Showing papers in "Immunopharmacology and Immunotoxicology in 2019"
TL;DR: The multiple roles of exosomes in PD could represent a specific drug delivery tool for a difficult target such as the brain, which poses an obstacle to most drugs and they could also represent new biomarkers to track the progression of PD.
Abstract: The extracellular vesicles (EVs) represent a relatively new field of research in neurodegenerative disease and they are thought to be one of the ways that neurodegenerative pathologies, such as Parkinson's Disease (PD), spread in the brain. EVs are membrane vesicles released from cells into the extracellular space and they are produced by all cells of the nervous tissue. The classification of the vesicle subtypes comprises exosomes, microvesicles/microparticles, apoptotic bodies. EVs change in number and content in response to environmental conditions and may function as shuttles for the delivery of cargo between cells. Recent data suggest that exosomes secreted by both activated microglia and neurons play an important role in α-synuclein (α-syn) spreading and increase of neuroinflammation, thus exacerbating neuronal dysfunction and disease progression. α-syn is a presynaptic protein secreted by neurons in small amounts, and it is the main component of Lewy bodies, one of the histopathological features of PD. Several factors have shown to induce and/or modulate α-syn structure and oligomerization in vitro. Under pathological conditions, progressive accumulation of α-syn and the formation of oligomers have been proposed to play a critical role in the pathogenesis of PD. This review gives an overview about the multiple roles of exosomes in PD, despite their role in the progression of neurodegeneration, exosomes could represent a specific drug delivery tool for a difficult target such as the brain, which poses an obstacle to most drugs and they could also represent new biomarkers to track the progression of PD.
40 citations
TL;DR: SIN can decrease the expression of CD14/TLR4 and intracellular free calcium level, activate JAK2/STAT3 pathway to inhibit inflammatory response through α7nAChR in macrophages.
Abstract: Objective: To investigate the cellular mechanism that sinomenine (SIN) inhibits inflammation in macrophages induced by LPS through α7 nicotinic acetylcholine receptor (α7nAChR). Materials and methods: RAW264.7 cells were stimulated with LPS and treated by SIN or nicotine (Nic). A selective antagonist of α7nAChR, α-bungarotoxin (BTX) was used to block α7nAChR. AG490 was used to inhibit JAK2 activation. ELISA was performed to detect the levels of TNF-α and MCP-1. Western blotting was used to analyze the expression of MIF, MMP-9, CD14, TLR4, STAT3 and p-STAT3. Intracellular-free calcium level was measured by Fluorescent probe fluo-3/AM Results: SIN inhibited the production of TNF-α, MCP-1, MIF, and MMP-9, decreased the expression of CD14 and TLR4, and inhibited the release of intracellular-free calcium from intracellular stores in RAW 264.7 cells stimulated by LPS. JAK-specific inhibitor AG490 attenuated the inhibitory effect of SIN on TNF-α. SIN increased the phosphorylation of STAT3. And the above effects of SIN were attenuated by antagonist of α7nAChR. Conclusions: SIN can decrease the expression of CD14/TLR4 and intracellular free calcium level, activate JAK2/STAT3 pathway to inhibit inflammatory response through α7nAChR in macrophages.
31 citations
TL;DR: Investigation of the effect of carvacrol on the suppression of liver fibrosis progression via regulation of yes-associated protein (YAP) and transcriptional coactivators with a PDZ-binding motif (TAZ) and transforming growth factor beta (TGF-β) pathway revealed that it suppresses the progression of Liver fibrosis via targeting of TAZ, YAP, and TGF- β signaling pathway.
Abstract: Objective: Little is known about the exact underlying molecular mechanisms of the hepatoprotective effect of carvacrol against liver fibrosis. In the current study, we aimed to investigate the effe...
30 citations
TL;DR: It is proposed that the anti-inflammatory activity of dapsone on acetic acid-induced colitis in rats may involve the inhibition of NF-kB pathway.
Abstract: Aim: The purpose of this study is to examine the protective effects of Dapsone on inflammation of intestinal tissue through inhibition of NF-kB pathway in acetic acid-induced colitis in rats.Method...
