Total glucosides of paeony attenuates animal psoriasis induced inflammatory response through inhibiting STAT1 and STAT3 phosphorylation

OBJECTIVE Psoriasis is an immune system meditated disease,especially T cells.It disturbed many people around the world and hard to therapy.Paeonia lactiflora Pall has been used as a medicine in china for thousands of years.Recent studies has found that the main component of Paeonia lactiflora Pall can alleviates the immune response in many diseases.In this study,we researched the effects and possible mechanisms of total glucosides of paeony(TGP)on animal psoriasis in order to study the therapeutic effects and mechanisms of TGP in 5%propranolol creaminduced psoriasis in guinea pigs and Imiquimod(IMQ)cream-induced psoriasis in mice.METHODS The effect of TGP was evaluated using a psoriasis-like model of guinea pigs and mice.Ear thickness was accessed,and pathology injury was observed by HE staining.The levels of serum IL-1β,IL-6,IL-12,IL-17,IL-23,TNF-α,and IFN-γ,skin IL-17A,IL-22 and orphan nuclear receptor(RORγt)mRNA expression,proliferating cell nuclear antigen(PCNA),total or phosphorylated signal transducers and activators of transcription(STAT1 and STAT3)were determined by ELISA,real time PCR,immu⁃nohistochemical staining,and Western blotting,respectively.RESULTS Compared with model group,TGP treatment decreased the ear thickness,improved pathology of psoriasis,alleviated IMQ-induced keratinocyte proliferation,reduced the inflammatory cytokine,and downregulated IL-17A,IL-22,and RORγt mRNA in mice.Further study indicated that TGP inhibited STAT1 and STAT3 phosphorylation in lesion skins of psoriasis-like mice.CONCLUSION TGP alleviates the symptoms of psoriasis-like guinea pigs and mice,and the possible mechanism may relate to inhibit T helper 17(TH17)cell differentiation and keratinocytes proliferation by inhibiting STAT1 and STAT3 phosphorylation.

Effects of total glucosides of peony on immunological hepatic fibrosis in rats

AIM: To study the effects of total glucosides of peony (TGP) on immunological hepatic fibrosis induced by human albumin in rats.METHODS: Sixty adult male Sprague-Dawley rats were randomly divided into: Normal group, model group, TGP (60 and 120 mg/kg) treatment groups and colchicines (0.1 mg/kg) treatment group. On the day before the rats were killed, those in TGP or colchicine groups received TGP or colchicine as above from the first day of tail vein injection of human albumin. The rats in normal and model groups were only administered with the same volume of vehicle. At the end of the 16th wk, rats in each group were killed. Blood and tissue specimens were taken. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), nitric oxide (NO), content of malondialdehyde (MDA), activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px), were measured by biochemical methods. Serum procollagen type Ⅲ (PC Ⅲ) and laminin (LN) were determined by radioimmunoassay. Liver collagen level was determined by measuring hydroxyproline content in fresh liver samples. Hepatic tissue sections were stained with hematoxylin-eosin and examined under a light microscope.RESULTS: Histological results showed that TGP improved the human albumin-induced alterations in the liver structure, alleviated lobular necrosis and significantly lowered collagen content. The antifibrotic effect of TGP was also confirmed by decreased serum content of LN and PCⅢ in TGP-treated group. Moreover, the treatment with TGP effectively reduced the hydroxyproline contentin liver homogenates. However, the level of ALT and AST increased in fibrotic rat but had no significance compared with normal control, whereas the ratio of A/G decreased without significance. TGP had no effect on level of ALT, AST and the ratio of A/G. Furthermore, TGP treatment significantly blocked the increase in MDA and NO, associated with a partial elevation in liver total antioxidant capacity including SOD and GSH-px.CONCLUSION: TGP has beneficial effects on hepaticfibrosis in rats by inhibition of collagen synthesis and decreasing oxidative stress.

Protective Effects of Total Glucosides of Paeony against the Liver Injury Induced by Anti-tuberculosis Drugs

[Objectives] This study was conducted to elucidate the mechanism of action of total glucosides of paeony （TGP） against the liver injury induced by isoniazid （INH） and rifampicin （RFP）, and to provide experimental evidence for rational use of anti-tuberculosis drugs.[Methods] Liver injury in mice was induced by the combination of INH and RFP in mice. After the mice were given different doses of Total Glucosides of White Paeony Capsules （TGP） for 10 d, the hepatosomatic index, biochemical indices in serum and liver homogenate were measured, and histopathological changes in liver tissue were observed. Glucurolactone was used as the positive control, and 0.9% sodium chloride was used as the negative control in the experiment.[Results] TGP reduced the activities of alanine transaminase （ALT） and aspartate transferase （AST） in serum and the level of malondialdehyde （MDA） in liver tissue, and increased the level of glutathione （GSH） and the activity of superoxidase dismutase （SOD） in liver tissue.[Conclusions] TAP has a protective effect against the liver injury induced by INH and RFP.

