By Cocer Peptides 
Watanni 1 da suka gabata
DUKKANIN LABARI DA BAYANIN KYAUTATAWA DA AKE BAYAR A WANNAN SHAFIN KAWAI DOMIN WATSA BAYANI NE DA MANUFOFIN ILIMI.
Kayayyakin da aka bayar akan wannan gidan yanar gizon an yi niyya ne kawai don binciken in vitro. Binciken in vitro (Latin: *a cikin gilashi*, ma'ana a cikin gilashin gilashi) ana gudanar da shi a wajen jikin mutum. Waɗannan samfuran ba magunguna ba ne, Hukumar Abinci da Magunguna ta Amurka (FDA) ba ta amince da su ba, kuma dole ne a yi amfani da su don hanawa, magani, ko warkar da duk wani yanayi na likita, cuta, ko cuta. Doka ta haramta shigar da waɗannan samfuran cikin jikin mutum ko dabba ta kowace hanya.
Bayanan asali game da KPV
KPV shine tripeptide tare da mahimman abubuwan hana kumburi, wanda ke ba shi damar taka rawa a fagage da yawa.
Hoto 1 Hanyoyin Magani na HA-KPV-NPs a kan UC Oral Administration na HA-KPV-NPs da aka saka a cikin hydrogel (chitosan / alginate) yana ba da tasirin maganin warkewa a kan UC ta hanyar hanzarta warkar da mucosa da rage kumburi.
Kayan aikin rigakafin kumburi na KPV
1. Ka'ida ta Hanyar Siginar salula
Hanyar Siginar Siginar NF-κB: NF-κB shine maɓalli mai mahimmanci wanda ke taka muhimmiyar rawa a cikin martani mai kumburi. Lokacin da aka fallasa ƙwayoyin sel zuwa abubuwan da ke haifar da kumburi, NF-κB suna canzawa daga cytoplasm zuwa tsakiya, farawa da kwafin kwayoyin halittar cytokine masu kumburi. KPV na iya hana kunna NF-κB. A cikin kwayoyin epithelial na hanji na mutum da ƙwayoyin T na mutum, an motsa kwayoyin halitta tare da cytokines masu kumburi, kuma an kara KPV a lokaci guda. Yin amfani da hanyoyi irin su NF-κB luciferase gene reporter assays, furotin immunoblotting, real-time reverse transcription polymerase chain reaction, da enzyme-linked immunosorbent assay (ELISA), an gano cewa KPV a ƙananan ƙwayoyin nanomolar na iya hana NF-κB kunnawa, ta haka ne rage ɓoyewar cytokines mai kumburi. Wannan tsari yana da mahimmanci a cikin tsari na kumburi na hanji, kamar yadda yawan kunna NF-kB a cikin kwayoyin epithelial na intestinal da kwayoyin rigakafi shine mahimmin sifa na cututtukan cututtuka na hanji (IBD) da sauran yanayin kumburi na hanji.
Hanyar siginar MAP kinase: Hanyar siginar furotin mai kunnawa (MAPK) wata hanya ce mai mahimmanci mai mahimmanci a cikin amsawar kumburi, ciki har da kinase mai daidaita siginar siginar (ERK), c-Jun N-terminal kinase (JNK), da p38 MAPK. Wadannan kinases suna kunna lokacin da kwayoyin halitta ke nunawa ga abubuwan da ke haifar da kumburi, wanda ke haifar da phosphorylation na abubuwan da aka rubuta a ƙasa da kuma inganta bayyanar cututtuka masu alaka da kumburi. KPV kuma na iya hana hanyar siginar kumburin MAP kinase. Lokacin da aka fallasa ƙwayoyin sel zuwa abubuwan motsa jiki, KPV na iya toshe kunnawa MAPK, rage phosphorylation na abubuwan da aka rubuta a ƙasa, ta haka yana rage samar da cytokines masu kumburi. A cikin yanayi mai kumburi, kunna p38 MAPK yana haifar da ƙara yawan maganganun cytokines masu kumburi irin su TNF-a da IL-6, yayin da KPV na iya hana aikin p38 MAPK, rage ɓoyewar waɗannan cytokines kuma ta haka ne ya rage amsawar kumburi.
