Metformin Ameliorates Scleroderma Via Inhibiting Th17 Cells and Reducing mTOR-STAT3 Signaling in Skin Fibroblasts

2021 ◽  
Author(s):  
Jeonghyeon Moon ◽  
Seon-yeong Lee ◽  
Jeong Won Choi ◽  
Aram Lee ◽  
Jin Hee Yoo ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Th17 Cells ◽  
Skin Fibroblasts ◽  
Inflammatory Factors ◽  
Metformin Treatment ◽  
Protective Effects ◽  
Stat3 Signaling ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Abstract Scleroderma is an autoimmune disease that causes dermal fibrosis. It occurs when collagen accumulates in tissue as a result of persistent inflammation. Th17 cells and pro-inflammatory cytokines such as IL-1β, IL-6, IL-17, and TNF-α play important roles in the pathogenesis of scleroderma. Because metformin, a medication used to treat diabetes, has effective immunoregulatory functions, we investigated its therapeutic function in scleroderma. Mice in a model of bleomycin-induced scleroderma were treated with metformin for 2 weeks. Histological assessment demonstrated protective effects of metformin against scleroderma. Metformin decreased the expression of pro-inflammatory factors in dermal tissue and lymphocytes. It also decreased mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-17, and TNF-α) and fibrosis-inducing molecules both in vivo and in vitro. These results suggest that metformin treatment has anti-inflammatory effects on lymphocytes via the inhibition of IL-17 and cytokines related to Th17 differentiation, such as IL-1β, IL-6, and TNF-α. To investigate how metformin modulates the inflammatory process in skin fibroblasts, we measured mTOR-STAT3 signaling in skin fibroblasts and found that mTOR and STAT3 protein expression were decreased by metformin treatment. These results suggest that metformin has potential to treat scleroderma by inhibiting pro-inflammatory cytokines and anti-inflammatory activity mediated by mTOR-STAT3 signaling.

scholarly journals Metformin ameliorates scleroderma via inhibiting Th17 cells and reducing mTOR-STAT3 signaling in skin fibroblasts

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jeonghyeon Moon ◽  
Seon-yeong Lee ◽  
Jeong Won Choi ◽  
A Ram Lee ◽  
Jin Hee Yoo ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Th17 Cells ◽  
Skin Fibroblasts ◽  
Inflammatory Factors ◽  
Metformin Treatment ◽  
Protective Effects ◽  
Stat3 Signaling ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

AbstractScleroderma is an autoimmune disease that causes dermal fibrosis. It occurs when collagen accumulates in tissue as a result of persistent inflammation. Th17 cells and pro-inflammatory cytokines such as IL-1β, IL-6, IL-17, and TNF-α play important roles in the pathogenesis of scleroderma. Because metformin, a medication used to treat diabetes, has effective immunoregulatory functions, we investigated its therapeutic function in scleroderma. Mice in a model of bleomycin-induced scleroderma were treated with metformin for 2 weeks. Histological assessment demonstrated protective effects of metformin against scleroderma. Metformin decreased the expression of pro-inflammatory factors in dermal tissue and lymphocytes. It also decreased mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-17, and TNF-α) and fibrosis-inducing molecules both in vivo and in vitro. These results suggest that metformin treatment has anti-inflammatory effects on lymphocytes via the inhibition of IL-17 and cytokines related to Th17 differentiation, such as IL-1β, IL-6, and TNF-α. To investigate how metformin modulates the inflammatory process in skin fibroblasts, we measured mTOR-STAT3 signaling in skin fibroblasts and found that phosphorylated mTOR and phosphorylated STAT3 protein expression were decreased by metformin treatment. These results suggest that metformin has potential to treat scleroderma by inhibiting pro-inflammatory cytokines and anti-inflammatory activity mediated by mTOR-STAT3 signaling.

Artemisinin improves neurocognitive deficits associated with sepsis by activating the AMPK axis in the microglia.

