Combined Cornus Officinalis and Paeonia Lactiflora Pall Therapy Alleviates Rheumatoid Arthritis by Regulating Synovial Apoptosis via AMPK-Mediated Mitochondrial Fission

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to cartilage destruction and bone erosion. In-depth exploration of the pathogenesis of RA and the development of effective therapeutic drugs are of important clinical and social value. Herein, we explored the medicinal value of Cornus officinalis Sieb. and Paeonia lactiflora Pall. in RA treatment using a rat model of collagen-induced arthritis (CIA). We compared the therapeutic effect of Cornus officinalis and Paeonia lactiflora with that of their main active compounds, ursolic acid and paeoniflorin, respectively. We demonstrated that the combination of Cornus officinalis and Paeonia lactiflora effectively inhibited the release of factors associated with oxidative stress and inflammation during RA, therein ameliorating the symptoms and suppressing the progression of RA. We further showed that the underlying mechanisms may be related to the regulation of apoptosis in synovial tissues, and we investigated the potential involvement of AMPK-mediated mitochondrial dynamics in the therapeutic action of the two drugs and their active components.

Download Full-text

The Role of Collagen Triple Helix Repeat-Containing 1 Protein (CTHRC1) in Rheumatoid Arthritis

International Journal of Molecular Sciences ◽

10.3390/ijms22052426 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2426

Author(s):

Askhat Myngbay ◽

Limara Manarbek ◽

Steve Ludbrook ◽

Jeannette Kunz

Keyword(s):

Rheumatoid Arthritis ◽

Drug Targets ◽

Triple Helix ◽

Cancer Metastasis ◽

Bone Erosion ◽

Cartilage Destruction ◽

Patient Treatment ◽

Collagen Triple Helix ◽

Potential Biomarker

Rheumatoid arthritis (RA) is a chronic autoimmune disease causing inflammation of joints, cartilage destruction and bone erosion. Biomarkers and new drug targets are actively sought and progressed to improve available options for patient treatment. The Collagen Triple Helix Repeat Containing 1 protein (CTHRC1) may have an important role as a biomarker for rheumatoid arthritis, as CTHRC1 protein concentration is significantly elevated in the peripheral blood of rheumatoid arthritis patients compared to osteoarthritis (OA) patients and healthy individuals. CTHRC1 is a secreted glycoprotein that promotes cell migration and has been implicated in arterial tissue-repair processes. Furthermore, high CTHRC1 expression is observed in many types of cancer and is associated with cancer metastasis to the bone and poor patient prognosis. However, the function of CTHRC1 in RA is still largely undefined. The aim of this review is to summarize recent findings on the role of CTHRC1 as a potential biomarker and pathogenic driver of RA progression. We will discuss emerging evidence linking CTHRC1 to the pathogenic behavior of fibroblast-like synoviocytes and to cartilage and bone erosion through modulation of the balance between bone resorption and repair.

Download Full-text

Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis

Cells ◽

10.3390/cells9040880 ◽

2020 ◽

Vol 9 (4) ◽

pp. 880 ◽

Cited By ~ 10

Author(s):

Yen-Ju Lin ◽

Martina Anzaghe ◽

Stefan Schülke

Keyword(s):

Rheumatoid Arthritis ◽

Side Effects ◽

Bone Erosion ◽

Treatment Options ◽

Joint Damage ◽

Cartilage Destruction ◽

Biologic Dmards ◽

Clinical Benefits ◽

Synthetic Dmards ◽

Inability To Work

Rheumatoid arthritis (RA) is an autoimmune disease that involves multiple joints bilaterally. It is characterized by an inflammation of the tendon (tenosynovitis) resulting in both cartilage destruction and bone erosion. While until the 1990s RA frequently resulted in disability, inability to work, and increased mortality, newer treatment options have made RA a manageable disease. Here, great progress has been made in the development of disease-modifying anti-rheumatic drugs (DMARDs) which target inflammation and thereby prevent further joint damage. The available DMARDs are subdivided into (1) conventional synthetic DMARDs (methotrexate, hydrochloroquine, and sulfadiazine), (2) targeted synthetic DMARDs (pan-JAK- and JAK1/2-inhibitors), and (3) biologic DMARDs (tumor necrosis factor (TNF)-α inhibitors, TNF-receptor (R) inhibitors, IL-6 inhibitors, IL-6R inhibitors, B cell depleting antibodies, and inhibitors of co-stimulatory molecules). While DMARDs have repeatedly demonstrated the potential to greatly improve disease symptoms and prevent disease progression in RA patients, they are associated with considerable side-effects and high financial costs. This review summarizes our current understanding of the underlying pathomechanism, diagnosis of RA, as well as the mode of action, clinical benefits, and side-effects of the currently available DMARDs.

