scholarly journals Anti-Rheumatoid Arthritic Effects of Paris Saponin VII in Human Rheumatoid Arthritis Fibroblast-Like Synoviocytes and Adjuvant-Induced Arthritis in Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Mei Meng ◽  
Zhenggang Yue ◽  
Lu Chang ◽  
Yanru Liu ◽  
Jinhang Hu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
P38 Mapk ◽  
Ankle Joint ◽  
Adjuvant Induced Arthritis ◽  
Mapk Pathways ◽  
Tnf Α ◽  
Apoptosis Proteins ◽  
Fibroblast Like Synoviocytes

In the pathogenesis of rheumatoid arthritis (RA), rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) have tumor-like characteristics, mainly manifested by hyperproliferation and resistance to apoptosis and then it will erode the bone and cartilage, eventually leading to joint destruction. Paris saponin VII (PS VII) is an active compound derived from a traditional herbal medicine named Trillium tschonoskii Maxim, which has anti-tumor, analgesic, and immunomodulatory effects. However, its anti-RA effect has not yet been reported. This study was to investigate the effect of PS VII on two rheumatoid arthritis fibroblast-like synoviocytes lines (RA-FLS and MH7A) and adjuvant-induced arthritis (AIA) in rats. In vitro, the effects of PS VII on the proliferation, cell cycle, and apoptosis of RA-FLS and MH7A cells were detected by MTT, flow cytometry, and western blot analysis. In vivo, the effect of PS VII on the weight of the rat, paw swelling, ankle joint diameter, arthritis index, serum inflammatory cytokines (TNF-α, IL-6, and IL-1β), histopathological assessment and apoptosis proteins in the synovial tissues were evaluated in AIA rats. The in vitro studies showed that PS VII inhibited the proliferation of RA-FLS and MH7A cells, induced S phase arrest and triggered cell apoptosis mainly through the mitochondrial apoptotic pathway and the regulation of JNK and p38 MAPK pathways. The in vivo studies revealed that PS VII could improve ameliorate body weight, paw swelling, ankle joint diameter, reduce the spleen and thymus index, suppress the production of TNF-α, IL-6 and IL-1β, improve histopathological changes and regulate the expressions of apoptosis proteins in AIA Rats. In conclusion, PS VII could inhibit the proliferation and trigger apoptosis of RA-FLS and MH7A cells by regulating the mitochondrial apoptosis pathway and the JNK and p38 MAPK pathways, and alleviate the symptoms of RA, signifying it to be one of the potential anti-RA therapeutics.

scholarly journals Microneedle-Assisted Transdermal Delivery of Etanercept for Rheumatoid Arthritis Treatment

Pharmaceutics ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 235 ◽  
Author(s):  
Jian Cao ◽  
Nan Zhang ◽  
Ziyi Wang ◽  
Jingjing Su ◽  
Jing Yang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Transdermal Delivery ◽  
In Vitro Bioactivity ◽  
In Vivo Evaluation ◽  
Adjuvant Induced Arthritis ◽  
Tnf Α ◽  
Good Biocompatibility ◽  
New Treatment

Rheumatoid arthritis (RA) is a complicated autoimmune disease. The clinical applications of etanercept (EN), a TNF-α inhibitor, can efficiently halt the development of RA. EN is mainly administrated by subcutaneous injection, which may cause low compliance, side effects, and infection risk. In this study, a hyaluronic acid crosslinked microneedle system (MN) was constructed as the transdermal alternative to deliver EN. We describe the formulation, fabrication, characterization, and transdermal insertion study of MN. In vitro bioactivity of EN was conducted and analyzed by dynamic light scattering and circular dichroism spectrum. In vivo evaluation of MN was studied on adjuvant-induced arthritis mice. The MN possessed sufficient mechanical strength, good biocompatibility, little influence on the bioactivity of EN, and high anti-inflammatory efficacy. This work represents a successful example of delivering macromolecule therapeutic treatment by MN for RA treatment. The transdermal delivery of EN by MN offers a new treatment option for RA patients.