2. Tasirin mai ɗaukar hoto mai ɗaukar hoto
PepT1 transporter: PepT1 di/tripeptide transporter yawanci bayyana a cikin ƙananan hanji amma jawo a cikin hanji a lokacin IBD. Sakamakon anti-kumburi na KPV an yi amfani da shi ta hanyar PepT1. A cikin gwaje-gwajen ɗauka, an yi amfani da KPV mai sanyi azaman mai hana mai gasa don hPepT1 a matsayin mai lakabin rediyoaktif, ko [⊃3; H] KPV an yi amfani da shi don tantance halayen motsa jiki na ɗaukar KPV. KPV yana shiga ƙwayoyin rigakafi da ƙwayoyin epithelial na hanji ta hanyar hPepT1. Wannan yana nuna cewa PepT1, a matsayin mai ɗaukar kaya, yana sauƙaƙe shigar da KPV cikin sel don aiwatar da tasirin cutar kansa. Lokacin da aka hana aikin PepT1, adadin KPV da ke shiga sel yana raguwa, kuma tasirinsa na anti-mai kumburi daidai yake da rauni. A cikin samfuran tantanin halitta tare da ƙwanƙwasa maganganun PepT1, ko da lokacin da aka gudanar da su a daidai wannan taro, KPV yana nuna raguwar tasirin hanawa akan kunnawa na NF-κB da rage ɓoyewar cytokines mai kumburi idan aka kwatanta da sel tare da maganganun PepT1 na yau da kullun, yana ƙara tabbatar da mahimmancin tsaka-tsaki na PepT1 a cikin tsarin rigakafin kumburi na KPV.
3. Tsarin cytokines mai kumburi
Hanawar cytokines masu kumburi: KPV na iya hana haɓakawa da sakin cytokines masu kumburi da yawa. TNF-a shine maɓallin cytokine mai mahimmanci a cikin martani mai kumburi, yana iya kunna ƙwayoyin rigakafi, haifar da samar da wasu cytokines masu kumburi, da haifar da lalacewar nama. A cikin nau'i-nau'i daban-daban na kumburi, matakan magana na TNF-a sun ragu sosai bayan maganin KPV. Alal misali, a cikin samfurin ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar cuta ta sodium sulfate, jiyya tare da KPV ya haifar da raguwa mai yawa a cikin maganganun mRNA na TNF-α a cikin ƙwayar hanji, kamar yadda aka gano ta hanyar RT-PCR na ainihi, da kuma raguwa mai mahimmanci a cikin abun ciki na furotin na TNF-α a cikin jini, kamar yadda ELISA ta gano. IL-1β, IL-6, da sauran cytokines pro-inflammatory kuma an hana su ta KPV. IL-1β na iya haifar da ƙwayar cuta mai kumburi, inganta sakin sauran masu shiga tsakani. KPV na iya rage maganganunsa da ɓoyewa a cikin kyallen takarda mai kumburi, ta haka ne ya rage ƙarfin amsawar kumburi.
Haɓakawa na cytokines masu kumburi: Baya ga hana cytokines masu kumburi, KPV kuma na iya haɓaka maganganun cytokines masu kumburi. Interleukin-10 (IL-10) wani muhimmin cytokine mai kumburi ne wanda zai iya hana kunna ƙwayoyin rigakafi kuma ya rage samar da cytokines masu kumburi.