29 citations
TL;DR: RSV can suppress LPS-induced inflammatory injury via modulating the miR-146a-5p/TRAF6/NF-κB axis in BV2 mouse microglial cells.
Abstract: Objective: To investigate the role of miR-146a-5p in the effects of resveratrol (RSV) on inflammatory response in BV2 mouse microglial cells. Materials and methods: BV2 cells were pretreated by RSV and stimulated with lipopolysaccharide (LPS). Cell Viability was checked using a MTT assay. Real-Time PCR was performed to detect the levels of pro-inflammatory cytokines (tumor necrosisfactor-α－TNF-α, interleukin-1β－IL-1β and interleukin-6 － IL-6) and miR-146a-5p expression. Western blot was used to analyze the protein expression of TNF receptor associated factor 6 (TRAF6) and phospho-nuclear factor kappa B (pNF-κB). Gain-of-function and loss-of-function analysis of miR-146a-5p was performed using transfection of miR-146a-5p mimic and miR-146a-5p inhibitor, respectively. Results: Pretreatment with RSV significantly and dose dependently inhibited LPS-induced production of TNF-α, IL-1β and IL-6 in BV2 cells. MiR-146a-5p was significantly upregulated after LPS treatment, and further increased in RSV and LPS-co-treated cells. MiR-146a-5p overexpression via miR-146a-5p mimic transfection downregulated the mRNA level of TNF-α, IL-1β and IL-6, as well as abrogated the protein expression of TRAF6 and pNF-κB in BV2 cells exposed to LPS. More importantly, the reducion of TNF-α, IL-1β and IL-6 level by RSV were reversed by miR-146a-5p silence via miR-146a-5p inhibitor transfection. Furthermore, silencing miR-146a-5p attenuated the inhibitory effect of RSV on the TRAF6/NF-κB pathway which was activated after induction with LPS. Conclusions: RSV can suppress LPS-induced inflammatory injury via modulating the miR-146a-5p/TRAF6/NF-κB axis in BV2 mouse microglial cells.
28 citations
TL;DR: Treg and Th17 cells play both positive and negative roles in regulating antitumor immune responses, underlining the importance of elucidating the clinical significance of Treg cells further.
Abstract: T helper 17 (Th17) cells were first described as a novel T helper cell lineage independent from Th1 and Th2 subsets. Th17 cells play vital roles in inflammation and tumor immunity. It causes the di...
25 citations
TL;DR: It is demonstrated that osthole attenuated inflammatory response by inhibiting the NF-κB pathway in TBI.
Abstract: Traumatic brain injury (TBI) is a common neurotrosis disorder of the central nervous system (CNS), which has dramatic consequences on the integrity of damaged tissue. In this study, we investigated the neuroprotective effect and anti-inflammatory actions of osthole, a natural coumarin derivative, in both in vivo and in vitro TBI models. We first prepared a mouse model of cortical stab wound brain injury, investigated the capacity for osthole to prevent secondary brain injury and further examined the underlying mechanism. We revealed that osthole significantly improved the neurological function, increased the number of neurons beside injured site. Additionally, osthole treatment reduced the expression of microglia and glial scar, lowered the level of the proinflammatory cytokines interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α), and blocked the activation of nuclear factor kappa B (NF-κB). Furthermore, the protective effect of osthole was also examined in SH-SY5Y cells subjected to scratch injury. Treatment of osthole prominently suppressed cell apoptosis and inflammatory factors release by blocking injury-induced IκB-α phosphorylation and NF-κB translocation, and upregulated the IκB-α which functions in the NF-κB signaling pathway of SH-SY5Y cells. However, NF-κB signaling pathway was inhibited by pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, the anti-inflammatory effect of osthole was abolished. In conclusion, our findings demonstrated that osthole attenuated inflammatory response by inhibiting the NF-κB pathway in TBI.
24 citations
TL;DR: It is found that isorhamnetin may reduce MIA-induced knee swelling by significantly reduction of articular cartilage damage in OA rats and may serve as a potential agent for the management of OA.
