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(A), Platelet endothelial cell adhesion molecule 1 (CD31) immunohistochemical staining photomicrographs of synovial membrane tissues from knee joints of normal, CIA model and CIA rats treated with 45 µg/kg triptolide (Trip), respectively. (B), Hematoxylin and eosin staining photomicrographs of synovial membrane tissues from knee joints of normal, vehicle and 45 µg/kg triptolide-treated CIA rats, respectively. (C), Doses of 11∼45 µg/kg triptolide significantly decreased the capillaries, small, medium and large vessel density (CD31 immunohistochemistry) in synovial membrane tissues of inflamed joints in CIA rats. (D), Doses of 11∼45 µg/kg triptolide significantly decreased the vessel density (assessed on hematoxylin and eosin-stained paraffin sections) in synovial membrane tissues of knee joints in CIA rats. Data are represented as means ± SE (n = 16). ###P<0.001, comparison with the control group. *P<0.05, **P<0.01, and ***P<0.001, comparison with the vehicle group.
Source publication
Rheumatoid arthritis (RA) is characterized by a pre-vascular seriously inflammatory phase, followed by a vascular phase with high increase in vessel growth. Since angiogenesis has been considered as an essential event in perpetuating inflammatory and immune responses, as well as supporting pannus growth and development of RA, inhibition of angiogen...
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Oral administration of antigen has long been considered as a promising alternative for the treatment of chronic autoimmune diseases including rheumatoid arthritis (RA), and oral application of type II collagen (CII) has been proven to improve pathogenic symptoms in RA patients without problematic side effects. To further current understandings abou...
Background
Apoptotic cell-based therapies have been proposed to treat chronic inflammatory diseases. The aim of this study was to investigate the effect of intravenous (i.v.) apoptotic cell infusion in ongoing collagen-induced arthritis (CIA) and the interaction of this therapy with other treatments used in rheumatoid arthritis (RA), including meth...
Background
The purpose of this study was to investigate the therapeutic efficacy of intravenously administered immunoselected STRO-3 + mesenchymal precursor cells (MPCs) on clinical scores, joint pathology and cytokine production in an ovine model of monoarthritis. Methods
Monoarthritis was established in 16 adult merino sheep by administration of...
Background: We have shown previously, in an animal model
of multiple sclerosis and in TNBS-induced colitis, that epicutaneous
(EC) immunization with protein antigen induces
T suppressor cells that strongly inhibit the inflammatory response
in contact hypersensitivity reactions. Methods: EC
immunization was performed by applying to the shaved skin
o...
Collagen-induced arthritis (CIA) was induced in female Wistar rats by intradermal injection of porcine immunization grade native collagen type II (Chondrex). Development and progression of CIA was monitored by studying histopathological, radiographical and biochemical features of arthritic manifestations in the knee joints, hind limb and blood plas...
Citations
... Two weeks after primary immunization, CIA rats were randomly divided into two groups: model group (CIA group, n = 6) and TP group (n = 6). TP can markedly decrease arthritis severity in CIA rats when administered at a dose of 45 μg/kg as previously described 13,14 ; therefore, this dosage of TP (MCE, HY-32735; Purity: 99.86%) was chosen for our experiment. The TP group was treated with 45 μg/kg/day of TP by gavage (Med-ChemExpress) for 21 days. ...
Introduction
Triptolide (TP), a natural product derived from the herbal medicine Tripterygium wilfordii, exhibits potent immunosuppressive activity. However, the mechanisms underlying its effects in rheumatoid arthritis remain incompletely understood.
Methods
Collagen‐induced arthritis (CIA) model was induced in Sprague−Dawley rats by immunization with bovine type II collagen, and TP was administrated as treatment. The therapeutic effect of TP was evaluated based on paw swelling, histopathology, and serum levels of inflammatory factors. Exosomes isolated from rat serum were characterized by transmission electron microscopy, dynamic light scattering, and western blot analysis. Proteomic profiling of exosomes was analyzed by direct DIA quantitative proteomics analysis. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes databases were employed for enrichment analysis related to molecular function, biological processes, and signaling pathways. Western blot analysis was used to analyze differentially expressed proteins.