scholarly journals Bakuchiol Suppresses Inflammatory Responses Via the Downregulation of the p38 MAPK/ERK Signaling Pathway

2019 ◽  
Vol 20 (14) ◽  
pp. 3574 ◽  
Author(s):  
Hye-Sun Lim ◽  
Yu Jin Kim ◽  
Bu-Yeo Kim ◽  
Soo-Jin Jeong
Keyword(s):  
Mrna Expression ◽  
P38 Mapk ◽  
Inflammatory Responses ◽  
Mitogen Activated Protein Kinase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mice Model ◽  
Tnf Α ◽  
Cox 2

The purpose of the present study was to evaluate the effects of bakuchiol on the inflammatory response and to identify the molecular mechanism of the inflammatory effects in a lipopolysaccharide (LPS)-stimulated BV-2 mouse microglial cell line and mice model. The production of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) was measured by enzyme-linked immunosorbent assay. The mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, and IL-6 was measured using reverse transcription–polymerase chain reaction analysis. Mitogen-activated protein kinase (MAPK) phosphorylation was determined by western blot analysis. In vitro experiments, bakuchiol significantly suppressed the production of PGE2 and IL-6 in LPS-stimulated BV-2 cells, without causing cytotoxicity. In parallel, bakuchiol significantly inhibited the LPS-stimulated expression of iNOS, COX-2, and IL-6 in BV-2 cells. However, bakuchiol had no effect on the LPS-stimulated production and mRNA expression of TNF-α or on LPS-stimulated c-Jun NH2-terminal kinase phosphorylation. In contrast, p38 MAPK and extracellular signal-regulated kinase (ERK) phosphorylation were inhibited by bakuchiol. In vivo experiments, Bakuchiol reduced microglial activation in the hippocampus and cortex tissue of LPS-injected mice. Bakuchiol significantly suppressed LPS-injected production of TNF-α and IL-6 in serum. These results indicate that the anti-neuroinflammatory effects of bakuchiol in activated microglia are mainly regulated by the inhibition of the p38 MAPK and ERK pathways. We suggest that bakuchiol may be beneficial for various neuroinflammatory diseases.

scholarly journals PTEN Methylation Promotes Inflammation and Activation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao-Feng Li ◽  
Sha Wu ◽  
Qi Yan ◽  
Yuan-Yuan Wu ◽  
He Chen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Articular Cartilage ◽  
Dna Methyltransferase ◽  
Underlying Mechanism ◽  
Cartilage Destruction ◽  
Specific Pcr ◽  
Methylation Inhibitor ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and subsequent destruction of adjacent articular cartilage and bone. In our previous work we showed that phosphatase and tension homolog deleted on chromosome 10 (PTEN) contributes to the activation of fibroblast-like synoviocytes (FLS) in adjuvant-induced arthritis (AIA), but the underlying mechanism is not unknown. In this study, we show that PTEN is downregulated while DNA methyltransferase (DNMT)1 is upregulated in FLS from RA patients and a rat model of AIA. DNA methylation of PTEN was increased by administration of tumor necrosis factor (TNF)-α in FLS of RA patients, as determined by chromatin immunoprecipitation and methylation-specific PCR. Treatment with the methylation inhibitor 5-azacytidine suppressed cytokine and chemokine release and FLS activation in vitro and alleviated paw swelling in vivo. PTEN overexpression reduced inflammation and activation of FLS via protein kinase B (AKT) signaling in RA, and intra-articular injection of PTEN-expressing adenovirus into the knee of AIA rats markedly reduced inflammation and paw swelling. Thus, PTEN methylation promotes the inflammation and activation of FLS in the pathogenesis of RA. These findings provide insight into the molecular basis of articular cartilage destruction in RA, and indicate that therapeutic strategies that prevent PTEN methylation may an effective treatment.

