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Hepatic fibrosis is a complex chronic liver disease in which both macrophages and hepatic stellate cells (HSCs) play important roles. Many studies have shown that clodronate liposomes (CLD-lipos) effectively deplete macrophages. However, no liposomes have been developed that target both HSCs and macrophages. This study aimed to evaluate the therapeutic efficacy of lipopolysaccharide-coupled clodronate liposomes (LPS-CLD-lipos) and the effects of liposomes size on hepatic fibrosis. Three rat models of hepatic fibrosis were established in vivo; diethylnitrosamine (DEN), bile duct ligation (BDL), and carbon tetrachloride (CCl 4 ). Hematoxylin and eosin staining and serological liver function indices were used to analyze pathological liver damage. Masson's trichrome and Sirius red staining were used to evaluate the effect of liposomes on liver collagen fibers. The hydroxyproline content in liver tissues was determined. In vitro cell counting kit-8 (CCK-8) and immunofluorescence assays were used to further explore the effects of LPS modification and liposomes size on the killing of macrophages and HSCs. Both in vitro and in vivo experiments showed that 200 nm LPS-CLD-lipos significantly inhibited hepatic fibrosis and the abnormal deposition of collagen fibers in the liver and improved the related indicators of liver function. Further results showed that 200 nm LPS-CLD-lipos increased the clearance of macrophages and induced apoptosis of hepatic stellate cells, significantly. The present study demonstrated that 200 nm LPS-CLD-lipos could significantly inhibit hepatic fibrosis and improve liver function-related indices and this study may provide novel ideas and directions for hepatic fibrosis treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Various studies have been investigated the phenotypic and functional distinctions of craniofacial and long bone cells involved in bone regeneration. However, the process of bone tissue regeneration after bone grafting involves complicated interactions between different cell types at the donor-recipient site. Additionally, differences in alterations of the immune microenvironment at the recipient site remained to be explored. Osteoblasts (OBs) and macrophages (MØ) play essential roles in the bone restoration and regeneration processes in the bone and immune systems, respectively. The modulation of MØ on OBs has been extensively explored in the literature, whereas limited research has been conducted on the influence of OBs on the MØ phenotype and function. In the present study, OBs from the mandible and femur (MOBs and FOBs, respectively) promoted cranial defect regeneration in rats, with better outcomes noted in the MOBs-treated group. After MOBs transplantation, a significant inflammatory response was induced, accompanied by an early increase in IL-10 secretion. And then, there was an upregulation in M2-MØ-related cell markers and inflammatory factor expression. Condition media (CM) of OBs mildly inhibited apoptosis in MØ, enhanced their migration and phagocytic functions, and concurrently increased iNOS and Arg1 expression, with MOB-CM demonstrating more pronounced effects compared to FOB-CM. In conclusion, our investigation showed that MOBs and FOBs have the ability to modulate MØ phenotype and function, with MOBs exhibiting a stronger regulatory potential. These findings provide a new direction for improving therapeutic strategies for bone regeneration in autologous bone grafts from the perspective of the immune microenvironment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Punicalagin (PUN) is a polyphenol derived from the pomegranate peel. It has been reported to have many beneficial effects, including anti-inflammatory, anti-oxidant, and anti-proliferation. However, the role of PUN in macrophage phagocytosis is currently unknown. In this study, we found that pre-treatment with PUN significantly enhanced phagocytosis by macrophages in a time- and dose-dependent manner in vitro. Moreover, KEGG enrichment analysis by RNA-sequencing showed that differentially expressed genes following PUN treatment were significantly enriched in phagocyte-related receptors, such as the C-type lectin receptor signaling pathway. Among the C-type lectin receptor family, Mincle (Clec4e) significantly increased at the mRNA and protein level after PUN treatment, as shown by qRT-PCR and western blotting. Small interfering RNA (siRNA) mediated knockdown of Mincle in macrophages resulted in down regulation of phagocytosis. Furthermore, western blotting showed that PUN treatment enhanced the phosphorylation of nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) in macrophages at the early stage. Mincle-mediated phagocytosis by PUN was inhibited by PDTC (a NF-κB inhibitor) and SB203580 (a p38 MAPK inhibitor). In addition, PUN pre-treatment enhanced phagocytosis by peritoneal and alveolar macrophages in vivo. After intraperitoneal injection of Escherichia coli (E.coli), the bacterial load of peritoneal lavage fluid and peripheral blood in PUN pre-treated mice decreased significantly. Similarly, the number of bacteria in the lung tissue significantly reduced after intranasal administration of Pseudomonas aeruginosa (PAO1). Taken together, our results reveal that PUN enhances bacterial clearance in mice by activating the NF-κB and MAPK pathways and upregulating C-type lectin receptor expression to enhance phagocytosis by macrophages., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Emerging studies have revealed that macrophages possess different dependences on the uptake, synthesis, and metabolism of serine for their activation and functionalization, necessitating our insight into how serine availability and utilization impact macrophage activation and inflammatory responses., Methods: This article summarizes the reports published domestically and internationally about the serine uptake, synthesis, and metabolic flux by the macrophages polarizing with distinct stimuli and under different pathologic conditions, and particularly analyzes how altered serine metabolism rewires the metabolic behaviors of polarizing macrophages and their genetic and epigenetic reprogramming., Results: Macrophages dynamically change serine metabolism to orchestrate their anabolism, redox balance, mitochondrial function, epigenetics, and post-translation modification, and thus match the distinct needs for both classical and alternative activation., Conclusion: Serine metabolism coordinates multiple metabolic pathways to tailor macrophage polarization and their responses to different pathogenic attacks and thus holds the potential as therapeutic target for types of acute and chronic inflammatory diseases., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

