Simvastatin Inhibits CYR61 Expression in Orbital Fibroblasts in Graves’ Ophthalmopathy through the Regulation of FoxO3a Signaling

Graves’ ophthalmopathy (GO), which is characterized by orbital tissue inflammation, expansion, and fibrosis, is the ocular manifestation in 25% to 50% of patients with Graves’ disease. As the pathology of GO is driven by autoimmune inflammation, many proinflammatory cytokines/chemokines, including TNF-α, IL-1β, IL-6, and CCL20, are crucial in the pathogenesis of GO to activate the orbital fibroblasts. Cysteine-rich protein 61 (CYR61), which is known to regulate cell proliferation, adhesion, and migration, plays a proinflammatory role in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis. CYR61 was considered a potential biomarker of GO in recent studies. Statins, which are cholesterol-lowering drugs, were found to reduce the risk of GO, probably through their anti-inflammatory and immunomodulatory effects. In this study, we established a link between CYR61 and statins in the pathogenesis and potential treatment for GO. Firstly, our data showed the overexpression of CYR61 in the orbital tissue ( n = 4 ) and serum specimens ( n = 6 ) obtained from the patients with inactive GO. CYR61 could induce the production of IL-6 and CCL20 in cultured GO orbital fibroblasts. The expression of CYR61 in cultured GO orbital fibroblasts was upregulated via TNF-α stimulation. Secondly, we pretreated cultured GO orbital fibroblasts using simvastatin, a statin, followed by TNF-α stimulation. The data revealed that simvastatin could inhibit TNF-α-induced CYR61 expression by modulating the activity of transcription factor FoxO3a. Our results provided insights into some cellular mechanisms that may explain the possible protective effects of simvastatin against the development of GO.

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Cytokines as Targets of Novel Therapies for Graves’ Ophthalmopathy

Frontiers in Endocrinology ◽

10.3389/fendo.2021.654473 ◽

2021 ◽

Vol 12 ◽

Author(s):

Poupak Fallahi ◽

Silvia Martina Ferrari ◽

Giusy Elia ◽

Francesca Ragusa ◽

Sabrina Rosaria Paparo ◽

...

Keyword(s):

Autoimmune Disorder ◽

Intravenous Immunoglobulins ◽

Novel Therapies ◽

Autoimmune Process ◽

Blocking Antibody ◽

Graves Ophthalmopathy ◽

Tnf Α ◽

Organ Specific ◽

Orbital Fibroblasts ◽

B And T Lymphocytes

Graves’ disease (GD) is an organ-specific autoimmune disorder of the thyroid, which is characterized by circulating TSH-receptor (TSH-R) stimulating antibodies (TSAb), leading to hyperthyroidism. Graves’ ophthalmopathy (GO) is one of GD extra-thyroidal manifestations associated with the presence of TSAb, and insulin-like growth factor-1 receptor (IGF-1R) autoantibodies, that interact with orbital fibroblasts. Cytokines are elevated in autoimmune (i.e., IL-18, IL-6) and non-autoimmune hyperthyroidism (i.e., TNF-α, IL-8, IL-6), and this could be associated with the chronic effects of thyroid hormone increase. A prevalent Th1-immune response (not related to the hyperthyroidism per se, but to the autoimmune process) is reported in the immune-pathogenesis of GD and GO; Th1-chemokines (CXCL9, CXCL10, CXCL11) and the (C-X-C)R3 receptor are crucial in this process. In patients with active GO, corticosteroids, or intravenous immunoglobulins, decrease inflammation and orbital congestion, and are considered first-line therapies. The more deepened understanding of GO pathophysiology has led to different immune-modulant treatments. Cytokines, TSH-R, and IGF-1R (on the surface of B and T lymphocytes, and fibroblasts), and chemokines implicated in the autoimmune process, are possible targets of novel therapies. Drugs that target cytokines (etanercept, tocilizumab, infliximab, adalimumab) have been tested in GO, with encouraging results. The chimeric monoclonal antibody directed against CD20, RTX, reduces B lymphocytes, cytokines and the released autoantibodies. A multicenter, randomized, placebo-controlled, double-masked trial has investigated the human monoclonal blocking antibody directed against IGF-1R, teprotumumab, reporting its effectiveness in GO. In conclusion, large, controlled and randomized studies are needed to evaluate new possible targeted therapies for GO.