Results
TP treatment ameliorated arthritic phenotypes in CIA rats as evidenced by reduced arthritis score, paw swelling, pathological injury severity scores, and serum levels of inflammatory cytokines. The proteomic analysis revealed that TP treatment significantly inhibited complement and coagulation cascades, interleukin‐17 signaling pathway, and cholesterol metabolism, which were reactivated in CIA rats. Importantly, lipocalin 2 (LCN2) and myeloperoxidase (MPO) levels were markedly upregulated in the CIA group but suppressed upon TP administration. Furthermore, in synovial tissues, LCN2 and MPO expression levels were also elevated in the CIA group but decreased following TP treatment.
Conclusion
Our findings demonstrate that TP alleviates CIA, possibly through modulation of exosomal LCN2 and MPO proteins.
... Triptolide is one of the most studied and characterized components of TwHF. Triptolide may possess an anti-RA effect by downregulating the angiogenic activators and inhibiting the activation of mitogen-activated protein kinase downstream signal pathway [19], decreasing the production of TNF-alpha, IL-1beta, and IL-6 [20,21], and preventing the bone destruction and inhibit osteoclast formation by reducing the expression of receptor activator of NF-kappa B ligand (RANKL) and RANK and increasing the expression of osteoprotegerin (OPG) [22]. Nobiletin, belonging to flavonoids, has the potential of anti-RA by inhibiting IL-1-induced prostaglandin E2 (PGE2) production, pannus formation, and matrix degradation of rabbit articular cartilage [23], suppressing aggrecanase-mediated degradation of aggrecan in CIA mice [24], and repressing the angiogenesis and inflammatory infiltration by down-regulating the protein expression level of the p38/NF-kappa B signaling pathway in the synovium of CIA rats [25]. ...
Background
Rheumatoid arthritis (RA) is a chronic inflammatory and disabling disease that imposes significant economic and social costs. Tripterygium wilfordii Hook F (TwHF) has a long history of use in traditional Chinese medicine for treating joint disorders, and it has been shown to be cost-effective in treating RA, but its exact mechanism is unknown.
Objective
The goal of the network pharmacology analysis and molecular docking was to investigate the potential active compounds and associated anti-RA mechanisms of TwHF.
Methods
TCMSP and UniProt databases were searched for active compounds and related targets of TwHF. PharmGKB, DrugBank, OMIM, TTD, and the Human Gene Databases were used to identify RA-related targets. The intersected RA and TwHF targets were entered into the STRING database to create a protein–protein interaction network. R software was used for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking technology was used to analyze the optimal effective components from TwHF for docking with the selected target gene.
Results
Following screening and duplicate removal, a total of 51 active compounds and 96 potential targets were chosen. The PPI network revealed that the target proteins are CXCL8, CXCL6, STAT3, STAT1, JUN, PPARG, TP53, IL14, MMP9, VEGFA, RELA, CASP3, PTGS2, IFNG, AKT1, FOS, ICAM1, and MAPK14. The results of the GO enrichment analysis focused primarily on the response to lipopolysaccharide, the response to molecules of bacterial origin, and the response to drugs. The KEGG results indicated that the mechanisms were closely related to lipid and atherosclerosis, chemical carcinogenesis-receptor activation, Kaposi sarcoma-associated, herpesvirus infection, hepatitis B, fluid shear stress and atherosclerosis, IL-17 signaling pathways, Th17-cell differentiation, and so on, all of which are involved in angiogenesis, immune cell chemotaxis, and inflammatory responses. Molecular docking results suggested that triptolide was the appropriate PTGS1, PTGS2, and TNF inhibitors.