High-dose ascorbate confers tubular mitophagy responsible for septic acute kidney injury (AKI) amelioration, yet its biological roles in immune regulation remain poorly understood. Methods: The role of tubular mitophagy in macrophage polarization upon high-dose ascorbate treatment was assessed by fluorescence-activated cell sorter analysis (FACS) in vitro and by immunofluorescence in AKI models of LPS-induced endotoxemia (LIE) from Pax8-cre ; Atg7 flox/flox High-dose ascorbate enables conversion of macrophages from a pro-inflammatory M1 subtype to an anti-inflammatory M2 subtype in murine AKI models of LIE, leading to decreased renal IL-1β and IL-18 production, reduced mortality and alleviated tubulotoxicity. Blockade of tubular mitophagy abrogates anti-inflammatory macrophages polarization under the high-dose ascorbate-exposed coculture systems. Similar abrogations are verified in LIE mice with tubular epithelium-specific ablation of Results: where the high-dose ascorbate-inducible renal protection and survival improvement are substantially weaker than their control littermates. Mechanistically, high-dose ascorbate stimulates tubular secretion of serpin family G member 1 (SerpinG1) through maintenance of mitophagy, for which nuclear factor-erythroid 2 related factor 2 (NRF2) transactivation is required. SerpinG1 perpetuates anti-inflammatory macrophages to prevent septic AKI, while kidney-specific disruption of SerpinG1 by adeno-associated viral vector serotype 9 (AAV9)-short hairpin RNA (shRNA) delivery thwarts the anti-inflammatory macrophages polarization and anti-septic AKI efficacy of high-dose ascorbate. Atg7, where the high-dose ascorbate-inducible renal protection and survival improvement are substantially weaker than their control littermates. Mechanistically, high-dose ascorbate stimulates tubular secretion of serpin family G member 1 (SerpinG1) through maintenance of mitophagy, for which nuclear factor-erythroid 2 related factor 2 (NRF2) transactivation is required. SerpinG1 perpetuates anti-inflammatory macrophages to prevent septic AKI, while kidney-specific disruption of SerpinG1 by adeno-associated viral vector serotype 9 (AAV9)-short hairpin RNA (shRNA) delivery thwarts the anti-inflammatory macrophages polarization and anti-septic AKI efficacy of high-dose ascorbate. Conclusion: Our study identifies SerpinG1 as an intermediate of tubular mitophagy-orchestrated myeloid function during septic AKI and reveals a novel rationale for ascorbate-based therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: This study aimed to investigate the effects of caprylic acid (C8:0) on lipid metabolism and inflammation, and examine the mechanisms underlying these effects in mice and cells., Methods: Fifty-six 6-week-old male C57BL/6J mice were randomly allocated to four groups fed a high-fat diet (HFD) without or with 2% C8:0, palmitic acid (C16:0) or eicosapentaenoic acid (EPA). RAW246.7 cells were randomly divided into five groups: normal, lipopolysaccharide (LPS), LPS+C8:0, LPS+EPA and LPS+cAMP. The serum lipid profiles, inflammatory biomolecules, and ABCA1 and JAK2/STAT3 mRNA and protein expression were measured., Results: C8:0 decreased TC and LDL-C, and increased the HDL-C/LDL-C ratio after injection of LPS. Without LPS, it decreased TC in mice ( P < 0.05). Moreover, C8:0 decreased the inflammatory response after LPS treatment in both mice and cells ( P < 0.05). Mechanistic investigations in C57BL/6J mouse aortas after injection of LPS indicated that C8:0 resulted in higher ABCA1 and JAK2/STAT3 expression than that with HFD, C16:0 and EPA, and resulted in lower TNF-α, NF-κB mRNA expression than that with HFD ( P < 0.05). In RAW 264.7 cells, C8:0 resulted in lower expression of pNF-κBP65 than that in the LPS group, and higher protein expression of ABCA1, p-JAK2 and p-STAT3 than that in the LPS and LPS+cAMP groups ( P < 0.05)., Conclusion: Our studies demonstrated that C8:0 may play an important role in lipid metabolism and the inflammatory response, and the mechanism may be associated with ABCA1 and the p-JAK2/p-STAT3 signaling pathway., (Copyright © 2022 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Hepatocellular carcinoma (HCC) usually occurs at the late stage of chronic liver injury. Oncostatin M (OSM) is a tumor-associated cytokine highly expressed in cirrhosis and HCC patients; however, its role in hepatocarcinogenesis has not been clearly elucidated. In this study, we investigated the effect of OSM on HCC occurrence in a rat model of N-diethylnitrosamine-induced HCC. OSM overexpression significantly increased the number of tumor nodules and shortened the overall survival of the rats. Notably, OSM promoted HPC activation in vivo but did not directly regulate the proliferation of the HPC cell line in vitro. Further, OSM induced tumor necrosis factor-α (TNF-α) secretion and CD68 + macrophage accumulation, which were positively correlated with HPC activation. Additionally, TNF-α or macrophage depletion inhibited the promoting effect of OSM on hepatocarcinogenesis and HPC activation. Furthermore, OSM expression in the peritumoral tissues of HCC was positively correlated with poor overall survival of patients. In conclusion, OSM plays an important role in hepatocarcinogenesis by regulating the liver inflammation environment. Hence, OSM could be used as a potential target for HCC prevention and therapy or as an indicator of HCC prognosis., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Ellipticine, a natural product from Ochrosia elliptica, has been broadly investigated for its anticancer effects. Although inflammation has been clearly identified as a key factor in the onset and progression of cancer, the relationship between ellipticine and inflammation remains unknown. Hence, the aims of the present study were to assess the effects of ellipticine on the inflammatory responses to lipopolysaccharide (LPS)-induced macrophages and to potentially identify the underlying mechanisms involved. Viability testing showed that ellipticine was not significantly toxic to Raw264.7 cells and actually conveyed protective effects to LPS-stimulated Raw264.7 cells and human peripheral blood monocytes by decreasing the secretion of inflammatory factors (TNF-α and IL-6). The results of western blot analysis and electrophoretic mobility shift assays showed that ellipticine markedly suppressed LPS-induced activation of the JNK/AP-1 (c-Fos and c-Jun) signaling pathway, but not ERK/p38/NF-κB pathway (p65 and p50) activation. Furthermore, ellipticine reduced the inflammatory response and mortality in a mouse model of LPS-induced endotoxic shock. Collectively, these data indicate that ellipticine may be a potential therapeutic agent for the treatment of inflammation-associated diseases.