Download Full-text

DMY protects the knee joints of rats with collagen-induced arthritis by inhibition of NF-κB signaling and osteoclastic bone resorption

Food & Function ◽

10.1039/d0fo00396d ◽

2020 ◽

Vol 11 (7) ◽

pp. 6251-6264

Author(s):

Jing Wu ◽

Kai-Jian Fan ◽

Qi-Shan Wang ◽

Bing-Xin Xu ◽

Qing Cai ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Animal Model ◽

Articular Cartilage ◽

Bone Resorption ◽

Bone Erosion ◽

Cartilage Destruction ◽

Osteoclastic Bone Resorption ◽

Knee Joints ◽

Collagen Induced Arthritis

Collagen-induced arthritis (CIA) is a widely used animal model for studying rheumatoid arthritis (RA), which manifests serious joint dysfunction, progressive bone erosion and articular cartilage destruction.

Download Full-text

Evaluating the Therapeutic Mechanisms of Selected Active Compounds in Cornus Officinalis and Paeonia Lactiflora in Rheumatoid Arthritis via Network Pharmacology Analysis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.648037 ◽

2021 ◽

Vol 12 ◽

Author(s):

Qinglin Li ◽

Shaoqi Hu ◽

Lichuang Huang ◽

Jida Zhang ◽

Gang Cao

Keyword(s):

Rheumatoid Arthritis ◽

Ursolic Acid ◽

Network Pharmacology ◽

Pharmacological Properties ◽

Paeonia Lactiflora ◽

Collagen Induced Arthritis ◽

Active Compounds ◽

Cornus Officinalis ◽

Therapeutic Mechanisms ◽

Compound Target

Cornus officinalis Sieb et. Zucc and Paeonia lactiflora Pall. have exhibited favorable therapeutic effects against rheumatoid arthritis (RA), but the specific mechanisms of their active compounds remain unclear. The aim of this study was to comprehensively analyze the therapeutic mechanisms of selected active compounds in Cornus officinalis (loganin, ursolic acid, and morroniside) and Paeonia lactiflora (paeoniflorin and albiflorin) via network pharmacology. The pharmacological properties of the five active compounds were evaluated and their potential target genes were identified by database screening. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional analysis were performed to determine the enriched molecular pathways associated with the active compounds. Using network pharmacology tools, eight genes (IL1β, VEGFA, STAT3, TP53, IL6, TNF, FOS, and LGALS3) were identified as common targets between RA and the five active compounds. Molecular docking simulation revealed the compound-target relationship between the five active compounds and three selected targets from the eight common ones (LGALS3, STAT3, and VEGFA). The compound-target relationships were subsequently validated via preliminary in vivo experiments in a rat model of collagen-induced arthritis. Rats subjected to collagen-induced arthritis showed increased protein expression of LGALS3, STAT3, and VEGFA in synovial tissues. However, treatment using Cornus officinalis or/and Paeonia lactiflora, as well as their most drug-like active compounds (ursolic acid or/and paeoniflorin, respectively, identified based on pharmacological properties), attenuated the expression of these three targets, as previously predicted. Collectively, network pharmacology allowed the pharmacological and molecular roles of Cornus officinalis and Paeonia lactiflora to be systematically revealed, further establishing them as important candidate drugs in the treatment and management of RA.

Download Full-text

Hypoxia-Induced ROS Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via HIF-1α/Mff Regulation

10.21203/rs.3.rs-114244/v1 ◽

2020 ◽

Author(s):

Kun Wu ◽

Yuan-yuan Mao ◽

Qi Chen ◽

Bolin Zhang ◽

Sheng Zhang ◽

...

Keyword(s):

Malignant Tumors ◽

Mitochondrial Dynamics ◽

Dynamic Balance ◽

Mitochondrial Fission ◽

Hypoxia Inducible Factor ◽

Hypoxic Condition ◽

Clinical Samples ◽

Α Subunit ◽

Hypoxic Conditions ◽

Underlying Mechanisms

Abstract BackgroundChemotherapy treatment based on Cisplatin (CDDP) is established as the drug of choice for head and neck squamous cell carcinoma (HNSCC). Malignant tumors respond to microenvironment alteration through a dynamic balance of mitochondrial fission and fusion. HNSCC is known to have hypoxic conditions, yet the effects and underlying mechanisms of hypoxia on chemosensitivity and mitochondrial dynamics remain unclear. ResultsWe found that hypoxia promoted mitochondrial fission and CDDP sensitivity in HNSCC cells. Importantly, Mff was shown to be correlated with chemosensitivity in clinical samples of HNSCC that underwent a hypoxic condition. Hypoxia-inducible factor 1 α-subunit (HIF-1α) dramatically increased Mff transcriptional expression and directly bound to Mff. Hypoxia enhanced the release of reactive oxygen species (ROS) and upregulated the expression of Mff via HIF-1α in HNSCC cells. ROS depletion in HNSCC cells attenuated HIF-1α, Mff expression, and mitochondrial fission. Moreover, a knockdown of Mff suppressed hypoxia-induced mitochondrial fission and decreased CDDP chemosensitivity in vivo and in vitro. ConclusionsOur findings revealed that the hypoxia-induced release of ROS promoted mitochondrial fission and CDDP chemosensitivity via the regulation of HIF-1α/Mff in HNSCC cells, indicating that Mff may serve as a new biomarker to predict neoadjuvant chemosensitivity in HNSCC patients.