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Protective Effects of Astragaloside IV against LPS-Induced Endometritis in Mice through Inhibiting Activation of the NF-κB, p38 and JNK Signaling Pathways

Molecules ◽

10.3390/molecules24020373 ◽

2019 ◽

Vol 24 (2) ◽

pp. 373 ◽

Cited By ~ 8

Author(s):

Fengge Wang ◽

Shuxiong Chen ◽

Liang Deng ◽

Lu Chen ◽

Yuwen Huang ◽

...

Keyword(s):

Signaling Pathways ◽

Inflammatory Diseases ◽

Signal Pathways ◽

Protective Effects ◽

Astragaloside Iv ◽

Active Components ◽

Jnk Signaling ◽

Tnf Α ◽

Anti Inflammatory ◽

New Evidence

Endometritis, inflammation of the endometrium, is a common reproductive obstacle disease that can lead to infertility in female animals. Astragaloside IV (AS IV), one of the major and active components of the Astragalus membranaceus (Fisch.) Bunge, is known for its anti-inflammatory effects. In the present study, the effects and mechanisms of AS IV on lipopolysaccharide (LPS)-induced endometritis were investigated using a mouse model. Female mice were prepared with AS IV (0.01 mg/g) by gavage for six days before being stimulated with LPS. The results showed that the histopathological changes, levels of inflammatory cytokines (IL-1β and TNF-α), concentration of NO, and myeloperoxidase (MPO) activity in LPS-induced uteri were attenuated significantly by pretreatment with AS IV. Furthermore, LPS-induced activations of NF-κB, p38, and JNK signal pathways were suppressed by pretreatment with AS IV. In conclusion, the data provided new evidence that AS IV effectively attenuates LPS-induced endometritis through inhibition of TLR4-mediated NF-κB, p38, and JNK signaling pathways, implying that AS IV might become a promising potential anti-inflammatory agent for endometritis and other inflammatory diseases.

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RAGE and HMGB1 Expression in Orbital Tissue Microenvironment in Graves’ Ophthalmopathy

Mediators of Inflammation ◽

10.1155/2021/8891324 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Dominika Łacheta ◽

Krzysztof B. Poślednik ◽

Katarzyna Czerwaty ◽

Nils Ludwig ◽

Marta Molińska-Glura ◽

...

Keyword(s):

Inflammatory Diseases ◽

Expression Profiles ◽

High Mobility ◽

Inflammatory Disorder ◽

Hmgb1 Protein ◽

Tissue Microenvironment ◽

Graves Ophthalmopathy ◽

Glycation End Products ◽

Hmgb1 Expression ◽

Orbital Tissue

Graves’ ophthalmopathy (GO) is a chronic autoimmune inflammatory disorder involving orbital tissues. A receptor for advanced glycation end products (RAGE) and its ligand high mobility group box 1 (HMGB1) protein trigger inflammation and cell proliferation and are involved in the pathogenesis of various chronic inflammatory diseases. This study was aimed to evaluate RAGE and HMGB1 expression in GO to determine its potential clinical significance. To the best of our knowledge, this is the first study showing RAGE and HMGB1 expression in orbital tissue using immunohistochemistry. Sections of orbital adipose tissue obtained from patients diagnosed with GO (23 patients; 36 orbits) and normal controls (NC) (15 patients; 15 orbits) were analyzed by immunohistochemistry for RAGE and HMGB1 expression. Expression profiles were then correlated with clinical data of the study group. RAGE and HMGB1 expression were elevated in GO patients in comparison with NC ( p = 0.001 and p = 0.02 , respectively). We observed a correlation between RAGE expression and occurrence of dysthyroid optic neuropathy (DON) ( p = 0.05 ) and levels of TSH Receptor Antibodies (TRAb) ( p = 0.01 ). Overexpression of RAGE and HMGB1 might be associated with GO pathogenesis. In addition, RAGE and HMGB1 proteins may be considered as promising therapeutic targets, but this requires further research.

