• Journal of Physiology & Pathology in Korean Medicine
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• v.38 no.1
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• pp.32-37
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• 2024

The aim of this study was to investigate the role of Daesiho-tang (Da Chai Hu-Tang) water extract (DSTE) in regulating chronic stress-induced cancer progression, focusing on its activity in modulating tumor-associated macrophages (TAMs). Different stimuli can polarize TAMs into immune-stimulating M1 macrophages or immunosuppressive M2 macrophages. During cancer progression, M2 phenotype increases and supports tumor growth, angiogenesis and metastasis. Notably, chronic stress-induced catecholamines promote M2 macrophage polarization. In this study, we investigated whether DSTE regulates norepinephrine (NE)-induced M2 macrophage polarization in RAW 264.7 mouse macrophage cells. Even though NE itself did not increase the expression of M2 markers, the conditioned media of NE-treated 4T1 mouse breast cancer cells (NE CM) significantly up-regulated M2 markers in RAW 264.7 cells, suggesting that NE-regulated cancer cell secretome stimulated M2 polarization. However, such increase was abrogated by DSTE. NE CM also induced phosphorylation of signal transducer and activator of transcription 6 (STAT6) in RAW 264.7 cells, which was clearly reversed by pretreatment with DSTE, demonstrating that DSTE inhibited M2 polarization by inactivating STAT6. Finally, M2-polarized RAW264.7 cells by NE CM markedly increased the migration of 4T1 cells. However, such increase was completely reversed by co-treating RAW264.7 cells with NE CM and DSTE, indicating that DSTE attenuated cancer cell migration by blocking M2 polarization. Taken together, our results suggest a probable use of DSTE for cancer patients under chronic stress by regulating M2 macrophage polarization.

• Nutrition Research and Practice
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• v.18 no.2
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• pp.194-209
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• 2024

BACKGROUND/OBJECTIVES: High levels of plasma low-density lipoprotein (LDL) cholesterol are an important determinant of atherosclerotic lesion formation. The disruption of cholesterol efflux or reverse cholesterol transport (RCT) in peripheral tissues and macrophages may promote atherogenesis. The aim of the current study was to examine whether bioactive ellagic acid, a functional food component, improved RCT functionality and high-density lipoprotein (HDL) function in diet-induced atherogenesis of apolipoproteins E (apoE) knockout (KO) mice. MATERIALS/METHODS: Wild type mice and apoE KO mice were fed a high-cholesterol Paigen diet for 10 weeks to induce hypercholesterolemia and atherosclerosis, and concomitantly received 10 mg/kg ellagic acid via gavage. RESULTS: Supplying ellagic acid enhanced induction of apoE and ATP-binding cassette (ABC) transporter G1 in oxidized LDL-exposed macrophages, facilitating cholesterol efflux associated with RCT. Oral administration of ellagic acid to apoE KO mice fed on Paigen diet improved hypercholesterolemia with reduced atherogenic index. This compound enhanced the expression of ABC transporters in peritoneal macrophages isolated from apoE KO mice fed on Paigen diet, indicating increased cholesterol efflux. Plasma levels of cholesterol ester transport protein and phospholipid transport protein involved in RCT were elevated in mice lack of apoE gene, which was substantially reduced by supplementing ellagic acid to Paigen diet-fed mice. In addition, ellagic acid attenuated hepatic lipid accumulation in apoE KO mice, evidenced by staining of hematoxylin and eosin and oil red O. Furthermore, the supplementation of 10 mg/kg ellagic acid favorably influenced the transcriptional levels of hepatic LDL receptor and scavenger receptor-B1 in Paigen diet-fed apoE KO mice. CONCLUSION: Ellagic acid may be an athero-protective dietary compound encumbering diet-induced atherogenesis though improving the RCT functionality.