Over-expression of PTEN attenuates the inflammation of fibroblast-like synoviocytes in rheumatoid arthritis

2020 ◽  
Author(s):  
Xiao-Feng Li ◽  
Qing-Qing Xu ◽  
Man-Wen Yang ◽  
He Chen ◽  
Su-Qin Yin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Dna Methylation ◽  
Inflammatory Cytokines ◽  
Pten Expression ◽  
Over Expression ◽  
Tnf Α ◽  
And Migration ◽  
Fibroblast Like Synoviocytes ◽  
Pro Inflammatory Cytokines

Abstract Background: Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and the subsequent destruction of adjacent articular cartilage and bone. Recent studies have shown that phosphatase and tension homolog deleted on chromosome 10 (PTEN) might contribute to the survival of fibroblast-like synoviocytes (FLS) and the production of pro-inflammatory cytokines in RA.Methods : The expression was determined in RA and adjuvant-induced arthritis (AIA) synovial tissues by immunohistochemistry. FLSs were treatment with bpv, PTEN-RNAi or over-expression plasmid in RA and AIA. FLSs migration was assessed. The ad-PTEN was also injected into the knee of AIA in vivo. Chromatin Immunoprecipitation (ChIP) and Methylation-special PCR (MSP) assay were used to study the expression of PTEN mRNA in DNA methylation.Results : Down-regulated level of PTEN expression was observed in RA and AIA. Inhibition PTEN expression by bpv or PTEN-RNAi could promote the expression of pro-inflammatory cytokines, chemokines and migration of FLS with TNF-α in RA and AIA. Consistently, over-expression of PTEN reduced their low-expression of pro-inflammatory cytokines, chemokines and migration. Intra-articular injection of ad-PTEN in AIA knees dramatically reduced inflammatory and paw swelling in vivo. The ChIP and MSP assay has clearly detected the DNA methylation of PTEN was increased in FLS with TNF-α. Moreover, intraperitoneally injected 5-Aza in AIA also suppressed the inflammatory and paws swelling in vivo.Conclusions: Our findings suggest that over-expression PTEN attenuates the formation of pro-inflammatory cytokines, chemokines and migration of FLS, and it may be regulated by DNA methylation in the pathogenesis of RA.

scholarly journals p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice

2005 ◽  
Vol 289 (1) ◽  
pp. F166-F174 ◽  
Author(s):  
Ganesan Ramesh ◽  
W. Brian Reeves
Keyword(s):  
Renal Dysfunction ◽  
P38 Mapk ◽  
Renal Injury ◽  
Acute Renal Injury ◽  
Mapk Activation ◽  
Mapk Activity ◽  
Tnf Α

Cisplatin is an important chemotherapeutic agent but can cause acute renal injury. Part of this acute renal injury is mediated through tumor necrosis factor-α (TNF-α). The pathway through which cisplatin mediates the production of TNF-α and injury is not known. Cisplatin activates p38 MAPK and induces apoptosis in cancer cells. p38 MAPK activation leads to increased production of TNF-α in ischemic injury and in macrophages. However, little is known concerning the role of p38 MAPK in cisplatin-induced renal injury. Therefore, we examined the effect of cisplatin on p38 MAPK activity and the role of p38 MAPK in mediating cisplatin-induced TNF-α production and renal injury. In vitro, cisplatin caused a dose-dependent activation of p38 MAPK in proximal tubule cells. Inhibition of p38 MAPK activation led to inhibition of TNF-α production. In vivo, mice treated with a single dose of cisplatin (20 mg/kg body wt) developed severe renal dysfunction at 72 h [blood urea nitrogen (BUN): 154 ± 34 mg/dl, creatinine: 1.4 ± 0.4 mg/dl], which was accompanied by an increase in kidney p38 MAPK activity and an increase in infiltrating leukocytes. However, animals treated with the p38 MAPK inhibitor SKF-86002 along with cisplatin showed less renal dysfunction (BUN: 55 ± 14 mg/dl, creatinine: 0.3 ± 0.02 mg/dl, P < 0.05), less severe histological damage, and fewer leukocytes compared with cisplatin+vehicle-treated animals. Serum levels of TNF-α, sTNFRI, and sTNFRII also increased significantly in cisplatin-treated mice compared with SKF-86002-treated mice ( P < 0.05). Kidney mRNA levels of TNF-α were significantly increased in cisplatin-treated mice compared with either SKF-86002- or saline-treated animals. The hydroxyl radical scavenger DMTU (100 mg·kg body wt−1·day−1) prevented the activation of p38 MAPK by cisplatin both in vitro and in vivo. DMTU also completely prevented cisplatin-induced renal injury (BUN: 140 ± 27 vs. 22 ± 2 mg/dl, P < 0.005) and the increase in serum TNF-α (33 ± 7 vs. 4 ± 2 pg/ml, P < 0.005) and kidney TNF-α mRNA in vivo. We conclude that hydroxyl radicals, either directly or indirectly, activate p38 MAPK and that p38 MAPK plays an important role in mediating cisplatin-induced acute renal injury and inflammation, perhaps through production of TNF-α.

