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The present study investigated the mechanism of artesunate in the treatment of bone destruction in experimental rheumatoid arthritis(RA) based on transcriptomics and network pharmacology. The transcriptome sequencing data of artesunate in the inhibition of osteoclast differentiation were analyzed to obtain differentially expressed genes(DEGs). GraphPad Prism 8 software was used to plot volcano maps and heat maps were plotted through the website of bioinformatics. GeneCards and OMIM were used to collect information on key targets of bone destruction in RA. The DEGs of artesunate in inhibiting osteoclast differentiation and key target genes of bone destruction in RA were intersected by the Venny 2.1.0 platform, and the intersection target genes were analyzed by Gene Ontology(GO)/Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment. Finally, the receptor activator of nuclear factor-κB(RANKL)-induced osteoclast differentiation model and collagen-induced arthritis(CIA) model were established. Quantitative real time polymerase chain reaction(q-PCR), immunofluorescence, and immunohistochemistry were used to verify the pharmacological effect and molecular mechanism of artesunate in the treatment of bone destruction in RA. In this study, the RANKL-induced osteoclast differentiation model in vitro was established and intervened with artesunate, and transcriptome sequencing data were analyzed to obtain 744 DEGs of artesunate in inhibiting osteoclast differentiation. A total of 1 291 major target genes of bone destruction in RA were obtained from GeneCards and OMIM. The target genes of artesunate in inhibiting osteoclast differentiation and the target genes of bone destruction in RA were intersected to obtain 61 target genes of artesunate against bone destruction in RA. The intersected target genes were analyzed by GO/KEGG enrichment. According to the results previously reported, the cytokine-cytokine receptor interaction signaling pathway was selected for experimental verification. Artesunate intervention in the RANKL-induced osteoclast differentiation model showed that artesunate inhibited CC chemokine receptor 3(CCR3), CC chemokine receptor 1(CCR1) and leukemia inhibitory factor(LIF) mRNA expression in osteoclasts in a dose-dependent manner compared with the RANKL-induced group. Meanwhile, the results of immunofluorescence and immunohistochemistry showed that artesunate could dose-dependently reduce the expression of CCR3 in osteoclasts and joint tissues of the CIA rat model in vitro. This study indicated that artesunate regulated the CCR3 in the cytokine-cytokine receptor interaction signaling pathway in the treatment of bone destruction in RA and provided a new target gene for the treatment of bone destruction in RA.
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Rats , Animals , Arthritis, Experimental/drug therapy , Artesunate/therapeutic use , Arthritis, Rheumatoid/genetics , Transcriptome , Network Pharmacology , Osteoclasts , Receptors, Cytokine/therapeutic useABSTRACT
ObjectiveTo study the clinical efficacy of Shire Biqing pill in the treatment of rheumatoid arthritis （damp-heat obstruction syndrome） and its effect on the expression of serum osteoprotegerin （OPG）， nuclear factor-κB receptor activating factor ligand （RANKL）， and tumor necrosis factor-α （TNF-α）， and to explore its mechanism from the perspective of bone destruction. MethodPatients with rheumatoid arthritis （damp-heat obstruction syndrome） were randomly divided into two groups， with 36 patients in each group. The control group was treated with methotrexate tablets and celecoxib capsule， while the treatment group was treated with Shire Biqing pill based on the control group. The treatment period was 3 months. The pain visual analogue scale （VAS） score， joint tenderness number， joint swelling number， disease activity score （DAS28-ESR）， traditional Chinese medicine （TCM） symptom quantitative score， and related adverse reactions were recorded before and after treatment， and the peripheral serum OPG， RANKL， TNF-α， erythrocyte sedimentation rate （ESR）， and Creactive protein （CRP） were detected. ResultAfter treatment， the total effective rate was 88.57% （31/35） in the treatment group and 79.41% （27/34） in the control group. The total effective rate of the treatment group was higher than that of the control group （Z=-2.089， P<0.05）. The pain VAS score， joint tenderness number， joint swelling number， and DAS28-ESR of the two groups were significantly lower than those before treatment （P<0.05）， and the pain VAS score， joint tenderness number， joint swelling number， and DAS28-ESR of the treatment group were significantly better than those of the control group after treatment （P<0.05）. Compared with that before treatment， the TCM symptom quantitative score in the two groups decreased significantly （P<0.05）， and the decrease was more obvious in the treatment group than in the control group （P<0.05）. Compared with those before treatment， the levels of RANKL， TNF-α， ESR， and CRP in the two groups decreased and the level of OPG increased （P<0.05）， and the changes in the treatment group were more obvious that in the control group （P<0.05）. There were no serious adverse events or serious adverse reactions during this clinical trial. ConclusionShire Biqing pill can effectively improve the clinical symptoms of rheumatoid arthritis （damp-heat obstruction syndrome） with good safety. Shire Biqing pill effectively regulate the OPG/RANKL/RANK system and reduce the pro-inflammatory factor TNF-α， which may be its mechanism in the intervention in rheumatoid arthritis bone destruction.