Download Full-text

A Computational Modeling Framework to Analyze Synovial-Tissue Based Drug Targets and Diagnostic Biomarkers in Rheumatoid Arthritis

10.1101/2021.11.08.467813 ◽

2021 ◽

Author(s):

Paridhi Latawa ◽

Brianna Chrisman

Keyword(s):

Rheumatoid Arthritis ◽

Synovial Tissue ◽

Drug Targets ◽

Bone Erosion ◽

Cartilage Destruction ◽

Modeling Framework ◽

Diagnostic Biomarkers ◽

Number Of Patients ◽

Targeted Treatments ◽

Inflammatory Autoimmune Disease

Rheumatoid Arthritis (RA) is an inflammatory autoimmune disease that affects 23 million people worldwide. It is a clinically heterogeneous disorder characterized by the attack of inflammatory chemicals on the synovial tissue that lines joints. It is advantageous to develop effective, targeted treatments and identify specific diagnostic biomarkers for RA before extensive joint degradation, bone erosion, and cartilage destruction. Current modes of RA treatments have alleviated and notably halted the progression of RA. Despite this, not many patients reach low disease activity status after treatment, and a significant number of patients fail to respond to medication due to drug non-specificity. While the reasons for these rates remain unknown, the cellular and molecular signatures present in the synovial tissue for RA patients likely play a role in the varied treatment response. Thus, a drug that particularly targets specific genes and networks may have a significant effect in halting the progression of RA. This study evaluates and proposes potential drug targets through in silico mathematical modeling of various pathways of interest in RA. To understand how drugs interact with genes, we built a mathematical model with 30 two-gene and three-gene network interactions and analyzed the effect of 92 different perturbations to rate constants. We determined that inhibition of the LCK-CD4, VAV1-CD4, and MLT-ROR pathways could potentially serve as drug targets. We also found that increased activity of the DEC2-IL1β and the NF-κB-interleukin pathway and the decreased activity of the TNF-α-REV-ERB pathway could serve as diagnostic biomarkers.

Download Full-text

Periploca forrestiiSaponin Ameliorates Murine CFA-Induced Arthritis by Suppressing Cytokine Production

Mediators of Inflammation ◽

10.1155/2016/7941684 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 7

Author(s):

Yingqin Liu ◽

Minghui Li ◽

Qiuhong He ◽

Xinping Yang ◽

Fang Ruan ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Transcription Factor ◽

Cytokine Production ◽

Bone Erosion ◽

Folk Medicine ◽

Intragastric Administration ◽

Pharmacological Effects ◽

Adjuvant Induced Arthritis ◽

Alternative Modality ◽

Underlying Mechanisms

Periploca forrestiiSchltr. has been used as a Chinese folk medicine due to its versatile pharmacological effects such as promoting wounds and rheumatoid arthritis. However, the antiarthritic activity ofPeriploca forrestiisaponin (PFS) and its active compound Periplocin has still not been demonstrated. Here, we evaluated the antiarthritic effects of PFS in adjuvant-induced arthritis (AIA) rats by intragastric administration at a dose of 50 mg/kg. The anti-inflammatory activities of Periplocin were also examined in LPS-induced AIA splenocytes and synoviocytes. PFS significantly ameliorated joint swelling; inhibited bone erosion in joints; lowered levels of IL-6 and TGF-β1 in AIA rat splenocyte; and reduced joint protein expression levels of phospho-STAT3 and IKKα. Using LPS-induced AIA splenocytes, we demonstrate that Periplocin suppressed the key proinflammatory cytokines levels of IL-6, IFN-γ, TGF-β1, and IL-13 and IL-22 and transcription factor levels of T-bet, GATA3, and C-Jun genes. Periplocin also suppressed LPS-induced cytokine secretion from synoviocytes. Our study highlights the antiarthritic activity of PFS and its derived Periplocin and the underlying mechanisms. These results provide a strong rationale for further testing and validation of the use ofPeriploca forrestiiSchltr. as an alternative modality for the treatment of RA.