2020 ◽  
Author(s):  
Shao-Peng Lin ◽  
Jue-Xian Wei ◽  
Shan Ye ◽  
Jiasong Hu ◽  
Jingyi Bu ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Inflammatory Cytokines ◽  
Nuclear Translocation ◽  
Neuronal Damage ◽  
Protective Mechanism ◽  
Protective Effects ◽  
Neurocognitive Deficits ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Abstract Background and purpose: Artemisinin has been in use as an anti-malarial drug for almost half a century in the world. There is growing evidence that artemisinin also possesses potent anti-inflammatory and immunoregulatory properties. However, the efficacy of artemisinin treatment in neurocognitive deficits associated with sepsis remains unknown. Here, we evaluate the possible protective effects and explore the underlying mechanism of artemisinin on cognitive impairment resulting from sepsis.Methods: Male C57BL/6 mice were pretreated with either vehicle or artemisinin, and then injected with LPS to establish an animal model of sepsis. The cognitive function was then assessed using the Morris water maze. Neuronal damage and neuroinflammation in the hippocampus were evaluated by immunohistochemical and ELISA analysis. Additionally, the protective mechanism of artemisinin was determined in vitro.Results: The results showed that artemisinin preconditioning attenuated LPS-induced cognitive impairment, neural damage, and microglial activation in the mouse brain. The in vitro experiment revealed that artemisinin could reduce the production of pro-inflammatory cytokines and suppress the microglial migration in the BV2 microglia cells. Meanwhile, western blot demonstrated that artemisinin suppressed nuclear translocation of nuclear factor kappa-B and the expression of pro-inflammatory cytokines (i.e. tumor necrosis factor alpha, interleukin-6) by activating adenosine monophosphate-activated protein kinaseα1 (AMPKα1) pathway. Furthermore, knock-down of AMPKα1 markedly abolished the anti-inflammatory effects of artemisinin.Conclusion: Artemisinin is a potential therapeutic agent for sepsis-associated neuroinflammation and cognitive impairment, and its effect was probably mediated by the activation of AMPKα1 signalling pathway in microglia.

scholarly journals P0527AROLE OF PROMOTING INFLAMMATION OF KLF6 IN ACUTE KIDNEY INURY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Dan Li ◽  
Chenyu Li ◽  
Yan Xu
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tnf Α ◽  
Public Dataset ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine ◽  
Pro Inflammatory Cytokines

Abstract Background and Aims Acute kidney injury (AKI), commonly appeared in cardiac arrest, surgery and kidney transplantation which involved in ischemia-reperfusion (IR) injury of kidney. However, the mechanisms underlying inflammatory response in IR AKI is still unclear. Method Public dataset showed kruppel-like factor 6 (KLF6) was significantly highly expressed (P<0.05) in AKI, implies KLF6 might be associated with AKI. To evaluate the mechanism of KLF6 on IR AKI, 30 rats were randomly divided into sham and IR group, and were sacrificed at 0 h, 3 h, 6 h, 12 h or 24 h after IR. Results The results showed KLF6 expression was peaking at 6 h after IR, and the expression of pro-inflammatory cytokines MCP-1 and TNF-α were increased both in serum and kidney tissues after IR, while anti-inflammatory cytokine IL-10 was decreased after IR. Furthermore, in vitro results showed KLF6 knock-down reduced the pro-inflammatory cytokines expression and increased the anti-inflammatory cytokines expression. Conclusion These results suggest that (1) KLF6 might be a novel biomarker for early diagnosis of AKI and (2) targeting KLF6 expression may offer novel strategies to protect kidneys from IR AKI Figure KLF6, AKI, Control Inflammation

Apoptosis perturbations and expression of regulatory inflammatory factors in cisplatin-depleted rat livers under l-arginine protection

2019 ◽  
Vol 97 (5) ◽  
pp. 359-369 ◽  
Author(s):  
Rehab M. El-Sayed ◽  
Hebatalla I. Ahmed ◽  
Abd El-Lateef S. Abd El-Lateef ◽  
Azza A. Ali
Keyword(s):  
Liver Function ◽  
Hepatic Injury ◽  
Inflammatory Factors ◽  
Protective Effects ◽  
Tnf Α ◽  
Apoptotic Marker ◽  
Apoptosis Markers ◽  
Anti Inflammatory ◽  
Rat Livers ◽  
Inflammatory Effect

