{"id":5289,"date":"2024-08-04T18:15:20","date_gmt":"2024-08-04T18:15:20","guid":{"rendered":"https:\/\/longchangextracts.com\/?p=5289"},"modified":"2024-08-04T18:15:20","modified_gmt":"2024-08-04T18:15:20","slug":"dihydromyricetin-2","status":"publish","type":"post","link":"https:\/\/longchangextracts.com\/da\/dihydromyricetin-2\/","title":{"rendered":"Udforskning af dihydromyricetins mekanisme til forbedring af nyrefibrose hos db\/db-mus baseret p\u00e5 netv\u00e6rksfarmakologi og eksperimentel verifikation"},"content":{"rendered":"<p>Udforskning af dihydromyricetins mekanisme til forbedring af nyrefibrose hos db\/db-mus baseret p\u00e5 netv\u00e6rksfarmakologi og eksperimentel verifikation<br \/>\nDiabetesnefropati (DKD) er en af de st\u00f8rste mikrovaskul\u00e6re komplikationer ved type 2-diabetes mellitus (T2DM) og den vigtigste \u00e5rsag til nyresygdom i slutstadiet. Dens vigtigste egenskaber er fortykkelse af den glomerul\u00e6re k\u00e6ldermembran, udvidelse af mesenteriet og tubulointerstitiel matrix og tab af podocytter, hvilket f\u00f8rer til udvikling af mikroalbuminuri og nedsat nyrefunktion. Med den fortsatte udvikling af diabetisk nyresygdom (DKD) gennemg\u00e5r nyrev\u00e6vets mikrostruktur vedvarende inflammation og skade, hvilket f\u00f8rer til diffus interstitiel fibrose, der \u00f8del\u00e6gger den normale renale mikrostruktur og i sidste ende udvikler sig til renal fibrose (RF). I \u00f8jeblikket fokuserer midlerne til at afhj\u00e6lpe udviklingen af DKD til RF prim\u00e6rt p\u00e5 at forbedre DKD. Mekanismen bag de fleste diabeteskomplikationer, herunder DKD, er dog endnu ikke afklaret, s\u00e5 den komplekse mekanisme i processen, hvor DKD udvikler sig til RF, er ikke klar, hvilket f\u00f8rer til utilfredsstillende terapeutiske effekter af DKD og RF. Derfor haster det med at udforske DKD's patogenese og opdage nye terapeutiske m\u00e5l for at h\u00e6mme dens udvikling.<br \/>\nDihydromyricetin (DHM) er en naturlig flavonoidforbindelse med forskellige farmakologiske virkninger, herunder antiinflammatorisk, antioxidant, fjernelse af frie radikaler, forbedring af mitokondriel dysfunktion og regulering af autofagi. P\u00e5 nuv\u00e6rende tidspunkt har flere unders\u00f8gelser vist, at DHM har et stort potentiale i behandlingen af metaboliske sygdomme. Det kan ikke kun forbedre insulinresistensen og s\u00e6nke blodsukkerniveauet ved at inducere autofagi, forbedre oxidativ stress, h\u00e6mme inflammation og \u00f8ge mitokondrieaktiviteten, men ogs\u00e5; Samtidig kan det forbedre mange komplikationer af diabetes, s\u00e5som diabetesencefalopati, diabeteskardiomyopati osv. Forskningen i DHM, der forbedrer komplikationerne af diabetes, er imidlertid ikke tilstr\u00e6kkelig, og den relaterede farmakologiske mekanisme skal stadig udforskes yderligere. Derudover er der begr\u00e6nset forskning i, om DHM yderligere kan forbedre RF for\u00e5rsaget af DHM, og den terapeutiske effekt er stadig uklar.