Effect of polysaccharide FMP-1 from Morchella esculenta on melanogenesis in B16F10 cells and zebrafish

2018 ◽  
Vol 9 (9) ◽  
pp. 5007-5015 ◽  
Author(s):  
Zheng-Nan Cai ◽  
Wan Li ◽  
Shomaila Mehmood ◽  
Wen-Juan Pan ◽  
Qing-Xi Wu ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Pathways ◽  
B16f10 Cells ◽  
Morchella Esculenta

Polysaccharide FMP-1 could inhibit melanogenesis in vitro and in vivo through CREB and p38 MAPK pathways.

scholarly journals Timosaponin AIII Induces G2/M Arrest and Apoptosis in Breast Cancer by Activating the ATM/Chk2 and p38 MAPK Signaling Pathways

2021 ◽  
Vol 11 ◽  
Author(s):  
Minjie Zhang ◽  
Jiaxi Qu ◽  
Zhiwei Gao ◽  
Qi Qi ◽  
Hong Yin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
P38 Mapk ◽  
Mapk Signaling ◽  
Mapk Pathways ◽  
Phase Arrest ◽  
M Phase ◽  
Timosaponin Aiii

Timosaponin AIII (TAIII), a steroidal saponin, exerts potent anti-tumor activity in various cancers, especially breast cancer. However, the concrete molecular mechanisms of TAIII against breast cancer are still unclear. Here, we find that TAIII triggers DNA damage, leads to G2/M arrest, and ultimately induces apoptosis in breast cancer both in vitro and in vivo. TAIII induced G2/M phase arrest and apoptosis in MDA-MB-231 and MCF7 cells accompanied with down-regulation of CyclinB1, Cdc2 and Cdc25C. Further data showed that the ATM/Chk2 and p38 pathways were activated representing by up-regulated levels of p-H2A.X and p-p38, which indicated an induction of DNA damage by TAIII, leading to cell cycle arrest and apoptosis. The effects of TAIII were further confirmed by employing inhibitors of ATM and p38 pathways. In vivo, TAIII suppressed the growth of subcutaneous xenograft tumor without obvious toxicity, which indicated by Ki67 and TUNEL analysis. Data also showed that TAIII stimulated the ATM/Chk2 and p38 MAPK pathways in vivo, which in consistent with the effects in vitro. Hence, our data demonstrate that TAIII triggers DNA damage and activates ATM/Chk2 and p38 MAPK pathways, and then induces G2/M phase arrest and apoptosis in breast cancer, which provide theoretical evidence for TAIII utilized as drug against breast cancer.

scholarly journals Novel Carboxylated Chitosan-Based Triptolide Conjugate for the Treatment of Rheumatoid Arthritis