Hepatic injury is one of the most common complications associated with cisplatin (CIS) use. Recently, liver protection lines are being discovered to stop the hepatic cell death due to inflammatory and apoptotic perturbations. l-arginine has protective effects in several models of liver injury. This study was designed to investigate the possible protective effect of l-arginine against CIS-induced acute hepatic injury in rats. Rats were divided into 4 groups: control, l-arginine, CIS, l-arginine + CIS. Liver function, oxidative stress, inflammatory cytokines, and apoptosis markers were assessed. l-arginine pretreatment protected the liver against CIS-induced toxicity as indicated by significantly alleviating the changes in liver function along with restoration of the antioxidant status. This finding was confirmed with the markedly improved pathological changes. l-arginine showed anti-inflammatory effect through the reduction of liver expression of iNOS, TNF-α, and NF-κβ, which were ameliorated to significant levels. Furthermore, l-arginine administration downregulated the liver expression of the apoptotic marker, caspase-3. The results recommend l-arginine as a hepatoprotective agent against CIS toxicity. Mostly, this hepatoprotective effect of l-arginine involved anti-inflammatory and anti-apoptotic activities.

Cytokine Levels in Critically Ill Children With Severe Sepsis and Their Relation With the Severity of Illness and Mortality

2020 ◽  
pp. 088506662091298
Author(s):  
Suresh Kumar Angurana ◽  
Arun Bansal ◽  
Jayashree Muralidharan ◽  
Ritu Aggarwal ◽  
Sunit Singhi
Keyword(s):  
Severe Sepsis ◽  
Critically Ill ◽  
Inflammatory Cytokines ◽  
Severity Of Illness ◽  
Critically Ill Children ◽  
Positive Correlation ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Objective: To study the baseline cytokine levels and their relation with the severity of illness and mortality in critically ill children with severe sepsis. Design: Subgroup analysis of a randomized, double-blind, placebo-controlled trial. Setting: Pediatric intensive care unit of a tertiary level teaching hospital in India. Patients: Fifty children with severe sepsis aged 3 months to 12 years. Material and Methods: Blood was collected at admission for estimation of pro-inflammatory (interleukin 6 [IL-6], IL-12p70, IL-17, and tumor necrotic factor α [TNF-α]) and anti-inflammatory (IL-10 and transforming growth factor β1 [TGF-β1]) cytokines. Primary Outcome: To find out correlation between cytokine levels and severity of illness scores (Pediatric Risk of Mortality [PRISM] III score, Sequential Organ Failure Assessment [SOFA], and Vasoactive-Inotropic Score [VIS]). Secondary Outcomes: To compare cytokine levels among survivors and nonsurvivors. Results: Baseline pro-inflammatory cytokine levels (median [interquartile range]) were IL-6: 189 (35-285) pg/mL, IL-12p: 48 (28-98) pg/mL, IL-17: 240 (133-345) pg/mL, and TNF-α: 296 (198-430) pg/mL; anti-inflammatory cytokine levels were IL-10: 185 (62-395) pg/mL and TGF-β1: 204 (92-290) ng/mL. Pro-inflammatory cytokines showed positive correlation with PRISM III score: IL-6 (Spearman correlation coefficient, ρ = 0.273, P = .06), IL-12 (ρ = 0.367, P = .01), IL-17 (ρ = 0.197, P = .17), and TNF-α (ρ = 0.284, P = .05), and anti-inflammatory cytokines showed negative correlation: IL-10 (ρ = −0.257, P = .09) and TGF-β (ρ = −0.238, P = .11). Both SOFA and VIS also showed weak positive correlation with IL-12 (ρ = 0.32, P = .03 and ρ = 0.31, P = .03, respectively). Among nonsurvivors (n = 5), the levels of all the measured pro-inflammatory cytokines were significantly higher as compared to survivors, IL-6: 359 (251-499) pg/mL versus 157 (97-223) pg/mL, P < .0001, IL-12p70: 167 (133-196) pg/mL versus 66 (30-100) pg/mL, P < .0001, IL-17: 400 (333-563) pg/mL versus 237 (122-318) pg/mL, P = .009, and TNF-α: 409 (355-503) pg/mL versus 330 (198-415) pg/mL, P = .002, respectively. Conclusion: In critically ill children with severe sepsis, pro-inflammatory cytokines (especially IL-12p70) showed a weak positive correlation with severity of illness and were significantly higher among nonsurvivors.

