scholarly journals GSK5182, 4-Hydroxytamoxifen Analog, a New Potential Therapeutic Drug for Osteoarthritis

2020 ◽  
Vol 13 (12) ◽  
pp. 429
Author(s):  
Yunhui Min ◽  
Dahye Kim ◽  
Godagama Gamaarachchige Dinesh Suminda ◽  
Xiangyu Zhao ◽  
Mangeun Kim ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Small Molecule ◽  
Articular Chondrocytes ◽  
Therapeutic Potential ◽  
Inverse Agonist ◽  
Therapeutic Drug ◽  
Articular Chondrocyte ◽  
Orphan Nuclear Receptors ◽  
Genetic Ablation ◽  
Pro Inflammatory Cytokines

Estrogen-related receptors (ERRs) are the first identified orphan nuclear receptors. The ERR family consists of ERRα, ERRβ, and ERRγ, regulating diverse isoform-specific functions. We have reported the importance of ERRγ in osteoarthritis (OA) pathogenesis. However, therapeutic approaches with ERRγ against OA associated with inflammatory mechanisms remain limited. Herein, we examined the therapeutic potential of a small-molecule ERRγ inverse agonist, GSK5182 (4-hydroxytamoxifen analog), in OA, to assess the relationship between ERRγ expression and pro-inflammatory cytokines in mouse articular chondrocyte cultures. ERRγ expression increased following chondrocyte exposure to various pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Pro-inflammatory cytokines dose-dependently increased ERRγ protein levels. In mouse articular chondrocytes, adenovirus-mediated ERRγ overexpression upregulated matrix metalloproteinase (MMP)-3 and MMP-13, which participate in cartilage destruction during OA. Adenovirus-mediated ERRγ overexpression in mouse knee joints or ERRγ transgenic mice resulted in OA. In mouse joint tissues, genetic ablation of Esrrg obscured experimental OA. These results indicate that ERRγ is involved in OA pathogenesis. In mouse articular chondrocytes, GSK5182 inhibited pro-inflammatory cytokine-induced catabolic factors. Consistent with the in vitro results, GSK5182 significantly reduced cartilage degeneration in ERRγ-overexpressing mice administered intra-articular Ad-Esrrg. Overall, the ERRγ inverse agonist GSK5182 represents a promising therapeutic small molecule for OA.

Abstract 319: Small Molecule Gβγ Inhibition Attenuates Cardiac Fibroblast Inflammatory and Pro-Fibrotic Signaling

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Joshua G Travers ◽  
Fadia A Kamal ◽  
Michael S Burhans ◽  
Burns C Blaxall
Keyword(s):  
Myocardial Fibrosis ◽  
Inflammatory Cytokines ◽  
Small Molecule ◽  
Therapeutic Potential ◽  
Interstitial Fibrosis ◽  
Pressure Overload ◽  
Cardiac Fibroblast ◽  
Ventricular Compliance ◽  
Pro Inflammatory Cytokines

Heart failure (HF) is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance. Prolonged sympathetic overstimulation promotes excess signaling through G-protein Gβγ subunits and ultimately results in pathologic GRK2-mediated β-adrenergic receptor (β-AR) downregulation. We have recently demonstrated the therapeutic potential of the small molecule Gβγ-GRK2 inhibitor Gallein in limiting HF progression. Pathologic activation of the cardiac fibroblast (CF) induces the transition to a myofibroblast phenotype, which plays a fundamental role in myocardial fibrosis and remodeling. We hypothesized that Gβγ-GRK2 inhibition plays an important functional role in the CF to attenuate pathologic CF activation, inflammation and interstitial fibrosis. To explore the effect of Gβγ-GRK2 inhibition on inflammation and pro-fibrotic signaling, mice were subjected to 7 days of transverse aortic constriction, a pressure-overload model of HF. In addition to the attenuation in overall cardiac hypertrophy, animals treated with Gallein displayed reduced expression of pro-inflammatory cytokines, including macrophage inflammatory protein 1 alpha (MIP-1α) and MIP-1β, along with Interleukin-6, as assessed by qPCR. Gallein-treated animals also exhibited diminished pro-fibrotic signaling, as evidenced by a reduction in the expression of TGFβ, a major driver of myocardial fibrosis, and decreased expression of collagen. To recapitulate these findings in vitro, primary adult mouse ventricular fibroblasts were pathologically stimulated using Isoproterenol (ISO, β-AR agonist) or Angiotensin II and treated +/- Gallein for 24 hours. CFs treated with Gallein displayed an analogous reduction in the expression of these pro-inflammatory cytokines and collagen. In summary, these data suggest a potential therapeutic role for small molecule Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, inflammation and interstitial fibrosis. We believe this fibroblast-targeted approach will lead to the refinement of existing targets and compounds, and possibly the generation of novel therapeutics for the treatment of HF.