Download Full-text

Commercial Bovine Proteoglycan Is Highly Arthritogenic and Can Be Used as an Alternative Antigen Source for PGIA Model

BioMed Research International ◽

10.1155/2014/148594 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 6

Author(s):

Larissa Lumi Watanabe Ishikawa ◽

Priscila Maria Colavite ◽

Larissa Camargo da Rosa ◽

Bianca Balbino ◽

Thais Graziela Donegá França ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Clinical Symptoms ◽

Bone Erosion ◽

Cartilage Destruction ◽

Cross Reactivity ◽

Experimental Models ◽

Systemic Autoimmune Disease ◽

New Therapies ◽

Extraction And Purification ◽

Antigenic Source

Rheumatoid arthritis (RA) is the most common systemic autoimmune disease. It affects mainly the joints, causing synovitis, cartilage destruction, and bone erosion. Many experimental models are used to study the mechanisms involved in immunopathogenesis and new therapies for this disease. Proteoglycan-induced arthritis (PGIA) is a widely used model based on the cross-reactivity of injected foreign (usually human) PG and mice self-PG. Considering the complexity of the extraction and purification of human PG, in this study we evaluated the arthritogenicity of bovine PG that is commercially available. Bovine PG was highly arthritogenic, triggering 100% incidence of arthritis in female BALB/c retired breeder mice. Animals immunized with bovine PG presented clinical symptoms and histopathological features similar to human RA and other experimental models. Moreover, bovine PG immunization determined higher levels of proinflammatory and anti-inflammatory cytokines in arthritic mice compared to healthy ones. As expected, only the arthritic group produced IgG1 and IgG2a antibodies against PG. Thus, commercial bovine PG can be used as an alternative antigenic source to PGIA for the study of many RA aspects, including the immunopathogenesis of the disease and also the development of new therapies.

Download Full-text

RANKL is a therapeutic target of bone destruction in rheumatoid arthritis

F1000Research ◽

10.12688/f1000research.17296.1 ◽

2019 ◽

Vol 8 ◽

pp. 533 ◽

Cited By ~ 7

Author(s):

Sakae Tanaka

Keyword(s):

Rheumatoid Arthritis ◽

Nuclear Factor Kappa B ◽

Bone Erosion ◽

Therapeutic Option ◽

Osteoclast Differentiation ◽

Bone Destruction ◽

Cartilage Destruction ◽

Human Antibody ◽

Receptor Activator ◽

Made In

Although remarkable advances have been made in the treatment of rheumatoid arthritis (RA), novel therapeutic options with different mechanisms of action and fewer side effects have been expected. Recent studies have demonstrated that bone-resorbing osteoclasts are critically involved in the bone destruction associated with RA. Denosumab, a human antibody against receptor activator of nuclear factor-kappa B ligand (RANKL), efficiently suppressed the progression of bone erosion in patients with RA by suppressing osteoclast differentiation and activation in several clinical studies, although it had no effect on inflammation or cartilage destruction. Denosumab, in combination with anti-rheumatic drugs, is considered a pivotal therapeutic option for the prevention of bone destruction in RA.

Download Full-text

The Role of Collagen Triple Helix Repeat-Containing 1 Protein (CTHRC1) in Rheumatoid Arthritis

10.20944/preprints202007.0206.v1 ◽

2020 ◽

Author(s):

Askhat Myngbay ◽

Limara Manarbek ◽

Steve B. Ludbrook ◽

Jeannette Kunz

Keyword(s):

Rheumatoid Arthritis ◽

Drug Targets ◽

Triple Helix ◽

Cancer Metastasis ◽

Bone Erosion ◽

Cartilage Destruction ◽

Patient Treatment ◽

Collagen Triple Helix ◽

Potential Biomarker

Rheumatoid arthritis (RA) is a chronic autoimmune disease, causing inflammation of joints, cartilage destruction and bone erosion. Biomarkers and new drug targets are actively sought and progressed to improve available options for patient treatment. The Collagen Triple Helix Repeat Containing 1 protein (CTHRC1) may have an important role as a biomarker for rheumatoid arthritis, as CTHRC1 protein concentration is significantly elevated in the peripheral blood of rheumatoid arthritis patients, compared to osteoarthritis (OA) patients and healthy individuals. CTHRC1 is a secreted glycoprotein that promotes cell migration and has been implicated in arterial tissue-repair processes. Furthermore, high CTHRC1 expression is observed in many types of cancer and this is associated with cancer metastasis to the bone and poor prognosis. However, the function of CTHRC1 in RA is still largely undefined. The aim of this review is to summarize recent findings on the role of CTHRC1 as a potential biomarker and pathogenic driver of RA progression that may be linked to the pathogenic behavior of fibroblast-like synoviocytes, cartilage destruction, and bone erosion.

Download Full-text