<br \/>\nNetv\u00e6rksfarmakologi kan konstruere et interaktionsnetv\u00e6rk for \"l\u00e6gemiddelkomponent-m\u00e5lsygdom\" baseret p\u00e5 strukturen af komponenter i traditionel kinesisk medicin, deres biologiske virkninger og sygdomsrelaterede m\u00e5l i forbindelse med et stort netv\u00e6rk af biologiske processer. Det er et effektivt middel til at udforske de effektive komponenter, molekyl\u00e6re mekanismer og potentielle m\u00e5l for traditionel kinesisk medicin. Molekyl\u00e6r docking kan simulere interaktionen mellem molekyler og proteiner, forudsige konformationen af ligander og receptorer, beregne og forudsige affinitet og bindingstilstande for at verificere den specifikke virkem\u00e5de af l\u00e6gemiddelkomponenter p\u00e5 vigtige m\u00e5l. Derfor brugte denne unders\u00f8gelse netv\u00e6rksfarmakologi til at screene og forudsige potentielle m\u00e5l for DHM p\u00e5 DKD og RF, konstruerede et interaktionsnetv\u00e6rk for \"komponent-m\u00e5lsygdom\" og validerede de forudsagte hovedm\u00e5l gennem molekyl\u00e6r docking og in vivo-eksperimenter. Den molekyl\u00e6re mekanisme for dihydromyricetin, der forbedrer nyrefibrose hos db\/db-mus, blev udforsket, hvilket gav et teoretisk grundlag for den kliniske anvendelse af DHM.<\/p>\n<p>&nbsp;<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-5290\" src=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/1-134.png\" alt=\"\" width=\"342\" height=\"209\" \/><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-5291\" src=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/2-121.png\" alt=\"\" width=\"355\" height=\"214\" \/><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-5292\" src=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/3-115.png\" alt=\"\" width=\"758\" height=\"279\" \/><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-5293\" src=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/4-103.png\" alt=\"\" width=\"769\" height=\"320\" \/><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-5294\" src=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/5-92.png\" alt=\"\" width=\"759\" height=\"196\" \/><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-5295\" src=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/6-85.png\" alt=\"\" width=\"726\" height=\"928\" srcset=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/6-85.png 726w, https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/6-85-563x720.png 563w\" sizes=\"(max-width: 726px) 100vw, 726px\" \/><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-5296\" src=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/7-76.png\" alt=\"\" width=\"642\" height=\"280\" \/><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-5297\" src=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/8-71.png\" alt=\"\" width=\"635\" height=\"302\" \/><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-5298\" src=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/9-64.png\" alt=\"\" width=\"698\" height=\"718\" \/><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-5299\" src=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/10-52.png\" alt=\"\" width=\"703\" height=\"339\" \/><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-5300\" src=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/11-46.png\" alt=\"\" width=\"742\" height=\"256\" \/><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-5301\" src=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/12-39.png\" alt=\"\" width=\"693\" height=\"318\" \/><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-5302\" src=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/13-34.png\" alt=\"\" width=\"699\" height=\"350\" \/><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-5303\" src=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/14-29.png\" alt=\"\" width=\"694\" height=\"292\" \/><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-5304\" src=\"https:\/\/longchangextracts.com\/wp-content\/uploads\/2024\/08\/15-22.png\" alt=\"\" width=\"735\" height=\"479\" \/><br \/>\nP\u00e5 nuv\u00e6rende tidspunkt afh\u00e6nger den almindelige behandling af diabetes hovedsageligt af kontrollen med blodsukkeret, mens DKD, en af de alvorligste komplikationer ved diabetes, ikke har nogen effektiv behandlingsstrategi. Derfor er det meget vigtigt at have en dyb forst\u00e5else af patogenesen af DKD og at finde effektive behandlingsstrategier for at undertrykke tendensen til, at DKD udvikler sig til nyrefibrose. Naturmedicin har vist sig at have unikke fordele i form af f\u00e6rre bivirkninger og multi-target-effektivitet, hvilket har gjort dem til en vigtig kilde til udvikling af nye l\u00e6gemidler til kroniske sygdomme i de senere \u00e5r. Yderligere forskning i DHM har afsl\u00f8ret et betydeligt terapeutisk potentiale i forbedringen af metaboliske sygdomme. Baseret p\u00e5 forbedringen af nyrefibrose hos db\/db-mus med DHM kombinerer denne unders\u00f8gelse derfor netv\u00e6rksfarmakologi og molekyl\u00e6r docking-teknologi for at udforske de potentielle terapeutiske m\u00e5l og molekyl\u00e6re mekanismer for DHM til forbedring af nyrefibrose hos db\/db-mus og verificerer dem gennem dyrefors\u00f8g.<\/p>\n<p>For det f\u00f8rste observerede vi, at 10 ugers DHM-intervention effektivt kan lindre blodsukker, kropsv\u00e6gt, kreatinin, urinstofnitrogen, urinprotein og nyrepatologiske manifestationer i db\/db-mus, hvilket indikerer, at DHM kan lindre nyrefunktionsskader og bremse udviklingen af DKD i db\/db-mus. Efter at have analyseret og screenet 37 krydsende m\u00e5l for DHM, DKD og RF blev det konstateret, at 10 m\u00e5l, herunder AKT1, ALB, CASP3, EGFR, MMP9, IGF1, PPARG, KDR, MMP2, ACE, kan v\u00e6re vigtige m\u00e5l for DHM til at forbedre DKD. Det er blevet bekr\u00e6ftet, at AKT1, CASP3, EGFR, MMP9, IGF1, MMP2 og ACE aktiveres i milj\u00f8et omkring diabetes, og specifik h\u00e6mning kan forbedre den beskadigede tilstand af DKD og bremse udviklingstendensen af fibrose. PPARG og KDR h\u00e6mmes i det fysiologiske milj\u00f8 ved diabetes og spiller en rolle i nyrebeskyttelsen efter aktivering. ALB er en vigtig biokemisk indikator for at observere graden af nyreskade under udviklingen af diabetes. Det stiger normalt med forekomsten af DKD og falder efter forbedring af DKD. Det betyder, at de 10 n\u00f8glegener, vi har screenet, ikke kun kan tjene som potentielle biomark\u00f8rer for DKD, men ogs\u00e5 som vigtige m\u00e5l for yderligere udforskning af patogenesen og behandlingen af DKD.<\/p>\n<p>KEGG pathway enrichment analysis viste, at forbedringen af DHM p\u00e5 DKD kan involvere AGE-RAGE-signalvej, diabetes kardiomyopati og FoxO-signalvej. AGE-RAGE-signalvejen og FoxO-signalvejen spiller vigtige regulerende roller i udviklingen af DKD. Forskning har vist, at AGE'er specifikt aktiveres i endotelceller, nyretubuli, mesangiale celler og podocytter hos DKD-patienter, og deres interaktion med RAGE forbedres, hvilket yderligere forv\u00e6rrer oxidativ stress og inflammation i nyrerne, hvilket f\u00f8rer til forringelse af DKD. Desuden kan aktiveret FoxO3a h\u00e6mme niveauet af oxidativ stress i nyrerne hos diabetesrotter, forbedre inflammation og derefter h\u00e6mme forekomsten af DKD. Det indikerer, at specifik regulering af AGE-RAGE-signalvejen eller FoxO-signalvejen kan v\u00e6re af stor betydning for forebyggelse og behandling af DKD.