cis-Aconitic Acid, a Constituent of Echinodorus grandiflorus Leaves, Inhibits Antigen-Induced Arthritis and Gout in Mice

Planta Medica ◽  
2021 ◽  
Author(s):  
Diego Pinto de Oliveira ◽  
Eliana de Faria Garcia ◽  
Mariana Assíria de Oliveira ◽  
Luiza C. M. Candido ◽  
Fernanda M. Coelho ◽  
...  

Abstract cis-Aconitic acid is a constituent from the leaves of Echinodorus grandiflorus, a medicinal plant traditionally used in Brazil to treat inflammatory conditions, including arthritic diseases. The present study aimed to investigate the anti-arthritic effect of cis-aconitic acid in murine models of antigen-induced arthritis and monosodium urate-induced gout. The possible underlying mechanisms of action was evaluated in THP-1 macrophages. Oral treatment with cis-aconitic acid (10, 30, and 90 mg/kg) reduced leukocyte accumulation in the joint cavity and C-X-C motif chemokine ligand 1 and IL-1β levels in periarticular tissue. cis-Aconitic acid treatment reduced joint inflammation in tissue sections of antigen-induced arthritis mice and these effects were associated with decreased mechanical hypernociception. Administration of cis-aconitic acid (30 mg/kg p. o.) also reduced leukocyte accumulation in the joint cavity after the injection of monosodium urate crystals. cis-Aconitic acid reduced in vitro the release of TNF-α and phosphorylation of IκBα in lipopolysaccharide-stimulated THP-1 macrophages, suggesting that inhibition of nuclear factor kappa B activation was an underlying mechanism of cis-aconitic acid-induced anti-inflammatory effects. In conclusion, cis-aconitic acid has significant anti-inflammatory effects in antigen-induced arthritis and monosodium urate-induced arthritis in mice, suggesting its potential for the treatment of inflammatory diseases of the joint in humans. Additionally, our findings suggest that this compound may contribute to the anti-inflammatory effect previously reported for E. grandiflorus extracts.

Author(s):  
С.В. Калиш ◽  
С.В. Лямина ◽  
Л.В. Кузнецова ◽  
О.П. Буданова ◽  
В.А. Логачев ◽  
...  

Подагра является частой причиной воспалительного артрита, разрушения суставов, образования камней в почках и почечной недостаточности. Причиной воспаления в суставе является взаимодействие кристаллов мочевой кислоты (monosodium urate - MSU) и пирофосфата кальция (calcium pyrophosphate - СаРР) с макрофагами. Мы предположили, что подавлять кристалл-индуцированное воспаление мог бы М3 фенотип макрофагов, который увеличивает продукцию антивоспалительных цитокинов при действии воспалительных индукторов (АВ-М3 фенотип). Цель работы состояла в проверке этой гипотезы. Методы. Подагрическое воспаление моделировали с помощью добавления кристаллов MSU и СаРР к культуре макрофагов. Для программирования АВ-М3 фенотипа использовали ингибитор инфламмасомы MCC950 и IL-4. Воспалительную реакцию оценивали по продукции IL-1b и TGFb1. Результаты. Реакция нативных (M0) макрофагов и на кристаллы MSU, и на кристаллы CaPP воспроизвела острое подагрическое воспаление в форме 3-кратного увеличения продукции IL-1b (p < 0,05). При добавлении кристаллов MSU к АВ-М3 макрофагам содержание IL-1b в культуральной среде было меньше в 25 раз (p < 0,05), а содержание TGFb больше почти в 2 раза (p < 0,05) по сравнению со средой М0 макрофагов с кристаллами MSU. Аналогичный результат был получен при добавлении кристаллов CaPP к АВ-М3 макрофагам. Заключение. Таким образом, АВ-М3 фенотип отвечает на провоспалительное действие кристаллов MSU и CaPP снижением продукции IL-1b и усилением продукции TGFb1. Результаты работы подтвердили гипотезу о том, что АВ-М3 фенотип может ограничить кристалл-индуцированное воспаление. Соответственно, разработка клинической версии технологии АВ-М3 макрофагов представляется весьма перспективной. Gout is a common cause of inflammatory arthritis, joint damage, kidney stones, and kidney failure. Joint inflammation is induced by interaction of uric acid (monosodium urate, MSU) crystals and calcium pyrophosphate (CaPP) crystals with macrophages. We hypothesized that the crystal-induced inflammation could be suppressed by the M3 switch phenotype, which increases production of anti-inflammatory cytokines under the action of inflammation inducers (AB-M3 phenotype). The aim of the present study was to test this hypothesis. Methods. Gouty inflammation was modeled by adding MSU and CaPP crystals to cultured macrophages. The inflammasome inhibitor, MCC950, and IL-4 were used for programming the AB-M3 phenotype. The inflammatory response was evaluated by production of IL-1β and TGFβ1. Results. The response of native (M0) macrophages to either MSU crystals or CaPP crystals reproduced acute gouty inflammation in the form of a 3-fold increase in IL-1 β production (p < 0.05). When MSU crystals were added to AB-M3 macrophages, the IL-1β content in the culture medium became 25 times lower (p < 0.05), and the TGF-β1 content became almost twice higher (p < 0.05) than the respective values in the M0 macrophage medium with MSU crystals. A similar result was obtained when CaPP crystals were added to AB-M3 macrophages. Conclusion. The AB-M3 phenotype responds to the pro-inflammatory action of MSU and CaPP crystals by decreasing the IL-1β production and increasing the TGF-β1 production. These results confirmed the hypothesis that the AB-M3 phenotype restricts the crystal-induced production of inflammatory IL-1β and increases the production of anti-inflammatory TGF-β1. Therefore, development of a clinical version of the AB-M3 macrophage technology is very promising.