• Journal of Microbiology and Biotechnology
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• v.34 no.2
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• pp.270-279
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• 2024

Macrophages are versatile immune cells that play crucial roles in tissue repair, immune defense, and the regulation of immune responses. In the context of skeletal muscle, they are vital for maintaining muscle homeostasis but macrophage-induced chronic inflammation can lead to muscle dysfunction, resulting in skeletal muscle atrophy characterized by reduced muscle mass and impaired insulin regulation and glucose uptake. Although the involvement of macrophage-secreted factors in inflammation-induced muscle atrophy is well-established, the precise intracellular signaling pathways and secretion factors affecting skeletal muscle homeostasis require further investigation. This study aimed to explore the regulation of macrophage-secreted factors and their impact on muscle atrophy and glucose metabolism. By employing RNA sequencing (RNA-seq) and proteome array, we uncovered that factors secreted by lipopolysaccharide (LPS)-stimulated macrophages upregulated markers of muscle atrophy and pro-inflammatory cytokines, while concurrently reducing glucose uptake in muscle cells. The RNA-seq analysis identified alterations in gene expression patterns associated with immune system pathways and nutrient metabolism. The utilization of gene ontology (GO) analysis and proteome array with macrophage-conditioned media revealed the involvement of macrophage-secreted cytokines and chemokines associated with muscle atrophy. These findings offer valuable insights into the regulatory mechanisms of macrophage-secreted factors and their contributions to muscle-related diseases.

• International Journal of Molecular Medicine
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• v.43 no.5
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• pp.2177-2186
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• 2019

The epidemiological, animal and cell effects of plant metabolites suggest versatile health benefits of flavonoids. However, whether flavonoids affect the deleterious biological activity of oxygenated cholesterol molecules remains to be elucidated. The present study investigated the effects of 4'-O-methylalpinumisoflavone (mAI) isolated from Maclura tricuspidata (Cudrania tricuspidata) on the 27-hydroxycholesterol (27OHChol)-induced activation of monocytes/macrophages using human THP-1 cells. mAI dose-dependently impaired the expression of C-C motif chemokine ligand (CCL)2 chemokine and the migration of monocytic cells enhanced by 27OHChol. mAI downregulated the surface and cellular levels of CD14 and inhibited the release of soluble CD14. This isoflavone significantly weakened the lipopolysaccharide responses that were enhanced in the presence of 27OHChol, and inhibited the transcription and secretion of the active gene product of matrix metalloproteinase-9. mAI also suppressed the expression of C-C motif chemokine receptor 5 ligands, including CL3 and CCL4, and M1-phenotype markers induced by 27OHChol. Furthermore, mAI impaired phosphorylation of the nuclear factor-κB p65 subunit without affecting the phosphorylation of Akt. These results indicate that mAI inhibits the activation of monocytes/macrophages to the immunostimulatory phenotype in a milieu rich in 27OHChol, suggesting potential benefits of the flavonoid for the treatment of diseases in which the pathogenesis is linked to 27OHChol-induced inflammatory responses.

• Tuberculosis and Respiratory Diseases
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• v.60 no.5
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• pp.554-563
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• 2006

Background: PM is known to induce various pulmonary diseases, including asthma, cancer, fibrosis and chronic bronchitis. Despite the epidemiological evidence the pathogenesis of PM-related pulmonary diseases is unclear. Methods: This study examined the effects of PM exposure on the secretion of $TNF-{\alpha}$ and $IL-1{\beta}$ in the cultured alveolar macrophages. The cultured primary alveolar macrophages were treated with the medium, PM ($5{\sim}20{\mu}g/cm^2$), LPS (5ng/ml), and PM with LPS for 24h and 48h respectively. ELISA was used to assay the secreted $TNF-{\alpha}$ and $IL-{\beta}$ in the culture medium. Western blotting was used to identify and determine the level of proteins isolated from the culture cells. The cells cultured in the $Lab-Tek^{(R)}$ chamber slides were stained with immunocytochemical stains. Results: PM induced $TNF-{\alpha}$ and $IL-1{\beta}$ secretion in the culturing alveolar macrophages, collected from the SPF and inflammatory rats. However, the effects were only dose-dependent in the inflammatory macrophages. When the cells were co-treated with PM and LPS, there was a significant synergistic effect compared with the LPS in the both cell types. Conclusion: PM might be play an important role in the induction and/or potentiation of various lung diseases by oversecretion of $TNF-{\alpha}$ and $IL-1{\beta}$.

