PMID: 

Mol Med Rep. 2017 Dec ;16(6):8265-8276. Epub 2017 Sep 25. PMID: 28944916

Abstract Title: 

Total glucosides of paeony ameliorates TNBS‑induced colitis by modulating differentiation of Th17/Treg cells and the secretion of cytokines.

Abstract: 

The imbalance between effector CD4+ T helper 17 (Th17) and regulatory CD4+ T cells (Treg) cells and their associated cytokines, have been associated with the pathogenesis of inflammatory bowel disease (IBD). Total glycosides of paeony (TGP) is an alternative immunomodulatory agent that is widely used for the treatment of autoimmune diseases.The present study aimed to evaluate the modulatory effect of TGP in a rat model of colitis induced by 2,4,6‑trinitrobenzene sulfonic acid (TNBS). TGP was administered intragastrically 24 h after the TNBS intrarectal instillation for 7 days. TGP treatment ameliorated the clinical status and reversed the histopathologic severity of acute TNBS colitis. Furthermore, TGP inhibited the levels of Th17‑associated cytokines interleukin (IL)‑17, IL‑6, tumor necrosis factor‑α, whereas the expression levels of Treg‑associated cytokines IL‑10, transforming growth factor‑β in the plasma, colon, spleen and mesenteric lymph nodes (MLN). Additionally, TGP reduced the percentage of Th17 cells; however, the proportion of Treg cells in the spleen and MLN was increased. The present study also observed a suppression of Th17‑associated transcription factor, termed retinoid‑related orphan receptor‑γt (ROR‑γt). However, expression of the Treg‑associated transcription factor forkhead boxp3 was increased in the TGP treatment group. Therefore, the present findings suggest that TGP has a regulatory role in modulating the balance of Th17 and Treg cells to ameliorate the TNBS‑induced colitis and support the strategy of using TGP to treat IBD.

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PMID: 

Biomed Pharmacother. 2018 Sep ;105:151-158. Epub 2018 May 29. PMID: 29852392

Abstract Title: 

Total glucosides of paeony improves the immunomodulatory capacity of MSCs partially via the miR-124/STAT3 pathway in oral lichen planus.

Abstract: 

Mesenchymal stem cells (MSCs) have been used clinically and experimentally to relieve severe immune-related diseases due to their immunomodulatory properties, but these are impaired by inflammation. Oral lichen planus (OLP) is a T cell-mediated chronic inflammatory mucosal disease. In the present study, we found MSCs from OLP with higher expression of interleukin (IL)-6, tumour necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β) and IL-10 compared with control. Total glucosides of paeony (TGP) significantly improves the immunomodulatory function of MSCs by inhibiting IL-6 and TNF-α expression and increasing TGF-β and IL-10 expression. Moreover, TGP can downregulate p-STAT3 expression through upregulation of miR-124. The changes of IL-6, TGF-β and p-STAT3 were further confirmed by overexpression and knockdown of miR-124 in MSCs. Taken together, the immune-regulating function of MSCs can be improved by TGP via the miR-124/STAT3 pathway.

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PMID: 

Mol Med Rep. 2018 Sep ;18(3):3332-3340. Epub 2018 Jul 30. PMID: 30066927

Abstract Title: 

The protective effects of total paeony glycoside on ischemia/reperfusion injury in H9C2 cells via inhibition of the PI3K/Akt signaling pathway.

Abstract: 

At present, cardiovascular disease is the global leading cause of mortality. Total paeony glycoside (TPG) is a traditional Chinese medicine, which serves a pivotal role in the cardiovascular system. In the present study, the effects and underlying mechanisms of TPG on ischemia/reperfusion (I/R) injury‑induced apoptosis of cardiomyocytes were investigated in vitro. Cell Counting kit‑8 and flow cytometry were used to assess the viability, reactive oxygen species (ROS) content and apoptosis of H9C2 cells. The activities of lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPX) were analyzed by commercial detection kits. Reverse transcription‑quantitative polymerase chain reaction and western blot analysis were conducted to evaluate the expression levels of various factors. The results demonstrated that the viability of H9C2 cellswas not significantly altered in response to various concentrations of TPG. However, following I/R injury, TPG markedly enhanced cell viability in a time‑ and dose‑dependent manner. Furthermore, TPG decreased the rate of apoptosis and ROS levels, and reduced the activities of MDA and LDH. Conversely, TPG increased SOD and GPX activities. In addition, TPG upregulated the expression levels of pro‑caspase‑3 and B‑cell lymphoma2 (Bcl‑2), whereas it downregulated cleaved‑caspase‑3, poly (ADP‑ribose) polymerase 1, Bcl‑2‑associated X protein, phosphorylated (p)‑phosphatidylinositol 3 kinase (PI3K) and p‑protein kinase B (Akt) expression. Treatment with insulin‑like growth factor‑1 increased the apoptosis of H9C2 cells, thus suggesting that activation of the PI3K/Akt signaling pathway reversed the protective effects of TPG. Taken together, TPG may suppress I/R‑induced apoptosis and oxidative stress of H9C2 cells possibly by inhibiting the PI3K/Akt signaling pathway; such a phenomenon may have a therapeutic effect on cardiovascular disease.