Berberine (BBR) is a traditional folk medicine with excellent anti-inflammatory properties. This study aimed to investigate the anti-arthritic effects of BBR in adjuvant arthritis (AA) in rats and its regulatory role in the polarization of macrophages. Rats were immunized with Complete Freund's Adjuvant (CFA), and then BBR (40, 80, 160 mg/kg) was administered orally for 14 days. BBR significantly reduced paw swelling and arthritis global assessment as well as alleviated joint destruction and inflammatory cell infiltration. The index of the thymus and thymocyte proliferation were significantly reduced by BBR. Moreover, BBR treatment restrained the phagocytic function of macrophages and restored the balance of M1/M2 by reducing the levels of M1 cytokines (tumour necrosis factor-α, interleukin-1β, and interleukin-6), increasing the levels of M2 cytokines (interleukin-10 and transforming growth factor-β1), increasing the expression of arginase 1(Arg1) (M2 marker) and decreasing the expression of inducible nitric oxide synthase (iNOS) (M1 marker). BBR also downregulated the ratio of Th17/Treg cells. Further research on the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/nuclear factor κB (NF-κB) pathway found that BBR upregulated the activity of AMPK, while it downregulated the expression of phospho-RelA (p-p65), phospho-NF-kappa-B inhibitor alpha (p-IκBα) and cyclooxygenase (COX)-2. Therefore, our findings suggest BBR has significantly therapeutic effects in AA rats by regulating the polarization of macrophages through the AMPK/NF-кB pathway., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The aryl hydrocarbon receptor (AhR) is an important immune regulator with a role in inflammatory response. However, the role of AhR in IL-10 production by inflammatory macrophages is currently unknown. In this study, we investigated LPS-induced IL-10 expression in macrophages from AhR-KO mice and AhR-overexpressing RAW264.7 cells. AhR was highly expressed after LPS stimulation through NF-κB pathway. Loss of AhR resulted in reduced IL-10 expression in LPS-induced macrophages. Moreover, the IL-10 expression was elevated in LPS-induced AhR-overexpressing RAW264.7 cells. Maximal IL-10 expression was dependent on an AhR non-genomic pathway closely related to Src and STAT3. Furthermore, AhR-associated Src activity was responsible for tyrosine phosphorylation of STAT3 and IL-10 expression by inflammatory macrophages. Adoptive transfer of AhR-expressing macrophages protected mice against LPS-induced peritonitis associated with high IL-10 production. In conclusion, we identified the AhR-Src-STAT3-IL-10 signaling pathway as a critical pathway in the immune regulation of inflammatory macrophages, It suggests that AhR may be a potential therapeutic target in immune response.

Prostate cancer (PCa) has become the second leading cause of male cancer-related mortality in the United States. Mesenchymal stem cells (MSCs) are able to migrate to tumor tissues, and are thus considered to be novel antitumor carriers. However, due to their immunosuppressive nature, the application of MSCs in PCa therapy remains limited. In this study, we investigated the effect of MSCs overexpressing an NAD-dependent deacetylase sirtuin 1 (MSCs-Sirt1) on prostate tumor growth, and we analyzed the underlying mechanisms. Our results show that MSCs accelerate prostate tumor growth, whereas MSCs-Sirt1 significantly suppresses tumor growth. Natural killer (NK) cells and macrophages are the prominent antitumor effectors of the MSCs-Sirt1-induced antitumor activity. IFN-γ and C-X-C motif chemokine ligand 10 (CXCL10) are highly expressed in MSCs-Sirt1 mice. The antitumor effect of MSCs-Sirt1 is weakened when CXCL10 and IFN-γ are inhibited. These results show that MSCs-Sirt1 can effectively inhibit prostate cancer growthrecruiting NK cells and macrophages in a tumor inflammatory microenvironment.

Background The giant cell tumor (GCT) is a benign tumor which consists of three types cells: mononuclear histiocytic cells (MNHCs), multinuclear giant cells (MNGCs), and GCT stromal cells (GCTSCs). Numerous studies claim that GCTSCs have mesenchymal stem cells (MSCs) characters and play an important role in osteoclastogenesis; however, there are no research studies concerning macrophage polarization among GCT, which can be regarded as an ingredient for tumor aggression. Method We tested the effect of GCTSCs from three GCT samples which were collected from patients on proliferation, apoptosis and polarization of macrophage. Result In this article, we verified that GCTSCs expressed MSCs markers and had higher proliferation and relative lower differentiation abilities compared with BMMSCs. What’s more, we found a higher proportion of M2 macrophages among neoplasm. Co-culturing GCTSCs with macrophages resulted in prominent macrophage M2 polarization and increased the release of IL-6 (Interleukin-6) and IL-10 (Interleukin-10)from GCTSCs. In conclusion, GCTSCs, as originating from MSCs, can secret IL-6 and IL-10, which may play a significant role in macrophage M2 polarization.