Abstract: Context: Osteoarthritis (OA) is a degenerative joint disease with damage to the articular cartilage. Active production of inflammatory cytokine/chemokine and matrix metalloproteinases may be found during the progression of OA. Isorhamnetin had the effects of anti-inflammatory, antioxidant, anti-ischemia, anti-atherosclerotic hepatoprotective and anticancer activities. Objective: Our study was focused on the effects of isorhamnetin treatment in OA. Materials and methods: We used monosodium iodoacetate (MIA)-induced OA rats to evaluate the effects of isorhamnetin related anti-inflammatory process. The rats in all groups were sacrificed on four weeks post-MIA injection. The measurements of knee joint swelling, histological analysis, serum inflammatory biomarkers and western blot were evaluated. Results: We found that isorhamnetin may reduce MIA-induced knee swelling by significantly reduction of articular cartilage damage.in rats. Suppression of pro-inflammatory cytokines production was found after isohamnetin treatment. Isorhamnetin inhibited the production of NO and PGE2, and the expression of iNOS and COX-2. The production of COMP, CTX-II and osteopontin (OPN) were also inhibited in MIA-induced OA rats. Discussion and conclusions: Isorhamnetin may modulate the inflammatory progression of OA in MIA-induced OA rats. The prevention of cartilage damage was found in OA after adequate isorhamnetin treatment. Isorhamnetin may serve as a potential agent for the management of OA.
20 citations
TL;DR: The present review discusses the different aspects of IL-23 including its structural features, signal transduction pathway, preclinical, and clinical role in RA as well as the very limited clinical studies regarding the use ofIL-23 modulators in RA patients.
Abstract: Rheumatoid arthritis (RA) is an autoimmune, chronic inflammatory disease and is characterized by destruction of the articular cartilage. A number of pro-inflammatory cytokines work sequentially and in concert with one another to induce the development of RA. IL-23, a member of IL-12 family, is composed of p19 and p40 subunits and it interacts with IL-23 receptor complex to trigger plethora of biochemical actions. A number of preclinical studies have shown the role of IL-23 in the development of RA in rodents. IL-23 receptor signaling is primarily linked to the activation of JAK-STAT, tyrosine kinase 2, NF-kB, and retinoic acid receptor-related orphan receptors. IL-23 produces its osteoclastogenic effects, mainly through IL-17 and Th17 cells suggesting the importance of IL-23/IL-17/Th17 in the joint inflammation and destruction in RA. Monoclonal antibodies targeted against IL-23, including tildrakizumab and guselkumab have been developed and evaluated in clinical trials. However, there are very limited clinical studies regarding the use of IL-23 modulators in RA patients. The present review discusses the different aspects of IL-23 including its structural features, signal transduction pathway, preclinical, and clinical role in RA.
19 citations
TL;DR: The overall findings in this review conclude the importance of macrophages in inducing toxic/inflammatory effects during RT of lung cancer, which is clinically vital to treat the radiation-induced fibrosis.
Abstract: Lung cancer continues to be the leading cause of cancer deaths and more than one million lung cancer patients will die every year worldwide. Radiotherapy (RT) plays an important role in lung cancer treatment, but the side effects of RT are pneumonitis and pulmonary fibrosis. RT-induced lung injury causes damage to alveolar-epithelial cells and vascular endothelial cells. Macrophages play an important role in the development of pulmonary fibrosis despite its role in immune response. These injury activated macrophages develop into classically activated M1 macrophage or alternative activated M2 macrophage. It secretes cytokines, interleukins, interferons, and nitric oxide. Several pro-inflammatory lipids and pro-apoptotic proteins cause lipotoxicity such as LDL, FC, DAG, and FFA. The overall findings in this review conclude the importance of macrophages in inducing toxic/inflammatory effects during RT of lung cancer, which is clinically vital to treat the radiation-induced fibrosis.
19 citations
TL;DR: It is demonstrated that the presence of phyllanthin and hypophyllanthin in P. amarus alleviated Th2 response in OVA-induced AHR via modulation of endogenous markers in a murine model of asthma, indicating a new therapeutic approach for the management of asthma.
Abstract: Background: Asthma is a chronic airway immunoinflammatory disorder characterized by airway remodeling. Phyllanthus amarus has been reported to possess antioxidant and anti-inflammatory potential.Ai...