Crucial Factors of the Inflammatory Microenvironment (IL-1 beta/TNF-alpha/TIMP-1) Promote Maintenance of the Malignant Hemopoietic Clone of Myelofibrosis By Stimulating the in Vitro Survival/Proliferation/Migration of Circulating CD34+ stem/Progenitor Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4094-4094
Author(s):  
Dorian Forte ◽  
Daria Sollazzo ◽  
Nicola Polverelli ◽  
Romano Marco ◽  
Lara Rossi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Inflammatory Cytokines ◽  
Stromal Cells ◽  
Colony Formation ◽  
Inflammatory Factors ◽  
Inflammatory Microenvironment ◽  
Cd34 Cells ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Abstract Introduction. Myelofibrosis (MF), an acquired clonal disorder of the hematopoietic stem/progenitor cell (HSPC) with a dysregulation in JAK/STAT signalling (mutations in JAK2, MPL and Calreticulin (CALR) genes), is characterized by a state of chronic inflammation. It is argued that the up-regulated production of proinflammatory cytokines by both HSPCs and the surrounding stromal cells generates a microenvironment that selects for the malignant clone. Only recently, it has been hypothesized that the sustained inflammatory microenvironment of MF can alter crucial biological processes, leading to genomic instability and cancer progression. Here we tested the in vitro functional effects of pivotal players of the inflammatory microenvironment (the extracellular ATP nucleotide and selected cytokines, such as Interleukin (IL)-1β, Tumor Necrosis Factor (TNF)-α or the Tissue Inhibitor of Metalloproteinases-1 (TIMP-1)) on the HSPCs from MF patients. Methods: Circulating CD34+/CD34+ CD38- cells from MF patients (JAK2V617F (17 cases) and CALR (9 cases) mutations) or cord blood (CB; 8 samples) were phenotypically and functionally characterized after in vitro incubation with or without ATP (1000 μM), IL-1β (10 ng/mL), TNF-α (10 ng/mL) or TIMP-1 (100 ng/mL) (alone or in combination). Cells were then analyzed for survival/apoptosis (Annexin-V/Propidium Iodide staining), phenotype (evaluation of CD63 (TIMP-1 receptor), CXCR4 and CD38 expression), cell cycle and clonogenic capacity. Migration was assessed first towards a CXCL12 gradient in the presence or absence of the pro-inflammatory factors. In parallel experiments, CD34+ cells from MF patients were co-cultured with normal mesenchymal stromal cells (MSCs) in the presence or absence of the pro-inflammatory cytokines and then evaluated for their ability to migrate towards a CXCL12 gradient. Plasma TIMP-1, TNF-α, IL-1β and CXCL12 were measured by ELISA assay. Results: The plasma levels of TIMP-1, TNF-α, IL-1β, CXCL12 and the number of circulating CD34+, CD34+ CD38-, CD34+ CD63+, CD34+ CD184+ cells were increased in MF patients. According to mutational status, the CD34+ CD63+ cells were higher in the CALR+ patients. The survival of MF CD34+ cells was strongly stimulated by in vitro incubation with TNF-α or IL-1β as compared with the CB-derived CD34+ cells or untreated cells. By multiple cytokine combinations, IL-1β/TIMP-1, IL-1β /ATP or IL-1β /TNF-α treatments significantly promote the survival of MF CD34+ cells as compared with the normal counterparts or the untreated cells. Various combinations with IL-1β were also effective in stimulating survival of CD34+CD38- cells. IL-1β/TIMP-1 and IL-1β/TNF-α/TIMP-1, but not factors alone, significantly increased the CFU-C growth of MF patients as compared with the CB-derived counterparts and the untreated cells. Moreover, comparing CALR+ vs JAK2V617F+ patients, the colony formation of JAK2V617F+ patients was mainly promoted by the IL-1β/TNF-α treatment. Along with clonogenic capacity stimulation, exposure of CD34+ cells from MF patients to IL-1β/TNF-α/TIMP-1 significantly increases the S-phase cells, suggesting that these pro-inflammatory factors stimulated cell-cycle progression in dormant CD34+ MF cells. Migration of CD34+ cells from MF was significantly increased in CXCL12 treated cells. In addition, exposure of MF CD34+ cells to IL-1β/TNF-α, IL-1β/TIMP-1 or IL-1β/TNF-α/TIMP-1 significantly promotes cell migration in comparison with the CB-derived counterparts or SDF-1 alone. MF migrated cells in the presence of IL-1β/TNF-α significantly upregulate CD63 expression. Intriguingly, colony formation of MF migrated CD34+ cells in the presence of IL-1β/TNF-α or IL-1β/TNF-α/TIMP-1 was potently increased. Finally, co-culture systems with normal MSCs in the presence of pro-inflammatory factors revealed that MF CD34+ cells display increased migration ability toward CXCL12 gradient. Conclusions: Altogether our findings suggest that in MF the inflammatory niche plays a key role in the maintenance of the malignant clone. Thus, the interplay between the pro-inflammatory cytokines promote and select the HSPCs with higher proliferative activity, clonogenic potential and migration capability. Targeting these microenvironmental interactions may be a clinically relevant approach. D.F. and D.S. equally contributed Disclosures Martinelli: Pfizer: Consultancy; Ariad: Consultancy; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy; AMGEN: Consultancy; BMS: Consultancy, Speakers Bureau; ROCHE: Consultancy.