THE MECHANISM OF ANTITUMOR ACTIVITY OF TOTAL GLUCOSIDES EXTRACTED FROM CYNANCHUM AURICULA-TUM ROYLE (CA)

Since the chemical structure of total glucosides from Cynanchum Auriculatum Royle (CA) is similar to that of the steroline of Marsdenia Condurago Reich, a compound which exhibits antitumor activity, research into the antitumor activity of CA was carried out. Its mechanism of action was studied in vivo with C 57BL/6 mice bearing Lewis lung carcinoma and in vitro, with two mouse tumor cell lines: S180 and EAC. CA inhibited to a certain extent the growth of subcutaneously inoculated Lewis lung carcinoma and its pulmonary metastasis, and augmented the antitumor effect of cyclophosphamide. It showed a killing effect on the EAC and S180 tumor cells of mice in vitro as well. It blocked the tumor cells of solid Lewis lung carcinoma from entering into the S stage from G1 and inhibited DNA synthesis of S180 and EAC tumor cells of mice in vitro. It also markedly increased the number of mononuclear Mφ of tumor bearing mice, stimulated the macrophagic activity of their intraperitoneal Mφ, raised the percentage of ANAE(+) lymphocytes in peripheral blood and enhanced the ABC reaction and antibody formation in tumor bearing mice.

Total glucosides of paeony alleviates Sjogren syndrome through inhibiting inflammatory responses in mice

OBJECTIVE To study the therapeutic effects of TGP on SS both in C57BL/6J mice immunized by immu⁃nological induction(SS mice)and NOD/ShiltJNju(NOD)mice.METHODS TGP(180,360,720 mg·kg^-1)was intragastri⁃cally administered for 6 or 16 weeks for SS mice and NOD mice,respectively.Weekly food and water intake,saliva flow,submandibular gland(SMG)and spleen index,and SMG pathology were measured.ELISA was used to evaluate serum interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),interferon-γ(IFN-γ)and autoantigens(SSA/Ro,SSB/La,andα-fodrin).Real-time PCR and Luminex liquid suspension chip assay were applied to analyze SMG inflammatory cytokines mRNA TNF-α,IL-17A,CXCL9,CXCL13,and B-cell activating factor(BAFF)and protein(IL-1β,IL-6,TNF-α,and IFN-γ)expres⁃sion.RESULTS Compared with SS mice,TGP(720 mg·kg^-1)treatment increased saliva flow,reduced organ indexes,and decreased serum IL-6 and IFN-γ concentration.TGP(360 mg·kg^-1)treatment decreased serum IFN-γ concentra⁃tion.TGP(180,360,720 mg·kg^-1)treatment improved SMG pathological damage.Compared with NOD mice,the saliva flowincreased from 9 to 15 weeks of administration.After 2 weeks of administration,TGP(720 mg·kg^-1)treatment decreased serum SSA/Ro,SSB/La and a-fodrin concentration,increased SMG index,inhibited SMG IFN-γ concentra⁃tion,and down-regulated SMG TNF-α,IL-17A,CXCL9,CXCL13 and BAFF mRNA expression.TGP(360 mg·kg^-1)treat⁃ment decreased serum SSB/La and a-fodrin,and SMG TNF-α and IFN-γ concentration,and down-regulated SMG TNF-α,IL-17A,CXCL9 and BAFF mRNA expression.TGP(180 mg·kg^-1)treatment decreased serum SSB/La,a-fodrin,and SMG IL-1β concentration,and down-regulated SMG TNF-α,IL-17A and BAFF mRNA expression.After 8 weeks of administration,TGP(180,360,720 mg·kg^-1)treatment increased SMG index,and decreased serum a-fodrin concentra⁃tion.TGP(720 mg·kg^-1)treatment down-regulated mRNA expression of SMG TNF-α,IL-17A,CXCL9,CXCL13,and BAFF.TGP(360 mg·kg^-1)treatment reduced mRNA expression of TNF-α,CXCL9,CXCL13 and BAFF,and concentra⁃tion of IL-6 and TNF-α.TGP(180 mg·kg^-1)treatment down-regulated mRNA expression of TNF-α,CXCL9,and CXCL13,and decreased IL-6 and TNF-αconcentration in SMG.After 16 weeks of administration,TGP(180,360,720 mg·kg^-1)treatment reduced serum SSA/Ro and a-fodrin concentration,increased SMG index,and decreased SMG CXCL13 and BAFF mRNA expression.TGP(360,720 mg·kg^-1)treatment decreased serum SSB/Laconcentration and SMG TNF-α,IL-17A and CXCL9 mRNA expression.Besides,TGP(180,360,720 mg·kg^-1)treatment alleviated the pathological damage of SMG after 2 and 16 weeks of administration.CONCLUSION TGP has a certain therapeutic effect onmice through inhibiting inflammatory responses.

