Mechanism Of Colchicine Research Articles

Colchicine Alleviates Interstitial Lung Disease in an Experimental Autoimmune Myositis Murine Model by Inhibiting the Formation of Neutrophil Extracellular Traps.

Our previous study has shown that neutrophil extracellular traps (NETs) were associated with idiopathic inflammatory myopathy-related interstitial lung disease (IIM-ILD). Colchicine plays an anti-inflammatory role mainly by inhibiting the activity and chemotaxis of neutrophils. This study aims to verify therapeutic effects and mechanism of colchicine in IIM-ILD. 20 experimental autoimmune myositis (EAM) model mice were randomly divided into EAM group, colchicine groups (1, 2mg/kg) and Cl-amidine group (positive control), five mice in the control group received sham modeling procedure. After 5weeks, the mice were sacrificed to evaluate the degree of pulmonary interstitial lesions and the formation of NETs. Human neutrophils were pretreated with colchicine (40nmol/L) and stimulated to form NETs. Human pulmonary microvascular endothelial cells (HPMECs) were pretreated with colchicine and stimulated with NETs, and markers of inflammation and pyroptosis were detected. Pathological staining of lung tissue showed that severity of ILD and NETs infiltration were significantly alleviated in colchicine groups (P < 0.01) and in the Cl-amidine group (P < 0.01), and the serum level of NETs was also significantly decreased in colchicine groups (P < 0.05) and in the Cl-amidine group (P < 0.05). Colchicine intervention significantly attenuated PMA-induced NETs formation in vitro (P < 0.0001). Colchicine intervention significantly reduced marker expressions of inflammasome and pyroptosis in HPMECs stimulated by NETs and in the lung tissue of EAM mice. Colchicine can alleviate ILD in EAM mice by inhibiting NETs formation, inflammasome activation and endothelial cell pyroptosis. These findings provide a basis for targeting NETs and colchicine administration in the treatment of myositis-associated ILD.

Colchicine as a therapeutic option for the treatment of pulmonary arterial hypertension (PAH) in a rat model

Abstract Introduction Pulmonary arterial hypertension (PAH) is a cardiovascular disease that is characterized by severe structural and functional damages, resulting from the obstructive remodeling of the pulmonary vasculature and consequent right ventricular pressure overload. The current therapy mainly focuses on the pulmonary vascular system, with uncertain efficacy. Therefore, it is crucial to explore new therapeutic approaches. The mechanism of colchicine is complex and not-fully understood, but it has been proven to exert cardiopulmonary protective effects. Methods PAH induction was carried out in 8-week-old male WKY rats with a single subcutaneous injection of 60 mg/kg monocrotaline. Monocrotaline, a pyrrolizidine alkaloid, is metabolized in liver and induces inflammatory processes, which can cause PAH in rats. Starting from day 14 after MCT injection, the animals received three times a week intraperitoneal colchicine treatment at a dose of 0.5 mg/kg for two weeks. Echocardiographic examinations were performed during the study. At the end of the study, besides histological examination of the right ventricles and lungs [arterial wall thickness (WT%) and area (WA%)], the expression and phosphorylation levels of the proteins involved in cardiac remodeling were evaluated using Western blot. We assessed the pyruvate dehydrogenase (PDH) enzyme activity in the heart, which plays an important role in energy metabolism. We also examined the production of cytokines and chemokines in the right ventricle. Results The VW/BW ratio in the colchicine-treated group was significantly reduced compared to the MCT group (p&amp;lt;0.01). Echocardiographic parameters, EF% and E/e' ratio – characterizing the left ventricular function – did not differ considerably between the groups during the treatment. The TAPSE and PAT values characterizing right ventricular function improved in the MCT+C group (p&amp;lt;0.05). Collagen deposition and TGFβ level were significantly reduced by colchicine (p&amp;lt;0.05) in PAH animals. In the MCT+C group, the vascular remodeling (WT% and WA%) significantly decreased compared to the MCT group (p&amp;lt;0.01). The expression of α-SMA in vessel walls was most pronounced in the MCT group (p&amp;lt;0.01), which was significantly reduced by colchicine treatment. The phosphorylation of prosurvival signaling factors (ERK1/2, Akt1, GSK3β) was significantly increased in the MCT+C group (p&amp;lt;0.01) compared to the MCT group. In the right ventricle, PDH enzyme activity increased in the MCT+C group compared to the MCT group (p&amp;lt;0.01). According to cytokine array, cytokines involved in mediating fibrosis and inflammatory processes (TIMP-1, VEGF, L-selectin, CXCL7) showed increased secretion in the MCT group, which was moderately attenuated by colchicine treatment. Conclusion Colchicine treatment reduced the extent of fibrosis and inflammation, improved the structure of the pulmonary vasculature, and enhanced right ventricular function and energy supply.

Colchicine Blocks Abdominal Aortic Aneurysm Development by Maintaining Vascular Smooth Muscle Cell Homeostasis.