Primary Radiation Stress, Inflammatory Reaction and the Mechanism of Early Postradiation Reparative Processes in Irradiated Tissues

2018 ◽  
Vol 63 (6) ◽  
pp. 71-81 ◽  
Author(s):  
М. Васин ◽  
M. Vasin ◽  
В. Соловьев ◽  
V. Solov'ev ◽  
В. Мальцев ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Inflammatory Cytokines ◽  
Cathepsin G ◽  
Inflammatory Factors ◽  
Hemopoietic Tissue ◽  
Post Radiation ◽  
Apoptotic Proteins ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

The products of radiolysis released from cellular compartment under the influence of ionizing radiation: highly mobile groups of proteins, damaged nuclear and mitochondrial DNA, extracellular ATP and oxidized low density lipoproteins, cause stress activation in irradiated tissues through a pattern of the receptors with start of the cascade r53 and NF-κB of pro-inflammatory ways conducting to an expression of pro-inflammatory genes stimulating synthesis of cytokines of the IL-1 family. Excessive activation of pro-inflammatory way under the influence of a radioactive stress is limited to synthesis, anti-inflammatory cytokines: IL-4, IL-10, IL-11, IL-13 and also antagonists of IL-1 receptor and TGF-β. G-CSF and MG-CSF induced by action of pro-inflammatory cytokines have anti-inflammatory and anti-apoptotic properties decreasing level of pro-inflammatory cytokines IL-6 and TNF. Glucocorticoids participate in regulation of primary radioactive stress, suppressing an excessive expression of genes of pro-inflammatory cytokines. Increased IL-1 level stimulates secretion of corticosteroids through mechanism of feedback. Adrenergic stimulation is capable to raise a gene IL-1β expression. The mechanism of radiation apoptosis of stem cells is implemented through p53-Puma way which blocks interaction anti-apoptotic proteins of Bcl-2 with pro-apoptotic proteins of Bax and Bak. After release from mitochondrion of cytochrome C and apoptosis-inducing factor there is an activation of effector caspases: caspases 3, 6 and 7 through caspase 9, and final cell destruction. Wnt way is crucial for post-radiation repair. Potential of the regenerative response of hemopoietic tissue to radiation injury depends on catenin and ability of Wnt way to stimulate post-radiation bone marrow reparation. Mesenchymal stem cells of bone marrow play a large role in post-radiation regeneration of hemopoietic tissue. Their main action is carried out through TLR2 and TLR4 receptors. Mobilization of hemopoietic stem cells is bound to release proteases from bone marrow, including neutrophil elastase and cathepsin G, and a matrix metalproteinase-9. Radioprotective properties of exogenous IL-1 aren’t limited only by induction of raised G-CSF and GM-CSF production. The larger role in radiation protection is played by the reaction induced by IL-1 in the form of feedback with production anti-apoptotic and anti-inflammatory factors. Primary radioactive stress limits time of radiomitigable effect of IL-1 by 1-2 h after its application after radiation.