Author(s):  
Mingzhu Luan ◽  
Huiyun Wang ◽  
Jiazhen Wang ◽  
Xiaofan Zhang ◽  
Fenglan Zhao ◽  
...  

: In vivo and in vitro studies reveal that ursolic acid (UA) is able to counteract endogenous and exogenous inflammatory stimuli, and has favorable anti-inflammatory effects. The anti-inflammatory mechanisms mainly include decreasing the release of histamine in mast cells, suppressing the activities of lipoxygenase, cyclooxygenase and phospholipase, and reducing the production of nitric oxide and reactive oxygen species, blocking the activation of signal pathway, down-regulating the expression of inflammatory factors, and inhibiting the activities of elastase and complement. These mechanisms can open up new avenues for the scientific community to develop or improve novel therapeutic approaches to tackle inflammatory diseases such as arthritis, atherosclerosis, neuroinflammation, liver diseases, kidney diseases, diabetes, dermatitis, bowel diseases, cancer. The anti-inflammatory activity, the anti-inflammatory mechanism of ursolic acid and its therapeutic applications are reviewed in this paper.


2021 ◽  
Vol 12 ◽  
Author(s):  
Yuanyuan Ling ◽  
Jie Yang ◽  
Di Hua ◽  
Dawei Wang ◽  
Chenglei Zhao ◽  
...  

Bone erosion is the most evident pathological condition of rheumatoid arthritis (RA), which is the main cause of joint deformities and disability in RA patients. At present, the conventional RA drugs have not achieved satisfactory effect in improving bone erosion. ZhiJingSan (ZJS), which is a traditional Chinese prescription composed of scolopendra (dried body of Scolopendra subspinipes mutilans L. Koch, scolopendridae) and scorpion (dried body of Buthus martensii Karsch, Buthus), exhibits anti-rheumatism, analgesic and joint deformities improvement effects. This study aimed to assess the therapeutic effect of ZJS on RA bone erosion and to elucidate the underlying mechanism. The effect of ZJS on RA bone erosion was investigated in a murine model of bovine collagen-induced arthritis (CIA), and the underlying mechanism was investigated in vitro in an osteoclast differentiation cell model. Administration of ZJS delayed the onset of arthritis, alleviated joint inflammation, and attenuated bone erosion in the CIA mice. Meanwhile, ZJS decreased the serum levels of TNF-α, IL-6, and anti-bovine collagen II-specific antibodies. Furthermore, ZJS treatment reduced the number of osteoclasts and the expression of cathepsin K in the ankle joints of CIA mice. ZJS also inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation and the expression of MMP9 and cathepsin K in vitro. Mechanistically, ZJS blocked RANKL-induced p65 phosphorylation, nucleation, and inhibited the expression of downstream NFATc1 and c-Fos in bone marrow-derived macrophages (BMMs). Taken together, ZJS exerts a therapeutic effect on bone erosion in CIA mice by inhibiting RANKL/NF-κB-mediated osteoclast differentiation, which suggested that ZJS is a promising prescription for treating RA bone erosion.


