scholarly journals Bovine κ-Casein Fragment Induces Hypo-Responsive M2-Like Macrophage Phenotype

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1688 ◽  
Author(s):  
Richard Lalor ◽  
Sandra O’Neill
Keyword(s):  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Signal Transduction Pathway ◽  
Sodium Caseinate ◽  
Nuclear Factor Κb ◽  
Proteolytic Processing ◽  
Therapeutic Effects ◽  
Macrophage Phenotype ◽  
Inflammatory Conditions ◽  
Tnf Α

Immunomodulatory nutraceuticals have garnered special attention due to their therapeutic potential for the amelioration of many chronic inflammatory conditions. Macrophages are key players in the induction, propagation and resolution of inflammation, actively contributing to the pathogenesis and resolution of inflammatory disorders. As such, this study aimed to investigate the possible therapeutic effects bovine casein derived nutraceuticals exert on macrophage immunological function. Initial studies demonstrated that sodium caseinate induced a M2-like macrophage phenotype that was attributed to the kappa-casein subunit. Kappa-casein primed macrophages acquired a M2-like phenotype that expressed CD206, CD54, OX40L, CD40 on the cell surface and gene expression of Arg-1, RELM-α and YM1, archetypical M2 markers. Macrophages stimulated with kappa-casein secreted significantly reduced TNF-α and IL-10 in response to TLR stimulation through a mechanism that targeted the nuclear factor-κB signal transduction pathway. Macrophage proteolytic processing of kappa-casein was required to elicit these suppressive effects, indicating that a fragment other than C-terminal fragment, glycomacropeptide, induced these modulatory effects. Kappa-casein treated macrophages also impaired T-cell responses. Given the powerful immuno-modulatory effects exhibited by kappa-casein and our understanding of immunopathology associated with inflammatory diseases, this fragment has the potential as an oral nutraceutical and therefore warrants further investigation.

Therapeutic Potential of Amniotic Fluid Derived Mesenchymal Stem Cells Based on their Differentiation Capacity and Immunomodulatory Properties

2019 ◽  
Vol 14 (4) ◽  
pp. 327-336 ◽  
Author(s):  
Carl R. Harrell ◽  
Marina Gazdic ◽  
Crissy Fellabaum ◽  
Nemanja Jovicic ◽  
Valentin Djonov ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Animal Models ◽  
Amniotic Fluid ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Therapeutic Effects ◽  
Differentiation Potential ◽  
Differentiation Capacity ◽  
Cell Based Therapy

Background: Amniotic Fluid Derived Mesenchymal Stem Cells (AF-MSCs) are adult, fibroblast- like, self-renewable, multipotent stem cells. During the last decade, the therapeutic potential of AF-MSCs, based on their huge differentiation capacity and immunomodulatory characteristics, has been extensively explored in animal models of degenerative and inflammatory diseases. Objective: In order to describe molecular mechanisms responsible for the therapeutic effects of AFMSCs, we summarized current knowledge about phenotype, differentiation potential and immunosuppressive properties of AF-MSCs. Methods: An extensive literature review was carried out in March 2018 across several databases (MEDLINE, EMBASE, Google Scholar), from 1990 to present. Keywords used in the selection were: “amniotic fluid derived mesenchymal stem cells”, “cell-therapy”, “degenerative diseases”, “inflammatory diseases”, “regeneration”, “immunosuppression”. Studies that emphasized molecular and cellular mechanisms responsible for AF-MSC-based therapy were analyzed in this review. Results: AF-MSCs have huge differentiation and immunosuppressive potential. AF-MSCs are capable of generating cells of mesodermal origin (chondrocytes, osteocytes and adipocytes), neural cells, hepatocytes, alveolar epithelial cells, insulin-producing cells, cardiomyocytes and germ cells. AF-MSCs, in juxtacrine or paracrine manner, regulate proliferation, activation and effector function of immune cells. Due to their huge differentiation capacity and immunosuppressive characteristic, transplantation of AFMSCs showed beneficent effects in animal models of degenerative and inflammatory diseases of nervous, respiratory, urogenital, cardiovascular and gastrointestinal system. Conclusion: Considering the fact that amniotic fluid is obtained through routine prenatal diagnosis, with minimal invasive procedure and without ethical concerns, AF-MSCs represents a valuable source for cell-based therapy of organ-specific or systemic degenerative and inflammatory diseases.

