scholarly journals Effects of a CCR2 antagonist on macrophages and Toll-like receptor 9 expression in a mouse model of diabetic nephropathy

2021 ◽  
Author(s):  
Seigo Ito ◽  
Hiroyuki Nakashima ◽  
Takuya Ishikiriyama ◽  
Masahiro Nakashima ◽  
Akira Yamagata ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Therapeutic Effects ◽  
Ros Production ◽  
Toll Like Receptor ◽  
Tlr9 Expression ◽  
Tnf Α ◽  
Factor Α ◽  
And Function ◽  
Ccr2 Antagonist ◽  
Necrosis Factor

The pathogenesis of diabetic nephropathy (DN) is related to macrophage (Mφ) recruitment to the kidneys, tumor necrosis factor-α (TNF-α) production, and oxidative stress. Toll-like receptor 9 (TLR9) activation is reportedly involved in systemic inflammation, and it exacerbates this condition in metabolic syndrome. Therefore, we hypothesized that TLR9 plays a role in the pathogenesis of DN. Two subsets of kidney macrophages in DN model (db/db) mice were analyzed using flow cytometry to evaluate their distribution and TLR9 expression and function. Mice were administered the CCR2 antagonist INCB3344 for 8 weeks; changes in macrophage distribution and function and its therapeutic effects on DN pathology were examined. Bone marrow-derived CD11bhigh (BM-) and tissue-resident CD11blow (Res-) Mφs were identified in the mouse kidneys. As DN progressed, the BM-Mφ number, TLR9 expression, and TNF-α production increased significantly. In Res-Mφs, reactive oxygen species (ROS) production and phagocytic activity were enhanced. INCB3344 decreased albuminuria, serum creatinine level, BM-Mφs abundance, TLR9 expression, and TNF-α production by BM-Mφs and ROS production by Res-Mφs. Both increased activation of BM-Mφs via TLR9 and TNF-α production and increased ROS production by Res-Mφs were involved in DN progression. Thus, inactivating macrophages and their TLR9 expressions by INCB3344 is a potential therapeutic strategy for diabetic nephropathy.

scholarly journals Andrographis paniculata and Its Bioactive Diterpenoids Against Inflammation and Oxidative Stress in Keratinocytes

Antioxidants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 530 ◽  
Author(s):  
Eugenie Mussard ◽  
Sundy Jousselin ◽  
Annabelle Cesaro ◽  
Brigitte Legrain ◽  
Eric Lespessailles ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Quantitative Polymerase Chain Reaction ◽  
Andrographis Paniculata ◽  
Ros Production ◽  
Inflammatory Conditions ◽  
Tnf Α ◽  
Dichlorofluorescein Diacetate ◽  
Polymerase Chain ◽  
Factor Α ◽  
Necrosis Factor

Andrographis paniculata was widely used in traditional herbal medicine to treat various diseases. This study explored the potential anti-aging activity of Andrographis paniculata in cutaneous cells. Human, adult, low calcium, high temperature (HaCaT) cells were treated with methanolic extract (ME), andrographolide (ANDRO), neoandrographolide (NEO), 14-deoxyandrographolide (14DAP) and 14-deoxy-11,12-didehydroandrographolide (14DAP11-12). Oxidative stress and inflammation were induced by hydrogen peroxide and lipopolysaccharide/TNF-α, respectively. Reactive oxygen species (ROS) production was measured by fluorescence using a 2′,7′-dichlorofluorescein diacetate (DCFH-DA) probe and cytokines were quantified by ELISA for interleukin-8 (IL-8) or reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for tumor necrosis factor-α (TNF-α). Hyaluronic acid (HA) secretion was determined by an ELISA. Our results show a decrease in ROS production and TNF-α expression by ME (5 µg/mL) in HaCaT under pro-oxidant and pro-inflammatory conditions, respectively. ME protected HaCaT against oxidative stress and inflammation. Our findings confirm that ME can be used for the development of bioactive compounds against epidermal damage.

scholarly journals Myosin motor Myo1c and its receptor NEMO/IKK-γ promote TNF-α–induced serine307 phosphorylation of IRS-1

2006 ◽  
Vol 173 (5) ◽  
pp. 665-671 ◽  
Author(s):  
Yoshitaka Nakamori ◽  
Masahiro Emoto ◽  
Naofumi Fukuda ◽  
Akihiko Taguchi ◽  
Shigeru Okuya ◽  
...  
Keyword(s):  
Motor Protein ◽  
Nuclear Factor Κb ◽  
Receptor Protein ◽  
Cytoskeletal Network ◽  
Iκb Kinase ◽  
Tnf Α ◽  
Ikk Complex ◽  
Factor Α ◽  
And Function ◽  
Necrosis Factor