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Objective:To analyze the serum levels of integrin-associated proteins (CD47) in patients with rheumatoid arthritis (RA), and to explore its association with disease activity and bone destruction in RA.Methods:Serum and clinical data were collected from 65 RA patients and 25 healthy subjects. RA patients were grouped into low, moderate, and high bone erosion groups according to 7-joint ultrasonography score (US7). The levels of serum CD47, thrombospondin-1 (TSP-1) and receptor activator of nuclear factor-κB ligand (RANKL) were measured by enzyme-linked immunosorbnent assay (ELISA) in patients with RA and healthy subjects. The statistical analysis was carried out with independent t-test, analysis of variance, nonparametric rank sum test, pearson or Spearman correlation and logistic regression. Results:① The Serum levels of CD47, TSP-1, and RANKL were higher in the RA group than in the healthy controls ( P<0.01). ② In RA patients, serum CD47 level was positively correlated with disease course ( r=0.301, P<0.05), C-reactionprotein (CRP)( r=0.316, P<0.05), number of tender joints (TJC) ( r=0.254, P<0.05), number of swollen joints (SJC) ( r=0.316, P<0.05), disease activity score in 28 joints (DAS28) ( r=0.255, P<0.05), RANKL ( r=0.252, P<0.05) and TSP-1 ( r=0.260, P<0.05). Serum TSP-1 level was positively correlated with CRP ( r=0.299, P<0.05), TJC ( r=0.335, P<0.01), DAS28 ( r=0.315, P<0.05), RANKL ( r=0.305, P<0.05). ③ The disease course [ OR(95% CI)=1.048(1.033, 1.017)] and TSP-1 [ OR(95% CI)=1.013(1.000, 1.026)] were independently relevant factors affecting bone destruction. Conclusion:CD47 levels is significantly higher in RA patients than in healthy controls, and is associated with disease activity and bone destruction. CD47 may be involved in the bone destruction process of RA by acting on TSP-1.
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For rheumatoid arthritis， glucocorticoids or immunosuppressive agents are currently used in clinical treatment， but long-term use of these drugs has large side effect on humans， and immunosuppressive agents are expensive. To a certain extent， its wide application is limited. The treatment of rheumatoid arthritis with traditional Chinese medicine（TCM） has a long history and little toxic and side effect， but its specific mechanism of action needs further exploration. The process of autophagy is an active biological process in which cells themselves are stimulated by the outside world through intracellular signal transduction to maintain a stable internal environment. Its abnormality is involved in the occurrence of many diseases. At present， studies have shown that abnormal autophagy is closely related to the occurrence and development of rheumatoid arthritis， which can interfere with the pathological changes of RA pannus formation， synovial inflammation and bone destruction and affect the disease process. In recent years， many studies have found that traditional Chinese medicine and its active ingredients can affect the pathological development of rheumatoid arthritis by regulating autophagy. This article investigates the relevant literature on the intervention of rheumatoid arthritis by regulating autophagy through using TCM， with a view to providing new ideas for basic research， new drug development and clinical treatment of rheumatoid arthritis.