Conclusion
Our findings provide an essential role and basis for further immune inflammatory studies into the molecular mechanisms of TwHF and PTGS1, PTGS2, and TNF inhibitor development in RA.
... The study by Kong et al. using a CIA model in rats demonstrated that TPL could inhibit the expression of pro-angiogenic factors including TNF-α, IL-17, VEGF, VEGFR, Ang-1, Ang-2, and Tie2. It also suppressed the activation of the downstream mitogen-activated protein kinase signaling pathway, thereby exerting an anti-angiogenic effect in RA [38]. This may also be the mechanism by which TPL exerts its anti-angiogenic effects in tumors. ...
Triptolide (TPL) is a compound sourced from Tripterygium wilfordii Hook. F., a traditional Chinese medicinal herb recognized for its impressive anti-inflammatory, anti-angiogenic, immunosuppressive, and antitumor qualities. Notwithstanding its favorable attributes, the precise mechanism through which TPL influences tumor cells remains enigmatic. Its toxicity and limited water solubility significantly impede the clinical application of TPL. We offer a comprehensive overview of recent research endeavors aimed at unraveling the antitumor mechanism of TPL in this review. Additionally, we briefly discuss current strategies to effectively manage the challenges associated with TPL in future clinical applications. By compiling this information, we aim to enhance the understanding of the underlying mechanisms involved in TPL and identify potential avenues for further advancement in antitumor therapy.
... Subsequently, DAB was used for color development and hematoxylin for nuclear staining. Eventually, a semi-quantitative analysis was conducted as described previously [26]. ...
Background
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by symmetric arthritis. Coix Seed Oil (CSO) has been shown to reduce inflammation in collagen induced arthritis (CIA) rats. However, the effect of CSO on synovial angiogenesis in RA is unknown. In this study, we aimed to explore whether CSO could inhibit RA synovial angiogenesis and elucidate the underlying mechanisms.
Methods
CIA rat models were established and subjected to different doses of CSO treatments for four weeks in vivo. Arthritis index, paw swelling, and weight were recorded to assess clinical symptoms. Hematoxylin and Eosin staining, Safarnin O fast green staining, Micro-CT, Immunohistochemical, and Immunofluorescence (IF) staining were performed to examined changes in synovial and joint tissues. The serum HIF-1α and VEGF-A levels were evaluated through enzyme-linked immunosorbent assay. Fibroblast-like synoviocytes (FLS) of rats was stimulated with tumor necrosis factor-α (TNF-α) for developing inflammatory model in vitro. Optimal concentrations of CSO and TNF-α for stimulation were measured through Cell Counting Kit-8 test. Wound healing and Transwell migration experiments were employed to determine FLS migratory ability. IF staining was performed to assess HIF-1α nuclear translocation in FLS. Protein levels of SIRT1, HIF-1α, VEGF-A, and CD31 were assessed through Western blot. The isolated aortic rings were induced with recombinant rat VEGF-A 165 (VEGF-A 165 ) to observe the CSO inhibitory impact on angiogenesis ex vivo.
Results
CSO attenuated the progression of arthritis in CIA rats, mitigated histopathological deterioration in synovial and joint tissues, significantly inhibited immature vessels labeled with CD31 ⁺ /αSMA ⁻ , and reduced the micro-vessels in VEGF-A 165 induced aortic rings. Moreover, it upregulated SIRT1 protein levels in CIA rats and TNF-α induced FLS, but decreased HIF-1α and VEGF-A protein levels. Furthermore, CSO inhibited the migration ability and HIF-1α nuclear translocation of TNF-α induced FLS. Finally, suppressing SIRT1 levels in TNF-α induced FLS enhanced their migration ability, HIF-1α nuclear translocation, and the protein levels of HIF-1α, VEGF-A, and CD31, whereas the inhibitory effect of CSO on TNF-α induced FLS was severely constrained.
Conclusions
This study indicates that CSO can alleviate synovial angiogenesis through suppressing HIF-1α/VEGF-A signaling pathways via SIRT1 in CIA rats.