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

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.

Increased Expression of Granzyme B and Transforming Growth Factor-β in Intralesional Plasma of Oral Lichenoid Reactions: A Preliminary Study

2020 ◽  
Author(s):  
Kai Sun ◽  
Lei Pan ◽  
Yi-wen Deng ◽  
Jun Chen ◽  
Guan-huan Du ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Granzyme B ◽  
Large Population ◽  
Therapeutic Effects ◽  
Peripheral Plasma ◽  
Cytokine Profiles ◽  
Tnf Α ◽  
Lichenoid Reactions ◽  
Tgf Β1

Abstract Background: Oral lichenoid reactions are intractable inflammatory diseases of oral mucosa. The cytokine profiles of intralesional blood remain unclear. We aim at revealing the intralesional cytokine profiles and providing some actual and stable intralesional cytokine biomarkers to evaluate the severity and therapeutic effects of oral lichenoid reactions.Methods: Paired intralesional and peripheral plasma from 26 patients with oral lichenoid reactions were collected. The concentration of 15 cytokines of granzyme B, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL17A, TNF-α, IFN-α, IFN-β, IFN-γ, TGF-β1, TGF-β2 and TGF-β3 was measured by Luminex assays. REU score was used for evaluating the severity of the disease. Results: Eleven cytokines including IL-10, IFN-α, IL-6, IL-17A, granzyme B, TGF-β1, TGF-β2, TGF-β3, IL-2, TNF-α, IL-12p70 were detected within the reliable working range. IL-10 was detected in less intralesional samples (19/26) than peripheral samples (26/26, p=0.01). The cytokine concentrations from intralesional plasma were significantly elevated in granzyme B (median 108.94 vs. 16.00), TGF-β1 (mean 30448.92 vs. 10199.04), TGF-β2 (mean 1659.73 vs. 1308.49) and TGF-β3 (mean 914.33 vs. 573.13) than that in peripheral plasma (p=0.001, p＜0.001, p＜0.001 and p＜0.001, respectively). The concentration of IL-12p70 in peripheral plasma was positively correlated with REU score (coefficient of correlation=0.463, p=0.02).Conclusions: The concentration of granzyme B and TGF-β are more abundant in intralesional microenvironment than in peripheral plasma of oral lichenoid reactions. IL-12p70 may be a potential molecular biomarker for evaluating the severity of oral lichenoid reactions. Cohort study of large population is required.

Pterostilbene Ameliorates Nephropathy Injury in Streptozotocin-Induced Diabetic Rats

Pharmacology ◽  
2019 ◽  
Vol 104 (1-2) ◽  
pp. 71-80 ◽  
Author(s):  
Ying Zhang ◽  
Shaoyu Ren ◽  
Ying Ji ◽  
Yafeng Liang
Keyword(s):  
High Fat Diet ◽  
Nuclear Factor Κb ◽  
Diabetic Rats ◽  
Inflammatory Factors ◽  
Therapeutic Effects ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Tnf Α ◽  
Necrosis Factor ◽  
Different Doses

Background: Our study investigated the therapeutic role and potential mechanisms of pterostilbene (PS) in diabetic nephropathy (DN) rats. Methods: DN models were established by high-fat diet after streptozotocin injection. A total of 50 Sprague-Dawley rats were randomly divided into control, DN, PS-treated groups (PS-H, PS-M, PS-L). PS was administered to rats by gavage for 8 weeks at 3 different doses (25, 10, and 5 mg/kg/day). The levels of oxidative stress activity (superoxide dismutase [SOD], malondialdehyde [MDA], glutathione peroxidase [GSH-PX]) and inflammatory factors (tumor necrosis factor [TNF]-α, interleukin (IL)-6, IL-1β, monocyte chemoattractant factor [MCP]-1) were detected by ­ELISA. TGF-β, Smad1, and fibronectin (FN) were measured through immunohistochemistry. The relative expressions of phospho-IκBα/IκBα, phospho-IκB kinases (IKK)β/IKKβ, phospho-nuclear factor-κB (NF-κB) p65/NF-κB p65 were detected by western blot. Results: Compared with DN group, the levels of TNF-α, IL-6, IL-1β, and MCP-1 were decreased in the PS-H group (p < 0.05). Meanwhile, the levels of SOD, MDA, GSH-PX improved in kidney and serum in PS-H groups (p< 0.05). PS also significantly decreased the level of phospho-NF-κB p65 and increased the levels of phospho- IKKβ and phospho-Iκ-Bα (p < 0.05). The results showed that PS treatment decreased TGF-β, Smad1, and FN expressions. Conclusion: PS had potential therapeutic effects on DN, which may be related to the regulation of NF-κB pathway.