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Natural Products for Regulating Macrophages M2 Polarization

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190523093535 ◽

2020 ◽

Vol 15 (7) ◽

pp. 559-569 ◽

Cited By ~ 1

Author(s):

Zhen Chang ◽

Youhan Wang ◽

Chang Liu ◽

Wanli Smith ◽

Lingbo Kong

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Therapeutic Strategies ◽

Research Progress ◽

Cellular Mechanisms ◽

Pharmacological Activities ◽

Current Review ◽

M2 Polarization ◽

Macrophages Polarization ◽

Herbal Plants

Macrophages M2 polarization have been taken as an anti-inflammatory progression during inflammation. Natural plant-derived products, with potential therapeutic and preventive activities against inflammatory diseases, have received increasing attention in recent years because of their whole regulative effects and specific pharmacological activities. However, the molecular mechanisms about how different kinds of natural compounds regulate macrophages polarization still unclear. Therefore, in the current review, we summarized the detailed research progress on the active compounds derived from herbal plants with regulating effects on macrophages, especially M2 polarization. These natural occurring compounds including flavonoids, terpenoids, glycosides, lignans, coumarins, alkaloids, polyphenols and quinones. In addition, we extensively discussed the cellular mechanisms underlying the M2 polarization for each compound, which could provide potential therapeutic strategies aiming macrophages M2 polarization.

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Chronic Inflammation in PCOS: The Potential Benefits of Specialized Pro-Resolving Lipid Mediators (SPMs) in the Improvement of the Resolutive Response

International Journal of Molecular Sciences ◽

10.3390/ijms22010384 ◽

2020 ◽

Vol 22 (1) ◽

pp. 384

Author(s):

Pedro-Antonio Regidor ◽

Anna Mueller ◽

Manuela Sailer ◽

Fernando Gonzalez Santos ◽

Jose Miguel Rizo ◽

...

Keyword(s):

Chronic Inflammation ◽

Unsaturated Fatty Acids ◽

Inflammatory Diseases ◽

Reproductive Age ◽

Lipid Mediator ◽

Female Population ◽

Tnf Α ◽

Potential Benefits ◽

Cardinal Symptoms ◽

Resolution Processes

PCOS as the most common endocrine disorder of women in their reproductive age affects between 5–15% of the female population. Apart from its cardinal symptoms, like irregular and anovulatory cycles, hyperandrogenemia and a typical ultrasound feature of the ovary, obesity, and insulin resistance are often associated with the disease. Furthermore, PCOS represents a status of chronic inflammation with permanently elevated levels of inflammatory markers including IL-6 and IL-18, TNF-α, and CRP. Inflammation, as discovered only recently, consists of two processes occurring concomitantly: active initiation, involving “classical” mediators including prostaglandins and leukotrienes, and active resolution processes based on the action of so-called specialized pro-resolving mediators (SPMs). These novel lipid mediator molecules derive from the essential ω3-poly-unsaturated fatty acids (PUFAs) DHA and EPA and are synthesized via specific intermediates. The role and benefits of SPMs in chronic inflammatory diseases like obesity, atherosclerosis, and Diabetes mellitus has become a subject of intense research during the last years and since PCOS features several of these pathologies, this review aims at summarizing potential roles of SPMs in this disease and their putative use as novel therapeutics.

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Comparing the protective effects of resveratrol, curcumin and sulforaphane against LPS/IFN-γ-mediated inflammation in doxorubicin-treated macrophages

Scientific Reports ◽

10.1038/s41598-020-80804-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Haidy A. Saleh ◽

Eman Ramdan ◽

Mohey M. Elmazar ◽

Hassan M. E. Azzazy ◽

Anwar Abdelnaser

Keyword(s):

Nitric Oxide ◽

Inflammatory Response ◽

Raw 264.7 Cells ◽

Inos Mrna ◽

No Production ◽

Raw 264.7 ◽

Mrna Levels ◽

Protective Effects ◽

Tnf Α ◽

Ifn Γ

AbstractDoxorubicin (DOX) chemotherapy is associated with the release of inflammatory cytokines from macrophages. This has been suggested to be, in part, due to DOX-mediated leakage of endotoxins from gut microflora, which activate Toll-like receptor 4 (TLR4) signaling in macrophages, causing severe inflammation. However, the direct function of DOX on macrophages is still unknown. In the present study, we tested the hypothesis that DOX alone is incapable of stimulating inflammatory response in macrophages. Then, we compared the anti-inflammatory effects of curcumin (CUR), resveratrol (RES) and sulforaphane (SFN) against lipopolysaccharide/interferon-gamma (LPS/IFN-γ)-mediated inflammation in the absence or presence of DOX. For this purpose, RAW 264.7 cells were stimulated with LPS/IFN-γ (10 ng/mL/10 U/mL) in the absence or presence of DOX (0.1 µM). Our results showed that DOX alone is incapable of stimulating an inflammatory response in RAW 264.7 macrophages. Furthermore, after 24 h of incubation with LPS/IFN-γ, a significant increase in tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS) mRNA levels was observed. Similarly, nitric oxide (NO) production and TNF-α and IL-6 protein levels were significantly upregulated. Moreover, in LPS/IFN-γ-treated macrophages, the microRNAs (miRNAs) miR-146a, miR-155, and miR-21 were significantly overexpressed. Interestingly, upon testing CUR, RES, and SFN against LPS/IFN-γ-mediated inflammation, only SFN was able to significantly reverse the LPS/IFN-γ-mediated induction of iNOS, TNF-α and IL-6 and attenuate miR-146a and miR-155 levels. In conclusion, SFN, at the transcriptional and posttranscriptional levels, exhibits potent immunomodulatory action against LPS/IFN-γ-stimulated macrophages, which may indicate SFN as a potential treatment for DOX-associated inflammation.