... Second, some of these patients may have sought treatment by using alternative medicines, which could have suppressed their immune function. For instance, triptolide is one such alternative medicine that is very often used to treat autoimmune diseases [41]. Finally, although we adjusted our data for age, sex, and comorbidities, some unknown confounding factors might still have impacted our conclusions. ...
Rheumatoid arthritis (RA) was associated with the risk of incident herpes zoster (HZ), which might be influenced by medication use by RA patients. We aimed to investigate the association of RA with the risk of incident HZ and how the HZ risk effected by RA medications in CIC RA patients. We conducted an observational study including population-based representative insurance claims data of 19,673 patients with RA and 39,346 matched patients without RA during 1997–2010 from the Taiwan National Health Insurance Research Database; we identified 1651 patients with catastrophic illness-certified (CIC) RA and 11,557 matched patients with non-CIC RA. Exploratory analyses assessed the association between RA/CIC RA and risk of incident HZ and its complications. The association of prescribed medications with HZ risk in CIC RA patients was also estimated. The incidence rates of HZ were higher in CIC RA patients and non-CIC RA than in the matched people without RA (21.95 and 14.03 vs. 7.36 events per 1000 person-years, respectively). The adjusted incidence rate ratio (95% confidence interval (CI)) for HZ was 1.74 (1.65–1.84) in RA patients vs. matched non-RA and 1.65(1.44–1.89) in CIC RA patients vs. non-CIC RA. For HZ complications, RA had a 2.85-fold higher risk than non-RA, and CIC RA had a 1.78-fold higher risk than non-CIC RA. Moreover, in CIC RA patients, prednisolone use was associated with incident HZ risk compared with prednisolone nonuse (adjusted odds ratio 1.48, 1.08–2.03); prolonged prednisolone use (approximately 5 years) increased the risk (adjusted odds ratio 2.16, 1.46–3.19). Our results suggested that RA was positively associated with HZ risk, particularly in RA patients with prednisolone use.
... Huang et al. (99) showed that triptolide could improve RA by down-regulating the inflammatory function of neutrophils (inhibiting the expression of pro-inflammatory cytokines, inhibiting migration, NETosis and autophagy, and promoting apoptosis). Kong et al. (100) found that Triptolide could inhibit angiogenesis of RA, down-regulate the expression of angiogenic activation factors (TNF-a, IL-17, VEGF, VEGFR, ANG-1, ANG-2 and Tie2), and inhibit the activation of MAPK signaling pathway (phosphorylation of ERK, p38 and JNK). These studies have shown that triptolide can exert anti-RA activity through a variety of pathways and can be used as a potential therapeutic agent for RA. ...
Rheumatoid arthritis (RA) is an autoimmune disease involving joints, with clinical manifestations of joint inflammation, bone damage and cartilage destruction, joint dysfunction and deformity, and extra-articular organ damage. As an important source of new drug molecules, natural medicines have many advantages, such as a wide range of biological effects and small toxic and side effects. They have become a hot spot for the vast number of researchers to study various diseases and develop therapeutic drugs. In recent years, the research of natural medicines in the treatment of RA has made remarkable achievements. These natural medicines mainly include flavonoids, polyphenols, alkaloids, glycosides and terpenes. Among them, resveratrol, icariin, epigallocatechin-3-gallate, ginsenoside, sinomenine, paeoniflorin, triptolide and paeoniflorin are star natural medicines for the treatment of RA. Its mechanism of treating RA mainly involves these aspects: anti-inflammation, anti-oxidation, immune regulation, pro-apoptosis, inhibition of angiogenesis, inhibition of osteoclastogenesis, inhibition of fibroblast-like synovial cell proliferation, migration and invasion. This review summarizes natural medicines with potential therapeutic effects on RA and briefly discusses their mechanisms of action against RA.