TL;DR: The co-administration of RES and BAPN can be considered as a promising therapeutic approach via targeting LOX for liver fibrosis progression via regulation of the gene expression and protein level of lysyl oxidase (LOX).
Abstract: Objectives: In the current study, we aimed to investigate the effect of administration of resveratrol (RES) and beta-aminopropionitrile (BAPN) separately and together on the liver fibrosis progression via regulation of the gene expression and protein level of lysyl oxidase (LOX).Materials and methods: The six-week old Wistar rats received carbon tetrachloride (CCl4) intraperitoneally and RES and BAPN were administrated orally for eight weeks. The hepatoprotective effects of RES, BAPN, and combination treatment were evaluated. Then the hepatic protein and gene expression levels of LOX were measured.Results: Both RES and BAPN showed the antifibrotic effect through the reduction of collagen fiber bundles, hepatic hydroxyproline content, and protein level of LOX. The antifibrotic effect increased when RES and BAPN up-taken together.Conclusion: The co-administration of RES and BAPN can be considered as a promising therapeutic approach via targeting LOX.
TL;DR: The findings suggest that the combination of APAP and SFN enhanced anti-inflammatory and anti-oxidant activities in stimulated macrophages, which provide an important rationale to utilize drug and food in combination for prevention and/or treatment inflammation-related diseases.
Abstract: Objectives: Accumulating evidence indicates that combination of therapeutic agents may increase their pharmacological properties with fewer undesired side effects. Acetaminophen (APAP) has been widely used to treat pain and fever in many countries. However, APAP only possesses a weak anti-inflammatory property at therapeutic dose, and exhibits hepatotoxicity at high dose. On other hand, sulforaphane (SFN) has been well-known as a potential anti-inflammatory and antioxidant agent. In this study, we investigated the anti-inflammatory and antioxidant effects of combination between APAP and SFN in LPS-stimulated RAW 264.7 macrophage cells. Methods: Nitric oxide (NO) assay was determined using the Griess assay. Reactive oxygen species (ROS) formation was measured using an ROS-sensitive fluorescence indicator, DCFH-DA. The protein expression was determined by western blot analysis. Results: Our results showed that the combination of SFN and APAP exhibited an inhibitory effect on inflammatory markers such as NO, iNOS, COX-2, and IL-1β, and this effect was more pronounced than the compound was used alone. In addition, the combination of SFN and APAP at low doses decreased intracellular ROS formation and increased the protein levels of CAT, GPx, Nrf2, NQO1, and HO-1, which were much better than APAP alone and were equivalent to SFN at full dose. Conclusions: Our findings suggest that the combination of APAP and SFN enhanced anti-inflammatory and anti-oxidant activities in stimulated macrophages, which provide an important rationale to utilize drug and food in combination for prevention and/or treatment inflammation-related diseases.
TL;DR: It is indicated that Madecassoside has potential to ameliorate inflammation in both acute gouty arthritis model and peritonitis model, probably via regulating IL-1β and NLRP3 expression.
Abstract: Objectives: Gouty arthritis is caused by the deposition of monosodium urate (MSU) crystals in joints, which is associated with the rise of serum urate content. This study aims to investigate the therapeutic effect of Madecassoside on gouty arthritis and hyperuricemia. Methods: DBA/1 mice were intradermally injected with MSU to stimulate joint inflammation or intraperitoneally injected with MSU to trigger peritonitis. Moreover, ICR mice were exposed to potassium oxonate to stimulate hyperuricemia. Results: Madecassoside repressed MSU-triggered pad swelling, joint 99mTc uptake, and joint inflammation in DBA/1 mice with gouty arthritis. Neutrophil infiltration and IL-1β & IL-6 & MCP-1 secretion was also alleviated in lavage fluids from DBA/1 mice with peritonitis due to Madecassoside treatment. Furthermore, Madecassoside decreased MSU-induced neutrophil cytosolic factor 1, caspase-1 and NLRP3 expression in mice with peritoneal inflammation. In hyperuricemic mice, Madecassoside improved renal dysfunction. Serum uric acid, BUN, and creatinine were down-regulated by Madecassoside. Conclusion: These findings indicate that Madecassoside has potential to ameliorate inflammation in both acute gouty arthritis model and peritonitis model, probably via regulating IL-1β and NLRP3 expression. Practical point: Madecassoside also exhibited a urate-lowering effect and a renal protective effect in hyperuricemic mice.
