaj tawm tias muaj txiaj ntsig zoo. siab dua li cov neeg mob uas muaj CKD thaum ntxov (CKD1-2), thiab nce qib hauv cov ntshav homocysteine ​​​​tau cuam tshuam nrog lub raum tsis ua haujlwm (19). Hyperhomocysteineemia tau pom tias ua rau ua rau muaj kev cuam tshuam ntawm extracellular matrix (ECM) cov protein thiab kev puas tsuaj ntawm connexin, thiab ua rau cov phosphorylation ntawm endothelial NO synthase (eNOS) nyob rau hauv lub raum vascular endothelial hlwb, yog li txo cov bioavailability ntawm NO kom induce vasoconstriction thiab txo. Lub raum cov ntshav khiav, uas yog tshwm sim los ntawm qhov txo qis hauv cov ntshav H2S qib thiab glomerular filtration rate (GFR)(27).H2S tuaj yeem nce zis sodium thiab potassium excretion los ntawm inhibiting Na-K-2Cl co-transporters thiab Na- K-ATPase. Hauv vivo thwmsim tau pom tias intra-renal artery infusion ntawm H2S pub NaHS tuaj yeem ua rau lub raum cov ntshav khiav, GFR thiab tso zis ntawm sodium [U (Na) x ntim] thiab potassium [U (K) x ntim), thiab cov infusion. ntawm L-cysteine ​​​​ntawm lub raum cov hlab ntsha kom nce qhov concentration ntawm H2S substrate tuaj yeem simulate cov nyhuv no (28). Tsis tas li ntawd, H2S tuaj yeem thaiv qhov qhib ntawm phosphatidylinositol 3,4,5-triphosphate-dependent distal raum epithelial sodium channels. induced los ntawm H2O, txo cov reabsorption ntawm sodium los ntawm nephrons, thiab nce urinary sodium excretion (29). Tsis tas li ntawd, kev siv CSE thiab CBS enzyme inhibitors propargylglycine thiab amino-oxoacetate tau pom tias ua kom cov zis ntim thiab txo cov zis osmotic siab hauv nas; qhov no muaj feem xyuam rau HS-vim txo qis hauv kev qhia ntawm aquaporin (AQP)-2 hauv lub raum medulla. Tom qab kev kho mob nrog GYY4137, H2S tus neeg pub dawb tau txhawb nqa tus neeg sawv cev tso tawm, qhia qib ntawm AQP-2 tau raug kho ntau heev (30).

H2S tuaj yeem ncaj qha rau qee qhov H2S-sensitive disulfide daim ntawv cog lus nyob rau hauv epidermal growth factor receptor (EGFR), uas tuaj yeem ua rau endocytosis thiab inhibition ntawm Na-K-ATPase hauv lub raum tubular epithelial hlwb los ntawm kev tswj EGFR / GAB1 / PI3K / Akt txoj hauv kev, yog li. txo sodium thiab potassium ion pauv ntawm lub raum tubular epithelial hlwb, thiab txhawb nqa sodium excretion (31). Txawm li cas los xij, yuav ua li cas EGFR / GAB1 / PI3K / Akt txoj hauv kev ua ntawm Na-K-ATPase tseem yuav txiav txim siab. EGFR paub tias muaj tyrosine kinase kev ua haujlwm, thiab nws cov neeg hauv tsev neeg tuaj yeem khi rau ntau yam ligands los ua homodimers lossis heterodimers, ua rau phosphorylation ntawm cov tyrosine residues hauv intracellular domains. Nyob rau hauv lub raum vascular endothelial hlwb, inhibition ntawm EGFR tau raug qhia kom dilate lub raum hlab ntsha thiab txhim kho lub raum ntshav txaus; nyob rau hauv podocytes, inhibition ntawm EGFR yuav txo tau podocyte puas thiab poob vim los ntawm cov ntshav qab zib ntau ntau, thiab txo proteinuria, whereas, nyob rau hauv lub raum tubular epithelial hlwb, inhibition ntawm EGFR tau qhia kom alleviate lub raum tubular raug mob thiab epithelial-mesenchymal hloov (EMT) (32). , 33). Txawm li cas los xij, kev tshawb fawb ntawm inhibitors ntawm EGFR tyrosine kinase kev ua haujlwm tau pom tias inhibition ntawm EGFR tuaj yeem ua rau lub raum puas thiab electrolyte cuam tshuam (34). Yog li, yuav tsum muaj kev tshawb fawb tob ntxiv, tshwj xeeb yog hais txog qhov zoo thiab qhov tsis zoo ntawm H2S hauv kev tswj hwm EGFR txoj hauv kev.