2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
June Seok Heo ◽  
Ja-Yun Lim ◽  
Dae Wui Yoon ◽  
Sangshin Pyo ◽  
Jinkwan Kim

The positive effects of mesenchymal stem cells (MSCs) are primarily activated through molecular secretions known as paracrine activity, which regulates the function of various cell types including immune cells. Accumulating evidence shows that exosomes of soluble factors released from MSCs are potential alternative agents for stem cell-based therapy, although the exact underlying mechanism has not been elucidated. The purpose of this study was to evaluate the potential effects of exosomes produced by adipose-derived MSCs and to examine the changes in anti-inflammatory genes in concurrence with the polarization of M2 macrophages in cellular models ex vivo. Isolated exosomes were used to investigate the inflammatory modulation in pro-inflammatory cytokine-treated fibroblasts and THP-1 cells. The anti-inflammatory mRNA expression associated with M2 macrophages was significantly upregulated after exosome treatment in an interferon gamma and tumor necrosis factor alpha-treated inflammatory environment. Furthermore, melatonin-stimulated exosomes exerted superior anti-inflammatory modulation via exosomal miRNAs miR-34a, miR-124, and miR-135b, compared with exosomes. Our results indicate that melatonin-stimulated exosomes originating from adipose-derived MSCs are safe and efficient tools for regenerative medicine to treat inflammatory diseases.


Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 284 ◽  
Author(s):  
Benjamin J. Swartzwelter ◽  
Francesco Barbero ◽  
Alessandro Verde ◽  
Maria Mangini ◽  
Marinella Pirozzi ◽  
...  

Innate immune memory is characterized by a modulation in the magnitude with which innate immune cells such as monocytes and macrophages respond to potential dangers, subsequent to previous exposure to the same or unrelated agents. In this study, we have examined the capacity of gold nanoparticles (AuNP), which are already in use for therapeutic and diagnostic purposes, to modulate the innate memory induced by bacterial agents. The induction of innate memory was achieved in vitro by exposing human primary monocytes to bacterial agents (lipopolysaccharide -LPS-, or live Bacille Calmette-Guérin -BCG) in the absence or presence of AuNP. After the primary activation, cells were allowed to return to a resting condition, and eventually re-challenged with LPS. The induction of memory was assessed by comparing the response to the LPS challenge of unprimed cells with that of cells primed with bacterial agents and AuNP. The response to LPS was measured as the production of inflammatory (TNFα, IL-6) and anti-inflammatory cytokines (IL-10, IL-1Ra). While ineffective in directly inducing innate memory per se, and unable to influence LPS-induced tolerance memory, AuNP significantly affected the memory response of BCG-primed cells, by inhibiting the secondary response in terms of both inflammatory and anti-inflammatory factor production. The reprogramming of BCG-induced memory towards a tolerance type of reactivity may open promising perspectives for the use of AuNP in immunomodulatory approaches to autoimmune and chronic inflammatory diseases.


Author(s):  
Basim Jasim Hameed ◽  
Usama Hamid Ramadhan

Objective: The current study was carried out to investigate the xanthine oxidase inhibitory, antihyperuricemic, anti-inflammatory, and antinociception activity of α-lipoic acid (LA) in gouty model of rats.Methods: Enzyme assay was done using bovine milk xanthine oxidase (XO). The XO inhibitory activity in vitro was performed using different doses of α-LA, and the degree of XO inhibition was expressed as IC50. The antihyperuricemic activity of α-LA was tested in the potassium oxonate-induced hyperuricemic rats for 7 consecutive days of oral treatment of 10, 25, and 50 mg/kg doses. The anti-inflammatory activity was achieved through monosodium urate crystal-induced inflammation hind paw model in mice. The antinociception effects of α-LA were explored using both of writhings induced by acetic acid test and hot plate test.Results: The study results revealed that the α-LA has a potent activity of XO inhibition with IC50 = 2.93 μg/mL. Furthermore, these results showed that all doses of α-LA were able to significant reduce of each the following: Serum uric acid levels in the hyperuricemic rats, hind paw thickness of mice at all periods of time assessment, and writhings number in the acetic acid-induced writhing test, while, the same doses significantly increased the reaction latency in mice at hot plate test.Conclusion: The α-LA showed a significant effect on the evaluated models, and therefore it may be a promising agent for the treatment of gout since it possesses XO inhibitory, antihyperuricemic, anti-inflammatory, and antinociception activity. 


