Enhanced efficacy with reduced toxicity of tripterygium glycoside tablet by compatibility with total glucosides of paeony for rheumatoid arthritis therapy.

BACKGROUND AND AIMS: Drug-induced liver injury remains a critical issue to hinder clinical application of Tripterygium Glycosides Tablets (TGTs) for rheumatoid arthritis (RA) therapy. Combination of TGTs with Total Glucosides of Peony (TGP) may be the most common therapeutic strategy for enhancing TGTs' efficacy and reducing its toxicity. Herein, we aimed to investigate the efficacy-enhancing and toxicity-reducing properties and mechanisms of TGT-TGP combination. METHODS: Both TGT-induced acute and chronic liver injury animal models were established. ELISA, transmission electron microscopy, immunohistochemistry, western blot and quantitative PCR were performed to determine the efficacy, toxicity and regulatory mechanisms of TGT-TGP combination. RESULTS: The compatibility of TGP significantly reduced the abnormal serum ALT and AST levels, and improved liver histopathological changes in both acute and chronic DILI animal models induced by TGTs, with the most effective dosage of TGP-M (medium-dose TGP, 450 mg/kg). Additionally, TGP and TGT synergistically alleviated joint swelling and improved the elevation of serum inflammatory factors, in line with the positive changes in joint histopathological features of collagen induced arthritis mice, with the same effective dosage of TGP-M following 5 weeks' drug combination treatment. Mechanically, TGT significantly increased the number of autophagosomes and the expression of LC3II protein while reducing p62 protein expression in the liver tissues, which were significantly reversed by the compatibility with TGP, similar to the findings based on the inflamed joint tissues. CONCLUSIONS: These findings suggest an enhanced efficacy with reduced toxicity of TGT by the compatibility with TGP for RA therapy, possibly through regulating various autophagy-related proteins.

Paeoniflorin modulates gut microbial production of indole-3-lactate and epithelial autophagy to alleviate colitis in mice.

BACKGROUND: Total glucosides of peony (TGP), extracted from the root and rhizome of Paeonia lactiflora Pall, has well-confirmed immunomodulatory efficacy in the clinic. However, the mechanism and active ingredients remain largely unclear. HYPOTHESIS/PURPOSE: Our previous study revealed a low systemic exposure but predominant gut distribution of TGP components. The aim of this study was to investigate involvement of the gut microbiota in the immunoregulatory effects and identify the active component. METHODS: Mice received 3% DSS to establish a model of colitis. The treatment group received TGP or single paeoniflorin (PF) or albiflorin (AF). Body weight, colon length, inflammatory and histological changes were assessed. Gut microbiota structure was profiled by 16s rRNA sequencing. Antibiotic treatment and fecal transplantation were used to explore the involvement of gut microbiota. Metabolomic assay of host and microbial metabolites in colon was performed. RESULTS: TGP improved colonic injury and gut microbial dysbiosis in colitis mice, and PF was responsible for the protective effects. Fecal microbiota transfer from TGP-treated mice conferred resilience to colitis, while antibiotic treatment abrogated the protective effects. Both TGP and PF decreased colonic indole-3-lactate (ILA), a microbial tryptophan metabolite. ILA was further identified as an inhibitor of epithelial autophagy and ILA supplementation compromised the benefits of TGP. CONCLUSION: Our findings suggest that TGP acts in part through a gut microbiota-ILA-epithelial autophagy axis to alleviate colitis.

Total glucosides of peony improve ovalbumin-induced allergic asthma by inhibiting mast cell degranulation.

ETHNOPHARMACOLOGICAL RELEVANCE: Paeonia lactiflora Pall. (peony) is a medicinal plant used in the Xiaoqinglong decoction, a commonly prescribed traditional Chinese medicine for asthma. The main active ingredients of peony roots-described as the total glucosides of peony (TGP)-have anti-inflammatory, immunomodulatory, and protective effects on endothelial cells, and they are known to improve rheumatoid arthritis. This study explored the underlying mechanism of TGP activity in the treatment of allergic asthma. MATERIALS AND METHODS: Allergic asthma was induced in BALB/c mice by administering injections of ovalbumin (OVA) mixed with aluminum hydroxide gel and inhaling nebulized OVA. The OVA-sensitized mice were treated with TGP by oral gavage, and the potentially anti-asthmatic treatment effect was studied by testing airway hyperresponsiveness, classifying and counting of leukocytes, performing cytokine assays, and analyzing the lung histopathology. The ß-hexosaminidase activity was assayed as a biomarker to evaluate the effect of TGP on mast cell degranulation. The mechanism of TGP was explored by monitoring the Ca2+ influx level in mast cells (RBL-2H3) using a Ca2+ fluorescent probe technique. RESULTS: In mice with OVA-induced allergic asthma, TGP reduced airway hyperresponsiveness and improved lung tissue pathology, which included a decrease in inflammatory cell infiltration and collagen deposition. TGP also significantly lowered BALF leukocyte, eosinophil, and neutrophil counts, along with chemokines and cytokines, such as eotaxin, TNF-α, IL-4, and MIP-1α, in serum and lungs of OVA-challenged mice. These effects were further confirmed with the decrease of ß-hexosaminidase release and the inhibition of Ca2+ influx in mast cell degranulation. CONCLUSIONS: Our findings suggest that TGP improved OVA-induced allergic asthma in mice mainly by suppressing Ca2+ influx-dependent mast cell degranulation.