scholarly journals MiR-24-3p Attenuates IL-1β-Induced Chondrocyte Injury Associated With Osteoarthritis by Targeting BCL2L12

2020 ◽  
Author(s):  
Jin Xu ◽  
Xiaozhong Qian ◽  
Ren Ding
Keyword(s):  
Cell Viability ◽  
Inflammatory Cytokines ◽  
Caspase 3 ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Luciferase Reporter ◽  
Pcr Analysis ◽  
Protective Effects ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Abstract Background: Osteoarthritis (OA) is a chronic and degenerative joint disease prevalent in the elderly. MiR-24-3p has been reported to be involved in an OA-resembling environment. However, the functional role and underlying mechanism of miR-24-3p in chondrocyte injury associated with OA remains unknown. Methods: The expression of miR-24-3p was determined in OA cases and control patients, as well as IL-1β-stimulated chondrocyte cell line CHON-001 using reverse transcription quantitative PCR analysis. Cell viability was analyzed by CCK-8 assay. Apoptosis status was assessed by caspase-3 activity detection. The pro-inflammatory cytokines (TNF-α and IL-18) were determined using ELISA assay. The association between miR-24-3p and BCL2L12 was confirmed by luciferase reporter assay.Results: We first observed that miR-24-3p expression level was lower in the OA cases than in the control patients and IL-1β decreased the expression of miR-24-3p in the chondrocyte CHON-001. Functionally, overexpression of miR-24-3p significantly attenuated IL-1β-induced chondrocyte injury, as reflected by increased cell viability, decreased caspase-3 activity, pro-inflammatory cytokines (TNF-α and IL-18). Western blot analysis showed that overexpression of miR-24-3p weakened IL-1β-induced cartilage degradation, as reflected by reduction of MMP13 (Matrix Metalloproteinase-13) and ADAMTS5 (A Disintegrin And Metalloproteinase with Thrombospondin Motifs-5) protein expression, as well as markedly elevation of COL2A1 (collagen type II). Importantly, BCL2L12 was demonstrated to be a target of miR-24-3p. BCL2L12 knockdown imitated, while overexpression significantly abrogated the protective effects of miR-24-3p against IL-1β-induced chondrocyte injury.Conclusions: In conclusion, our work provides important insight into targeting miR-24-3p/BCL2L12 axis in OA therapy.

scholarly journals Anti-inflammatory Effect of Curcumin, Homotaurine, and Vitamin D3 on Human Vitreous in Patients With Diabetic Retinopathy

2021 ◽  
Vol 11 ◽  
Author(s):  
Mariaelena Filippelli ◽  
Giuseppe Campagna ◽  
Pasquale Vito ◽  
Tiziana Zotti ◽  
Luca Ventre ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Inflammatory Cytokines ◽  
Vitamin D3 ◽  
Bioactive Molecules ◽  
Mediators Of Inflammation ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Post Hoc ◽  
Pro Inflammatory Cytokines ◽  
Inflammatory Effect