• Journal of Veterinary Clinics
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• v.26 no.2
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• pp.138-143
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• 2009

Ischemia/reperfusion injury(I/RI) is the major cause of acute renal failure and delayed graft function(DGF) unavoidable in renal transplantation. Enormous studies on ischemia damage playing a role in activating graft rejection factors, such as T cells or macrophages, are being reported. Present study was performed to determine whether ischemia time would play an important role in activating rejection-related factors or not in rat models of I/RI. Male Sprague-Dawley rats were submitted to 30, 45, and 60 minutes of warm renal ischemia with nephrectomy or control animals underwent sham operation(unilateral nephrectomy). Renal function and survival rates were evaluated on day 0, 1, 2, 3, 5 and 7. Immunofluorescence staining of dendritic cells(DCs), natural killer(NK) cells, macrophages, B cells, CD4+ and CD8+ T cells were measured on day 1 and 7 after renal I/RI. Survival rates dropped below 50% after day 3 in 45 minutes ischemia. Histologic analysis of ischemic kidneys revealed a significant loss of tubular architecture and infiltration of inflammatory cells. DCs, NK cells, macrophages, CD4+ and CD8+ T cells were infiltrated from a day after I/RI depending on ischemia time. Antigen presenting cells(DCs, NK cells or macrophages) and even T cells were infiltrated 24 hours post-I/RI, which is at the time of acute tubular necrosis. During the regeneration phase, not only these cells increased but B cells also appeared in more than 45 minutes ischemia. The numbers of the innate and the adaptive immune cells increased depending on ischemia as well as reperfusion time. These changes of infiltrating cells resulting from each I/RI model show that ischemic time plays a role in activating rejection related immune factors and have consequences on progression of renal disease in transplanted and native kidneys.

• Journal of Life Science
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• v.26 no.1
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• pp.50-58
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• 2016

The root bark of Ulmus macrocarpa has been used in traditional medicine for the treatment of various diseases such as edema, infection and inflammation. Nevertheless, the biological activities and underlying mechanisms of the immunomodulatory effects remain unclear. In this study, as part of our ongoing screening program to evaluate the immunomodulatory potential of new compounds from traditional medicinal resources, we investigated the effects of U. macrocarpa water extract (UME) on immune modulation in a murine RAW 264.7 macrophage model. As immune response parameters, the productions of as nitric oxide (NO) and cytokines such tumor necrotic factor (TNF)-α, interleukin (IL)-1β and IL-10 were evaluated. Although the release of IL-1β remained unchanged in UME-treated RAW 264.7 macrophages, the productions of NO, TNF-α and IL-10 were significantly increased, along with the increased expression of inducible NO synthase, TNF-α and IL-10 expression at concentrations with no cytotoxicity. UME treatment also induced the nuclear translocation of nuclear factor κB (NF-κB), and phosphorylation of Akt and mitogen-activated protein kinases (MAPKs) indicating that UME activated macrophages through the activation of NF-κB, phosphoinositide-3-kinase (PI3K)/Akt and MAPKs signaling pathways in RAW 264.7 macrophages. Furthermore, pre-treatment with UME significantly attenuated the production of NO, but not TNF-α, IL-1β and IL-10, in lipopolysaccharide-stimulated RAW 264.7 cells suggesting that UME may be useful in preventing inflammatory diseases mediated by excessive production of NO. These findings suggest that the beneficial therapeutic effects of UME may be attributed partly to its ability to modulate immune functions in macrophages.

• Tuberculosis and Respiratory Diseases
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• v.39 no.4
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• pp.304-309
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• 1992