Tumor necrosis factor-α (TNF-α) signaling through the IκB kinase (IKK) complex attenuates insulin action via the phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser307. However, the precise molecular mechanism by which the IKK complex phosphorylates IRS-1 is unknown. In this study, we report nuclear factor κB essential modulator (NEMO)/IKK-γ subunit accumulation in membrane ruffles followed by an interaction with IRS-1. This intracellular trafficking of NEMO requires insulin, an intact actin cytoskeletal network, and the motor protein Myo1c. Increased Myo1c expression enhanced the NEMO–IRS-1 interaction, which is essential for TNF-α– induced phosphorylation of Ser307–IRS-1. In contrast, dominant inhibitory Myo1c cargo domain expression diminished this interaction and inhibited IRS-1 phosphorylation. NEMO expression also enhanced TNF-α–induced Ser307–IRS-1 phosphorylation and inhibited glucose uptake. In contrast, a deletion mutant of NEMO lacking the IKK-β–binding domain or silencing NEMO blocked the TNF-α signal. Thus, motor protein Myo1c and its receptor protein NEMO act cooperatively to form the IKK–IRS-1 complex and function in TNF-α–induced insulin resistance.

Cyclosporine Ameliorates Silica-Induced Autoimmune Hepatitis in Rat Model by Altering the Expression of Toll-Like Receptor-4, Interleukin-2 and Tumor Necrosis Factor-α

2022 ◽  
Vol 22 ◽  
Author(s):  
Moustafa M. Mohamed ◽  
Ahmed M. M. Okasha ◽  
Amany H. Abdel Naiem ◽  
Reham F. Mohamed ◽  
Sayed F. Abdelwahab ◽  
...  
Keyword(s):  
Autoimmune Hepatitis ◽  
Interleukin 2 ◽  
Hepatic Function ◽  
Treated Group ◽  
Control Group ◽  
Toll Like Receptor ◽  
Hepatic Diseases ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Background: Autoimmune hepatitis (AIH) is an inflammatory liver disease which is characterized histologically by interface hepatitis, biochemically by elevated transaminase levels, and serologically by the presence of autoantibodies. Toll-like receptor (TLR)-4 is a TLR family member that, upon activation in hepatocytes, initiates a cascade of events. Interleukin-2 (IL-2) and tumour necrosis factor-α (TNF-α) are potent inflammatory cytokines secreted in AIH playing an important role in the early development of inflammation, and hepatocyte damage. Objective: This study examined cyclosporine role in AIH and tried to illustrate its actions on altered hepatic function in silica-induced AIH model. Methods: AIH was induced in Wester rats using Sodium Silicate. The rats were divided into four groups: control group, Silica-AIH group, cyclosporine-treated group, and prevention group. TLR-4, and IL-2 mRNA expression in liver tissues was tested by RT-PCR. Results: AIH was associated with up-regulation of liver enzymes, IL-2, and TLR-4 gene expression while cyclosporine significantly down-regulated the expression of both. The relative quantity of TLR-4 mRNA was 1±0, 13.57±1.91, 4±0.38, and 2±0 in the control, AIH, cyclosporine, and prevention groups, respectively (p<0.001). Also, the relative quantity of IL-2 mRNA was 1±0, 14.79±1.42, 7.07±0.96, and 3.4±0.55 in the same groups, respectively (p<0.001). Additionally, immuno-histochemical staining for TNF-α in liver sections was increased in the silica-AIH group but it was decreased in the cyclosporine-treated and prevention groups. Conclusion: This study advocates a therapeutic role of cyclosporine in treating immune-mediated hepatic diseases. Cyclosporine improves histological alterations in the liver and inhibits the production of proinflammatory cytokines.

scholarly journals Elevated levels of netrin-1 in the serum of patients with diabetic nephropathy: Relationship with renal function and inflammation

2018 ◽  
Vol 16 ◽  
pp. 205873921880928
Author(s):  
Chenxiao Liu ◽  
Qi Li ◽  
Xiu Feng ◽  
Qian Li
Keyword(s):  
Diabetic Nephropathy ◽  
Glycosylated Hemoglobin ◽  
Animal Experiments ◽  
Enzyme Linked Immunosorbent Assay ◽  
Urine Albumin ◽  
Tnf Α ◽  
Factor Α ◽  
The Relationship ◽  
Necrosis Factor