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@#BACKGROUND: To investigate the clinical characteristics and risk factors of human immunodeficiency virus (HIV)-negative patients with Talaromyces marneffei (T. marneffei) infection. METHODS: We retrospectively collected the clinical information of HIV-negative patients with T. marneffei infection from January 1, 2010 to June 30, 2019, and analyzed the related risk factors of poor prognosis. RESULTS: Twenty-five cases aging 22 to 79 years were included. Manifestations of T. marneffei infection included fever, cough, dyspnea, chest pain or distress, lymphadenopathy, ear, nose, and throat (ENT) and/or skin lesions, bone or joint pain, edema and pain in the lower extremities, digestive symptoms, icterus, malaise, and hoarseness. Two cases had no comorbidity, while 23 cases suffered from autoimmune disease, pulmonary disease, cancer, and other chronic diseases. Sixteen cases had a medication history of glucocorticoids, chemotherapy or immunosuppressors. Pulmonary lesions included interstitial infiltration, nodules, atelectasis, cavitary lesions, pleural effusion or hydropneumothorax, bronchiectasis, pulmonary fibrosis, pulmonary edema, and consolidation. The incidence of osteolytic lesions was 20%. Eight patients received antifungal monotherapy, and 11 patients received combined antifungal agents. Fifteen patients survived and ten patients were dead. The Cox regression analysis showed that reduced eosinophil counts, higher levels of blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactic dehydrogenase (LDH), myoglobin (Mb), procalcitonin (PCT), and galactomannan were related to poor prognosis (hazard ratio [HR]>1, P<0.05). CONCLUSIONS: Bone destruction is common in HIV-negative patients with T. marneffei infection. Defective cell-mediated immunity, active infection, multiple system, and organ damage can be the risk factors of poor prognosis.
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BACKGROUND: Studies have shown that the loss of sex combing protein 1 (Asxl1) can lead to the occurrence of bone dysplasia and bone defects, but the relationship between this factor and bone destruction in the microenvironment of apical periodontitis has not been reported. OBJECTIVE: To study the effect of Asxl1 on proliferation and differentiation of osteoblasts in an inflammatory microenvironment. METHODS: MC3T3-E1 cells were excited by lipopolysaccharide to establish an in vitro inflammatory microenvironment. The best concentration and optimal action time of lipopolysaccharide were screened by cell counting kit-8 test. MC3T3-E1 cells were then stimulated with 20 mg/L lipopolysaccharide for 24 hours. The expression levels of Asxl1 protein and mRNA were detected by immunofluorescence and real-time PCR, respectively. After lipopolysaccharide stimulated the formation of inflammatory microenvironment, Asxl1-Si RNA was transfected for 24 hours, cell counting kit-8 was applied to detect the activity of cell proliferation, and real-time PCR was used to detect the expression levels of Asxl1 and osteogenic related genes ALP and RUNX2 mRNA. RESULTS AND CONCLUSION: After lipopolysaccharides stimulation of MC3T3-E1 cells, the expression levels of Asxl1 protein and mRNA were decreased. Under the inflammatory microenvironment, the proliferation activity of MC3T3-E1 cells transfected with Asxl1-Si RNA for 24 hours was significantly decreased, and the expression levels of Asxl1, ALP and RUNX2 mRNA were markedly decreased. These findings indicate that Asxl1 may influence the proliferation and differentiation of osteoblasts by involvement in the process of inflammatory reaction, thereby participating in bone destruction.
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BACKGROUND: MicroRNA-21 (miR-21) is a regulator of osteoclastogenesis and a promoter of osteoclast differentiation, but its role in periodontitis remains unclear. OBJECTIVE: To investigate whether miR-21 is involved in bone destruction in periodontitis. METHODS: Real-time PCR was used to detect and analyze the differential expression of miR-21 in periodontitis samples. Using liposome transfection method, miR-21 mimics (up-regulating miR-21) or miR-21 inhibitor (down-regulating miR-21) was used to transfect osteoclasts. Expressions of miR-21 and bone destruction markers TRAP and CTSK were detected by real-time PCR. Cell counting kit-8 was used to detect the miR-21 effect on osteoclast proliferation. RESULTS AND CONCLUSION: (1) MiR-21 expression increased in periodontitis samples. (2) When miR-21 mimics was transfected into osteoclasts, miR-21, TRAP and CTSK mRNA expression increased; when miR-21 inhibitor was transfected into osteoclasts, miR-21, TRAP and CTSK mRNA expression decreased. (3) Transfection with miR-21 mimics promoted the proliferation of osteoclasts, while transfection with miR-21 inhibitor inhibited the proliferation of osteoclasts. To conclude, miR-21 can be used as an important target for the treatment of periodontitis.