2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Stephanie Flore Djuichou Nguemnang ◽  
Eric Gonzal Tsafack ◽  
Marius Mbiantcha ◽  
Ateufack Gilbert ◽  
Albert Donatien Atsamo ◽  
...  

Dissotis thollonii Cogn. (Melastomataceae) is a tropical plant widely used in traditional Cameroonian medicine to relieve and treat many pathologies. It is widespread in the western region where it is used to treat typhoid fever, gastrointestinal disorders, and inflammatory diseases. The purpose of this study is to scientifically demonstrate the anti-inflammatory and antiarthritic properties of the aqueous and ethanolic extracts of the leaves of Dissotis thollonii. The anti-inflammatory properties were evaluated in vitro by inhibition tests for cyclooxygenase, 5-lipoxygenase, protein denaturation, extracellular ROS production, and cell proliferation; while antiarthritic properties were evaluated in vivo in rats using the zymosan A-induced monoarthritis test and the CFA-induced polyarthritis model. This study shows that aqueous and ethanolic extracts at a concentration of 1000 μg/ml inhibit the activity of cyclooxygenase (47.07% and 63.36%) and 5-lipoxygenase (66.79% and 77.7%) and protein denaturation (42.51% and 44.44%). Similarly, both extracts inhibited extracellular ROS production (IC50 = 5.74 μg/ml and 2.96 μg/ml for polymorphonuclear leukocytes, 7.47 μg/ml and 3.28 μg ml for peritoneal macrophages of mouse) and cell proliferation (IC50 = 16.89 μg/ml and 3.29 μg/ml). At a dose of 500 mg/kg, aqueous and ethanolic extracts significantly reduce edema induced by zymosan A (69.30% and 81.80%) and CFA (71.85% and 79.03%). At the same dose, both extracts decreased sensitivity to mechanical hyperalgesia with 69.00% and 70.35% inhibition, respectively. Systemic and histological analyzes show that both extracts maintain the studied parameters very close to normal and greatly restored the normal architecture of the joint in animals. Dissotis thollonii would therefore be a very promising source for the treatment of inflammatory diseases.


Author(s):  
Tatyana S. Khlebnicova ◽  
Yuri A. Piven ◽  
Fedor A. Lakhvich ◽  
Iryna V. Sorokina ◽  
Tatiana S. Frolova ◽  
...  

Background: Prevention and treatment of chronic inflammatory diseases require effective and low-toxic medicines. Molecular hybridization is an effective strategy to enhance the biological activity of new compounds. Triterpenoid scaffolds are in the focus of attention owing to their anti-inflammatory, antiviral, antiproliferative, and immunomodulatory activities. Heteroprostanoids have different pleiotropic effects in acute and chronic inflammatory processes. Objective: The study aimed to develop structurally new and low toxic anti-inflammatory agents via hybridization of betulinic acid with azaprostanoic acids. Methods: A series of betulinic acid-azaprostanoid hybrids was synthesized. The synthetic pathway included the transformation of betulin via Jones' oxidation into betulonic acid, reductive amination of the latter and coupling obtained by 3β-amino-3-deoxybetulinic acid with the 7- or 13-azaprostanoic acids and their homo analogues. The hybrids 1-9 were investigated in vivo on histamine-, formalin- and concanavalin A-induced mouse paw edema models and two models of pain - the acetic acid-induced abdominal writhing and the hotplate test. The hybrids were in vitro evaluated for cytotoxic activity on cancer (MCF7, U- 87 MG) and non-cancer humane cell lines. Results: In the immunogenic inflammation model, the substances showed a pronounced anti-inflammatory effect, which was comparable to that of indomethacin. In the models of the exudative inflammation, none of the compounds displayed a statistically significant effect. The hybrids produced weak or moderate analgesic effects. All the agents revealed low cytotoxicity on human immortalized fibroblasts and cancer cell lines compared with 3β- amino-3-deoxybetulinic acid and doxorubicin. Conclusion: The results indicate that the principal anti-inflammatory effect of hybrids is substantially provided with the triterpenoid scaffold and in some cases with the azaprostanoid scaffold, but the latter makes a significant contribution to reducing the toxicity of hybrids. Hybrid 1 is of interest as a potent low toxic agent against immune-mediated inflammation.