Netrin-1, a survival factor, is highly induced and excreted after renal injury in animal experiments. We aimed to research the relationship between serum netrin-1 and parameters of renal tubule function as well as circulating inflammatory cytokines and to evaluate effect factors for netrin-1 in humans with type 2 diabetes mellitus (T2DM) undergoing different levels of albuminuria. In total, 81 T2DM patients were included and divided into three groups according to their amount of 24-h urine albumin excretion (UAE) after receiving consent. Plasma netrin-1, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were quantified by commercially available enzyme-linked immunosorbent assay kits and the data were analyzed to assess whether serum netrin-1 correlates significantly with disease progression. The results showed that plasma netrin-1 level in patients with macroalbuminuria was significantly higher than that in those with microalbuminuria and normoalbuminuria. Plasma netrin-1 level was significantly associated with UAE, estimated glomerular filtration rate (eGFR), IL-6, and TNF-α independently of age, sex, diabetes duration, and glycosylated hemoglobin (HbA1c). However, no correlation was found between netrin-1 and β2-microglobulin (β2-MG). Our studies may suggest that serum netrin-1 concentrations are increased with diabetic nephropathy progression, particularly in patients with macroalbuminuria, which are associated with renal insufficiency and compensatory responses after inflammation.

scholarly journals Assessments of Therapeutic Effects of Platelet-rich Plasma in Knee Osteoarthritis: Possible Role of Inflammatory Cytokines

2020 ◽  
Author(s):  
Mohammed H. Hassan ◽  
Tahia H. Saleem ◽  
Sawsan Abuhamdah ◽  
Hamdy Tammam ◽  
Nehal Ashraf Zaki ◽  
...  
Keyword(s):  
Pain Score ◽  
Macrophage Migration Inhibitory Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Platelet Rich Plasma ◽  
Therapeutic Effects ◽  
Knee Oa ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Abstract Background: Osteoarthritis (OA) is a multifactorial disease that commonly affects the knee. Tumor necrosis factor-α (TNF-α) is able to regulate inflammation in OA. Macrophage migration inhibitory factor (MIF) may be involved in the pathophysiology of arthritis. Platelet-rich plasma (PRP) may reduce pain associated with OA. The current study aimed to assess the possible therapeutic effects of PRP in patients with knee OA of various severities. Methods: A prospective study was performed on 90 patients were included and categorized into mild (30 cases, moderate (30 cases) and severe (30 cases) knee OA. Three intra-articular (I.A) injections of PRP, 2 weeks a part, were received. Pain score and MRI Osteoarthritis Knee Score (MOAKS) were assessed. Serial synovial fluid cytokines assays in the form of Tumor necrosis factor-α (TNF-α) and Macrophage migration inhibitory factor (MIF), were performed using commercially available ELISA assay kits. The assays were performed pre-injection (S1), two weeks from the 1st I.A injection and two weeks from the 2nd I.A injection (S3) for all included patients. Results: The mean values of pain score and synovial TNF-α and MIF levels were significantly higher levels (S1, pre-injection) among severe OA when compared with both mild and moderate cases, p˂0.05 for all. There were significantly lower pain score and synovial TNF-α and MIF levels at S3 in mild, moderate and severe knee OA when compared with S1 values, p˂0.05 for all. There was significant improvement in synovitis in both mild and moderate cases (p˂0.05 for both). Conclusion: I.A injection of PRP significantly reduces the synovial fluid TNF-α and MIF levels with great therapeutic effects on both synovitis via reducing inflammatory cytokines, and bone marrow lesions mainly for mild knee OA and to a lesser extent for moderate cases.

Clostridioides difficile toxins enhanced the in vitro production of CXC chemokine ligand 2 and tumor necrosis factor-α via Toll-like receptors in macrophages

2021 ◽  
Vol 70 (4) ◽  
Author(s):  
Hiroe Konishi McKee ◽  
Chiaki Kajiwara ◽  
Tetsuo Yamaguchi ◽  
Yoshikazu Ishii ◽  
Norikazu Shimizu ◽  
...  
Keyword(s):  
Type Species ◽  
Toll Like Receptor ◽  
Hek 293 ◽  
Content Type ◽  
Clostridioides Difficile ◽  
Tnf Α ◽  
Chemokine Ligand ◽  
Factor Α ◽  
Chemokine Ligand 2 ◽  
Necrosis Factor

Introduction. Clostridioides difficile infection (CDI) causes toxin-mediated enteropathy, such as antibiotic-associated diarrhoea and pseudomembranous colitis. Rho-glucosylating toxin A (TcdA) and toxin B (TcdB) have been clearly implicated in pathogenesis, whereas the virulence of binary toxin (CDT) is still debated. Hypothesis statement. We hypothesized that CDT is involved in the host immune response and plays a pivotal role in establishing virulence by modulating pro-inflammatory cytokine production; this is achieved through the integral Toll-like receptor (TLR) signalling pathways. Aim. The aim of the present study was to determine whether and how CDT impacts macrophages compared to TcdA or TcdB by examining the induction of CXC chemokine ligand 2 (CXCL2) and tumour necrosis factor-α (TNF-α), both of which are crucial in mediating local and systematic inflammatory responses. Methodology. RAW264.7 cells or transfected human embryonic kidney (HEK) 293 T cells were incubated with TcdA, TcdB, or CDT. In some experiments, a neutralizing antibody against TLR2 or TLR4, or myeloid differentiation 88 inhibitory peptide were added. The amount of CXCL2 and TNF-α secreted was then measured. Results. In RAW264.7 macrophages, CXCL2 and TNF-α were produced via the Toll-like receptor 2 (TLR2) or Toll-like receptor 4 (TLR4) pathway in a TcdA, TcdB, or CDT dose-dependent manner. Interleukin-8 secretion was induced in TLR4/MD2/CD14-transfected, but not in TLR2-transfected, HEK 293 T cells following TcdB or CDT exposure. Conclusion. Our results showed that C. difficile toxins, including CDT, enhanced macrophage-mediated CXCL2 and TNF-α production via TLR2 and TLR4, indicating that CDT affects host immune responses.