Development of non-surgical treatment of human abdominal aortic aneurysm (AAA) has clinical significance. Colchicine emerges as an effective therapeutic regimen in cardiovascular diseases. Yet, whether colchicine slows AAA growth remain controversy. Here, we demonstrated that daily intragastric administration of low-dose colchicine blocked AAA formation, prevented vascular smooth muscle cell (SMC) phenotype switching and apoptosis, and vascular inflammation in both peri-aortic CaPO4 injury and subcutaneous angiotensin-II infusion induced experimental AAA mice models. Mechanistically, colchicine increased global mRNA stability by inhibiting the METTL14/YTHDC1-mediated m6A modification, resulting in increased sclerostin (SOST) expression and consequent inactivation of the WNT/β-catenin signaling pathway in vascular SMCs from mouse AAA lesions and in cultured human aortic SMCs. Moreover, human and mouse AAA lesions all showed increased m6A methylation, decreased SOST expression, and skewed synthetic SMC de-differentiation phenotype, compared to those without AAA. This study uncovers a novel mechanism of colchicine in slowing AAA development by using the METTL14/SOST/WNT/β-catenin axis to control vascular SMC homeostasis in mouse aortic vessels and in human aortic SMCs. Therefore, use of colchicine may benefit AAA patients in clinical practice.

Colchicine Attenuates Microvascular Obstruction after Myocardial Ischemia-Reperfusion Injury by Inhibiting the Proliferation of Neutrophil in Bone Marrow

Abstract Purpose Complete and rapid recanalization of blood flow by percutaneous coronary intervention (PCI) is the most effective intervention for patients with ST-segment elevation myocardial infarction (STEMI). However, myocardial ischemia/reperfusion (I/R) injury leads to microvascular obstruction (MVO), limiting its efficacy. Colchicine can reduce myocardial I/R injury, but its effect on MVO is unclear. Hence, this study aimed to assess the role and mechanism of colchicine on MVO. Methods Clinical data on STEMI patients with PCI were collected and risk factors related to MVO were analyzed. The rat myocardial I/R model was established to evaluate the MVO by thioflavin S staining. The myocardial I/R model of mice was treated with PBS or colchicine at the reperfusion. The effect of colchicine on cardiomyocyte apoptosis after I/R was evaluated by TUNEL and expression of cleaved caspase-3. ROS levels were detected in H9c2 cells to evaluate the colchicine effect on myocardial oxidative stress. Moreover, the mechanism through which colchicine attenuated MVO was examined using flow cytometry, WB, ELISA, immunohistochemistry, bioinformatics analysis, and immunofluorescence. Results Multivariate analysis showed that elevated neutrophils were associated with extensive MVO. Colchicine could attenuate MVO and reduce neutrophil recruitment and NETs formation after myocardial I/R. In addition, colchicine inhibited cardiomyocyte apoptosis in vivo and ROS levels in vitro. Furthermore, colchicine inhibited neutrophil proliferation in the bone marrow (BM) by inhibiting the S100A8/A9 inflammatory signaling pathway. Conclusions Colchicine attenuated MVO after myocardial I/R injury by inhibiting the proliferation of neutrophils in BM through the neutrophil-derived S100A8/A9 inflammatory signaling pathway.

Effect of Colchicine on Th1 and Th17 Cytokines, Cytokine Receptors, and Chemokine Gene Expression Profiles in Behçet's Disease

Objective: Colchicine has been used in recent years as an effective drug for controlling attacks in Behcet’s disease. In the present study, we investigated expression levels of IL1R, IL2R, IL12RB, IL23R, IL17, CXCR3, CXCR10 and IL8 genes in patients with active and inactive Behcet’s disease. We also evaluated how colchicine use in patients with active and inactive disease affected these genes and evaluated their role in the etiopathogenesis of the disease. Methods: Thirty-five patients who were diagnosed with Behcet’s disease according to the International Working Group criteria (28 with active disease, 7 inactive) and were taking colchicine were enrolled in the study. Twenty healthy subjects were included as a control group. Expression levels of the IL1R, IL2R, IL12RB, IL23R, IL17, CXCR3 ,CXCR10 and IL8, genes were evaluated. Results: Expression levels of CXCR3 and IL23R were significantly lower in patients with active Behcet's disease when compared with the inactive disease and control groups. However, the differences in CXCR3 and IL23R expression between the inactive Behcet’s patient group and the control group were nonsignificant. Expression levels of the other genes did not differ statistically between the active Behcet’s patients, inactive Behcet’s patients, and control subjects. Conclusion: While the expression levels of the CXCR3 and IL23R genes in active Behcet’s patients were statistically lower than controls, there was no statistical difference between active and inactive Behcet’s patients or controls in terms of IL1R, IL2R, IL17, IL12RB, CXCR10 and IL8, gene expression levels. This study may form the basis for further studies to determine the molecular mechanism of colchicine in the treatment of Behcet's disease.

Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain.

Microtubules are cytoskeletal polymers of tubulin involved in many cellular functions. Their dynamic instability is controlled by numerous compounds and proteins, including colchicine and stathmin family proteins. The way in which microtubule instability is regulated at the molecular level has remained elusive, mainly because of the lack of appropriate structural data. Here, we present the structure, at 3.5 A resolution, of tubulin in complex with colchicine and with the stathmin-like domain (SLD) of RB3. It shows the interaction of RB3-SLD with two tubulin heterodimers in a curved complex capped by the SLD amino-terminal domain, which prevents the incorporation of the complexed tubulin into microtubules. A comparison with the structure of tubulin in protofilaments shows changes in the subunits of tubulin as it switches from its straight conformation to a curved one. These changes correlate with the loss of lateral contacts and provide a rationale for the rapid microtubule depolymerization characteristic of dynamic instability. Moreover, the tubulin-colchicine complex sheds light on the mechanism of colchicine's activity: we show that colchicine binds at a location where it prevents curved tubulin from adopting a straight structure, which inhibits assembly.