4. Tsarin ƙwayoyin rigakafi
Ka'idar aikin cell T: Kwayoyin T suna taka muhimmiyar rawa a cikin martani na rigakafi da tsarin kumburi. A ƙarƙashin yanayin kumburi, ƙwayoyin T suna kunna kuma suna ɓoye cytokines masu kumburi. Nazarin ya nuna cewa KPV na iya daidaita aikin T cell. A cikin gwaje-gwajen tare da layin T cell na Jurkat, lokacin da kwayoyin Jurkat suka motsa tare da cytokines masu kumburi, ƙari na KPV ya hana T cell kunnawa kuma ya rage siginar cytokines masu kumburi irin su IFN-γ. Ana iya samun wannan ta hanyar hana hanyoyin siginar NF-κB da MAPK a cikin ƙwayoyin T. Bugu da ƙari, a cikin wasu nau'ikan dabbobi, irin su CD45RB (hi) samfurin kumburi na colonic, maganin KPV zai iya tsara tsarin shigar da kwayar cutar T da aiki a cikin hanji, rage ƙananan ƙwayoyin T cell masu alaka da kumburi irin su Th1 da Th17 sel, da kuma ƙara yawan adadin ƙwayoyin T na tsari, don haka yana rage kumburin hanji.
Modulation na aikin macrophage: Macrophages sune mahimman ƙwayoyin rigakafi a cikin amsawar kumburi kuma ana iya rarraba su cikin macrophages M1 da aka kunna da macrophages na M2 maimakon kunna su dangane da yanayin kunnawa. M1 macrophages suna ɓoye adadi mai yawa na cytokines pro-inflammatory, yayin da M2 macrophages suna da aikin rigakafin kumburi da nama. KPV na iya daidaita macrophage polarization. Gwaje-gwajen in vitro sun nuna cewa lokacin da aka motsa macrophages tare da lipopolysaccharide (LPS) don daidaitawa zuwa nau'in M1, haɗin gwiwar gudanarwar KPV ya hana macrophage polarization zuwa nau'in M1, ya rage ma'anar M1 macrophage alamomi, yayin da inganta polarization su zuwa ga nau'in M2 na macrophage, ƙara yawan maganganun M2. Arg-1). A cikin vivo nau'ikan kumburi, irin su DSS-induced colitis a cikin berayen, jiyya tare da KPV ya haifar da ƙarin macrophages a cikin nama na hanji zuwa nau'in M2, ta haka yana rage martanin kumburi da haɓaka gyaran nama.
5. Tasirin kariya akan kwayoyin epithelial na hanji
Haɓaka aikin shinge na epithelial: Katangar jiki da aka kafa ta ƙwayoyin epithelial na hanji yana aiki a matsayin layin farko na kariya daga kamuwa da cuta da cutarwa. A cikin jihohin masu kumburi, rashin aikin shinge na epithelial na hanji yana haifar da canzawar kwayoyin cuta da zubar da endotoxin, yana kara tsananta martani mai kumburi. KPV na iya haɓaka aikin shinge na ƙwayoyin epithelial na hanji. Gwaje-gwajen cell vitro, inda aka bi da layin epithelial na hanji tare da cytokines pro-inflammatory don daidaita yanayin mai kumburi, ya haifar da raguwar maganganun sunadaran haɗin gwiwa (kamar ZO-1 da occludin) da ƙarancin aikin shinge. Duk da haka, ƙari na KPV yana kula da maganganun ƙwayoyin sunadaran haɗin gwiwa, yana haɓaka haɗin kai, kuma yana mayar da aikin shinge na ƙwayoyin epithelial na hanji. A cikin ƙananan ƙwayoyin cuta na DSS da aka yi amfani da su tare da KPV, immunohistochemistry da Western blot bincike sun nuna ƙara yawan maganganun ƙwayoyin ƙwayoyin cuta a cikin ƙwayar hanji da kuma rage karfin hanji, yana nuna cewa KPV yana kare shingen epithelial na hanji a cikin vivo, yana rage mamayewa na abubuwa masu cutarwa, kuma yana rage martanin kumburi.