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Serum IL-35 is decreased in overweight patients with rheumatoid arthritis: its correlation with Th1/Th2/Th17-related cytokines

BMC Immunology ◽

10.1186/s12865-021-00431-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yuxuan Li ◽

Yang Jie ◽

Xiaofei Wang ◽

Jing Lu

Keyword(s):

Rheumatoid Arthritis ◽

Medical Records ◽

Clinical Information ◽

Serum Cytokines ◽

Healthy Donors ◽

Potential Biomarker ◽

Tnf Α ◽

Ifn Γ ◽

Quantitative Changes ◽

Anti Inflammatory Cytokine

Abstract Background Obesity is correlated with worse drug responses and high disease activity in patients with rheumatoid arthritis (RA). Interleukin (IL)-35 is a novel anti-inflammatory cytokine that mainly produced by regulatory T (Treg). This study was performed to analyze whether IL-35 was correlated with obesity in RA and investigate the correlation between other Th1/Th2/Th17-related cytokines and obesity in RA. Results The serum IL-35 level was analyzed in RA (n = 81) and healthy donors (n = 53) by ELISA assay, and was compared between three groups (body mass index (BMI) < 18.5,≥18.5 to 25, > 25). Serum cytokines including IL-2, IL-4, IL-10, IL-17, INF-γ, TNF-α levels were measured using Flowcytometry assay. Clinical information was extracted from medical records. Serum IL-35 level in overweight patients were significantly decreased than those in lean patients. Furthermore, Th1/Th2/Th17-related cytokines from overweight patients with RA showed the characteristic immunological features. Serum IL-6, IL-17 and TNF-α levels were positively correlated with BMI. However, serum IL-2, IL-4, IL-10 and IFN-γ concentrations were not correlated with BMI. Conclusions Quantitative changes in serum IL-35 level were characteristic in overweight patients with RA. These findings indicate that IL-35 plays an important role in the development of RA and may prove to be a potential biomarker of active RA.

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Skullcapflavone II Suppresses TNF-α/IFN-γ-Induced TARC, MDC, and CTSS Production in HaCaT Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22126428 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6428

Author(s):

Hanon Lee ◽

Dong Hun Lee ◽

Jang-Hee Oh ◽

Jin Ho Chung

Keyword(s):

P38 Mapk ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Mapk Signaling ◽

Hacat Cells ◽

Protein Levels ◽

Tnf Α ◽

Ifn Γ ◽

Mapk Signaling Pathways ◽

Pro Inflammatory Cytokines

Skullcapflavone II (SFII), a flavonoid derived from Scutellaria baicalensis, has been reported to have anti-inflammatory properties. However, its therapeutic potential for skin inflammatory diseases and its mechanism are unknown. Therefore, this study aimed to investigate the effect of SFII on TNF-α/IFN-γ-induced atopic dermatitis (AD)-associated cytokines, such as thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC). Co-stimulation with TNF-α/IFN-γ in HaCaT cells is a well-established model for induction of pro-inflammatory cytokines. We treated cells with SFII prior to TNF-α/IFN-γ-stimulation and confirmed that it significantly inhibited TARC and MDC expression at the mRNA and protein levels. Additionally, SFII also inhibited the expression of cathepsin S (CTSS), which is associated with itching in patients with AD. Using specific inhibitors, we demonstrated that STAT1, NF-κB, and p38 MAPK mediate TNF-α/IFN-γ-induced TARC and MDC, as well as CTSS expression. Finally, we confirmed that SFII significantly suppressed TNF-α/IFN-γ-induced phosphorylation of STAT1, NF-κB, and p38 MAPK. Taken together, our study indicates that SFII inhibits TNF-α/IFN-γ-induced TARC, MDC, and CTSS expression by regulating STAT1, NF-κB, and p38 MAPK signaling pathways.