The efficacy and safety of total glucosides of peony in the treatment of primary Sjögren's syndrome: a multi-center, randomized, double-blinded, placebo-controlled clinical trial.

To evaluate the efficacy and safety of total glucosides of peony (TGP) in adults with primary Sjögren's syndrome (pSS). A multi-center, randomized, double-blinded, placebo-controlled study was conducted between March 2012 and July 2014 at ten Chinese hospitals. In total, 320 pSS patients-classified according to the 2002 American-European Consensus Group Criteria-were randomized (2:1 ratio) to receive TGP(600 mg, tid) in the TGP group or placebo for 24 weeks in the placebo group. Study personnel, investigators, and patients were blinded to the treatment grouping. The primary endpoint was the improvement of EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) at week 24. The secondary endpoints were dry eyes/mouth/skin/nose/throat/vagina visual analogue scale (VAS), pain and discomfort VAS, fatigue VAS, mental discomfort VAS, patient global assessment (PGA), EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), Schirmer's test, basal/stimulated salivary flow-rate values, and erythrocyte sedimentation rate (ESR). All adverse events were recorded during the trial period. ESSPRI improved more in the TGP than the placebo group (p < 0.001). Dry eyes/throat/vagina VAS, fatigue VAS, mental discomfort VAS, PGA, Schirmer's test, and ESR also improved more in the TGP group than in the placebo group (all p < 0.05). Stimulated salivary flow-rate values increased in the TGP group at week 12 but not at week 24. Adverse events in TGP group were 10.9%. TGP can alleviate some dryness symptoms as well as disease activity in pSS patients over 24 weeks. TGP was well tolerated by study subjects. TGP seems to be an effective and safe treatment for pSS.

Study on Efficacy Enhancing Effects of Compatibility of Aconitum carmichaeli Liposoluble Alkaloids and Total Glucosides of Peony in the Treatment of Wind-Cold-Dampness Type Bi-Syndrome Model Rats / 中国药房

OBJECTIVE： To study the efficacy enhancing effect of compatibility of Aconitum carmichaeli liposoluble alkaloids and total glucosides of peony in the treatment of wind-cold-dampness type bi-syndrome model rats. METHODS： Totally 100 SD male rats were randomly divided into blank group （water）， model group （water）， rotundine group [positive control， 10.0    mg/（kg·d）]， dexamethasone group [positive control， 0.3 mg/（kg·d）]，A. carmichaeli alkaloids low-dose and high-dose groups [A. carmichaeli  liposoluble alkaloid extract 12.5， 25.0 mg/（kg·d）]， total glucosides of peony low-dose and high-dose groups [total glucosides of peony powder 200.0，400.0 mg/（kg·d）]， compatibility low-dose and high-dose groups [A. carmichaeli  liposoluble alkaloid+total glucosides of peony powder were 12.5 mg/（kg·d）+400.0 mg/（kg·d）， 25.0 mg/（kg·d）+800.0 mg/（kg·d） respectively]， with 10 rats in each group. Except for blank group， other groups were given complete Freund’s adjuvant 0.1 mL on the right hind paw and wind-cold-dampness stimulation to induce wind-cold-dampness type bi-syndrome model. Nineteen days after modeling， they were given relevant medicine or water intragastrically， once a day， for consecutive 14 d. The joint tenderness threshold （except for dexamethasone group） and joint swelling index （except for rotundine group） were measured at 0 （before medication）， 3rd and 6th day after administration respectively. HE staining was used to observe the pathological changes of synovial membrane of ankle joint in rats （except for rotundine group）. ELISA assay was used to determine anti-cyclic citrullinated peptide （CCP） antibody in serum of rats （except for rotundine group）， and compatibility index （CI） were calculated. RESULTS： Compared with blank group， joint tenderness threshold of rats were decreased significantly in model group at different time points， while joint swelling index was increased significantly （P＜0.01）. Inflammatory lesions in synovial tissue were obvious， and the content of anti-CCP antibody in serum was significantly increased （P＜0.01）. Compared with model group， the joint tenderness threshold， joint swelling index， synovial tissue pathological changes and anti-CCP antibody content in serum of rats in medication groups were improved in varying degrees， most of the indicators had significant difference （P＜0.05 or P＜0.01）， and the improvement effect of the compatibility groups was better than single component treatment groups. CI value calculated based on anti-CCP antibody content was 0.213，suggesting that the compatibility of the two components had synergistic effect. CONCLUSIONS： The compatibility of A. carmichaeli liposoluble alkaloids and total glucosides of peony in the treatment of wind-cold-dampness type bi-syndrome model rats has analgesia，anti-inflammation and synovial tissue protection， with synergistic efficacy-enhancing effect.

Suppression of TGP on myocardial remodeling by regulating the NF-κB pathway.