Haɓaka haɓakar ƙwayar ƙwayar cuta da gyarawa: Kumburi na iya haifar da lalacewa da kuma mutuwar kwayoyin epithelial na hanji, yana lalata aikin hanji na al'ada. KPV yana da ikon inganta haɓakawa da gyaran ƙwayoyin epithelial na hanji. Gwaje-gwajen al'adun sel a cikin vitro sun nuna cewa yin maganin ƙwayoyin epithelial na hanji da suka lalace tare da KPV sun haɓaka haɓakar tantanin halitta, kamar yadda Kit ɗin Ƙididdigar Kwayoyin Halitta (CCK-8) ta gano. Bugu da ƙari, nazarin immunofluorescence ya nuna ƙarar bayyanar da haɓakar antigen na nukiliya (PCNA), yana nuna cewa sel suna cikin yanayin haɓakawa. A cikin samfurin bera mai ciwon ciki wanda ya haifar da TNBS, bayan jiyya tare da KPV/SH-PGA hydrogel, binciken tarihi ya nuna cewa an gyara lalacewar ƙwayoyin epithelial na colonic, kuma tsarin crypt a hankali ya koma al'ada. Wannan na iya kasancewa yana da alaƙa da haɓakar KPV na haɓakar ƙwayoyin epithelial da gyarawa, wanda ke taimakawa rage kumburi da haɓaka dawo da nama na hanji.
Hoto 2 KPV yana warkewa a cikin DSS colitis.
6. Antioxidant illa
Ka'idar alamomin da ke da alaƙa da damuwa: Kumburi yana sau da yawa tare da halayen damuwa na oxidative, tare da ƙara yawan samar da nau'in oxygen mai amsawa (ROS) da nau'in nitrogen mai amsawa (RNS), wanda ke haifar da lalacewar oxidative ga sel da kyallen takarda. KPV yana nuna tasirin antioxidant kuma yana iya daidaita alamun da ke da alaƙa da damuwa. A cikin wasu nau'ikan kumburi, irin su samfurin granuloma na linzamin kwamfuta na auduga da kuma samfurin kwai da aka haifar da bera dorsal sac synovitis model, matakan girma na malondialdehyde (MDA) da rage ayyukan superoxide dismutase (SOD) an gano su a cikin kyallen takarda. Bayan jiyya na KPV, matakan MDA sun ragu sosai, kuma aikin SOD ya karu. MDA samfur ne na peroxidation na lipid, kuma raguwar matakansa yana nuna raguwar lalacewar peroxidation na sel; SOD muhimmin enzyme ne na antioxidant, kuma ƙara yawan ayyukansa yana nuna haɓakar ikon ɓata radicals kyauta. KPV na iya rage lalacewar oxidative a cikin kyallen takarda mai kumburi ta hanyar daidaita matakan damuwa na oxidative, ta haka yana haifar da tasirin anti-mai kumburi.
7. Wasu Hanyoyi masu yuwuwa
Dangantaka tare da mai karɓar melanocortin: KPV tripeptide ne wanda aka samo daga α-MSH. Ko da yake tasirin sa na hana kumburi suna ɗan zaman kansu daga siginar MC1R, ana iya haɗa su da MC1R a wasu mahallin. A cikin dabbobin da ke bayyana MC1Re / e, KPV magani bayan DSS-induced colitis har yanzu yana yin tasiri mai mahimmanci na maganin kumburi, ceton duk dabbobin da ke cikin rukunin jiyya daga mutuwa a lokacin DSS-induced colitis, yana nuna cewa KPV's anti-inflammatory effects ne a kalla partially m daga MC1R sigina. A cikin dabbobi tare da maganganun MC1R na yau da kullun, KPV na iya haɓaka tasirin anti-mai kumburi ta hanyar hulɗa tare da MC1R ko daidaita hanyoyin siginar ta ƙasa.