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BACKGROUND: In recent years, the PI3K/AKT signaling pathway is closely related to bone destruction-related diseases. Inhibitors targeting this signaling pathway are also undergoing extensive research, which provides new ideas for clinical treatment of bone destruction-related diseases. OBJECTIVE: To review the research of PI3K/AKT signaling pathway in bone destruction. METHODS: WanFang and PubMed databases were searched for relevant articles published from January 1998 to August 2019. The retrieval key words were “PI3K/Akt signaling pathway; osteoclasts; osteoblasts; bone destruction” in Chinese and English, respectively. To exclude duplicate studies by reading the title and abstract, finally 67 articles were included in result analysis. RESULTS AND CONCLUSION: An appropriate balance between osteoblast and osteoclast-mediated osteogenesis and bone resorption is necessary to maintain bone homeostasis, and an imbalance between these two biological processes will result in bone destructi on. PI3K/Akt signaling pathway is a signal transduction pathway that regulates cell activities and plays an important role in cell proliferation, apoptosis and differentiation. The PI3K/Akt signaling pathway is involved in the inhibition of osteoporosis by promoting osteoblast proliferation, differentiation and bone formation. These results reveal that further exploration on the inhibitors of the PI3K/Akt signaling pathway related to bone destruction will provide new ideas for drug therapy in clinical practice.
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In this paper, we review the results of previous studies and summarize the effects of various factors on the regulation of bone metabolism in traumatic bone infections. Infection-related bone destruction incorporates pathogens and iatrogenic factors in the process of bone resorption dominated by the skeletal and immune systems. The development of bone immunology has established a bridge of communication between the skeletal system and the immune system. Exploring the effects of pathogens, skeletal systems, immune systems, and antibacterials on bone repair in infectious conditions can help improve the treatment of these diseases.
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Humans , Anti-Bacterial Agents/administration & dosage , Bone and Bones/metabolism , Cellular Microenvironment , Immune System/immunology , Lymphocyte Subsets/immunology , Osteitis/microbiology , Osteoblasts/physiology , Osteoclasts/physiology , Staphylococcal InfectionsABSTRACT
Objective: To analyze the clinical characteristics of a patient with of Gaucher's disease with bone destruction as the main performance, and to provide the reference for its clinical diagnosis and treatment. Methods: The clinical data of a case of Gaucher's disease with bone destruction as the main performance was summarized. Combined with the related literature review, the clinical performance, complications, treatment plan, prognosis and the latest relevant research progress of the patients with Gaucher's disease were analyzed. Results: A male patient, 49 years old, was admitted to the hospital due to intermittent right thigh pain for two years, with family history of Gaucher's disease and his parents were consanguineous marriage. The patient was diagnosed as Gaucher's disease 7 years ago. Combined with the patient's history, clinical performance, family history and various auxiliary examination results, the patient was diagnosed as Gaucher's disease, right femur bone destruction, hypersplenism. The patient's right femur was extensively damaged, and the right thigh was severely painful. The patient could not afford the long-term enzyme replacement treatment and planned to have a lesion resection. Because hypersplenism and thrombocytopenia were contraindication for surgery, partial embolization of the splenic artery was performed twice (the first embolization volume was 25%, and the second embolization volume was 35%). Blood cell count was performed one week after spleen embolization, which was significantly improved: platelet count 87×109L-1, hemoglobin 91 g · L-1, and surgical treatment was planned. However, the pain was relieved and the patient gave up surgery. The patient was recommended to avoid injury, reduce weight-bearing, and prevent the pathological fractures; the patient was followed up regularly. Conclusion: The incidence of Gaucher's disease is increased in consanguineous marriage. A preliminary diagnosis was made based on the family history, clinical performance, and various auxiliary examinations, and further confirmed according to the detection of glucocerebrosidase activity. The patients with type I Gaucher's disease are eligible for enzyme replacement therapy. Without enzyme replacement therapy, the patients with chronic history will be concurrent bone destruction, hypersplenism, need symptomatic treatment such as surgery.