scholarly journals IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 and other diseases with tissue inflammation

2020 ◽  
Author(s):  
Fan Zhang ◽  
Joseph R. Mears ◽  
Lorien Shakib ◽  
Jessica I. Beynor ◽  
Sara Shanaj ◽  
...  
Keyword(s):  
Immune Cell ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
Macrophage Phenotype ◽  
Tnf Α ◽  
Key Driver ◽  
Ifn Γ ◽  
Immunomodulatory Therapies ◽  
Disease Analysis ◽  
Inflammatory Macrophage

AbstractImmunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. Using an integrative strategy, we built a reference by meta-analyzing > 300,000 immune cells from COVID-19 and 5 inflammatory diseases including rheumatoid arthritis (RA), Crohn’s disease (CD), ulcerative colitis (UC), lupus, and interstitial lung disease. Our cross-disease analysis revealed that an FCN1+ inflammatory macrophage state is common to COVID-19 bronchoalveolar lavage samples, RA synovium, CD ileum, and UC colon. We also observed that a CXCL10+ CCL2+ inflammatory macrophage state is abundant in severe COVID-19, inflamed CD and RA, and expresses inflammatory genes such as GBP1, STAT1, and IL1B. We found that the CXCL10+ CCL2+ macrophages are transcriptionally similar to blood-derived macrophages stimulated with TNF-α and IFN-γ ex vivo. Our findings suggest that IFN-γ, alongside TNF-α, might be a key driver of this abundant inflammatory macrophage phenotype in severe COVID-19 and other inflammatory diseases, which may be targeted by existing immunomodulatory therapies.

scholarly journals AntimiR-30b Inhibits TNF-α Mediated Apoptosis and Attenuated Cartilage Degradation through Enhancing Autophagy

2016 ◽  
Vol 40 (5) ◽  
pp. 883-894 ◽  
Author(s):  
Zhe Chen ◽  
Tao Jin ◽  
Yong Lu
Keyword(s):  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Direct Interaction ◽  
Cartilage Degradation ◽  
Protective Role ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Tnf Α ◽  
Ecm Degradation ◽  
Induced Apoptosis

Objective: Cell death plays an important role in the pathology associated with inflammatory diseases such as osteoarthritis. It has been reported that autophagy can protect cells against tumour necrosis factor-α (TNF-α)-induced apoptosis. This study aimed to determine the potential role of microRNA-30b (miR-30b) in TNF-α-induced apoptosis, autophagy and differentiation in the chondrogenic ADTC5 cell line. Methods: To analyse the effect of TNF-α on the viability of ADTC5 cells, cell counting kit-8 and Hoechst 33342 staining were employed and the expression levels of caspase-3 and -9 were assessed. Autophagy was examined by analysing the levels of LC3B-II and p62 and quantitating GFP-LC3B by fluorescence microscopy. A luciferase reporter assay investigated the putative binding sites of miR-30b. The effects of miR-30b and antimiR-30b on autophagy, apoptosis and osteogenic differentiation of TNF-α-treated cells were determined by autophagosome, apoptosis and alkaline phosphatase assays, respectively. Results: TNF-α exposure decreased cell viability, increased apoptosis and positively regulated autophagy in ADTC5 cells. A direct interaction was detected between miR-30b and the mRNA 3ʹ-UTRs of autophagy genes BECN1 and ATG5. Overexpression of miR-30b downregulated autophagy genes and upregulated pro-apoptotic gene expression in TNF-α-treated cells, while treatment with antimiR-30b had the inverse effect. Overexpression of miR-30b also downregulated ECM degradation and anti-miR-30b reverse TNF-α-induced ECM degradation. Conclusions: Anti-miR-30b enhanced autophagy and attenuated cartilage degradation and played a protective role in TNF-α-induced apoptosis of ATDC5 cells. Anti-miR-30b may therefore elevate cellular survival during inflammation and has therapeutic potential for inflammatory diseases such as osteoarthritis.