Cardiovascular disease events are the result of functional and structural abnormalities in the arteries and heart. Atherosclerosis is the main cause and pathological basis of cardiovascular diseases. Atherosclerosis is a multifactorial disease associated with dyslipidemia, inflammation, and oxidative stress, among which dyslipidemia and chronic inflammation occur in all processes. Under the influence of lipoproteins, the arterial intima causes inflammation, necrosis, fibrosis, and calcification, leading to plaque formation in specific parts of the artery, which further develops into plaque rupture and secondary thrombosis. Foam cell formation from macrophages is an early event in the development of atherosclerosis. Lipid uptake causes a vascular inflammatory response, and persistent inflammatory infiltration in the lesion area further promotes the development of the disease. Inhibition of macrophage differentiation into foam cell and reduction of the level of proinflammatory factors in macrophages can effectively alleviate the occurrence and development of atherosclerosis. Peroxisome proliferator‐activated receptor γ (PPARγ) is a ligand‐activated nuclear receptor that plays an important antiatherosclerotic role by regulating triglyceride metabolism, lipid uptake, cholesterol efflux, macrophage polarity, and inhibiting inflammatory signaling pathways. In addition, PPARγ shifts its binding to ligands and co‐activators or co‐repressors of transcription of target genes through posttranslational modification, thereby affecting the regulation of its downstream target genes. Many ligand agonists have also been developed targeting PPARγ. In this review, we summarized the role of PPARγ in lipid metabolism and inflammation in development of atherosclerosis, the posttranslational regulatory mechanism of PPARγ, and further discusses the value of PPARγ as an antiatherosclerosis target. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a disease largely driven by resident and recruited macrophages. The phenotypic switch of hepatic macrophages can be achieved by chemo-attractants and cytokines. During a screening of plants traditionally used to treat liver diseases in China, paeoniflorin was identified as a potential drug that affects the polarization of macrophages. The aim of this study was to evaluate the therapeutic effects of paeoniflorin in an animal model of liver fibrosis and explore its underlying mechanisms. Liver fibrosis was induced in Wistar rats via an intraperitoneal injection of CCl4. In addition, the RAW264.7 macrophages were cultured in the presence of CoCl2 to simulate a hypoxic microenvironment of fibrotic livers in vitro. The modeled rats were treated daily with either paeoniflorin (100, 150, and 200 mg/kg) or YC-1 (2 mg/kg) for 8 weeks. Hepatic function, inflammation and fibrosis, activation of hepatic stellate cells (HSC), and extracellular matrix (ECM) deposition were assessed in the in vivo and in vitro models. The expression levels of M1 and M2 macrophage markers and the NF- κ B/HIF-1 α pathway factors were measured using standard assays. Paeoniflorin significantly alleviated hepatic inflammation and fibrosis, as well as hepatocyte necrosis in the CCl4-induced fibrosis model. Furthermore, paeoniflorin also inhibited HSC activation and reduced ECM deposition both in vivo and in vitro. Mechanistically, paeoniflorin restrained M1 macrophage polarization and induced M2 polarization in the fibrotic liver tissues as well as in the RAW264.7 cells grown under hypoxic conditions by inactivating the NF- κ B/HIF-1 α signaling pathway. In conclusion, paeoniflorin exerts its anti-inflammatory and anti-fibrotic effects in the liver by coordinating macrophage polarization through the NF- κ B/HIF-1 α pathway. [ABSTRACT FROM AUTHOR]

Objective Interleukin (IL)-37 is a natural suppressor of inflammation. Macrophages play an important role in acute gout flare by dominating the inflammation and spontaneous relief. We have reported that IL-37 could limit runaway inflammation in gout. Here we focus on whether IL-37 inhibits gouty inflammation by altering macrophage functions, and how it does so. Methods Macrophage functions were evaluated in terms of phagocytosis, pyroptosis, polarization and metabolism. Phagocytosis and polarization of macrophages were detected by side scattering and double-labelling induced nitrogen monoxide synthase (iNOS)/arginase-1 (Arg-1) using flow cytometry, respectively. Transcription of pyroptosis-related molecules was detected by qPCR. Metabolomics was performed by liquid chromatograph mass spectrometer. Human IL-37 knock-in mice and a model with point mutation (S9A) at mouse Gsk3b locus were created by CRISPR/Cas-mediated genome engineering. MSU was injected into the paws and peritoneal cavity to model acute gout. Vernier calliper was used to measure the thickness of the paws. The mice paws and human synovium tissues or tophi were collected for pathological staining. Peritoneal fluid of mice was used to enrich macrophages to detect polarization. Results IL-37 promoted non-inflammatory phagocytic activity of macrophages by enhancing phagocytosis of MSU, reducing transcription of pyroptosis-related proteins and release of inflammatory cytokines, protecting mitochondrial function, and mediating metabolic reprogramming in MSU-treated THP-1 cells. These multifaceted roles of IL-37 were partly depended on the mediation of glycogen synthase kinase-3β (GSK-3β). Conclusions Our study revealed that IL-37 could shape macrophages into a 'silent' non-inflammatory phagocytic fashion. IL-37 may become a potentially valuable treatment option for patients of chronic gout, especially for those with tophi. [ABSTRACT FROM AUTHOR]