Successful treatment of Morbihan disease with total glucosides of paeony:A case report

BACKGROUND Morbihan disease is a rare cutaneous disorder characterized by non-pitting edema and erythema of the upper two-thirds of the face.In severe cases,orbital and facial contour changes may affect the visual field,and there is no guideline for the standard treatment of this disease.Existing treatment methods have been reported to be associated with long medication cycle,easy recurrence after drug withdrawal,and multiple adverse reactions.CASE SUMMARY A 55-year-old Chinese woman presented to our hospital with non-pitting edema and erythema of the upper two thirds of her face for 5 mo.Physical examination showed obvious edema and erythema on the upper face.The boundary was unclear,the lesions were hard and non-pitting,and infiltration was obvious by touch.Pathological examination revealed mild hyperkeratosis of the epidermis,nodular inflammatory lesions in the dermis,epithelioid granuloma,and inflammatory cell infiltration with lymphocytes and histiocytes around skin appendages and blood vessels.Alcian blue staining,acid fast staining,silver staining and periodic acid-Schiff staining were negative.The patient was diagnosed with Morbihan disease.She was treated with prednisone acetate and tripterygium wilfordii polyglycoside tablets for 4 mo,and the edema was slightly reduced,but transaminase levels were significantly increased.Compound glycyrrhizin capsules were administered for liver protection for 1 mo;however,facial edema did not significantly improve and transaminase levels continued to increase.Total glucosides of paeony capsules were then administered for 4 mo,and transaminase level returned to normal and the patient’s facial edema disappeared completely.CONCLUSION Total glucosides of paeony has a remarkable effect in Morbihan disease,without adverse reactions.

Effect of total glucosides of paeony on serum cytokines in patients with psoriasis and its clinical efficacy:A meta-analysis

Objective:To evaluate the relationship between the changes of inflammatory cytokines and clinical efficacy in patients with psoriasis treated with Total glucosides of paeony by Meta analyses,and to explore the microcosmic mechanism of effective treatment of psoriasis with Total glucosides of paeony from the point of view of evidence-based medicine.Methods:The databases of CNKI,Wanfang,VIP,SinoMed,PuMed,Embase and Cochrane Library were searched by computer,and the time range was from the establishment of the database to May 2020.After screening,data extraction and bias risk assessment,Revman5.3 software was used for statistical analysis.Results:A total of 998 patients were included in 11 clinical studies,including 502 patients in the trial group and 496 patients in the control group.The results of Meta analysis showed that there was significant difference in the expression of cytokines between the two groups(MD=-10.97,95%Cl[-15.56,-6.37]).The effective rate of treatment(OR=3.57,95%Cl[2.58,4.94])and the decrease of PASI score(MD=-4.55,95%Cl[-5.91,-3.20])in the combined use of Total glucosides of paeony group were superior to those in the control group.Conclusion:Total glucosides of paeony can regulate immune and inflammatory response and improve skin lesions by inhibiting the expression of cytokines such as IL-2,IL-8,IL-23 and TNF-αin serum of patients with psoriasis.In view of the low overall quality of the included studies,larger samples and higher quality clinical trials are still needed to obtain more sufficient evidence.