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OBJECTIVE@#To observe the effect of Bruton's tyrosine kinase (BTK) on the proliferation and differentiation of osteoclasts and to explore the mechanism of BTK on bone destruction in periapical periodontitis.@*METHODS@#After RAW264.7 cells induced with 100 ng·L⁻¹ receptor activator for nuclear factor-κB ligand (RANKL) for 5 days, osteoclast induction was confirmed by light microscopy, tartrate-resistant acid phosphatase (TRAP) staining, and quantitative real-time PCR (RT-qPCR). Then, BTK-small interfering RNA (BTK-siRNA) was transfected into cells induced for 5 days. After 24 h, the expression of TRAP mRNA was measured using RT-qPCR, and the proliferation and differentiation of osteoclasts were detected using CCK-8 and TRAP activity assay. Statistical analysis was performed.@*RESULTS@#After RAW264.7 was induced with RANKL for 5 days, a large number of round, ellipse, irregularly protuberant, and TRAP-positive macrophages were observed under light microscopy. The expression of TRAP mRNA significantly reduced after 24 h of BTK-siRNA transfection (P<0.05). The detection of CCK-8 and TRAP activities showed that the proliferation and differentiation of osteoclasts significantly decreased (P<0.05).@*CONCLUSIONS@#Silencing of BTK can inhibit the proliferation and differentiation of osteoclasts. BTK can be used as a new target for the inhibition of osteoclasts.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase , Cell Differentiation , Cell Proliferation , Macrophages , Osteoclasts , RANK LigandABSTRACT
Aim To analyse the anti-inflammatory effect of isochlorogenic acid A in rats with collagen-induced arthritis and the potential mechanism . Methods Male SD rats were randomly divided into normal group, model group, isochlorogenic acid A high and low dose groups. The model was constructed in all groups except control group. After continuous administration for six weeks, the plantar thickness and spleen organ coefficient were measured in rats. NLRP3, caspase-1, NF-ΚB p65, P-NF-ΚB p65, P-IΚB and RANKL protein in synovium of joint were detected by Western blot, and IL-lβ, IL-6, TNF-α, CRP, IFN-γ, IL-18 expressions in blood plasma were detected by ELISA kit. Results Compared with normal group, the swelling degree of plantar and the spleen organ coefficient in model group increased significandy. Western blot showed that the expression of NLRP3, caspase-1, NF-ΚB p65, P-NF-ΚB p65, P-IΚB-O and RANKL protein were up-regulated in synovium of joint tissues in model group. ELISA showed that the expression of blood plasma IL-lβ, IL-6, TNF-α, CRP, IFN-γ and IL-18 were significantly up-regulated in model group. Different doses of isochlorogenic acid A can significantly reduce the performance of the above indicators in model group. Conclusions Isochlorogenic acid A has a good anti-inflammatory effect on collagen-induced arthritis, and its anti-inflammatory activity may be related to the decrease of NLRP3 inflammatory complex activation and NF-ΚB phosphorylation.
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Background: Reconstruction of customized cranial implants with a mesh structure using computer-assisted design and additive manufacturing improves the implant design, surgical planning, defect evaluation, implant-tissue interaction and surgeon's accuracy. The objective of this study is to design, develop and fabricate cranial implant with mechanical properties closer to that of bone and drastically decreases the implant failure and to improve the esthetic outcome in cranial surgery with precision fitting for a better quality of life. A customized cranial mesh implant is designed digitally, based on the Digital Imaging and Communication in Medicine files and fabricated using state of the Art-Electron Beam Melting an Additive Manufacturing technology. The EBM produced titanium implant was evaluated based on their mechanical strength and structural characterization. Results: The result shows, the produced mesh implants have a high permeability of bone ingrowth with its reduced weight and modulus of elasticity closer to that the natural bone thus reducing the stress shielding effect. Scanning electron microscope and micro-computed tomography (CT) scanning confirms, that the produced cranial implant has a highly regular pattern of the porous structure with interconnected channels without any internal defect and voids. Conclusions: The study reveals that the use of mesh implants in cranial reconstruction satisfies the need of lighter implants with an adequate mechanical strength, thus restoring better functionality and esthetic outcomes for the patients.
