| Objective:To explore the effects and mechanism of liraglutide on glycometabolism and psoriatic skin lesions and the expression of IL-23/Th17 axis in obesity diabetic mice Methods:Thirty six specific-pathogen-free male BKS-DB/Nju db/db and wt/wt mice were purchased from Model Animal Research Center of Nanjing University.afte r one week adaption,all mice were randomly divided into six groups,A group(w t/wt+vaseline+vehicle),B group(wt/wt+IMQ+vehicle),C group(db/db+vaseline+vehi cle),D group(db/db+vaseline+Liraglutide),E group(db/db+IMQ+vehicle),F group(d b/db+IMQ+Liraglutide);before the experiment,the fasting glucose and weigh wer e measured;D and F group were treated with liraglutide(300ug/kg)by intreperito neal injection for 4 weeks;A,B,C and E group were treated with vehicle instea d;after 4 weeks treatments,all the mice were shaved and depilated on their bac ks.A daily topical dose of 62.5 mg of commercially available imiquimod cream(5%)(Imiquimod Cream;MingXin liddy,Sichuan,China)or control cream(Vas eline and a cream containing isostearic acid)was applied to the shaved back s kin of mice for 7 consecutive days(days 0-6).at the end of the experiment,all mice were sacrificed and the serum,urine and back tissue were collected to det ected the indexes of metabolism as well as the relative protein and mRNA exp ression of IL-23,IL-17,IL-22,TNF-α.Results:1.After 4 weeks treatment,compared to A group,the weigh of db/db mice in B group were not increased(P>0.05);there were not significance between B,C,E and F group(P>0.05);Compared to C group,the level of FBG,FINS and H OMA-IR were slightly decreased in D and F group(P<0.05);Compare to A gro up,the level of FBG was slightly decreased and FINS increased(P<0.05)but no significance of HOMA-IR(P>0.05)in B group;compared to C group,the level o f HbA1 c in D,E and F groups were slightly decreased but no statistic differen ce(P>0.05),compared to E group,the FBG and HOMA-IR were decreased(P<0.05),but no significance of HbA1 c and FINS.2.After 4 weeks treatment,compared to A group,the level of FFA,TG,LDLC were not significantly difference(P>0.05)in B group,but the level of TC wa s increased and HDL-C decreased(P<0.05).compared to C group,the level of FF A,TG were decreased and HDL-C was increased in D and F group(P<0.05)but no significance of TC level(P>0.05),in addition,the level of LDL-C were decre ased in D group(P<0.05)but no significantly difference in F group(P>0.05).co mpared to E group,the FFA and TG were decreased(P<0.05),as well as the lev el of HDL-C increased(P<0.05),but no significance of TC and LDL-C(P>0.05);3.After 4 weeks treatment,compared to A group,the serum creatinine and urea nitrogen were no significance in B group(P>0.05).there were no significan ce difference between C,D,E and F groups.compared to C group,the level of B UN were decreased in D and F groups(P<0.05).compare to A group,the level o f UACR was not significantly difference in B group(P>0.05).compare to C gro up,the level of UACR were markedly decreased in D and F groups(P<0.05).co mpared to E group,the BUN and UACR were decreased(P<0.05)but no signific antly difference of Scr(P>0.05);4.After the imiquimod and vaseline cream treated consecutive 7 days,com pared to A,the back skin showed markedly erythema and scale and increased t hickness in B,E and F group(P<0.01);compared to B group,the erythema and s cale and back skin thickness were increased in E group(P<0.05);compared to E group,the erythema and scale and back skin thickness were slightly decrease d in F group(P<0.05).the scoring of severity of inflammation of the back skin based on the clinical Psoriasis Area and Severity Index(PASI)showed the same results with all above described(P<0.05).5.After the imiquimod and vaseline cream treated consecutive 7 days,the HE staining of the back skin tissue showed that the epithelial hyperproliferati on and the cell layers increased,as well as abundant mononuclear cells infiltrate d were observed in B,E and F group which received IMQ-treatment;all these si gns of inflammation phenomenons were not observed in A,C and D group whi ch received the control cream vaseline.we also found that the E group which a ffirmed the obesity diabetic phenotype mice that showed the stronger signs of i nflammation,compared to the B group which affirmed the non-diabetic mice(P<0.05).compared to E group,the epithelial hyperproliferation and its cell layers a nd inflammatory cell infiltration were decreased in F group.6.After the imiquimod and vaseline cream treated consecutive 7 days,the r elative expression of mRNA of back skin tissue showed that the expression of IL-23,IL-17,IL-22 and TNF-α were markedly increased in B,E and F group w hich received IMQ-treatment,compared to A group which received control crea m(P<0.01).compared to B group,the expression of mRNA of IL-17,IL-22,IL-23 and TNF-α were slightly increased in E group(P<0.05).compared to E group,,th e expression of mRNA of IL-17,IL-22,IL-23 and TNF-α were decreased in F g roup(P<0.05).7.After the imiquimod and vaseline cream treated consecutive 7 days,the i mmunohistochemistry of back skin tissue showed that positive cells in epitheliu m layer what indicated the expression of IL-23,IL-17,IL-22 and TNF-α were m arkedly increased in B,E and F group which received IMQ-treatment,compared to A group which received control cream(P<0.01).compared to B group,the posi tive cells of IL-17 and IL-22 were increased(P<0.05)but no significance of IL-23 and TNF-α(P>0.05).compared to E group,the positive cells of IL-23,IL-17,I L-22 and TNF-α in epithelium layer as well as dermis layer were slightly decr eased in F group(P<0.05).8.After the imiquimod and vaseline cream treated consecutive 7 days,the Pearson correlation analysis shows that the correlation between PASI and IL-23,IL-17,IL-22,TNF-α were positive correlation(r=0.9153、0.9457、0.9436、0.8989)(P<0.01).Conclusions:1.The obeisty and diabetes may aggravate and prolong the psoriatic skin infla mmation.2.Imiquimod may influenced the glycometabolism and lipid metabolism.3.Liraglutide could improve glycometabolism and lipid metabolism 4.Liraglutide could improve the psoriatic skin inflammation and decrease the e xpression of IL-23,IL-17,IL-22,TNF-α,its effects may via suppressed the IL-23/Th17 axis expression. |
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