Systematic review/meta-analysis re-evaluation of clinical effects of total glucosides of paeony in the treatment of rheumatoid arthritis

Objective: To re-evaluate the systematic review of Rheumatoid arthritis (RA) treatmentwith total glucosides of paeony (TGP) to provide evidence-based evidence for the treatmentof RA with TGP in the clinic. Methods: A total of eight databases including CNKI, Wan FangData, CBM, VIP, PubMed, Embase, Cochrane Library, and Web of Science were searched bycomputer for the systematic reviews/meta-analyses concerning the treatment of RA withTGP. The retrieval period was from the establishment of the database to May 2, 2022.Literature screening was conducted based on the randomized controlled trial, and thematerials of the included literature were extracted. Using the preferred reporting items forsystematic reviews and meta-analyses statement. The a measurement tool to assesssystematic reviews 2 scale and grades of recommendation, assessment, development, andevaluation system evaluated the reporting quality, methodological quality, and outcomeindicators evidence levels included in the literature. Results: Six systematicreviews/meta-analysis literature were finally included. Evaluation of the preferred reportingitems for systematic reviews and meta-analyses statement showed that the overall reportingquality of included literature was low, and only one piece with high quality was included.The results of the a measurement tool to assess systematic reviews 2 scale evaluationshowed that the qualities of included literature were all low-level and highly low-level. Thegrades of recommendation, assessment, development, and evaluation evidence qualityevaluation showed a total of 39 outcome indicators in the six included literature, and alloutcome indicators were intermediate, low-level, and extremely low in evidence evaluation.Conclusion: Many pieces of evidence show that TGP has certain advantages in alleviatingclinical symptoms, reducing adverse reactions, and reducing hepatotoxicity in the treatmentof RA, but this conclusion lacks high-level evidence to support it, which needs to be provedby more studies in the future.

Total glucosides of paeony alleviates cGAS-STING-mediated diseases by blocking the STING-IRF3 interaction

In the realm of autoimmune and inflammatory diseases,the cyclic GMP-AMP synthase(cGAS)stimulator of interferon genes(STING)signaling pathway has been thoroughly investigated and established.Despite this,the clinical approval of drugs targeting the cGAS-STING pathway has been limited.The Total glucosides of paeony(TGP)is highly anti-inflammatory and is commonly used in the treatment of rheumatoid arthritis(RA),emerged as a subject of our study.We found that the TGP markedly reduced the activation of the cGAS-STING signaling pathway,triggered by various cGAS-STING agonists,in mouse bone marrow-derived macrophages(BMDMs)and Tohoku Hospital Pediatrics-1(THP-1)cells.This inhibition was noted alongside the suppression of interferon regulatory factor 3(IRF3)phosphorylation and the expression of interferon-beta(IFN-β),C-X-C motif chemokine ligand 10(CXCL10),and inflammatory mediators such as tumor necrosis factor-alpha(TNF-α)and interleukin-6(IL-6).The mechanism of action appeared to involve the TGP’s attenuation of the STING-IRF3 interaction,without affecting STING oligomerization,thereby inhibiting the activation of downstream signaling pathways.In vivo,the TGP hindered the initiation of the cGAS-STING pathway by the STING agonist dimethylxanthenone-4-acetic acid(DMXAA)and exhibited promising therapeutic effects in a model of acute liver injury induced by lipopolysaccharide(LPS)and D-galactosamine(D-GalN).Our findings underscore the potential of the TGP as an effective inhibitor of the cGAS-STING pathway,offering a new treatment avenue for inflammatory and autoimmune diseases mediated by this pathway.

Total Glucosides of Paeony Regulate Immune Imbalance Mediated by Dermal Mesenchymal Stem Cellsin Psoriasis Mice

Objective To investigate the therapeutic effects of total glucosides of paeony(TGP)on psoriasis based on the immunomodulatory effect of dermal mesenchymal stem cells(DMSCs).Methods A total of 30 male BALB/c mice were divided into 6 groups(n=5 in each)by a random number table method,including control,psoriasis model(model,5%imiquimod cream 42 mg/d),low-,medium-and high-dose TGP(50,100,and 200 mg/kg,L,M-,and H-TGP,respectively),and positive control group(2.5 mg/kg acitretin).After 14 days of continuous administration,the skin’s histopathological changes,apoptosis,secretion of inflammatory cytokines,and proportion of regulatory T cells(Treg)and T helper cell 17(Th17)were evaluated using hematoxylin-eosin(HE)staining,TdT-mediated dUTP nick end labeling staining,enzyme-linked immunosorbent assay,and flow cytometry,respectively.DMSCs were further isolated from the skin tissues of normal and psoriatic mice,and the cell morphology,phenotype,and cycle were observed.Furthermore,TGP was used to treat psoriatic DMSCs to analyze the effects on the DMSCs immune regulation.Results TGP alleviated skin pathological injury,reduced epidermis layer thickness,inhibited apoptosis,and regulated the secretion of inflammatory cytokines and the proportion of Treg and Th17 in the skin tissues of psoriatic mice(P<0.05 or P<0.01).There was no significant difference in cell morphology and phenotype between control and psoriatic DMSCs(P>0.05),however,more psoriatic DMSCs remained in G0/G1 phase compared with the normal DMSCs(P<0.01).TGP treatment of psoriatic DMSCs significantly increased cell viability,decreased apoptosis,relieved inflammatory response,and inhibited the expression of toll-like receptor 4 and P65(P<0.05 or P<0.01).Conclusion TGP may exert a good therapeutic effect on psoriasis by regulating the immune imbalance of DMSCs.