TL;DR: Combined sitagliptin and VitD3 can be safely utilized to modulate the inflammatory conditions of T2DM by exerting synergic anti-inflammatory effects on immune system through upregulation of FOXP3 and IL-37, and downregulation of RORγt and BCL6 as well as IFN-γ, IL-17 andIL-21 production.
Abstract: Objective: Gene expression level of T helper cell transcription factors and cytokines production in type-2 diabetes mellitus (T2DM) patients treated with mono- or combined sitagliptin and vitamin D3 (VitD3) were evaluated. Methods: Fifty-four nephropathic and 57 non-nephropathic T2DM patients were divided into the subgroups based on their treatment with/without sitagliptin and VitD3. The expression of T-bet, RORγt, BCL6, and FOXP3 was evaluated using real-time PCR. The levels of IFN-γ, IL-6, IL-17, IL-21, TGF-β, and IL-37 were assessed in PBMC supernatants using ELISA. Results: The production of IFN-γ and IL-17 was increased in untreated (without sitagliptin and VitD3) nephropathic and non-nephropathic T2DM patients compared with healthy controls, whereas FOXP3 expression was decreased. Treatment with sitagliptin alone or in combination with VitD3 reduced the production of IFN-γ in the patients. Production of IL-17 and IL-21 and the expression of RORγt and BCL6 was diminished in patients treated with combined sitagliptin and VitD3, whereas the production of IL-37 and FOXP3 expression were increased in the patients treated with sitagliptin or sitagliptin plus VitD3. Conclusion: These data demonstrate that sitagliptin in combination with VitD3 may accelerate the process of T2DM treatment by exerting synergic anti-inflammatory effects on immune system through upregulation of FOXP3 and IL-37, and downregulation of RORγt and BCL6 as well as IFN-γ, IL-17 and IL-21 production. Combined sitagliptin and VitD3 can be safely utilized to modulate the inflammatory conditions of T2DM.
TL;DR: Findings indicated that the assembly of NR2B–CaMKII–PSD95 signal module is related to LPS-induced neuroinflammation,NR2B plays a key role in the assembly, and NR2 B antagonists could alleviate L PS-related inflammation through the reduced assembly ofNR2 B–Ca MKII– PSD 95 signal module in frontal cortex and hippocampus.
Abstract: Background: Accumulating evidence suggests that inflammation is a contributor to the cause and progression of neurodegenerative disease, such as Alzheimer's disease (AD) and Parkinson disease (PD)....
TL;DR: In vivo, astragaloside ameliorate the degeneration of cartilage in mouse model of OA and potentially serve as a promising and effective therapeutic agent for treating OA patients.
Abstract: Background: Osteoarthritis (OA) is a chronic joint-degeneration disease and accounts for the most frequent arthritis in aging people. OA is characterized by the degeneration of articular ca...
TL;DR: Findings indicate the potential therapeutic effects of G31P in suppressing the development of atherosclerosis by antagonizing the IL-8 receptor and inhibits the proliferation and migration of VSMCs through regulating the Rho-kinase, ERK, and calcium-dependent pathways.
Abstract: Context: Atherosclerosis is a chronic inflammatory disease in which the plaques were built up inside of the artery. Interleukin-8 (IL-8, CXCL8) is an inflammatory factor, known to play an important...
TL;DR: It is indicated that nano-SiO2 had a toxic effect on A549 cells, and this effect could increase IL-1β on the A549 cell-induced inflammatory response.
Abstract: Objective: The industrial production and combustion of coal can produce silica nanoparticles (nano-SiO2). It enters the human body mainly through the respiratory tract and exerts a toxic effect. Ho...
TL;DR: The antitumor functions of Morin in human colorectal cancer cells might be partially due to inhibition of NF-κB signaling.
Abstract: Background: To explore the effects and underlying mechanisms of Morin in human colorectal cancer.Methods: Effects of Morin on proliferation of human colorectal cells in vitro were detected by MTT a...