<\/p>\n<p>De molekyl\u00e6re dockingresultater viste, at DHM udviste god bindingsaffinitet med de top 5 udvalgte m\u00e5l, hvilket indikerer, at DHM's effektivitet i behandlingen af DKD er blevet valideret p\u00e5 molekyl\u00e6rt niveau. Derudover bem\u00e6rkede vi, at det vigtigste m\u00e5lgen AKT1, som rangerede f\u00f8rst i screeningen, var t\u00e6t forbundet med AGE-RAGE-signalvejen og FoxO-signalvejen i udviklingen af DKD gennem berigelsesanalyse af KEGG-vejen. AGE-RAGE-signalvejen kan i synergi med PI3K\/Akt-signalvejen fremkalde oxidativ stress og kronisk inflammation i nyrerne, hvilket f\u00f8rer til nyresygdom. Aktivering af PI3K\/Akt\/FoxO3a-signalvejen kan forbedre nyrernes fysiologiske funktion ved diabetes. Derfor fors\u00f8gte vi yderligere at unders\u00f8ge interaktionen mellem Notch-vejen opstr\u00f8ms for AKT1 og DHM og gennemf\u00f8rte molekyl\u00e6r docking-validering. De molekyl\u00e6re dockingresultater viste, at DHM udviste god bindingsaffinitet med Notch1 og PTEN.<\/p>\n<p>Tidligere unders\u00f8gelser har vist, at Notch-vejen er overaktiveret under udviklingen af DKD, hvilket viser sig ved \u00f8get udtryk af Notch1, NICD, Hes1 og Hey1. H\u00e6mmere af Notch1 kan aktivere PTEN ved at reducere aktiveringen af Hes1 og derved forbedre autofagi-forstyrrelser og bremse forekomsten af RF. Derudover har andre unders\u00f8gelser vist, at PTEN-aktivering ogs\u00e5 kan lindre udviklingen af DKD ved at h\u00e6mme PI3K\/Akt-vejen. Baseret p\u00e5 ovenst\u00e5ende resultater spekulerer vi i, at DHM kan forbedre DKD ved at regulere Notch\/PTEN\/AKT-vejen. Western blot-resultater viste en unormal stigning i aktiveringen af Notch-stien, et fald i PTEN-ekspression og en stigning i AKT-phosphorylering i nyrerne hos db\/db-mus. Og DHM-indtag kan h\u00e6mme aktiveringen af Notch-vejen, aktivere PTEN og h\u00e6mme fosforyleringen af AKT. Selvom Notch\/PTEN\/AKT-signalaksen som en hel vej sj\u00e6ldent er blevet unders\u00f8gt i forbindelse med nyrebeskyttelse ved diabetes, har vores forskning til en vis grad forbedret relevant forskning og beriget den molekyl\u00e6re mekanisme for DHM's biologiske beskyttelse gennem flere m\u00e5l.<\/p>\n<p>Sammenfattende, baseret p\u00e5 observationen af DHM, der forbedrer de patologiske manifestationer af DKD, kombinerede denne unders\u00f8gelse netv\u00e6rksfarmakologi og molekyl\u00e6r dockingteknologi for forel\u00f8bigt at demonstrere, at DHM's rolle i forbedring af udviklingen af DKD kan opn\u00e5s gennem n\u00f8glem\u00e5l som AKT1, ALB, CASP3, EGFR, MMP9, IGF1, PPARG, KDR, MMP2, ACE og analyserede de relevante veje; Endelig blev der foretaget en forel\u00f8big validering og analyse af de potentielle AKT-m\u00e5l for DHM gennem dyrefors\u00f8g, og det blev konstateret, at DHM kan spille en rolle i forebyggelse og behandling af DKD ved at regulere Notch\/PTEN\/AKT-vejen (se figur 14). Der er dog i \u00f8jeblikket relativt lidt forskning i komplikationerne ved DHM i T2DM, og dets terapeutiske potentiale skal stadig unders\u00f8ges n\u00e6rmere.<\/p>","protected":false},"excerpt":{"rendered":"<p>Exploring the mechanism of dihydromyricetin in improving renal fibrosis in db\/db mice based on network pharmacology and experimental verification Diabetes nephropathy (DKD) is one of the major microvascular complications of type 2 diabetes mellitus (T2DM) and the main cause of end-stage renal disease. 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