A higher ratio of M1/M2 macrophages and an elevated chemerin level are both related to increased risk of preeclampsia. However, the crosstalk between these two events and their collective contribution to preeclampsia are not well understood. In this study, we assessed the impacts of chemerin chemokine-like receptor 1 (CMKLR1)/p-Akt/CEBPα axis in regulating macrophage polarization and mediating the pathogenic effects of chemerin on preeclampsia. We showed that chemerin, in a dose- and time-dependent manner, stimulated M1 macrophage polarization, inhibited macrophage-induced trophoblast invasion and migration, and suppressed macrophage-mediated angiogenesis. All these chemerin-induced phenotypes are essentially mediated by sequentially CMKLR1, Akt activation, and CEBPα. Mechanistically, CEBPα acted as a transcriptional activator for both IRF8 and chemerin. In vivo, chemerin aggravated preeclampsia, while α-NETA, an inhibitor for CMKLR1, significantly suppressed M1 macrophage polarization and alleviated preeclampsia. In summary, chemerin, by activating CMKLR1/Akt/CEBPα axis, forms a positive feedback loop, promotes M1 macrophage polarization, suppresses trophoblast migration/invasion and angiogenesis, and contributes to preeclampsia. Therefore, targeting chemerin signaling may benefit the prevention and/or treatment of preeclampsia. [ABSTRACT FROM AUTHOR]

Pressure overload induced cardiac remodeling is associated with a complex spectrum of pathophysiological mechanisms. As inflammatory cells, macrophages maintain a critical position in mechanical stress-induced myocardial remodeling. HMGB1 is a highly conserved, ubiquitous protein in various types of cells whose biological roles are closely dependent on subcellular sites. However, whether HMGB1 expressed in macrophages performs the protective or pathological responses in cardiac remodeling is unknown. In this study, we generated the myeloid-specific HMGB1 knockout mice and detected the effects of macrophage HMGB1 in response to pathophysiological stress. Our data showed HMGB1 in macrophages played a protective role against the pressure overload induced cardiac pathophysiology. The deletion of HMGB1 in macrophages gains more differentiation of M1-type pro-inflammatory macrophage during the mechanical stress-induced myocardial remodeling, thereby aggravating the inflammatory response in whole heart, resulting in accelerated deterioration of cardiac function. Moreover, in vitro data also validated HMGB1 got involved in the process of macrophage polarization. Macrophages without HMGB1 are more inclined to differentiate into M1 during the stretch process. In summary, the present results indicated that loss of HMGB1 in macrophages can exacerbate heart failure through increased differentiation of pro-inflammatory macrophages and enhanced inflammatory response. • HMGB1 in macrophage nucleus played a protective role against the pressure overload induced cardiac pathophysiology. • Deleting HMGB1 in macrophages gains more differentiation of M1 macrophage and expression of inflammatory genes after TAC. • Macrophages without nuclear HMGB1 are more inclined to differentiate into M1 macrophage during the in vitro stretch process. [ABSTRACT FROM AUTHOR]