TL;DR: TIP displayed higher cytotoxicity against macrophages than TBP and TCP, its brominated and chlorinated analogs, and this finding may provide novel insights into evaluating the toxicity of environmental pollutants on the immune system.
Abstract: Objective: 2,4,6-trichlorophenol (TCP), 2,4,6-tribromophenol (TBP), and 2,4,6-triiodophenol (TIP) are three aromatic halogenated disinfection byproducts (DBPs) identified in chlorinated saline effl...
TL;DR: DC pulsed with tumor exosomes induce regression of the TVT in dogs and its administration in dogs with CTVT as treatment against this disease is demonstrated.
Abstract: Context: Exosomes secreted by tumor cells are a good source of cellular components that stimulate the immune response, such as alarmins (mRNA, tetraspanins (CD9, CD63, CD81), heat-shock proteins, major histocompatibility complex class I molecules) and tumor-associated antigens. These properties permit to pulsed dendritic cells in the immunotherapy for many cancers types. The aim of this study was to demonstrate the use of exosomes derived from canine transmissible venereal tumor (CTVT) as an antigen to pulsed dendritic cells and its administration in dogs with CTVT as treatment against this disease. Material and methods: From primary culture of CTVT cells the exosomes were isolated and characterized by scanning electron microscopy assay, dot blot and protein quantification. The monocytes of each patient were differentiated to dendritic cells (DC) and pulsed with CTVT exosomes (CTVTE). Phagocytosis, tumor size, populations of lymphocytes and IFN-c levels were evaluated. Results: The CTVTE showed a size around 90 nm. CD81, CD63, CD9 and Hsp70 were expressed. Monocytes showed an expression of 85.71% for CD14+, 12.3% for CD80+, 0.1% for CD83+ and 0.8% for DLA-II. In DC 5.1% for CD14+, 86.7% for CD80+, 90.1% for CD83+ and 92.6% for DLA-II and a phagocytosis of 63% was obtained by FITC Dextran test. No side effects were observed in the experimental groups with our therapy. Tumor regression was of 100% at the seventh week, as well as an increase in the level of IFN-γ (142 pg/ml), and CD4+ (28%) and CD8+ (34%) cell percentage. Discusion and conclusion: These results have shown that DC pulsed with tumor exosomes induce regression of the TVT in dogs.
TL;DR: Pulegone exerts anti-inflammatory effects on LPS-induced sepsis mice via inhibition of the NLRP3 expression and Histological analysis results indicated that the histological changes of lungs caused by LPS were ameliorated by pulegone.
Abstract: Context: Pulegone, a key compound in Schizonepeta essential oil, has been identified as an anti-inflammatory. However, its underlying molecular mechanisms on NLR family pyrin domain containing 3 (N...
TL;DR: The application of FK506 combined with MMF may be superior to Fk506 monotherapy for the patients to further induce the immune tolerance after liver transplantation.
Abstract: Context: Recent studies have shown that a combination treatment of mycophenolate mofetil (MMF) and tacrolimus (FK506) may be an option for organ transplantation patients.Objective: In this study, w...
TL;DR: Omega-3 fatty acids, although a precursor for R vE1 formation, had no additive effects on RvE1 decreases in airway inflammation and airway reactivity, suggesting that omega-3 supplementation has little effect on airwayinflammatory and reactivity in the model of asthma.