Background: The alveolar macrophage may metabolize arachidonic acid through cyclooxygenase- and lipoxygenase- catalyzed pathways to produce a variety of metabolites of arachidonic acid. The production of these metabolites of arachidonic acid may enhance the defensive ability of the challenged lung. However, continued stimulation with the consequent production of proinflammtory metabolites of arachidonic acid, may ultimately enhance the disease process by contributing to chronic bronchoconstriction, fibrosis, and the persistent release of toxic oxygen species. Silicosis is an example of a disease process resulting from chronic exposure of the lung to foreign particles. This study was carried out to evaluate the changes of arachidonic acid metabolites from macrophages in experimental silicosis. Methods: We measured $PGE_2$, and $LTB_4$ in cultured macrophages taken from rats by radioimmunoassay at 24 and 48 hours after stimulation by silica dust, natural carbon dust, lipopolysaccharide, calcium ionophore (A23187) and medium (RPMI) as a control. For the experimental silicosis, 50 mg silica in 0.5 ml saline was administered intratracheally into the rat and grown to 20 weeks and measured $PGE_2$, and $LTB_4$ in the cultured macrophages lavaged from that rat. The used stimulants were the same as above. Results: 1) The amount of $PGE_2$ in the cultred macrophages from normal rat was significantly decreased in the group which was stimulated with silica dust for 48 hours compare with control non-stimulated group. 2) In the experimental silicosis group, $PGE_2$, release in cultured macrophages after 48 hours incubation with silica and natural carbon dust tended to be lower than those of non-stimulated group. 3) There were marked changes of $LTB_4$ in the groups of normal rats which were incubated with silica for 24, 48 hours and natural carbon for 48 hours compared with non-stimulated group. 4) In the experimental silicosis group, the release of $LTB_4$ was significantly increased macrophages cultured with silica and natural carbon dust after 24 and 48 hours incubation compared with non-stimulated group. Conclusion: The results of these studies suggest that the in vitro exposure of rat alveolar macrophge to silica and coal dust results in an alteration in alveolar macrophage metabolism of arachidonic acid that may promote an inflammatory reaction in lung tissue.

• Korean Journal of Food Science and Technology
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• v.48 no.3
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• pp.289-295
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• 2016

To elucidate the new biologically active ingredient in commercial instant coffee, a crude polysaccharide (ICP-0) was isolated by ethanol precipitation, and its immunostimulatory activity was estimated. ICP-0 mainly consisted of galactose (55.5%), mannose (25.7%), arabinose (6.0%), and galacturonic acid (10.1%), suggesting the possibility of its existence as a mixture of galactomannan or pectic polysaccharide. ICP-0 showed proliferative activity in peritoneal macrophages and splenocytes. ICP-0 dose-dependently augmented the production of nitric oxide and reactive oxygen species by peritoneal macrophages. In addition, murine peritoneal macrophages stimulated by ICP-0 showed enhanced production of various cytokines (tumor necrosis factor-${\alpha}$, interleukin-6, and interleukin-12) as compared to unstimulated murine peritoneal macrophages. In an in vitro assay for assessing intestinal immunomodulation, the ICP-0-treated Peyer's patch cells showed higher bone marrow cell proliferation activity at $100{\mu}g/mL$ and higher production of granulocyte-macrophage colony-stimulating factor, compared to the untreated Peyer's patch cells. These results suggest that polysaccharides in commercial instant coffee have a potentiality for macrophage functions and the intestinal immune system.

• Biomolecules & Therapeutics
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• v.23 no.1
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• pp.45-52
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• 2015

To explore the anti-allergic and anti-inflammatory effects of extracts of Petasites genus, we studied the effects of s-petasin, a major sesquiterpene from Petasites formosanus (a butterbur species) on asthma and peritonitis models. In an ovalbumin-induced mouse asthma model, s-petasin significantly inhibited the accumulations of eosinophils, macrophages, and lymphocytes in bronchoalveolar fluids. S-petasin inhibited the antigen-induced degranulation of ${\beta}$-hexosamidase but did not inhibit intracellular $Ca^{2+}$ increase in RBL-2H3 mast cells. S-petasin inhibited the LPS induction of iNOS at the RNA and protein levels in mouse peritoneal macrophages. Furthermore, s-petasin inhibited the production of NO (the product of iNOS) in a concentration-dependent manner in the macrophages. Furthermore, in an LPS-induced mouse model of peritonitis, s-petasin significantly inhibited the accumulation of polymorpho nuclear and mononuclear leukocytes in peritoneal cavity. This study shows that s-petasin in Petasites genus has therapeutic effects on allergic and inflammatory diseases, such as, asthma and peritonitis through degranulation inhibition in mast cells, suppression of iNOS induction and production of NO in macrophages, and suppression of inflammatory cell accumulation.