Subject(s)
Humans , Prosthesis Design/methods , Skull , Surgical Mesh , Titanium/chemistry , Computer-Aided Design , Plastic Surgery Procedures/instrumentation , Mechanical Phenomena , Prostheses and Implants , Porosity , Imaging, Three-Dimensional , Elasticity , ElectronsABSTRACT
Objective:To explore the role of Semaphorins 3A(Sema 3A) and its receptor Neuropilin-1 (Nrp1) in the development of chronic periodontitis of rats and clinical samples.Methods:20 SD rats were divided into 2 groups.Rats in the experimental group were induced into chronic periodontitis models.Rats in control group were not treated.After 8 weeks,maxilla of all the rats were collected for micro-CT scanning and IHC staining.The distance from cementoenamel junction to alveolar bone crest(CEJ-ABC) and the IOD of Sema3A/Nrp1 positive staining in rats were analyzed.20 clinical samples of chronic periodontitis(n =10) and normal periodontal tissues (n =10) were collected for immunofluorescence and qRT-PCR analysis.Results:The CEJ-ABC distance of chronic periodontitis group was higher than that of the control group(P ＜ 0.05).The IOD of Sema3A/Nrp1 in experimental group was lower than that of the control group (P ＜ 0.05) and with a negative correlation with bone loss (P ＜ 0.05).Immunofluorescence and qRT-PCR analysis showed that the expression level of Sema3a/Nrpl in clinical samples with chronic periodontitis was also lower than that of the healthy subjects(P ＜ 0.05).Conclusion:The reduced Sema3A/Nrp1 plays an important role in the development of bone destruction in chronic periodontitis.
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Objective:To study the effects of deoxyadenosine(dAdo) on methotrexate (MTX) induced suppression of inflammatory bone destruction.Methods:The culture system of whole bone marrow cells (WBMCs) was utilized to evaluate osteoclastogenesis.TRAP staining and μCT analysis were utilized to evaluate osteoclastogenesis and bone destruction in adjuvant arthritis rats.Results:In the bone marrow culture system,MTX-induced suppression of osteoclastogenesis was abrogated by the addition of dAdo.dAdo canceled MTX-induced suppression of osteoclastogenesis in the rats with arthritis,and significantly abolished the therapeutic effects of MTX on inflammatory bone destruction in the rats.Conclusion:The accumulation of dAdo may be one cause of the losing effectiveness of MTX in bone destruction.
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Objective To measure the serum levels of angiopoietin-like protein (ANGPTL) 3, ANGPTL4 and RANKL in patients with rheumatoid arthritis (RA), and the relationship between ANGPTL3/ANGPTL4 and clinical manifestations were analyzed. Methods Blood samples were drawn from 72 patients with RA and 28 healthy subjects. Serum levels of ANGPTL3, ANGPTL4 and RANKL were tested by enzyme linked immuno-sorbent assay (ELISA). Nonparametric rank sum test was used for the comparisons between groups and Spearmanˊs correlation test was used for correlation analysis. Results ① The serum level of ANGPTL3 was significantly increased in RA group compared to healthy group [800.325(577.477, 1 750.636) pg/ml vs 487.900 (382.340, 565.499) pg/ml, P<0.05, Z=-6.082]. ② The serum level of ANGPTL4 was significantly increased in RA group compared to healthy group [1 036.199(853.347, 1 746.677) pg/ml vs 706.095(558.571, 807.302) pg/ml, Z=-5.962, P<0.05].③ The serum levels of ANGPTL3 and ANGPTL4 in RA patients were increased with the rise of disease activity (DAS 28) [ANGPTL3 in the low disease activity groupwas 457.265 (373.709, 605.296) pg/ml, that of the moderate disease activity group was 785.815(679.156, 1 308.785) pg/ml, that of the high disease activity group was 1 502.038 (817.713, 1 960.493) pg/ml, P<0.05; ANGPTL4 in the low disease activity group was 737.604 (467.040, 918.222) pg/ml, that of the moderate disease activity group was 991.227 (819.456, 1 699.972) pg/ml, and that of the high disease activity group was 1 842.310 (1 252.023, 2 669.902) pg/ml, P<0.05].④ANGPTL3 and ANGPTL4 was positively correlated with RANKL (r=0.554, 0.619, P<0.01).⑤ The serum level of ANGPTL4 was significantly increased in patients with bone destruction, compared to those without bone destruction [1 624.071(949.432, 2 622.371) pg/ml vs 927.590(737.604, 1 409.798) pg/ml, Z=-2.483, P<0.05]. Conclusion The serum levels of ANGPTL3 and ANGPTL4 are increased in RA, and are both positively correlated with disease activity, moreover, ANGPTL4 is associated with pathological bone destruction.