Regulation of iRhom-2/Tumor Necrosis Factor-α Converting Enzyme Pathway and Oxidative Stress Protects the Renal Injury with Anemonin in Streptozotocin-Induced Diabetic Nephropathy Neonatal Rat Model

Pharmacology ◽  
2019 ◽  
Vol 104 (5-6) ◽  
pp. 258-266
Author(s):  
Lingyan Qiao ◽  
Yusheng Liu ◽  
Cheng Li ◽  
Juan Ge ◽  
Tang Li
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Injury ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Kidney Tissue ◽  
Treated Group ◽  
Converting Enzyme ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Diabetic nephropathy (DN) is a chronic complication of diabetes, and thus the present investigation evaluates the nephroprotective effect of anemonin against streptozotocin (STZ)-induced DN rats. Diabetes was induced by intraperitoneal administration of STZ (50 mg/kg) on day 2 and 3 postnatal, and rats were kept as such for the duration of 12 weeks. Thereafter, rats were treated with anemonin 75 and 150 mg/kg per oral for the period 4 week which means between the period of 12–16 weeks. Effect of anemonin was estimated by determining the blood glucose, markers of nephropathy, and mediators of inflammation in the serum and activity of tumor necrosis factor-α (TNF-α)converting enzyme (TACE) in the kidney tissue of DN rats. Moreover, reverse transcriptase polymerase chain reaction and western blot assay were determined in the kidney tissue homogenate of DN rats. Histopathology study was done by Periodic acid-Schiff’s and masson staining for the pathological changes and apoptosis of podocytes in the kidney tissue of DN rats. Moreover, production of reactive oxygen species (ROS) was estimated in the kidney tissue by 2’,7’-dichlorofluorescein staining. Data of study reveal that anemonin significantly reduces (p < 0.01) the blood glucose and markers of renal injury in the serum and urine of DN rats. There was a reduction in the level of cytokines in the serum, and production of ROS and activity of TACE were reduced in the kidney tissue of the anemonin-treated group than in the DN group. Expression of iRhom-2, TACE, TNF-α, and inducible nitric oxide synthase protein and histopathology of kidney tissue were attenuated in the anemonin-treated group in DN rats. In conclusion, data of study reveal that treatment with anemonin ameliorates progression of renal injury by regulating TACE/iRhom-2 signaling pathway.

scholarly journals Toll-like receptor-4, but not toll-like receptor-2 mediates secretion of tumour necrosis factor α and interleukin-8 in lipopolysaccharide-stimulated mouse mammary epithelial cells

2013 ◽  
Vol 57 (3) ◽  
pp. 393-397 ◽  
Author(s):  
Chang-Liang He ◽  
Qiong Yi ◽  
Yuan-Fang Li ◽  
Hang Yang ◽  
Lu Wang
Keyword(s):  
Epithelial Cells ◽  
Tumour Necrosis ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Tumour Necrosis Factor Α ◽  
Toll Like Receptor ◽  
Tnf Α ◽  
Toll Like Receptor 2 ◽  
Factor Α ◽  
Necrosis Factor

Abstract Mammary epithelial cells (MECs) from Kunming mice were isolated and stimulated in vitro with 10 μg/mL of Escherichia coli lipopolysaccharide (LPS). The release of tumour necrosis factor α (TNF-α) and interleukin-8 (IL-8) into culture supernatants was measured by ELISA. Furthermore, blocking experiments with Toll-like receptor 2 (TLR2) and TLR4 antibodies were performed to verify whether cytokine secretion depended on LPS-induced activation of TLR2 or TLR4. The results revealed that LPS-stimulated mouse MECs significantly secreted TNF-α and IL-8. Blocking of the TLR4 pathway inhibited the secretion of TNF-α and IL-8, while inhibition of LPS-induced TNF-α and IL-8 production was not observed when TLR2 was blocked. Thus, TLR4 can mediate the LPS-induced expression of cytokines such as TNF-α and IL-8 in mouse MECs.

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