Activation of the renin–angiotensin system has been implicated in hypertension. Angiotensin (Ang) II is a potent proinflammatory mediator. The present study investigated the role of myeloid angiotensin type 1 receptor (AT1R) in control of macrophage phenotype in vitro and vascular injury in deoxycorticosterone acetate (DOCA)/salt hypertension. In human THP-1/macrophages, Ang II increased mRNA expressions of M1 cytokines and decreased M2 cytokine expressions. Overexpression of AT1R further increased Ang II-induced expressions of M1 cytokines and decreased M2 cytokines. Silenced AT1R reversed Ang II-induced changes in M1 and M2 cytokines. Ang II upregulated hypoxia-inducible factor (HIF)1α, toll-like receptor (TLR)4, and the ratio of pI κ B/I κ B, which were prevented by silenced AT1R. Silenced HIF1α prevented Ang II activation of the TLR4/NF κ B pathway. Furthermore, Ang II increased HIF1α via reactive oxygen species-dependent reduction in prolyl hydroxylase domain protein 2 (PHD2) expression. The expressions of AT1R and HIF1α and the ratio of pI κ B/I κ B were upregulated in the peritoneal macrophages of DOCA hypertensive mice, and the specific deletion of myeloid AT1R attenuated cardiac and vascular injury and vascular oxidative stress, reduced the recruitment of macrophages and M1 cytokine expressions, and improved endothelial function without significant reduction in blood pressure. Our results demonstrate that Ang II/AT1R controls the macrophage phenotype via stimulating the HIF1α/NF κ B pathway, and specific myeloid AT1R KO improves endothelial function, vascular inflammation, and injury in salt-sensitive hypertension. The results support the notion that myeloid AT1R plays an important role in the regulation of the macrophage phenotype, and dysfunction of this receptor may promote vascular dysfunction and injury in salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is inflammation-related cancer. Persistent inflammatory injury of the liver is an important factor mediating the occurrence and development of liver cancer. Hepatic macrophages play an important role in the inflammatory microenvironment, which mediates tumor immune escape, tumor growth, and metastasis. Previous studies have suggested that L-3,5,3-triiodothyronine (T3) can regulate inflammation; however, its use is associated with serious cardiac side effects, and its role in hepatocarcinogenesis remains unclear. In this study, we aimed to develop an effective T3 delivery system with reduced cardiac toxicity and to explore its effects on HCC occurrence. Methods: T3 liposomes (T3-lipo) were prepared using the thin-film hydration method, and their characteristics, including particle size, polydispersity index, zeta potential, encapsulation efficiency, drug loading, drug release, and stability, were evaluated in vitro. We assessed the effect of T3-lipo on hepatocarcinogenesis in diethylnitrosamine (DEN)–induced primary HCC in rats and examined the biodistribution of T3 and T3-lipo by high-performance liquid chromatography–mass spectrometry. Furthermore, we explored the potential molecular mechanism of T3-lipo in hepatocarcinogenesis by immunohistochemistry and immunofluorescence analyses, Bio-Plex assays, real-time polymerase chain reaction analysis, and Western blotting assays. Results: Compared with T3, T3-lipo had an enhanced inhibitory effect on hepatocarcinogenesis and reduced cardiac side effects in DEN-induced primary HCC in rats. Mechanistically, T3-lipo were absorbed by hepatic macrophages and regulated the secretion of inflammatory cytokines in macrophages by inhibiting inflammatory signaling pathways. Conclusions: T3-lipo may suppress hepatocarcinogenesis by regulating the inflammatory microenvironment in the liver and reduce the cardiac side effects meanwhile. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) have emerged as therapeutic interests in cancer nanomedicine because TAMs play a pivotal role in the immune microenvironment of solid tumors. Dextran and its derived nanocarriers are among the most promising nanomaterials for TAM targeting due to their intrinsic affinities towards macrophages. Various dextran-based nanomaterials have been developed to image TAMs. However, the effects of physiochemical properties especially for surface charges of dextran nanomaterials on TAM-targeting efficacy were ambiguous in literature. To figure out the surface charge effects on TAM targeting, here we developed a facile non-covalent self-assembly strategy to construct oppositely charged dextran nanogels (NGs) utilizing the coordination interaction of ferric ions, chlorine e6 (Ce6) dye and three dextran derivatives, diethylaminoethyl-, sulfate sodium- and carboxymethyl-dextran. The acquired dextran NGs exhibit different charges but similar hydrodynamic size, Ce6 loading and mechanical stiffness, which enables a side-by-side comparison of the effects of NG surface charges on TAM targeting monitored by the Ce6 fluorescence imaging. Compared with negative NGs, the positive NG clearly displays a superior TAM targeting in murine breast cancer model. This study identifies that positively charged dextran NG could be a promising approach to better engineer nanomedicine towards an improved TAM targeting. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives: This paper aims to study the effect of the active form of vitamin D (calcitriol) on the internalized Porphyromonas gingivalis in macrophages and to assess the role of autophagy during this process. Materials and methods: Quantitative RT‐PCR and bacteria culture were used to quantify live P. gingivalis internalized into U937‐derived macrophages. Western blot assays were performed to detect the effect of P. gingivalis and calcitriol on autophagy in macrophages. Transmission electron microscope was used to observe the effect of calcitriol on the status of internalized P. gingivalis. Colocalization of P. gingivalis with the autophagosome and lysosome markers was observed by confocal laser scanning microscopy. Results: Calcitriol caused a dose‐dependent decrease in live P. gingivalis numbers and promoted both the endogenous and P. gingivalis‐induced autophagy in macrophages. Calcitriol significantly promoted the destruction of P. gingivalis and the colocalization of P. gingivalis with autophagosome and lysosome markers. Conversely, with 3‐MA, live P. gingivalis numbers in macrophages increased significantly and inhibition effect of calcitriol on the number of live P. gingivalis was attenuated. Conclusion: In U937‐derived macrophages, calcitriol may promote colocalization of P. gingivalis with autophagosomes and lysosomes, namely autophagy process, to degrade live P. gingivalis. [ABSTRACT FROM AUTHOR]

Macrophages are key responders of inflammation and are closely related with oxidative stress. Activated macrophages can enhance oxygen depletion, which causes an overproduction of reactive oxygen species (ROS) and leads to further excessive inflammatory response and tissue damage. Agmatine, an endogenous metabolite of L-arginine, has recently been shown to have neuroprotective effects based on its antioxidant properties. However, the antioxidant effects of agmatine in peripheral tissues and cells, especially macrophages, remain unclear. In this study we explored the role of agmatine in mediating antioxidant effects in RAW 264.7 cells and studied its antioxidant mechanism. Our data demonstrate that agmatine is an activator of Nrf2 signaling that markedly enhances Nrf2 nuclear translocation, increases nuclear Nrf2 protein level, up-regulates the expression of the Nrf2 downstream effector HO-1, and attenuates ROS generation induced by Lipopolysaccharide (LPS). We further demonstrated that the agmatine-induced activation of Nrf2 is likely through the PI3K/Akt pathway. LY294002, a specific PI3K/Akt inhibitor, abolished agmatine-induced HO-1 up-regulation and ROS suppression significantly. Inhibiting HO-1 pathway significantly attenuated the antioxidant effect of agmatine which the products of HO-1 enzymatic activity contributed to. Furthermore, the common membrane receptors of agmatine were evaluated, revealing that α2-adrenoceptor, I1-imidazoline receptor or I2-imidazoline receptor are not required by the antioxidant properties of agmatine. Taken together, our findings revealed that agmatine has antioxidant activity against LPS-induced ROS accumulation in RAW 264.7 cells involving HO-1 expression induced by Nrf2 via PI3K/Akt pathway activation. [ABSTRACT FROM AUTHOR]