... Consistently, (pre)clinical TNF blocking therapy studies reduced the joint inflammation by decreasing the expression of adhesion molecules as key players in the angiogenesis process [191][192][193][194][195]. Moreover, several novel natural and synthetic drugs such as triptolide, evening primrose oil (EPO) rich in gamma linolenic acid (GLA), niclosamide, wen luo yin, etc. have been shown to inhibit TNF-α production along with the inhibition of angiogenesis in vitro and in vivo in arthritis models [192,[196][197][198][199]. ...
Extensive angiogenesis is a characteristic feature in the synovial tissue of rheumatoid arthritis (RA) from a very early stage of the disease onward and constitutes a crucial event for the development of the proliferative synovium. This process is markedly intensified in patients with prolonged disease duration, high disease activity, disease severity, and significant inflammatory cell infiltration. Angiogenesis is therefore an interesting target for the development of new therapeutic approaches as well as disease monitoring strategies in RA. To this end, nuclear imaging modalities represent valuable non-invasive tools that can selectively target molecular markers of angiogenesis and accurately and quantitatively track molecular changes in multiple joints simultaneously. This systematic review summarizes the imaging markers used for single photon emission computed tomography (SPECT) and/or positron emission tomography (PET) approaches, targeting pathways and mediators involved in synovial neo-angiogenesis in RA.
... This is the first time that the specific impact of the whole LGT extract on cell adhesion was shown in human cells in vitro, as most studies deal with single components and/or specific target-related in vivo models trying to evaluate single MoA. In a previous work from Kong et al. (2013), triptolide, a diterpenoid triepoxide LGT component, was shown to adversely affect matrigel-induced cell adhesion in human fibroblast-like rheumatoid arthritis synoviocytes and human umbilical vein endothelial cells. If the LGTinduced altered adhesion of hNPCs to laminin is also caused by triptolide is not known, however, it can be assumed since triptolide represents one of the main active component of LGT (He et al. 2013). ...
Adverse outcome pathways (AOPs) are organized sequences of key events (KEs) that are triggered by a xenobiotic-induced molecular initiating event (MIE) and summit in an adverse outcome (AO) relevant to human or ecological health. The AOP framework causally connects toxicological mechanistic information with apical endpoints for application in regulatory sciences. AOPs are very useful to link endophenotypic, cellular endpoints in vitro to adverse health effects in vivo. In the field of in vitro developmental neurotoxicity (DNT), such cellular endpoints can be assessed using the human “Neurosphere Assay,” which depicts different endophenotypes for a broad variety of neurodevelopmental KEs. Combining this model with large-scale transcriptomics, we evaluated DNT hazards of two selected Chinese herbal medicines (CHMs) Lei Gong Teng (LGT) and Tian Ma (TM), and provided further insight into their modes-of-action (MoA). LGT disrupted hNPC migration eliciting an exceptional migration endophenotype. Time-lapse microscopy and intervention studies indicated that LGT disturbs laminin-dependent cell adhesion. TM impaired oligodendrocyte differentiation in human but not rat NPCs and activated a gene expression network related to oxidative stress. The LGT results supported a previously published AOP on radial glia cell adhesion due to interference with integrin-laminin binding, while the results of TM exposure were incorporated into a novel putative, stressor-based AOP. This study demonstrates that the combination of phenotypic and transcriptomic analyses is a powerful tool to elucidate compounds’ MoA and incorporate the results into novel or existing AOPs for a better perception of the DNT hazard in a regulatory context.
Graphical abstract
... Triptolide inhibited the IL-1-induced phosphorylation of ERK, p38, and JNK at protein levels in bovine type II collagen-induced arthritis DA rats treated with 11-45 g/kg/day (i.g.) for 28 days and significantly decreased the expression of angiogenic activators such as TNF-α, IL-17, vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), and Ang-1 [81]. Triptolide also lowered the production of TNF-α, IL-1β, and IL-6 in blood and joints of collagen-induced arthritic rats [82]. ...