Hanyoyin Anti-mai kumburi na KPV
1. Matsayi a cikin ƙirar kumburin hanji
DSS-induced colitis model: A cikin DSS-induced mouse colitis model, KPV ya nuna gagarumin anti-mai kumburi sakamako. Dangane da canje-canjen nauyi, berayen da aka yi musu magani tare da KPV sun dawo da nauyinsu a baya kuma zuwa mafi girma idan aka kwatanta da berayen da ba a kula da su ba. Abubuwan lura na tarihi sun nuna raguwar raguwa mai kumburi a cikin ƙwayar hanji na berayen da aka yi wa KPV, wanda ya kara tabbatar da raguwar raguwar ayyukan myeloperoxidase (MPO). MPO wani enzyme ne da ke cikin neutrophils, kuma matakan ayyukansa suna nuna girman kutsawar kwayar halitta mai kumburi a cikin kyallen takarda. Rage ayyukan MPO bayan jiyya na KPV yana nuna raguwar kutsawar neutrophil a cikin nama na hanji da kuma rage martanin kumburi. Ta hanyar gano ma'anar mRNA na cytokines pro-inflammatory a cikin ƙwayar ƙwayar cuta, irin su TNF-α da IL-1β, an gano cewa maganin KPV ya rage girman matakan maganganun waɗannan cytokines masu kumburi. KPV ya rage bayyanar cututtuka na DSS da ke haifar da colitis daga bangarori da yawa, ciki har da rage ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar ƙwayar cuta ce ta KPV, da kuma rage yawan ƙwayar ƙwayar cuta, da kuma inganta farfadowar nauyi.
CD45RB (hi) samfurin kumburi na hanji: A cikin CD45RB (hi) ƙirar kumburin ƙwayar cuta, KPV kuma ya nuna sakamako mai kyau na rigakafin kumburi. An jawo wannan ƙirar ta hanyar canja wurin ƙwayoyin T da ke bayyana CD45RB sosai cikin ɓeraye marasa ƙarfi. Bayan jiyya na KPV, berayen sun nuna ingantattun alamun kumburi, dawo da nauyi a hankali, da binciken tarihi ya nuna raguwar canje-canjen kumburin hanji. The KPV-treated group showed decreased inflammatory cell infiltration and reduced crypt structural damage in intestinal tissues, indicating that KPV effectively alleviates CD45RB(hi)-induced intestinal inflammation and restores normal intestinal tissue structure and function.
TNBS-induced ulcerative colitis model: A cikin TNBS-induced ulcerative colitis rat model, KPV kuma ya nuna gagarumin tasiri na warkewa. Bayan gudanar da KPV/SH-PGA hydrogel ga berayen, alamun colitis sun inganta sosai. An rage ma'aunin asarar nauyi a cikin berayen, kuma ƙimar ayyukan cutar (DAI) ta ragu. Makin DAI gabaɗaya yana la'akari da alamomi kamar canje-canje a cikin nauyin jikin bera, halayen fecal, da hematochesia. Ragewarta yana nuna cewa KPV/SH-PGA hydrogel na iya rage tsananin tsananin ciwon ulcer da TNBS ke haifarwa. KPV/SH-PGA hydrogel magani kuma yana hana rage hanji a cikin berayen, rage matakan myeloperoxidase na colonic, da kuma dawo da tsarin tsarin halittar mazauni, gami da shingen epithelial, crypts, da ƙwayoyin goblet mara kyau. The expression of pro-inflammatory cytokines, TNF-α and IL-6, in colonic tissue was also significantly reduced, further demonstrating the anti-inflammatory effect of KPV in the TNBS-induced ulcerative colitis model.
Kammalawa
KPV, a matsayin tripeptide tare da kaddarorin anti-mai kumburi, yana nuna sakamako mai ban sha'awa a cikin rigakafi da maganin kumburin hanji da sauran cututtukan da ke da alaƙa da kumburi. Hanyoyin sa na maganin kumburi sun haɗa da bangarori da yawa, ciki har da tsara hanyoyin siginar salula, damuwa na antioxidant, da daidaitawa na apoptosis da autophagy.
Sources
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