Background: Cerebral hypoperfusion is a pivotal risk factor for vascular dementia (VD), for which effective therapy remains inadequate. Persistent inflammatory responses and excessive chemotaxis of microglia/macrophages in the brain may accelerate the progression of VD. Endocannabinoids are involved in neuronal protection against inflammation-induced neuronal injury. Cannabinoids acting at cannabinoid receptor 2 (CB2R) can decrease inflammation. Based on the identification of paeoniflorin (PF) as a CB2R agonist, we investigated the neuroprotective and microglia/macrophages M1 to M2 polarization promoting effects of PF in a permanent four-vessel occlusion rat model. Methods: One week after surgery, PF was intraperitoneally administered at a dose of 40 mg/kg once a day for 28 successive days. The effects of PF on memory deficit were investigated by a Morris water maze test, and the effects of PF on hippocampal neuronal damage were evaluated by light microscope and electron microscope. The mRNA and protein expression levels of key molecules related to the M1/M2 polarization of microglia/macrophages were assessed by RT-qPCR and Western blotting, respectively. Results: Administration of PF could significantly attenuate cerebral hypoperfusion-induced impairment of learning and memory and reduce the morphological and ultrastructural changes in the hippocampal CA1 region of rats. Moreover, PF promoted an M1 to M2 phenotype transition in microglia/macrophages in the hippocampus of rats. In addition to its inhibitory property against proinflammatory M1 mediator expression, such as IL-1β, IL-6, TNF-α and NO, PF dramatically up-regulated expression of anti-inflammatory cytokines IL-10 and TGF-β1. Importantly, CB2R antagonist AM630 abolished these beneficial effects produced by PF on learning, memory and hippocampus structure in rats, as well as the polarization of microglia/macrophages to the M2 phenotype. Additionally, PF treatment significantly inhibited cerebral hypoperfusion-induced mTOR/NF-κB proinflammatory pathway and enhanced PI3K/Akt anti-inflammatory pathway. Effects of PF on these signaling pathways were effectively attenuated when rats were co-treated with PF and AM630, indicating that the mTOR/NF-κB and PI3K/Akt signaling pathways were involved in the PF effects through CB2R activation. Conclusion: These findings demonstrated PF exerts its neuroprotective effect and shifts the inflammatory milieu toward resolution by modulation of microglia/macrophage polarization via CB2R activation. [ABSTRACT FROM AUTHOR]

Mogrol, the aglycone of well-known sweeter mogrosides, shows potent anti-inflammatory activity. In this study, forty-two mogrol derivatives bearing various pharmacophores with oxygen or nitrogen atoms were designed and synthesized via structural modification at C 24 site, and their anti-inflammatory activity were screened against lipopolysaccharide (LPS)-induced RAW264.7 cells. Compared with mogrol, most of derivatives exhibited stronger inhibition of NO production without cytotoxicity. In particular, compound B5 that contained an indole motif effectively suppressed the secretion of inflammatory mediators including TNF-α and IL-6, and inhibited the expression levels of TLR4, p-p65 and iNOS proteins. Molecular docking showed that the active B5 interacted with amino acid residues of iNOS protein through π-π stacking and hydrophobic interactions with binding affinity value of −12.1 kcal/mol, which was much stronger than mogrol (−8.9 kcal/mol). These results suggest that derivative B5 is a promising anti-inflammatory molecule and the strategy of hybridizing indole skeleton on mogrol is worthy for further attention. [Display omitted] [ABSTRACT FROM AUTHOR]

Multi-drug-resistant bacterial infections, which have become a global threat, lack effective treatments. The discoveries of non-antibiotics with different modes of antibacterial action, such as methylsulfonylmethane (MSM), are a promising new treatment for multi-drug-resistant pathogens. We constructed a mouse peritonitis infection model to evaluate the effects of MSM against methicillin-resistant Staphylococcus aureus (MRSA) infection. The time-kill kinetics of MSM against MRSA and the effect of MSM on the integrity of bacterial cell membrane were measured. Viability effects of MSM on THP1 cells were performed by CCK-8 cytotoxicity assay. Systematic inflammatory factor levels of mice were detected using ELISA. The immune response of peritoneal macrophages during MRSA-infection was evaluated using RNA sequencing. Gene Ontology function, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, and correlation analyses were applied to analysis RNA sequencing data. RT-qPCR, western blotting and flow cytometry were performed to analysis the gene and protein expression levels of macrophages. In in vitro experiments, MSM did not show significant killing effects on the growth of MRSA directly and did not destroy bacterial membrane integrity. MSM also displayed no significant effects on the proliferative capacity of THP1 cells. However, MSM treatment protected mice against a lethal dose MRSA-infection and decreased systemic inflammation. MSM upregulated metabolic pathway in peritoneal macrophages, especial glycolysis, during MRSA infection. MSM increased the expression of M2 markers (such as Arg1), promoted phosphorylation of STAT3 (which regulates M2 polarization), and decreased the expression of M1 markers in peritoneal macrophages. Additionally, MSM treatment increased the expression of H3K18 lactylation specific target genes, including Arg1. GNE-140, the LDHA-specific inhibitor of glycolysis, blocked the MSM-induced Arg1 expression in this disease model. MSM protects against MRSA infection through immunomodulation. MSM promotes the expression of Arg1 by lactate-H3K18la pathway to control macrophage to M2 polarization; it firstly provides therapeutic potential for drug-resistant infections and sepsis. • MSM relieves inflammation and improves mice survival rate after MRSA infection. • MSM promotes M2 polarization of peritoneal macrophages via H3K18la-Arg1 pathway. • MSM could be a potential therapeutic agent against lethal MRSA-induced sepsis. [ABSTRACT FROM AUTHOR]