Abstract: Objective: ResolvinE1 (RvE1), an endogenous lipid mediator derived from omega 3 fatty acids contributes to resolution of allergic inflammatory responses. We investigated effects of RvE1 (R) and omega 3 fatty acids (O) on airway reactivity and inflammation using allergic mice. Methods: Mice were divided into control (nonasthmatic; CON) and allergen sensitized-challenged (asthmatic; SEN) groups, and were sensitized i.p. on days 1, 6 with 0.2 μg ovalbumin (OVA) followed by 5% OVA aerosol challenges on days 11-13. RvE1 was administered i.p. postallergen challenge, while omega 3 fatty acids (fish oil) were administered via oral gavage once daily (days 1-13). Whole body plethysmography and bronchoalveolar lavage (BAL) studies were performed on day 14. Results: RvE1 attenuated airway responsiveness to methacholine (48 mg/ml) in treated asthmatic mice vs. nontreated (150 ± 27.88% in SEN vs. 54 ± 7.52% in SEN + R, p < .05). No difference was observed with omega-3 supplementation (115 ± 19.28% in SEN + O) or treatment with both RvE1 and omega 3 fatty acids (39 ± 12.37% in SEN + R + O vs. 54 ± 7.52% in SEN + R). Differential BAL cell analysis showed that RvE1 decreased eosinophils and neutrophils in SEN mice (p < .005) while no difference was observed with omega-3 fatty acids. SEN + R + O group had similar results as RvE1 treated mice, suggesting that only RvE1 attenuated inflammation. Conclusions: RvE1 attenuated airway responsiveness and inflammation in asthmatic mice. Omega-3 fatty acids, although a precursor for RvE1 formation, had no additive effects on RvE1 decreases in airway inflammation and airway reactivity. Our data suggests that omega-3 supplementation has little effect on airway inflammation and reactivity in our model of asthma.
TL;DR: The findings indicate that FA metabolism plays an important role in the activation of both pDCs and c DCs and suggest that its modulation is an exploitable therapeutic target to suppress DC activation in inflammation or autoimmunity.
Abstract: Objective: Dendritic cells (DCs) are important players in immunity against pathogens, but overactive DCs have been implicated in autoimmune diseases, like lupus, in which a paucity of targeted therapies remains. Recent research shows that DCs upregulate their immunometabolism when activating. We explored whether modulating fatty acid (FA) metabolism needed for oxidative phosphorylation can affect the activation of two main DC subsets. Material and methods: Sorted murine plasmacytoid DCs (pDCs) and conventional DCs (cDCs), generated in FLT3-L medium, were treated with etomoxir, an inhibitor of FA oxidation, or TOFA, an inhibitor of FA synthesis, then stimulated with TLR9 agonist CpGA. Surface activation markers and viability were analyzed by flow cytometry, cytokine, and chemokine production and were measured by ELISA. Results: Modulation of FA metabolism suppressed the upregulation of costimulatory molecules and the production of proinflammatory cytokine IL-6 and type I Interferon-dependent chemokine CXCL10 by both subsets of DCs, without affecting DC viability, neither of resting DCs or upon activation. Etomoxir inhibited pDCs at lower doses than cDCs, suggesting that pDCs may be more susceptible to FA metabolic modulation. Conclusions: Both cDCs, the primary antigen presenting cell, and pDCs, the primary type I IFN producer, exhibit a suppressed ability to activate but normal viability when their FA metabolism is inhibited by etomoxir or TOFA. Our findings indicate that FA metabolism plays an important role in the activation of both pDCs and cDCs and suggest that its modulation is an exploitable therapeutic target to suppress DC activation in inflammation or autoimmunity.
TL;DR: It is demonstrated that paeonol could alleviate CCl4-induced liver fibrosis through suppression of hepatic stellate cells activation via inhibiting the TGF-β/Smad3 signaling.
Abstract: Objective: Paeonol is a natural phenolic component isolated from the root bark of peony with multiple pharmacological activities. We investigated the anti-fibrotic effect and underlying mechanism of paeonol. Methods: Twenty-four male C57BL/6J mice were divided into 4 groups (n = 6 in each group), injected with CCl4 to induce liver fibrosis and administrated with paeonol according to the regimen. The serum activity of ALT and AST, and H&E staining were to assess liver injury. Sirius and Masson staining, and hydroxyproline content were to evaluate the degree of liver fibrosis. TNF-α, IL-6, TGF-β, MDA, GSH-PX, SOD, and CAT were detected to reflect inflammation and oxidative stress. RT-qPCR and Western blot analysis to assess the activation of HSCs and TGF-β/Smad3 signaling. Results: Paeonol ameliorated liver injury and liver fibrosis, reflected by the decrease of ALT, AST, less lesion in H&E staining, mitigated fibrosis in Sirius and Masson staining, lessened content of hydroxyproline. Paeonol attenuated the level of IL-6 and TNF-α, and elevated the activity of GSH-PX, SOD, and CAT with reducing the level of MDA. The expression of col 1a, α-SMA, vimentin, and desmin were down-regulated and TGF-β/Smad3 signaling pathway was inhibited. Conclusion: These data demonstrated that paeonol could alleviate CCl4-induced liver fibrosis through suppression of hepatic stellate cells activation via inhibiting the TGF-β/Smad3 signaling.