scholarly journals Effect of Inflammatory Signaling on Human Articular Chondrocyte Hypertrophy: Potential Involvement of Tissue Repair Macrophages

Cartilage ◽  
2021 ◽  
pp. 194760352110219
Author(s):  
Mauricio N. Ferrao Blanco ◽  
Yvonne M. Bastiaansen-Jenniskens ◽  
Mark G. Chambers ◽  
Andrew A. Pitsillides ◽  
Roberto Narcisi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Cytokines ◽  
Tissue Repair ◽  
Articular Chondrocytes ◽  
Human Articular Chondrocytes ◽  
Human Chondrocytes ◽  
Articular Chondrocyte ◽  
Inflammatory Signaling ◽  
Chondrocyte Hypertrophy ◽  
Pro Inflammatory Cytokines

Objective In osteoarthritis, chondrocytes tend to acquire a hypertrophic phenotype, which contributes to the modification of the extracellular matrix, resulting in permanent cartilage changes. In mouse chondrocytes, pro-inflammatory macrophages and pro-inflammatory cytokines have been shown to stimulate hypertrophy via the activation of the nuclear factor kappa B (NF-κB) pathway. Whether or not this also occurs in human chondrocytes remains unclear. We therefore aimed to investigate whether hypertrophy-like responses in human cartilage are driven mainly by intrinsic inflammatory signaling or shaped by specific macrophage populations. Design Human articular chondrocytes were cultured with pro-inflammatory cytokines or medium conditioned by defined macrophage subsets. Furthermore, the effect of inhibition of NF-κB-dependent gene expression was evaluated using the NF-κB inhibitor SC-514. Hypertrophy was assessed by measuring the transcription level of alkaline phosphatase ( ALPL), type X collagen ( COL10A1), Indian hedgehog ( IHH), and runt-related transcription factor 2 ( RUNX2). Results The expression of hypertrophic genes was not promoted in human chondrocytes by pro-inflammatory cytokines neither pro-inflammatory M(IFNγ + TNFα) macrophages. Inhibition of the NF-κB-dependent gene expression did not affect human articular chondrocyte hypertrophy. However, tissue repair M(IL4) macrophages induced hypertrophy by promoting the expression of COL10A1, RUNX2, and IHH. Conclusion Intrinsic inflammatory signaling activation is not involved in the hypertrophic shift observed in human articular chondrocytes cultured in vitro. However, tissue repair macrophages may contribute to the onset of this detrimental phenotype in human osteoarthritic cartilage, given the effect observed in our experimental models.

scholarly journals Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm

Vaccines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 436
Author(s):  
Ali A. Rabaan ◽  
Shamsah H. Al-Ahmed ◽  
Javed Muhammad ◽  
Amjad Khan ◽  
Anupam A Sule ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Markers ◽  
Therapeutic Drug ◽  
Molecular Pathways ◽  
Cytokine Storm ◽  
Immunomodulatory Drugs ◽  
Alveolar Cells ◽  
Systemic Complications ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a severe pandemic of the current century. The vicious tentacles of the disease have been disseminated worldwide with unknown complications and repercussions. Advanced COVID-19 syndrome is characterized by the uncontrolled and elevated release of pro-inflammatory cytokines and suppressed immunity, leading to the cytokine storm. The uncontrolled and dysregulated secretion of inflammatory and pro-inflammatory cytokines is positively associated with the severity of the viral infection and mortality rate. The secretion of various pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6 leads to a hyperinflammatory response by recruiting macrophages, T and B cells in the lung alveolar cells. Moreover, it has been hypothesized that immune cells such as macrophages recruit inflammatory monocytes in the alveolar cells and allow the production of large amounts of cytokines in the alveoli, leading to a hyperinflammatory response in severely ill patients with COVID-19. This cascade of events may lead to multiple organ failure, acute respiratory distress, or pneumonia. Although the disease has a higher survival rate than other chronic diseases, the incidence of complications in the geriatric population are considerably high, with more systemic complications. This review sheds light on the pivotal roles played by various inflammatory markers in COVID-19-related complications. Different molecular pathways, such as the activation of JAK and JAK/STAT signaling are crucial in the progression of cytokine storm; hence, various mechanisms, immunological pathways, and functions of cytokines and other inflammatory markers have been discussed. A thorough understanding of cytokines’ molecular pathways and their activation procedures will add more insight into understanding immunopathology and designing appropriate drugs, therapies, and control measures to counter COVID-19. Recently, anti-inflammatory drugs and several antiviral drugs have been reported as effective therapeutic drug candidates to control hypercytokinemia or cytokine storm. Hence, the present review also discussed prospective anti-inflammatory and relevant immunomodulatory drugs currently in various trial phases and their possible implications.