Pharmaceutics ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 202
Author(s):  
Lan Zhang ◽  
Min Yan ◽  
Kun Chen ◽  
Qikang Tian ◽  
Junying Song ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mortality Rate ◽  
Drug Toxicity ◽  
Aqueous Solubility ◽  
In Vitro Experiments ◽  
Tnf Α ◽  
Toxicity In Vitro ◽  
Bony Erosion

A new platform for triptolide (TP) delivery was prepared by conjugating TP to a carboxylmethyl chitosan (CMCS). Compared with the natural TP, the TP-conjugate (TP-CMCS) containing TP of ~5 wt% exhibited excellent aqueous solubility (>5 mg/mL). Results of in vitro experiments showed that TP-CMCS could relieve TP-induced inhibition on RAW264.7 cells and apoptosis, respectively. Compared with the TP group, TP-CMCS could effectively alleviate the toxicity injury of TP and decreased the mortality rate of the mice (p < 0.05). TP-CMCS did not cause much damage to the liver (AST and ALT) and kidney (BUN and CRE) (p < 0.05). After administration, the levels of IL-6, IL-1β, and TNF-α decreased, and the arthritis detumescence percentages increased significantly, and the bony erosion degree was distinctly decreased in the TP-CMCS groups and TP group. Our results suggested that TP-CMCS was a useful carrier for the treatment of RA, which enhanced aqueous solubility of free TP and reduced drug toxicity in vitro and in vivo.

scholarly journals Validating potent anti-inflammatory and anti-rheumatoid properties of Drynaria quercifolia rhizome methanolic extract through in vitro, in vivo, in silico and GC-MS-based profiling

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Debabrata Modak ◽  
Subhashis Paul ◽  
Sourav Sarkar ◽  
Subarna Thakur ◽  
Soumen Bhattacharjee
Keyword(s):  
Rheumatoid Arthritis ◽  
In Silico ◽  
Methanolic Extract ◽  
Paw Edema ◽  
Active Components ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory

Abstract Background The fronds of Drynaria quercifolia have traditionally been used in rheumatic pain management. The goal of the present study was to validate the potent anti-inflammatory and anti-rheumatoid properties of the methanolic-extract of its rhizome using in vitro, in vivo and in silico strategies. Methods The plant was collected and the methanolic extract was prepared from its rhizome. Protein denaturation test, hypotonicity and heat-induced haemolysis assays were performed in vitro. The in vivo anti-rheumatoid potential was assessed in Freund’s complete adjuvant (FCA)-induced Wistar rat model through inflammatory paw-edema, haematological, biochemical, radiological and histopathological measurements. Moreover, metabolites of methanolic extract were screened by gas chromatography-mass spectrometry (GC-MS) and 3D molecular structures of active components were utilized for in silico docking study using AutoDock. Results In vitro results evinced a significant (p < 0.05) anti-inflammatory activity of the rhizome methanolic extract in a dose-linear response. Further, Drynaria quercifolia rhizome methanolic extract (DME) significantly ameliorated rheumatoid arthritis as indicated by the inhibition of arthritic paw-edema (in millimeter) in the rat rheumatoid arthritis models in both the low (57.71 ± 0.99, p < 0.01) and high dose groups (54.45 ± 1.30, p < 0.001) when compared to arthritic control. Treatment with DME also normalized the haematological (RBC, WBC, platelet counts and hemoglobin contents) and biochemical parameters (total protein, albumin, creatinine and ceruloplasmin) significantly (p < 0.05), which were further supported by histopathological and radiological analyses. Furthermore, GC-MS analysis of DME demonstrated the presence of 47 phytochemical compounds. Compounds like Squalene, Gamma Tocopherol, n-Hexadecanoic acid showed potent inhibition of cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF-α), and interleukin (IL-6) in the docking analysis. Conclusion Results from in vivo and in vitro studies indicated that DME possesses a potent anti-inflammatory and anti-arthritic activity. In silico studies delineated the emergent potent inhibitory effects of several bio-active components on the target inflammatory markers (COX-2, TNF-α and IL-6).

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