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PMID: 

Front Pharmacol. 2019 ;10:231. Epub 2019 Mar 19. PMID: 30941036

Abstract Title: 

Synergistic and Hepatoprotective Effect of Total Glucosides of Paeony on Ankylosing Spondylitis: A Systematic Review and Meta-Analysis.

Abstract: 

The objective of this systematic review was to conduct a meta-analysis of the efficacy and safety of total glucosides of paeony (TGP) for the treatment of ankylosing spondylitis (AS). TGP is commonly applied as a complementary medicine, especially in combination with disease-modifying antirheumatic drugs (DMARDs) and/or non-steroidal anti-inflammatory drugs (NSAIDs) to treat AS in China. Nevertheless, the efficacy and safety of TGP combination treatment still needs more validation. A systematic literature search was conducted using PubMed, EMBASE, Web of Science, the Cochrane library, ClinicalTrials, the Chinese Biomedical Literature database (CBM), the China National Knowledge Internet (CNKI), the Wan Fang Medical Database and the VIP Database for available randomized controlled trials (RCTs) investigating the efficacy and safety of TGP on AS up to November 2018. Review Manager 5.3 software and Stata 12.0 software were used to analyze all included studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol. The pooled results of 23 RCTs exhibited better symptoms improvement (SI) (95% CI 1.16 to 1.36), lower erythrocyte sedimentation rate (ESR) (95% CI -5.89 to -1.32), lower levels of C-reactive protein (CRP) (95% CI -5.01 to -1.49), morning stiffness (MS) time (95% CI -3.46 to -1.86), finger to floor distance (FFD) (95% CI -4.80 to -0.86), peripheral joint pain index (PJPI) (95% CI -3.48 to -0.69), and higher level of thoracic expansion (TE) (95% CI 0.18-0.40) in TGP group. While Schober's test (Schober) showed no significant difference between the two groups. Adverse events (AEs) were significantly decreased (95% CI 0.48-0.79) with the usage of TGP. It is worthwhile to apply TGP as an auxiliary medicine on AS for better efficacy and less side effects, especially when considering the impact of traditional treatment on the liver. Still, further clinical trials with larger sample and better methodological quality are warranted to ascertain the potential benefits of TGP on AS.

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PMID: 

Drug Des Devel Ther. 2019 ;13:1969-1984. Epub 2019 Jun 17. PMID: 31354242

Abstract Title: 

Efficacy and safety of total glucosides of paeony combined with methotrexate and leflunomide for active rheumatoid arthritis: a meta-analysis.

Abstract: 

Total glucosides of paeony (TGP) have been confirmed to reduce hepatotoxicity caused by methotrexate (MTX) and leflunomide (LEF) in rheumatoid arthritis (RA). Nevertheless, high-quality evidence-based meta-analysis data on the issue are unavailable. This study aimed to evaluate the efficacy and safety of this combination treatment for RA.PubMed, EMBASE, Web of Science, Cochrane Library, ClinicalTrials, Chinese Biomedical Literature database, China National Knowledge Internet, Wan Fang, and VIP were searched up to February 2019. Randomized controlled trials (RCTs) on the efficacy and safety of TGP combined MTX and LEF for RA were included.Eight RCTs were included in the final meta-analysis. Pooled results showed better therapeutic effects against RA in the TGP-treated group (RR =1.10, 95% CI: 1.04 -1.16). The TGP+MTX+LEF group showed a reduced erythrocyte sedimentation rate (MD = -2.80 mm/h, 95% CI: -5.08 – -0.52), C-reactive protein level (MD = -4.17 mg/L, 95% CI: -7.84 – -0.51), and rheumatoid factor (MD = -12.09 IU/mL, 95% CI: -14.05 – -10.14). Besides, the combination treatment tended to benefit lipid profiles (total cholesterol: 95% CI: -1.27-0.06; triglycerides: 95% CI: -0.49 – -0.08; high-density lipoprotein cholesterol: 95% CI: 0.15-0.83; and low-density lipoprotein cholesterol: 95% CI: -0.54 – -0.02). Adverse events, hepatotoxicity in particular, significantly decreased (RR =0.55, 95% CI: 0.38-0.80) in the TGP group.Compared to MTX and LEF therapy, TGP combination treatment may be a more effective and safer strategy. It is advisable to apply TGP as an adjuvant given its hepatoprotective and possible lipid-regulating effect. However, further large-scale and high-quality clinical trials are warranted, and the efficacy of TGP in terms of its effect on lipid profiles should be further confirmed.