Myocardial remodeling is one of the main mechanism which leads to chronic heart failure (CHF). Thus, the drugs which suppressed the process of myocardial remodeling showed better clinical outcomes to deal with CHF. Total glucosides of paeony (TGP) which is used in many traditional Chinese medicines (TCM) exhibited promising ethno-pharmacological effects such as immunosuppressant, anti-inflammatory, analgesia, anti-stress, liver disease, allergies, anticoagulant, and cardiovascular activities. This study aims to investigate the effects of TGP on myocardial remodeling by regulating the nuclear factor kappa B cells (NF-κB) pathway. SD rats were selected and divided into five groups (n = 8), control, sham-operated, Captopril, low dose TGP and high dose TGP respectively. The pressure-overload method was adopted by abdominal aorta ligation to induce the CHF. Furthermore, collagen fibers detected by picrosirius red staining and expression of NF-kB, TGF-ß1 by immunohistochemistry and observed under a polarized microscope and assessed by image-pro plus 6.0. Matrix metalloproteinase's (MMP)-2, -9 mRNA levels by reverse transcription PCR (RT-PCR), the concentration of angiotensin II was determined by radioimmunoassay and ELISA was employed to determine the cytokine IL-1ß. It was observed that TGP could relieve myocardial remodeling in rats induced by abdominal aorta ligation and decrease the level of angiotensin II and I/III collagen ratio, pathogenic cytokines and inhibit the expression and activities of MMPs. Consequently, the observations suggested that myocardial remodeling was mediated by the NF-κB pathway.

A systemic review and meta-analysis of the clinical efficacy and safety of total glucosides of peony combined with methotrexate in rheumatoid arthritis.

To assess the efficacy and safety of the combination of total glucoside of peony (TGP) and methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). Randomized controlled trial (RCT) data on the traditional Chinese active component TGP combined with MTX vs. MTX alone for the treatment of RA was collected by searching the Pubmed, Embase, Cochrane Library, CNKI, VIP Journals database, and Wanfang database up to February 2017. Study selection, data extraction, data synthesis, and data analyses were performed according to the Cochrane standards. A total of eight RCTs involving 522 participants were included in this meta-analysis. Compared with MTX alone, the use of TGP combined with MTX exhibited better therapeutic effects for the treatment of RA (P = 0.004). In addition, TGP combined with MTX caused a more significant decrease in erythrocyte sedimentation rate (ESR) (P < 0.0001) and swollen joint count (SJC) (P < 0.00001). However, no significant differences were found in C-reactive protein (CRP) (P = 0.19), duration of morning stiffness (DMS) (P = 0.32), or tender joint count (TJC) (P = 0.23) between the two groups. In addition, adverse events were more frequently reported in the MTX monotherapy group than in the TGP and MTX combination group (P = 0.0007). Our study demonstrates that TGP combined with MTX is more effective than MTX alone for the treatment of RA. Nevertheless, the adverse effects of the combination of TGP and MTX need to be further assessed. Due to the poor methodological quality of included trials, well-designed, multi-center, and large-scale RCTs are necessary to draw a more definitive conclusion.

[Research progress of pharmacokinetics and pharmacodynamics of total glucosides of peony in hepatoprotective effects].

Total glucosides of peony (TGP), containing the effective components of paeoniflorin (Pae), albiflorin (Alb) and so on, are effective parts of Radix Paeoniae Alba. And it possesses extensive pharmacological actions, one of which is hepatoprotective effect. In recent years, abundant of pharmacokinetics and pharmacodynamics research of TGP in hepatoprotective effects have been performed. However, the relative medicine of TGP in hepatoprotective effect has not been developed for clinical application. In order to provide reference for the development and rational clinical application of TGP, the research progresses of pharmacokinetics and pharmacodynamics of TGP in hepatoprotective effect were summarized in this paper. Pharmacokinetics research has clarified the process of absorption, distribution, metabolism and excretion of TGP in vivo, and liver injury disease can significantly influence its metabolic processes. Pharmacodynamics studies suggested that TGP can protect against acute liver injury, non-alcoholic fatty liver diseases (NAFLD), chronic liver fibrosis and liver cancer. However, the action mechanism and in vivo process about hepatoprotective effects of TGP have not been clearly revealed. How liver injury influences the metabolism of TGP and its integrated regulation through multiple targets need to be further studied. The combined pharmacokinetics and pharmacodynamics studies should be performed in favour of medicine development and clinical application of TGP in hepatoprotective effects.

Total glucosides of peony attenuates experimental autoimmune encephalomyelitis in C57BL/6 mice.

Total glucosides of peony (TGP), an active compound extracted from the roots of Paeonia lactiflora Pall, has wide pharmacological effects on nervous system. Here we examined the effects of TGP on experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis (MS). The results showed that TGP can reduce the severity and progression of EAE in C57 BL/6 mice. In addition, TGP also down-regulated the Th1/Th17 inflammatory response and prevented the reduced expression of brain-derived neurotrophic factor and 2',3'-cyclic nucleotide 3'-phosphodiesterase of EAE. These findings suggest that TGP could be a potential therapeutic agent for MS.