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Cytokines are believed to be involved in a "vicious circle" of progressive interactions in bone metastasis. Iguratimod is a novel anti-rheumatic drug which is reported to have the capability of anti-cytokines. In this study, a rat model was constructed to investigate the effect of iguratimod on bone metastasis and it was found that iguratimod alleviated cancer-induced bone destruction. To further explore whether an anti-tumor activity of iguratimod contributes to the effect of bone resorption suppression, two human breast cancer cell lines MDA-MB-231 and MCF-7 were studied. The effect of iguratimod on tumor proliferation was detected by CCK-8 assay and flow cytometry. The effects of iguratimod on migration and invasion of cancer cells were determined by wound-healing and Transwell assays. Results showed that high dose (30 μg/mL) iguratimod slightly suppressed the proliferation of cancer cells but failed to inhibit their migration and invasion capacity. Interestingly, iguratimod decreased the transcription level of IL-6 in MDA-MB-231 cells in a concentration-dependent manner. Moreover, iguratimod partially impaired NF-κB signaling by suppressing the phosphorylation of NF-κB p65 subunit. Our findings indicated that iguratimod may alleviate bone destruction by partially decreasing the expression of IL-6 in an NF-κB-dependent manner, while it has little effect on the tumor proliferation and invasion.
Subject(s)
Animals , Female , Humans , Rats , Apoptosis , Bone Neoplasms , Drug Therapy , Pathology , Bone Resorption , Drug Therapy , Pathology , Breast Neoplasms , Drug Therapy , Genetics , Pathology , Carcinogenesis , Cell Movement , Cell Proliferation , Chromones , Interleukin-6 , Genetics , MCF-7 Cells , Neoplasm Invasiveness , Genetics , Pathology , Sulfonamides , Transcription Factor RelA , GeneticsABSTRACT
Aim Kadsuraheteroclita ( Roxb ) Craib ( Schizandraceae) is a medicinal plant termed Xuetong in Chinese Tujia ethnomedicine. Xuetong possesses therapeutic effects of, in the terms of Chinese medical theories, reinforcing vital energy, promoting blood cir-culation, expelling wind-evil, and removing damp-e-vil, and has been long used for the prevention and treatment of rheumatic and arthritic diseases, especial-ly in the southern China. The HPLC analysis has iden-tified that the ethanol extract of Xuetong contains large-ly biologically active lignans and triterpenoids. Our previous studies have shown that KHS exhibits very fa-vorable safety profile and potent anti-inflammatory and analgesic activities. In the present study, we investiga-ted anti-arthritic effects and the possible mechanisms of Xuetongon adjuvant-induced arthritis ( AIA ) in rats. Methods AIA was established in male Sprague-Daw-ley ( SD ) rats as described previously, and animals were daily treated by gavage with Xuetong ethanol ex-tract ( 1. 0 g · kg-1 ) or vehicle ( 0. 3% CMC-Na ) throughout the 30-day experiment. The incidence and severity of arthritis were evaluated using clinical pa-rameters. On day 30, bone destruction of the arthritic joints was assessed by computed tomography( CT) and histopathological analyses. The serum levels of pro-in-flammatory cytokines TNF-α, IL-1β, and IL-6 were measured by ELISA. Results Treatment with 1. 0 g/kg Xuetong significantly inhibited the onset and pro-gression of AIA. The vehicle-treated rats all developed severe arthritis, while the incidence of AIA in the Xue-tong-treated rats was as low as 55%( P=0. 035 ) . The Xuetong -treated rats exhibited 1. 8 to 2. 3 fold reduc-tion of paw swelling, and gained 10 to 20% more body weight than the vehicle-treated AIA rats throughout the experiment. CT and histopathological examinations re-vealed that Xuetong markedly protected AIA rats from cartilage and bone destruction of joints. Moreover, the serum levels of TNF-α, IL-1β, and IL-6 were signifi-cantly decreased in the Xuetong-treated rats than the vehicle-treated AIA rats. Conclusions These data strongly support the clinical use of Xuetong for rheu-matic and arthritic diseases, and suggest that Xuetong is a valuable candidate for further investigation to be a new anti-arthritic drug with favorable safety profile.