2020 ◽  
Vol 295 (32) ◽  
pp. 10926-10939 ◽  
Author(s):  
Benoit Darlot ◽  
James R. O. Eaton ◽  
Lucia Geis-Asteggiante ◽  
Gopala K. Yakala ◽  
Kalimuthu Karuppanan ◽  
...  

Chemokines mediate leukocyte migration and homeostasis and are key targets in inflammatory diseases including atherosclerosis, cytokine storm, and chronic autoimmune disease. Chemokine redundancy and ensuing network robustness has frustrated therapeutic development. Salivary evasins from ticks bind multiple chemokines to overcome redundancy and are effective in several preclinical disease models. Their clinical development has not progressed because of concerns regarding potential immunogenicity, parenteral delivery, and cost. Peptides mimicking protein activity can overcome the perceived limitations of therapeutic proteins. Here we show that peptides possessing multiple chemokine-binding and anti-inflammatory activities can be developed from the chemokine-binding site of an evasin. We used hydrogen–deuterium exchange MS to map the binding interface of the evasin P672 that physically interacts with C–C motif chemokine ligand (CCL) 8 and synthesized a 16-mer peptide (BK1.1) based on this interface region in evasin P672. Fluorescent polarization and native MS approaches showed that BK1.1 binds CCL8, CCL7, and CCL18 and disrupts CCL8 homodimerization. We show that a BK1.1 derivative, BK1.3, has substantially improved ability to disrupt P672 binding to CCL8, CCL2, and CCL3 in an AlphaScreen assay. Using isothermal titration calorimetry, we show that BK1.3 directly binds CCL8. BK1.3 also has substantially improved ability to inhibit CCL8, CCL7, CCL2, and CCL3 chemotactic function in vitro. We show that local as well as systemic administration of BK1.3 potently blocks inflammation in vivo. Identification and characterization of the chemokine-binding interface of evasins could thus inspire the development of novel anti-inflammatory peptides that therapeutically target the chemokine network in inflammatory diseases.


2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Tarfa Albrahim ◽  
Moonerah M. Alnasser ◽  
Mashael R. Al-Anazi ◽  
Muneera D. ALKahtani ◽  
Saad Alkahtani ◽  
...  

Background. Pulicaria crispa (P. crispa) is a plant from the Compositae family that exhibits antioxidant, anti-inflammatory, antibacterial, and cytotoxic activities. Objective. The current study aimed at investigating the immunomodulatory effects of P. crispa extract in lipopolysaccharide- (LPS-) stimulated human monocytic THP-1 cells. Methods. To induce macrophage differentiation, THP-1 cell lines were treated with phorbol-12-myristate 13-acetate, followed by exposure to LPS with or without 50 or 100 μg/ml of P. crispa extract. The following tests were employed to test the immunomodulatory effects of the extract: MTT assay, ELISA, Western blotting analysis, cell migration and phagocytosis assays, and Annexin V staining method. Results. Exposure to 100 μg/ml P. crispa extract significantly reduced THP-1 cell proliferation, migration, and phagocytosis (in LPS-stimulated cells, but not in unstimulated cells). Moreover, the extract alone significantly reduced the rate of THP-1 cell apoptosis, while it increased the rate of late apoptosis. Molecular investigations showed that treatment with P. crispa extract significantly upregulated the expression of ERK1, p-MAPK, P-P38, and Bcl2, while it significantly reduced the expression of ERK5, Bax, NF-κB, P-NF-κB, CCL1, CCL2, CCL5, CCL22, CXCL1, and CXCL10. Conclusion. Pulicaria crispa extract exhibited anti-inflammatory, antiproliferative, antimigratory, and antiphagocytic effects in LPS-stimulated THP-1 cells. Future studies should investigate these mechanisms in animal models with chronic inflammatory diseases.


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