scholarly journals HDAC inhibition potentiates anti-tumor activity of macrophages and enhances anti-PD-L1-mediated tumor suppression

Oncogene ◽  
2021 ◽  
Author(s):  
Xiaolei Li ◽  
Xiao Su ◽  
Rui Liu ◽  
Yongsha Pan ◽  
Jiankai Fang ◽  
...  
Keyword(s):  
Low Dose ◽  
Immune Escape ◽  
Therapeutic Potential ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Suppressor Cells ◽  
Immune Checkpoints ◽  
Therapeutic Effects ◽  
Macrophage Phenotype ◽  
Hdac Inhibition

AbstractDespite the widespread use of the blockade of immune checkpoints, for a significant number of cancer patients, these therapies have proven ineffective, presumably due to the immunosuppressive nature of the tumor microenvironment (TME). Critical drivers of immune escape in the TME include tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), which not only mediate immune suppression, but also facilitate metastatic dissemination and impart resistance to immunotherapies. Thus, strategies that convert them into tumor fighters may offer great therapeutic potential. In this study, we evaluated whether pharmacologic modulation of macrophage phenotype by HDAC inhibitors (HDACi) could produce an anti-tumor effect. We demonstrated that low-dose HDACi trichostatin-A (TSA) markedly reshaped the tumor immune microenvironment by modulating the suppressive activity of infiltrating macrophages and inhibiting the recruitment of MDSCs in various tumors. These actions, in turn, augmented anti-tumor immune responses and further enhanced anti-tumor effects of immunotherapies. HDAC inhibition, however, also upregulated PD-L1, thereby limiting the beneficial therapeutic effects. Indeed, combining low-dose TSA with anti-PD-L1 in this model significantly enhanced the durability of tumor reduction and prolonged survival of tumor-bearing mice, compared with the effect of either treatment alone. These data introduce HDAC inhibition as a potential means to harness the anti-tumor potential of macrophages in cancer therapy.

scholarly journals HIF-1α Dependent Upregulation of ZIP8, ZIP14, and TRPA1 Modify Intracellular Zn2+ Accumulation in Inflammatory Synoviocytes

2021 ◽  
Vol 22 (12) ◽  
pp. 6349
Author(s):  
Noriyuki Hatano ◽  
Masaki Matsubara ◽  
Hiroka Suzuki ◽  
Yukiko Muraki ◽  
Katsuhiko Muraki
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Functional Expression ◽  
Nuclear Factor Κb ◽  
Expression Vectors ◽  
Inflammatory Conditions ◽  
Hek Cells ◽  
Tnf Α ◽  
Transient Receptor ◽  
Factor Α

Intracellular free zinc ([Zn2+]i) is mobilized in neuronal and non-neuronal cells under physiological and/or pathophysiological conditions; therefore, [Zn2+]i is a component of cellular signal transduction in biological systems. Although several transporters and ion channels that carry Zn2+ have been identified, proteins that are involved in Zn2+ supply into cells and their expression are poorly understood, particularly under inflammatory conditions. Here, we show that the expression of Zn2+ transporters ZIP8 and ZIP14 is increased via the activation of hypoxia-induced factor 1α (HIF-1α) in inflammation, leading to [Zn2+]i accumulation, which intrinsically activates transient receptor potential ankyrin 1 (TRPA1) channel and elevates basal [Zn2+]i. In human fibroblast-like synoviocytes (FLSs), treatment with inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and interleukin-1α (IL-1α), evoked TRPA1-dependent intrinsic Ca2+ oscillations. Assays with fluorescent Zn2+ indicators revealed that the basal [Zn2+]i concentration was significantly higher in TRPA1-expressing HEK cells and inflammatory FLSs. Moreover, TRPA1 activation induced an elevation of [Zn2+]i level in the presence of 1 μM Zn2+ in inflammatory FLSs. Among the 17 out of 24 known Zn2+ transporters, FLSs that were treated with TNF-α and IL-1α exhibited a higher expression of ZIP8 and ZIP14. Their expression levels were augmented by transfection with an active component of nuclear factor-κB P65 and HIF-1α expression vectors, and they could be abolished by pretreatment with the HIF-1α inhibitor echinomycin (Echi). The functional expression of ZIP8 and ZIP14 in HEK cells significantly increased the basal [Zn2+]i level. Taken together, Zn2+ carrier proteins, TRPA1, ZIP8, and ZIP14, induced under HIF-1α mediated inflammation can synergistically change [Zn2+]i in inflammatory FLSs.