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PMID: 

Phytomedicine. 2019 Apr 25 ;62:152940. Epub 2019 Apr 25. PMID: 31100680

Abstract Title: 

Total glucosides of paeony for the treatment of psoriasis: A systematic review and meta-analysis of randomized controlled trials.

Abstract: 

BACKGROUND: Psoriasis is a common chronic relapsing immune-mediated inflammatory disease, the prevalence of which has increased in recent years. At present, there are many treatment methods available for the condition, but the curative effect is unsatisfactory.HYPOTHESIS/PURPOSE: This study aimed to evaluate the efficacy, adverse reactions, and recurrence rates of using paeoniflorin capsules for psoriasis treatment.STUDY DESIGN: systematic review and meta-analysis.METHODS: Randomized controlled trials comparing total glycosides of paeony (TGP) with other treatments for patients with psoriasis were retrieved by searching EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials electronic databases. Cochrane bias risk tool was used to evaluate the quality of randomized controlled trial (RCT) methodology. The primary outcome measure is the effective number. Secondary outcomes included psoriasis area and severity index (PASI), adverse reactions, recurrence, and inflammatory biomarkers.RESULTS: In all, 30 RCTs with 2,802 participants were included in this meta-analysis. The studies were generally of low methodological quality. Although there was no statistically significant difference between the use of TGP capsule alone and other monotherapies in the treatment of psoriasis (RR: 0.93; 95% CI: 0.76-1.15; p = 0.50), the addition of TGP to other therapies had an advantage over monotherapy with regard to the effective number (RR: 1.31; 95% CI: 1.26-1.37; p

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PMID: 

Phytomedicine. 2019 Jul 29 ;63:153058. Epub 2019 Jul 29. PMID: 31394414

Abstract Title: 

Crucifera sulforaphane (SFN) inhibits the growth of nasopharyngeal carcinoma through DNA methyltransferase 1 (DNMT1)/Wnt inhibitory factor 1 (WIF1) axis.

Abstract: 

BACKGROUND: Sulforaphane (SFN), a natural compound present in cruciferous vegetable, has been shown to possess anti-cancer activities. Cancer stem cell (CSC) in bulk tumor is generally considered as treatment resistant cell and involved in cancer recurrence. The effects of SFN on nasopharyngeal carcinoma (NPC) CSCs have not yet been explored.PURPOSE: The present study aims to examine the anti-tumor activities of SFN on NPC cells with CSC-like properties and the underlying mechanisms.METHODS: NPC cells growing in monolayer culture, CSCs-enriched NPC tumor spheres, and also the NPC nude mice xenograft were used to study the anti-tumor activities of SFN on NPC. The population of cells expressing CSC-associated markers was evaluated using flow cytometry and aldehyde dehydrogenase (ALDH) activity assay. The effect of DNA methyltransferase 1 (DNMT1) on the growth of NPC cells was analyzed by using small interfering RNA (siRNA)-mediated silencing method.RESULTS: SFN was found to inhibit the formation of CSC-enriched NPC tumor spheres and reduce the population of cells with CSC-associated properties (SRY (Sex determining Region Y)-box 2 (SOX2) and ALDH). In the functional study, SFN was found to restore the expression of Wnt inhibitory factor 1 (WIF1) and the effect was accompanied with the downregulation of DNMT1. The functional activities of WIF1 and DNMT1 were confirmed using exogenously added recombinant WIF1 and siRNA knockdown of DNMT1. Moreover, SFN was found to inhibit the in vivo growth of C666-1 cells and enhance the anti-tumor effects of cisplatin.CONCLUSION: Taken together, we demonstrated that SFN could suppress the growth of NPC cells via the DNMT1/WIF1 axis.

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PMID: 

Theranostics. 2019 ;9(16):4827-4840. Epub 2019 Jul 9. PMID: 31367260

Abstract Title: 

Sulforaphane Inhibits the Acquisition of Tobacco Smoke-Induced Lung Cancer Stem Cell-Like Propertiesthe IL-6/ΔNp63α/Notch Axis.