Purpose: To determine the levels of pro-inflammatory cytokines and soluble mediators (TNF-α, IL6, IL2, and PDGF-AB) in 28 vitreous biopsies taken from patients with proliferative diabetic retinopathy (PDR) and treated with increasing doses of curcumin (0. 5 and 1 μM), with or without homotaurine (100 μM) and vitamin D3 (50 nM).Materials and Methods: ELISA tests were performed on the supernatants from 28 vitreous biopsies that were incubated with bioactive molecules at 37°C for 20 h. The concentration of the soluble mediators was calculated from a calibration curve and expressed in pg/mL. Shapiro-Wilk test was used to verify the normality of distribution of the residuals. Continuous variables among groups were compared using the General Linear Model (GLM). Homoscedasticity was verified using Levene and Brown-Forsythe tests. Post-hoc analysis was also performed with the Tukey test. A p ≤ 0.05 was considered statistically significant.Results: The post-hoc analysis revealed statistically detectable changes in the concentrations of TNF-α, IL2, and PDGF-AB in response to the treatment with curcumin, homotaurine, and vitamin D3. Specifically, the p-values for between group comparisons are as follows: TNF-α: (untreated vs. curcumin 0.5 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.008, (curcumin 0.5 μM vs. curcumin 0.5 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.0004, (curcumin 0.5 μM vs. curcumin 1 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.02, (curcumin 1 μM vs. curcumin 0.5 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.025, and (homotaurine 100 μM + vitamin D3 50 nM vs. curcumin 0.5 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.009; IL2: (untreated vs. curcumin 0.5 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.0023, and (curcumin 0.5 μM vs. curcumin 0.5 μM+ homotaurine 100 μM + vitamin D3 50 nM) p = 0.0028; PDGF-AB: (untreated vs. curcumin 0.5 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.04, (untreated vs. curcumin 1 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.0006, (curcumin 0.5 μM vs. curcumin 1 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.006, and (homotaurine 100 μM + vitamin D3 50 nM vs. curcumin 1 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.022. IL6 levels were not significantly affected by any treatment.Conclusions: Pro-inflammatory cytokines are associated with inflammation and angiogenesis, although there is a discrete variability in the doses of the mediators investigated among the different vitreous samples. Curcumin, homotaurine, and vitamin D3 individually have a slightly appreciable anti-inflammatory effect. However, when used in combination, these substances are able to modify the average levels of the soluble mediators of inflammation and retinal damage. Multi-target treatment may provide a therapeutic strategy for diabetic retinopathy in the future.Clinical Trial Registration : The trial was registered at clinical trials.gov as NCT04378972 on 06 May 2020 (“retrospectively registered”) https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid = S0009UI8&amp;selectaction = Edit&amp;uid = U0003RKC&amp;ts = 2&amp;cx = dstm4o.

scholarly journals Protective Effects of Total Saponins of Aralia elata (Miq.) on Endothelial Cell Injury Induced by TNF-α via Modulation of the PI3K/Akt and NF-κB Signalling Pathways

2018 ◽  
Vol 20 (1) ◽  
pp. 36 ◽  
Author(s):  
Ping Zhou ◽  
Weijie Xie ◽  
Yun Luo ◽  
Shan Lu ◽  
Ziru Dai ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Injury ◽  
Inflammatory Responses ◽  
Inflammatory Factors ◽  
Early Event ◽  
Protective Effects ◽  
Bax Protein ◽  
Aralia Elata ◽  
Tnf Α ◽  
Anti Inflammatory

Atherosclerosis is an arterial disease associated with inflammation. Hence, the discovery of novel therapeutic agents for suppressing inflammatory responses is urgent and vital for the treatment of atherosclerosis in cardiovascular diseases. The total saponins of Aralia elata (Miq.) Seem. (TAS) are the main components extracted from the Chinese traditional herb Longya Aralia chinensis L., a folk medicine used in Asian countries for treating numerous diseases, enhancing energy and boosting immunity. However, the protective effects of TAS against inflammation-triggered vascular endothelial dysfunction, a critical early event during the course of atherosclerosis, and the potential mechanisms of this protection have been not demonstrated. Accordingly, the aim of this study was to investigate the anti-inflammatory and anti-apoptotic effects and the protective mechanisms of TAS, and show how TAS ameliorates human umbilical vein endothelial cell (HUVEC) damage caused by tumour necrosis factor-α (TNF-α). The results indicated that TAS exerted cytoprotective effects by inhibiting TNF-α-triggered HUVEC apoptosis, mitochondrial membrane potential depolarisation, and the regulation of inflammatory factors (IL-6, MCP-1, and VCAM-1) while suppressing NF-κB transcription. Furthermore, this phenomenon was related to activation of the phosphoinositide 3-kinase (PI3K)/Akt signalling pathway. Blocking the Akt pathway with LY294002, a PI3K inhibitor, reversed the cytoprotective effect of TAS against TNF-α-induced endothelial cell death. Moreover, LY294002 partially abolished the effects of TAS on the upregulation of the Bcl-2 family of proteins and the downregulation of Bax protein expression. In conclusion, the results of our study suggest that TAS suppresses the inflammation and apoptosis of HUVECs induced by TNF-α and that PI3K/Akt signalling plays a key role in promoting cell survival and anti-inflammatory reactions during this process.

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