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La periodontitis es una enfermedad inflamatoria crónica multifactorial, la cual se inicia a partir de la biopelícula que se forma alrededor de los dientes y se acumula en margen gingival, colonizando el surco gingival. La complejidad de la biopelícula madura genera estímulos para las células epiteliales e inflamatorias y sobre las demás células del tejido conectivo activando los mecanismos de la respuesta inmune innata y adaptativa. Se reconoce que la acumulación de placa dental genera de forma indefectible gingivitis, pero se desconocen las señales específicas que disparan la periodontitis. Se reconoce también que microorganismos periodontopáticos como Aggregatibacter actynomicetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Prevotella intermedia, Prevotella nigrescens, entre otros, poseen mediadores osteolíticos que actúan directa o indirectamente en las células del hueso y que son responsables del proceso de remodelación ósea, lo cual desequilibra el eje RANKL-RANK/OPG. Los productos microbianos y la respuesta inflamatoria inducen la secreción de citoquinas específicas como IL-1B, TNFalfa y otros mediadores pro-inflamatorios como PGE2, metalloproteinases, MMP-8, MMP-3, RANKL, además los linfocitos T y B activados inducen la pérdida de hueso alveolar al sintetizar y secretar directamente RANKL. Debido a que la pérdida de hueso alveolar es uno de los signos patognomónicos de la enfermedad periodontal, se hace importante revisar los mecanismos moleculares que explican la destrucción ósea, así como algunos avances en el tratamiento óseo.
Periodontitis is a multifactorial chronic inflammatory disease started by biofilm accumulation around the teeth and the gingival margin including the gingival sulcus. Mature biofilm is complex in microbial nature and it triggers signals to the boundary connective tissue and epithelial cells activating mechanisms of innate and acquired immune response. It is known that the dental plaque accumulation indefectibly results in gingivitis. However the specific signals that lead to periodontitis are unknown. The main periodontopathic organisms are Aggregatibacter actynomicetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Prevotella intermedia, Prevotella nigrescens among others. Those microorganisms produce osteolytic mediators that act directly and indirectly on bone cells affecting the bone turnover rate, regulated by the axis RANKL-RANK/OPG. Microbial products and periodontal inflammation induce the release of specific cytokines IL-1B, TNFalpha, PGE2, metalloproteinases, MMP-8, MMP-3, RANKL, T and B lymphocytes elicit bone resorption. Indeed, alveolar bone loss is one of the most pathognomonic features of periodontal disease. Therefore it is essential to review the molecular mechanisms explaining periodontal destruction, as well as the advances in bone therapy.
Subject(s)
Humans , Periodontitis/etiology , Periodontitis/physiopathology , Bacterial Physiological Phenomena , Bone Resorption , Interleukins , Lymphocytes , Matrix Metalloproteinases , Periodontitis/immunology , Periodontitis/microbiology , Periodontitis/therapy , RANK Ligand , Tumor Necrosis Factor-alphaABSTRACT
Neuroblastoma is one of the solid tumors in children which easily metastasizes to bone.It causes radiographic appearance of osteoclastic reactions after bone metastases.In the process,neuroblastoma cells,osteoblasts and bone stromal cells secrete a series of related factors to promote bone metastases.In this paper,the progress of the mechanism in bone destruction caused by neuroblastoma is reviewed.