TL;DR: The mode of action of α-MMC is to guide functional immunosuppressive regulation at low doses and induce apoptosis at high doses, which may be an important mechanism of its antitumor effects.
Abstract: Background and aim: Alpha-momorcharin (α-MMC) is a type I ribosome-inactivating protein (RIP) that is purified from Momordica charantia. Despite its strong antitumor activities, α-MMC exerts the un...
TL;DR: The findings demonstrate a promising therapeutic effect of modafinil for animal models of stroke and show promising effects on remission of behavioral deficits and the number of degenerated neurons in ischemic hippocampus CA1 region.
Abstract: Background: The phenomenon of ischemic stroke receives maximal attention nowadays. Many studies are designed to discover new therapies for reducing debilitating consequences of this disorder. Development of stroke-related tissue damage is due to the combination of blood flow occlusion and reperfusion phase. Inflammatory pathways participate in excess oxidative stress formation after reperfusion. Modafinil is a well-known medication prescribed for sleep disorders. Recently, several studies have focused on finding new indications for modafinil treatment. Anti-inflammatory effects of modafinil through disrupting NF-κB signaling pathway is reported previously. Downregulation of inflammatory cytokines and further oxidative damage have also been mentioned in various experiments. So far, no specific experiment had been conducted to assess the anti-inflammatory effects of modafinil on ischemic stroke. Material and methods: We evaluated outcomes of acutely administered modafinil on post-stroke behaviors and histopathological features (including apoptotic caspase-3 expressing neurons) through bilateral common carotid artery occlusion in rats. Alterations in concentrations of TNFɑ and IL-1β were assessed, together with malon di-aldehyde (MDA) to represent oxidation level. Western blotting was used to reveal the involvement of NF-κB downregulation. Considering possible alterations in blood flow and neuronal metabolism, we also assessed the effects of modafinil on cerebral glucose metabolism through PET scan. Results and discussion: Modafinil exhibited promising effects on remission of behavioral deficits and the number of degenerated neurons in ischemic hippocampus CA1 region. IL-1β and MDA levels were downregulated in treated animals. However, no significant alteration was observed in PET results and TNFɑ between treated and non-treated ischemic brains. Decreased protein levels of NF-κB was also measured in modafinil treated animals. Conclusion: Our findings demonstrate a promising therapeutic effect of modafinil for animal models of stroke.
TL;DR: TAAR1 is a mediator of macrophage inflammation and a potential therapeutic target to attenuate UC symptomology, and its upregulation and activation in response to LPS and TYR is demonstrated.
Abstract: Context: Tissue resident macrophages and peripherally infiltrating macrophages play a prominent role in maintaining homeostasis in the gastrointestinal tract (GIT), though aberrant activation is implicated in inflammatory conditions, including ulcerative colitis (UC). Recent metabolomic studies indicate that tyramine (TYR) is elevated in the stool of patients with UC. TYR activates the mammalian trace amine associated receptor 1 (TAAR1). Our previous work identified TAAR1 expression in mixed populations of immune cells, whereas a limited number of other studies have identified TAAR1-dependent effects in cytokine secretion and gene expression in T-cells and B-cells.Objective: To investigate whether TAAR1 may serve as a novel target for an anti-inflammatory therapeutic in UC, we explored TAAR1 expression in mouse bone marrow-derived macrophages (BMDMs), and its upregulation and activation in response to LPS and TYR.Results: Here, we demonstrate for the first time that TAAR1 is expressed in BMDM and undergoes agonist-induced upregulation. Additionally, TYR elicits significant increases in inflammatory cytokine gene expression in non-polarized and LPS-polarized BMDM, and the TAAR1 antagonist EPPTB inhibits the TYR-mediated upregulation of TAAR1 and inflammatory cytokine gene expression in BMDM. Conclusions: Our data suggest that TAAR1 is a mediator of macrophage inflammation and a potential therapeutic target to attenuate UC symptomology.