Abstract: 

Tobacco smoke (TS) critically contributes to the development of lung cancer; however, the underlying molecular mechanisms remain unclear. The induction of cancer stem cells (CSCs) by TS represents an early event in tumor initiation. The lung cancer-related geneΔNp63α is highly expressed in epithelial tissues and drives tumor formation and cancer stem cell properties. This study investigated the role of ΔNp63α in the long-term acquisition of TS-induced lung CSC-like properties.The expression levels ofΔNp63α, lung CSC markers, and interleukin (IL)-6 in lung carcinoma specimens were determined by western blotting and enzyme linked immunosorbent assays. Human bronchial epithelial (HBE) cells were chronically exposed to 2 % cigarette smoke extract for 55 passages, following which colony formationcapacity, expression of proteins associated with malignant transformation, lung CSC markers, and tumor incidence were investigated. The effects of ΔNp63α on long-term TS exposure-induced lung CSC-like properties and Notch activation were analyzed using tumorsphere formation ability, immunofluorescence assays, luciferase reporter assays, and western blotting. The roles of IL-6 on chronic TS exposure-induced lung CSC-like properties and ΔNp63α expression were also examined. Moreover, the effects of sulforaphane (SFN) on TS-transformed lung CSC-like properties, IL-6 and ΔNp63α expression, and Notch signaling were investigatedand.Higher levels ofΔNp63α were observed in the lung cancer tissues of smokers than in those of non-smokers, whereas ΔNp63α was positively correlated with CD133 and Oct4 expression in lung cancer tissues. Data from theandexperiments demonstrated that long-term TS exposure-transformed HBE (THBE) cells acquired lung CSC-like properties. Furthermore,ΔNp63α transcriptionally activated the Notch signaling pathway to promote the acquisition of CSC-like properties by the THBE cells. TS upregulated IL-6, which increased ΔNp63α expression in THBE sphere-forming cells. Finally, SFN inhibited the TS-induced CSC-like properties of THBE cellsthe IL-6/ΔNp63α/Notch axis.: Our data suggest that the IL-6/ΔNp63α/Notch axis plays an important role in the long-term TS exposure-induced acquisition of lung CSC-like properties and SFN intervention.

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PMID: 

Hum Cell. 2019 Oct ;32(4):403-410. Epub 2019 Jul 5. PMID: 31278688

Abstract Title: 

Sulforaphane inhibits the activation of hepatic stellate cell by miRNA-423-5p targeting suppressor of fused.

Abstract: 

Liver fibrosis, a common pathological process in chronic liver diseases, is characterized by excessive accumulation of extracellular matrix proteins and considered as a wound healing response to chronic liver injury. Hepatic stellate cell (HSC) activation plays a key role in liver fibrosis development. Previous studies showed that sulforaphane (SFN)has wide protective effects against tissue injury and inflammation. Accumulating evidence has shown that microRNAs play important roles in the development of hepatic fibrosis, some of which have been identified as potential therapeutic targets. This study was conducted to explore the role of SFN inthe suppression of HSC activation. Quantitative real-time PCR showed that HSC miR-423-5p levels were up-regulated during HSC activation and down-regulated after SFN administration. Further, transfection of a miR-423-5p mimic demonstrated that inhibition of HSC activation by SFN required down-regulation of miR-423-5p. We showed that suppressor of fused is the direct target of miR-423-5p. SFN may play a role in inhibiting hepatic fibrosis by downregulating miRNA-423-5p. MiRNA-423-5p may be useful as a therapeutic target for treating hepatic fibrosis.

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PMID: 

Int J Immunopathol Pharmacol. 2019 Jan-Dec;33:2058738419861777. PMID: 31266422

Abstract Title: 

Sulforaphane alleviates retinal ganglion cell death and inflammation by suppressing NLRP3 inflammasome activation in a rat model of retinal ischemia/reperfusion injury.

Abstract: 

This study aims to study the potentials of sulforaphane (SFN) against retinal ischemia/reperfusion (I/R) injury. A rat retinal I/R injury method was established. Retinal thickness change and retinal ganglion cell (RGC) death were determined using hematoxylin and eosin (H&E) staining and Fluoro-Gold (FG) labeling. The inflammatory cytokines production and microglia activation were evaluated by using quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and enzyme-linked immunosorbent assay (ELISA). Knockdown NLRP3 was performed, and the according changes of retinal RGCs were assessed. SFN administration significantly inhibited I/R and caused retinal thickness change and prevented RGCs death in retinal I/R model. SFN suppressed inflammatory cytokines production, microglia activation, and inflammasome activation. In accordance, NLRP3 knockdown presented the similar inhibitory effect on I/R rats. This study demonstrates that SFN prevents RGCs death and acts as a potent neuroprotective modulator in retinal I/R injury, which may be associated with inhibition of the NLRP3 inflammasome activation.

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