Clinical Observation on the Treatment of Chronic Urticaria with Total Glucosides of Paeony Capsule Combined with Citirizine

Objective： To assess the effect and adverse reaction of total glucosides of paeony capsule （TGPC） in combining with citirizine for the treatment of chronic urticaria. Methods： A total of 120 patients were assigned to two groups by lottery, 65 in the treated group and 55 in the control group. They all were orally treated with citirizine tablet 10 mg per day, but to the treated group, additional 0.2 g TGPC was given three times per day, the therapeutic course for both groups was 4 weeks. The effectiveness of treatment was observed, and the changes of total symptom score, serum levels of interleukin-4 （IL-4）, and immunoglobulin E （IgE） were measured before and after treatment. Moreover, a follow- up was carded out one month after ending the treatment. Results： The dropped cases were two in the treated group and seven in the control group; so, the study was accomplished on 63 patients in the treated group and 48 patients in the control group. The total effective rate was assessed at 73.02% （46/63） in the treated group, which was significantly higher than 47.92% （23/48） in the control group （P〈0.01）. After treatment, the total symptom score decreased in both groups, but the decrement in the treated group was more significant （P〈0.05）. Serum levels of IL-4 and IgE in the treated group lowered significantly, while the changes in the control group were insignificant, so statistical significant differences were shown between groups （P〈0.01）. A follow-up study showed that the relapse rate in the treated group was 30.00% （6/20）, while that in the control group was 90.00% （9/10）, and the former was lower than the latter （P〈0.01）. Adverse reactions, revealed as drowsiness, dizziness, and weakness, were seen in eight cases and seven cases in the two groups, respectively. Besides, mild diarrhea occurred in two cases of the treated group. Conclusions： The treatment of TGPC combining citirizine shows definite curative effect in treating chronic urticaria, with low relapse rate and without evident adverse reaction. Its therapeutic effect might be realized by means of regulating patients＇ immune function. Besides, the medication should be continued for a rather long peried to achieve the full effect.

A Randomized Controlled Trial Comparing Total Glucosides of Paeony Capsule and Compound Glycyrrhizin Tablet for Alopecia Areata

Objective： To observe the efficacy and safety of total glucosides of paeony capsule （TGPC） in patients with mild and moderate alopecia areata. Methods： A total of 86 outpatients were randomly allocated into two groups of TGPC （treatment, 44 cases） and compound glycyrrhizin tablet （control, 42 cases）. The treatment group was given oral TGPC, three times daily and 600 mg per time; the control group was given oral compound glycyrrhizin tablets, three times daily and 50 mg per time. In addition, both groups were given 10 mg of vitamin B2 and tapped the bold patches with massage. The treatment course was three months for both groups. Peripheral blood T-cell subsets （CD3^＋CD4^＋, CD3^＋CD8^＋, Th, Ts, Th/Ts） of 10 patients randomly selected from each group respectively were tested before and after three months of treatment. The effectiveness and adverse reaction of all cases were observed each month. The safety was evaluated according to the incidence rate of adverse reaction. Results： In the treatment group, the cured and markedly effective rate was 36.36% （16/44）, 50.00% （22/44） and 68.18% （30/44） at the end of first, second and third month of treatment, respectively, and the incidence rate of adverse reaction was 13.64% （6/44）. In the control group, the cured and markedly effective rate was 38.10% （16/42）, 57.14% （24/42） and 71.43% （30/42）, respectively, and the incidence rate of adverse reaction was 16.67% （7/42）. The cured and markedly effective rate and the incidence rate of adverse reaction were similar in both groups （P〉0.05）. TGPC and compound glycyrrhizin tablet can inhibit CD3^＋CD4^＋ and CD3^＋CD8^＋, and decrease the ratio of Th/Ts （P〈0.05）. Conclusion： TGPC is effective and safe in the treatment of alopecia areata.