scholarly journals BMP-7 attenuates adverse cardiac remodeling mediated through M2 macrophages in prediabetic cardiomyopathy

2014 ◽  
Vol 307 (5) ◽  
pp. H762-H772 ◽  
Author(s):  
Princess Urbina ◽  
Dinender K. Singla
Keyword(s):  
Cardiac Function ◽  
Inflammatory Cytokines ◽  
Cardiac Remodeling ◽  
Therapeutic Potential ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Citrate Buffer ◽  
Morphogenetic Protein ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

The main objective of this study was to determine whether or not monocyte infiltration occurs in the prediabetic (PD) heart and its role in PD cardiomyopathy. We hypothesized that the PD heart is significantly populated with monocytes and that bone morphogenetic protein (BMP)-7, a novel mediator of monocyte polarization, activates infiltrated monocytes into anti-inflammatory M2 macrophages, thereby inhibiting apoptosis and fibrosis and improving cardiac function. C57Bl6 mice were assigned to control, PD, or PD + BMP-7 groups. PD and PD + BMP-7 groups were administered streptozotocin (50 mg/kg), whereas control animals received sodium citrate buffer. Afterward, the PD + BMP-7 group was administered BMP-7 (200 μg/kg) for 3 days. Our data showed significantly increased infiltrated monocytes and associated pro-inflammatory cytokines, adverse cardiac remodeling, and heart dysfunction in the PD group ( P < 0.05). Interestingly, M2 macrophage differentiation and associated anti-inflammatory cytokines were enhanced and there were reduced adverse cardiac remodeling and improved cardiac function in the PD + BMP-7 group ( P < 0.05). In conclusion, our data suggest that PD cardiomyopathy is associated with increased monocyte infiltration and released proinflammatory cytokines, which contributes to adverse cardiac remodeling and cardiac dysfunction. Moreover, we report that BMP-7 possesses novel therapeutic potential in its ability to differentiate monocytes into M2 macrophages and confer cardiac protection in the PD heart.

scholarly journals Interferon-gamma and TNF-alpha synergistically enhance the immunomodulatory capacity of Endometrial-Derived Mesenchymal Stromal Cell secretomes by differential microRNA and extracellular vesicle release

2021 ◽  
Author(s):  
Maria de los Angeles de Pedro ◽  
Federica Marinaro ◽  
Esther Lopez ◽  
Maria Pulido ◽  
Francisco Miguel Sanchez Margallo ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Target Genes ◽  
Therapeutic Potential ◽  
Lymphocyte Activation ◽  
Extracellular Vesicle ◽  
Potent Effect ◽  
Inflammatory Reactions ◽  
Immunomodulatory Capacity ◽  
Pro Inflammatory Cytokines

Endometrial Mesenchymal Stromal Cells (endMSCs) can be easily isolated from menstrual blood by plastic adherence. These cells have a potent pro-angiogenic and immunomodulatory capacity, and their therapeutic effect is mediated by paracrine mechanisms where secretome have a key role. In this paper, we aimed to evaluate different priming conditions in endMSCs using pro-inflammatory cytokines and Toll-Like Receptor ligands. Our in vitro results revealed a synergistic and additive effect of IFNγ and TNFα on endMSCs. The combination of these pro-inflammatory cytokines significantly increased the release of Indoleamine 2,3-dioxygenase (IDO1) in endMSCs. Additionally, this study was focused on the phenotype of IFNγ/TNFα-primed endMSCs (endMSCs*). Here we found that immune system-related molecules such as CD49d, CD49e, CD54, CD56, CD58, CD63, CD126, CD152, or CD274 were significantly altered in endMSCs* when compared to control cells. Afterward, our study was completed with the characterization of released miRNAs by Next Generation Sequencing (NGS). Briefly, our system biology approaches demonstrated that endMSCs* showed an increased release of 25 miRNAs whose target genes were involved in immune response and inflammation. Finally, the cellular and molecular characterization was completed with in vitro functional assays. In summary, the relevance of our results lies in the therapeutic potential of endMSCs*. The differences in cell surface molecules involved in migration, adhesion and immunogenicity, allowed us to hypothesize that endMSCs* may have an optimal homing and migration capacity towards inflammatory lesions. Secondly, the analysis of miRNAs, target genes and the subsequent lymphocyte activation assays demonstrated that IFNγ/TNFα-primed secretome may exert a potent effect on the regulation of adverse inflammatory reactions.