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Inflammatory Markers May Inform the Effects of Electroconvulsive Therapy on Cognition in Patients with Depression

Neuropsychobiology ◽

10.1159/000515931 ◽

2021 ◽

pp. 1-9

Author(s):

Jan-Baptist Belge ◽

Linda Van Diermen ◽

Bernard Sabbe ◽

Manuel Morrens ◽

Violette Coppens ◽

...

Keyword(s):

Episodic Memory ◽

Cognitive Functioning ◽

Electroconvulsive Therapy ◽

Inflammatory Markers ◽

Verbal Learning ◽

Potential Biomarker ◽

Tnf Α ◽

Autobiographic Memory ◽

Learning Test ◽

Verbal Episodic Memory

Introduction: The neurobiological mechanisms underlying the acute cognitive effects of electroconvulsive therapy (ECT) remain poorly understood. Prior research has shown that proinflammatory cytokines such as IL-6, TNF-α, IL1-β, and IL-10 may interfere with cognitive functioning. Interestingly, immunomodulation is one of the proposed modes of action of ECT. This study investigates whether changes of peripheral levels of IL-6, TNF-α, IL1-β, and IL-10 are related to changes in cognitive functioning following ECT. Methods: In the week before and 1 week after an acute course of ECT, 62 patients suffering from depression underwent a neuropsychological evaluation to assess their processing speed using the Symbol Digit Substitution Test (SDST), verbal episodic memory using the Hopkins Verbal Learning Test-Revised (HVLT-R), and their retrospective autobiographic memory using the Autobiographical Memory Interview (AMI) with the peripheral inflammatory markers being measured at the same 2 time points. Results: Patients improved drastically following ECT, while their main performance on both the HVLT-R and AMI declined and their SDST scores remained stable. The levels of IL-6 and IL1-β had both decreased, where the decrease in IL-6 was related to the decrease in HVLT-R scores. Higher baseline IL-10 levels were associated with a more limited decrease of the HVLT-R scores. Conclusion: Our findings tentatively suggest that the effects of ECT on verbal episodic memory may be related to the treatment’s immunomodulatory properties, most notably due to decreased IL-6 levels. Moreover, baseline IL-10 appears to be a potential biomarker to predict the effects of ECT on verbal episodic memory. Whilst compelling, the results of this study should be interpreted with caution as, due to its exploratory nature, no correction for multiple comparisons was made. Further, a replication in larger cohorts is warranted.

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Phytowaste as nutraceuticals in boosting public health

Clinical Phytoscience ◽

10.1186/s40816-021-00260-w ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Chinyere S. Dike ◽

Chinna N. Orish ◽

Chukwuemeka R. Nwokocha ◽

Francis D. Sikoki ◽

Bolaji B. Babatunde ◽

...

Keyword(s):

Animal Studies ◽

Fruits And Vegetables ◽

Protective Effects ◽

Bioactive Substances ◽

Environment Friendly ◽

Human Trial ◽

Production Improvement ◽

Tnf Α ◽

Therapeutic Activities ◽

Seed Extracts

AbstractThe utilization of bioactive constituent of peels and seeds provide an effective, environment friendly and inexpensive therapy for different forms of human disease, and the production, improvement and documentation of novel nutraceuticals. This review systematically presents findings and further understanding of the reported benefits and therapeutic applications of peel and seed extracts on innovative cell culture and animal studies, as well as phased clinical human trial research. The extracts of seed and peels were reported to possess high quantities of bioactive substances with antioxidative, antidiabetic, hepatorenal protective, antithyroidal, anti-inflammatory, antibacterial, cardiovascular protective, neuro-protective effects, anticancer and wound healing activities. Therapeutic activities of the bioactive substances of peel and seed extracts include elevation of Superoxide dismutase (SOD), GSH-Px, t-GPx, Catalase and GST activities, with the suppression of MDA levels, hydroperoxide generation and lipid peroxidized products, the extracts also regulate inflammatory mediators and cytokines as they are reported to suppress the secretion of inflammatory cytokines, which include; IL-1β, PGE2, TGF-β and TNF-α and induces apoptosis and cell differentiation. This review revealed the therapeutic importance and best utilization of peels and seed extracts of fruits and vegetables.

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