Yog li, cov kev tshawb fawb yav dhau los no tau qhia tias H2S muaj lub luag haujlwm hauv cov metabolism hauv dej thiab electrolytes ntawm ntau txoj hauv kev. Feem ntau, nws tau pom zoo tias qhov nce siab ntawm H_S yog qhov tsim nyog rau kev tswj cov kua dej tawm ntawm lub raum, qhov inhibition ntawm nws cov khoom tuaj yeem khaws cov kua dej. Yog li, H2S-generating enzyme CBS thiab CSE inhibitors tej zaum yuav muaj peev xwm diuretics.

Oxygen sensing.H2S-mediated O, kev nkag siab tau kuaj pom nyob rau hauv ntau yam O2-sensing cov ntaub so ntswg nyob rau hauv lub plawv thiab ua pa systems ntawm vertebrates (35,36). Cov nyhuv ntawm Hson downstream signaling cov xwm txheej zoo ib yam nrog hypoxia ua kom (37,38).Nyob rau hauv lub raum ib txwm, vim lub intrarenal arteriovenous oxygen shunt, lub raum nyob rau hauv lub xeev ntawm qis oxygen ib nrab siab piv nrog rau lwm yam kabmob, thiab cov Lub raum medulla oxygen ib nrab siab qis dua li ntawm lub raum parenchyma (39,40). Yog li, H2S yog suav tias yog ib qho oxygen sensor nyob rau hauv lub raum, tshwj xeeb tshaj yog nyob rau hauv lub medulla (41). Raws li cov pa oxygen sensor, H2S yog inseparable ntawm nws tiam thiab oxidative metabolic tshuav nyiaj li cas.H2S tiam tsis yog nyob ntawm O, tab sis nws oxidative metabolism hauv mitochondria yog nyob ntawm oxygen, raws li tau hais tseg; Yog li ntawd, hypoxia tuaj yeem ua rau muaj kev nce hauv H2S concentration thiab kev sib raug zoo ntawm ob (37). Lub mitochondrial oxidative respiratory electron thauj saw yog lub ntsiab txhais ntawm lub zog tsim; Yog li nws yog qhov tsim nyog thiab tseem ceeb los ua pov thawj tias H2S koom nrog kev tsim hluav taws xob nyob rau hauv lub cev muaj zog hauv lub raum medulla nyob rau hauv ib txwm hypoxia. Raws li oxygen sensor, H2S tuaj yeem cuam tshuam cov ntshav ntws thiab tswj cov pa oxygen hauv lub plawv thiab lub ntsws. Txawm hais tias H2S tseem tswj hwm kev faib cov pa oxygen hauv lub raum cortex thiab medulla nyob rau hauv cov xwm txheej ntawm lub cev los ntawm cov txheej txheem no lossis ntawm lwm txoj kev tseem yuav txiav txim siab. Kev tshawb xyuas qhov chaw thiab cov txheej txheem molecular ntawm H2S raws li cov pa oxygen sensor cuam tshuam rau qhov tshwm sim ntawm cov xwm txheej qis qis yuav ua rau peb nkag siab ntxiv txog H2S raws li oxygen sensor.

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