A probiotic combination attenuates experimental colitis through inhibition of innate cytokine production

2017 ◽  
Vol 8 (2) ◽  
pp. 231-241 ◽  
Author(s):  
M.S. Kim ◽  
J.S. Byun ◽  
Y.S. Yoon ◽  
D.Y. Yum ◽  
M.J. Chung ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Lactobacillus Rhamnosus ◽  
Experimental Colitis ◽  
Intestinal Bleeding ◽  
Myeloperoxidase Activity ◽  
Tissue Destruction ◽  
Raw264.7 Macrophages ◽  
Pro Inflammatory Cytokines

Inflammatory bowel disease (IBD) is a severe immune cell-mediated syndrome characterised by extensive inflammatory and effector mucosal responses leading to tissue destruction in the colon and small intestine. The leading hypothesis is that dysbiosis of the gut flora causes an excessive immune response and inflammation in the gastrointestinal track. Lactic acid bacteria (LAB) can correct dysbiosis of the normal microbiota. In the current study, the therapeutic potential of seven LAB strains in combination to treat IBD was evaluated using experimental colitis model. This LAB cocktail, designated GI7, includes four strains of Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus rhamnosus, Lactococcus lactis, two strains of Bifidobacterium bifidum, Bifidobacterium breve, and one strain of Streptococcus thermophilus. We confirmed that GI7 suppressed pro-inflammatory cytokines in Raw264.7 macrophages. When dextran sulphate sodium-induced colitic mice were treated with GI7, their symptoms of colitis, as assessed by body weight, colon length, myeloperoxidase activity, intestinal bleeding, and histological damage, were reduced compared to untreated mice. In addition, GI7 treatment significantly inhibited the production of innate pro-inflammatory cytokines during colitic progression. Therefore, we suggest that GI7, a combination of seven LAB, has a potential role in the treatment of IBD.

scholarly journals Super Critical Fluid Extracted Fatty Acids from Withania somnifera Seeds Repair Psoriasis-Like Skin Lesions and Attenuate Pro-Inflammatory Cytokines (TNF-α and IL-6) Release

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 185 ◽  
Author(s):  
Acharya Balkrishna ◽  
Pradeep Nain ◽  
Anshul Chauhan ◽  
Niti Sharma ◽  
Abhishek Gupta ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Inflammatory Cytokines ◽  
Withania Somnifera ◽  
Therapeutic Potential ◽  
Skin Lesions ◽  
Luciferase Reporter ◽  
Plant Parts ◽  
Tnf Α ◽  
Psoriatic Lesions ◽  
Pro Inflammatory Cytokines

(1) Background: Withania somnifera Dunal (Ashwagandha) is a widely used medicinal herb in traditional medicinal systems with extensive research on various plant parts. Surprisingly, seeds of W. somnifera have never been investigated for their therapeutic potential. (2) Methods: W. somnifera seeds were extracted for fatty acids (WSSO) using super critical fluid extraction, and was analyzed by gas chromatography. Its therapeutic potential in psoriasis-like skin etiologies was investigated using a 12-O tetradecanoyl phorbol 13-acetate (TPA)-induced psoriatic mouse model. Psoriatic inflammation along with psoriatic lesions and histopathological scores were recorded. WSSO was also tested on murine macrophage (RAW264.7), human epidermoid (A431), and monocytic (THP-1) cells, stimulated with TPA or lipo poly-saccharide (LPS) to induce pro-inflammatory cytokine (IL-6 and TNF-α) release. NFκB promoter activity was also measured by luciferase reporter assay. (3) Results: Topical application of WSSO with concurrent oral doses significantly reduced inflammation-induced edema, and repaired psoriatic lesions and associated histopathological scores. Inhibition of pro-inflammatory cytokines release was observed in WSSO-treated A431 and THP-1 cells, along with reduced NFκB expression. WSSO also inhibited reactive nitrogen species (RNS) in LPS-stimulated RAW264.7 cells. (4) Conclusion: Here we show that the fatty acids from W. somnifera seeds have strong anti-inflammatory properties, along with remarkable therapeutic potential on psoriasis-like skin etiologies.

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