scholarly journals Naringenin downregulates inflammation-mediated nitric oxide overproduction and potentiates endogenous antioxidant status during hyperglycemia

2020 ◽  
Author(s):  
Kanwal Rehman ◽  
Ikram Ilahee Khan ◽  
Muhammad Sajid Hamid Akash ◽  
Komal Jabeen ◽  
Kamran Haider ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lipid Profile ◽  
Insulin Level ◽  
Diabetic Rat ◽  
Therapeutic Effects ◽  
Analgesic Effects ◽  
Inflammatory Conditions ◽  
Tnf Α ◽  
Anti Oxidant ◽  
Endogenous Antioxidant

AbstractNitric oxide (NO) is a key regulating factor for physiological functions, when elevated during inflammatory conditions can lower endogenous antioxidant levels. Increased NO interacts with oxygen or other ROS to generate peroxynitrite, a potent oxidant which induces oxidative stress. Analgesic effects of naringenin (NRN), a flavanone has been demonstrated by inducing anti-inflammatory effects in O2−•-mediated inflammation. NRN stimulates antioxidant enzymes and also improves glucose uptake. Hence this study was designed to look for therapeutic effects of NRN and in comparison, to metformin (MET) on inflammation-mediated increased NO and decreased antioxidant superoxide dismutase (SOD) in diabetic rat model with compromised glycemic and lipid profile. After single intraperitoneal injection of alloxan (120 mg/kg), the rats were equally divided as Group 1 and 2 which received normal saline and no-treatment respectively while group 3 and 4 received MET 50 mg/kg/day and NRN 50 mg/kg/day respectively. Blood samples were collected at 0, 15th and 30th day of treatment period. Results showed that alloxan significantly increased serum level of glucose (P<0.001), NO (P<0.001) and inflammatory biomarkers (TNF-α, IL-6), however, it expressively decreased serum SOD and insulin level. While, NRN significantly downregulated glucose (P<0.05), lipid profile, TNF-α, IL-6 and normalized level of NO (P<0.01). It also improved SOD level as compared to that of MET-treatment. Histopathology of pancreas also showed significant improvement in morphology after NRN treatment. This work delivers that NRN exerts anti-oxidant effect in part by downregulating the inflammation-mediated NO overproduction and improving level of SOD resulting in potentiation of endogenous antioxidant defense.

scholarly journals Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2906
Author(s):  
Hiroyuki Ogasawara ◽  
Masato Noguchi
Keyword(s):  
Mast Cells ◽  
Immunoglobulin E ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Neuromuscular Blocking ◽  
Drug Induced ◽  
Functional Studies ◽  
Inflammatory Conditions ◽  
Functional Analyses

Mast cells (MCs) act as primary effectors in inflammatory and allergic reactions by releasing intracellularly-stored inflammatory mediators in diseases. The two major pathways for MC activation are known to be immunoglobulin E (IgE)-dependent and -independent. Although IgE-dependent signaling is the main pathway to MC activation, IgE-independent pathways have also been found to serve pivotal roles in the pathophysiology of various inflammatory conditions. Recent studies have shown that human and mouse MCs express several regulatory receptors such as toll-like receptors (TLRs), CD48, C300a, and GPCRs, including mas-related GPCR-X2 (MRGPRX2). MRGPRX2 has been reported as a novel GPCR that is expressed in MCs activated by basic secretagogues, neurokinin peptides, host defense antimicrobial peptides, and small molecule compounds (e.g., neuromuscular blocking agents) and leads to MC degranulation and eicosanoids release under in vitro experimental condition. Functional analyses of MRGPRX2 and Mrgprb2 (mouse ortholog) indicate that MRGPRX2 is involved in MC hypersensitivity reactions causing neuroinflammation such as postoperative pain, type 2 inflammation, non-histaminergic itch, and drug-induced anaphylactic-like reactions. In this review, we discuss the roles in innate immunity through functional studies on MRGPRX2-mediated IgE-independent MC activation and also the therapeutic potential of MRGPRX2 inhibitors on allergic and inflammatory diseases.

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