... Triptolide (0.01-10 μM) downregulated PPAR-c activation and induced DNA fragmentation in RSF in rheumatoid synovial fibroblasts from RA patients [79]. It also decreased arthritis scores and significantly reduced capillaries, small, medium, and large vessel density in the synovial membrane tissues of inflamed joints in bovine type II collagen-induced arthritis DA rats [81]. Moreover, triptolide inhibited Matrigel-induced cell adhesion of HFLS-RA, and HUVEC as well as disrupted tube formation of HUVEC on Matrigel, and suppressed the VEGF-induced chemotactic migration of HFLS-RA and HUVEC, respectively, in arthritis rats. ...
Diterpenes and their derivatives have many biological activities, including anti-inflammatory and immunomodulatory effects. To date, several diterpenes, diterpenoids, and their laboratory-derived products have been demonstrated for antiarthritic activities.This study summarizes the literature about diterpenes and their derivatives acting against rheumatoid arthritis (RA) depending on the database reports until 31 August 2021. For this, we have conducted an extensive search in databases such as PubMed, Science Direct, Google Scholar, and Clinicaltrials.gov using specific relevant keywords. .e search yielded 2708 published records, among which 48 have been included in this study. .e findings offer several potential diterpenes and their derivatives as anti-RA in various test models. Among the diterpenes and their derivatives, andrographolide, triptolide, and tanshinone IIA have been found to exhibit anti-RA activity through diverse pathways. In addition, some important derivatives of triptolide and tanshinone IIA have also been shown to have anti-RA effects. Overall, findings suggest that these substances could reduce arthritis score, downregulate oxidative, proinflammatory, and inflammatory biomarkers, modulate various arthritis pathways, and improve joint destruction and clinical arthritic conditions, signs, symptoms, and physical functions in humans and numerous experimental animals, mainly through cytokine and chemokine as well as several physiological protein interaction pathways. Taken all together, diterpenes, diterpenoids, and their derivatives may be promising tools for RA management.
... In a previous study, IL-17 mRNA was overexpressed in kidney biopsy specimens from IMN patients [44]. The inhibitory effect of T. wilfordii on IL-17 has been demonstrated in autoimmune diseases including psoriasis, ankylosing spondylitis, and rheumatoid arthritis [45][46][47], but not in IMN yet. In another study, TNF-a was directly cytotoxic to many glomerular cell types and promoted procoagulant activity with the formation of microthrombi that could contribute to renal vein thrombosis associated with MN [48]. ...
Background
Although thunder god vine (Tripterygium wilfordii) has been widely used for treatment of idiopathic membranous nephropathy (IMN), the pharmacological mechanisms underlying its effects are still unclear. This study investigated potential therapeutic targets and the pharmacological mechanism of T. wilfordii for the treatment of IMN based on network pharmacology.
Methods
Active components of T. wilfordii were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. IMN-associated target genes were collected from the GeneCards, DisGeNET, and OMIM databases. VENNY 2.1 was used to identify the overlapping genes between active compounds of T. wilfordii and IMN target genes. The STRING database and Cytoscape 3.7.2 software were used to analyze interactions among overlapping genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the targets were performed using Rx64 4.0.2 software, colorspace, stringi, DOSE, clusterProfiler, and enrichplot packages.
Results
A total of 153 compound-related genes and 1485 IMN-related genes were obtained, and 45 core genes that overlapped between both categories were identified. The protein–protein interaction network and MCODE results indicated that the targets TP53, MAPK8, MAPK14, STAT3, IFNG, ICAM1, IL4, TGFB1, PPARG, and MMP1 play important roles in the treatment of T. wilfordii on IMN. Enrichment analysis showed that the main pathways of targets were the AGE signaling pathway, IL-17 signaling pathway, TNF signaling pathway, and Toll-like receptor signaling pathway.
Conclusion
This study revealed potential multi-component and multi-target mechanisms of T. wilfordii for the treatment of IMN based on network pharmacological, and provided a scientific basis for further experimental studies.