Objectives: The knowledge that agmatine is found in the human body has existed for several years; however, its role in sepsis has not yet been studied. In the present study, we investigate the role of agmatine in the progression and treatment of sepsis.Design: Clinical/laboratory investigations.Setting: Medical centers/University-based research laboratory.Subjects: Elective ICU patients with severe sepsis and healthy volunteers; C57BL/6 mice weighing 18-22 g.Interventions: Serum agmatine level and its associations with inflammatory markers were assessed in patients with sepsis. Agmatine was administered intraperitoneally to mice before a lipopolysaccharide challenge. Human peripheral blood mononuclear cells and murine macrophages were pretreated with agmatine followed by lipopolysaccharide stimulation.Measurements and Main Results: Serum agmatine levels were significantly decreased in patients with sepsis and lipopolysaccharide-induced mice, and correlated with Acute Physiology and Chronic Health Evaluation II score, procalcitonin, tumor necrosis factor-α, and interleukin-6 levels. In a therapeutic experiment, exogenous agmatine attenuated the cytokine production of peripheral blood mononuclear cells from patients with sepsis and healthy controls. Agmatine also exerted a significant beneficial effect in the inflammatory response and organ damage and reduced the death rate in lipopolysaccharide-induced mice. Imidazoline I2 receptor agonist 2-benzofuran-2-yl blocked the pharmacological action of agmatine; whereas, other imidazoline receptor ligands did not. Furthermore, agmatine significantly impaired the inflammatory response by inactivating nuclear factor-κB, but not protein 38 mitogen-activated protein kinase, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and inducible nitric oxide synthase signaling in macrophages. Activation of imidazoline I2 receptor or knockdown of ribosomal S6 kinase 2 counteracted the effects of agmatine on phosphorylation and degradation of inhibitor of nuclear factor-κBα.Conclusions: Endogenous agmatine metabolism correlated with the progression of sepsis. Supplemental exogenous agmatine could ameliorate the lipopolysaccharide-induced systemic inflammatory responses and multiple organ injuries through the imidazoline I2 receptor-ribosomal S6 kinase 2-nuclear factor-κB pathway. Agmatine could be used as both a clinical biomarker and a promising pharmaconutrient in patients with severe sepsis. [ABSTRACT FROM AUTHOR]

The purpose of this paper was to investigate the anti-inflammatory and anti-angiogenic activities of a purified polysaccharide (CCPS n ) from flesh of Cipangopaludina chinensis in lipopolysaccharide (LPS) activated RAW264.7 macrophages and human umbilical vein endothelial cells (HUVECs), respectively. Anti-inflammatory results showed that CCPS n not only greatly decreased the pro-/anti-inflammatory cytokine secretion ratios, including TNF-α/IL-10, IL-6/IL-10 and IL-1β/IL-10, but also reduced release levels of nitric oxide (NO) and prostaglandin E 2 (PGE 2 ), and suppressed expressions of cyclooxygenase2 (COX2) and inducible nitric oxide synthase (iNOS). The results from anti-angiogenic activities revealed that proliferation, migration, tube formation and vascular endothelial growth factor (VEGF) of HUVECs were significantly inhibited by CCPS n treatment. Even more remarkable was the fact that anti-inflammatory and anti-angiogenic activities of CCPS n exhibited a clear dose-response manner, and these activities were irrelevant to the cytotoxicities of CCPS n to RAW264.7 macrophages and HUVECs. These results indicated that CCPS n possessed strong anti-inflammatory and anti-angiogenic activities. [ABSTRACT FROM AUTHOR]

Co-delivery of clodronate-liposomes and doxorubicin-liposomes inhibited hepatic progenitor activation and increased drug concentrations in tumor cells by depleting macrophages, thereby inhibiting hepatocellular carcinoma development and progression. [Display omitted] • Co-delivery of clodronate-liposomes and doxorubicin-liposomes by intra-spleen injection. • Combination of doxorubicin-liposomes and clodronate-liposomes inhibited the occurrence and progression of primary hepatocellular carcinoma effectively and feasibly in DEN-induced rat HCC model without evident damage on vital organs. • Delivery of clodronate-liposomes accompanied with doxorubicin-liposomes inhibited the activation of hepatic progenitor cells, improve the tumor microenvironment and increased drug concentrations in the plasma by depleting macrophages in the liver and spleen. Macrophages in the liver have capacities of capturing and phagocytosing nanocarriers. Macrophages also play an important role in the inflammatory microenvironment and in the tumorigenesis, development and progression of hepatocellular carcinoma (HCC). Several studies have shown that depletion of macrophages is a viable strategy for drug delivery and tumor microenvironment regulation. We prepared liposomes containing doxorubicin and clodronate using an ammonium sulfate gradient and thin film hydration method. The repressive therapeutic effects of liposomes were compared by intrasplenic injection at different stages of a primary HCC model induced by diethylnitrosamine (DEN) in rats. Doxorubicin-liposome (DOX-LIP) and clodronate-liposome (CL-LIP) about 180–200 nm were successfully prepared and characterized. We found that DOX-LIP combined with CL-LIP could effectively inhibit the occurrence and development of liver cancer without major organ damage and side effects. The combination of doxorubicin and clodronate liposomes notably decreased hepatic CD68 + macrophages, enriched DOX in plasma and accumulated it for a long time in the liver and spleen, thus improving the tumor microenvironment, inhibiting the activation of hepatic progenitor cells (HPCs) and promoting the apoptosis of tumor cells, and finally producing the inhibitory and therapeutic effects of HCC in rats. Results of this study were expected to provide a new prospect for the chemotherapy of HCC. [ABSTRACT FROM AUTHOR]

One new sesquineolignan, piperneolignan A (1), four new neolignans, piperneolignans B–E (2 – 5), and eight known compounds were isolated from the leaves of Piper betle (Piperaceae) collected from Myanmar. These new structures were determined by analysis of MS and NMR data, and the absolute configuration of piperneolignan A was elucidated by electronic circular dichroism (ECD) calculations. Piperneolignan A (1), piperneolignan B (2), hydroxychavicol (6), p -hydroxycinnamaldehyde (10), and diallylcatechol (13) possessed anti-inflammatory activity against nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells with IC 50 values of 9.87, 45.94, 4.80, 26.40, and 40.45 μM, respectively, compared with the positive control NG-monomethyl- l -arginine (l -NMMA, IC 50 = 33.84 μM). The two hydroxy groups in the structure of hydroxychavicol are essential for activity, and dimerization or trimerization of hydroxychavicol decreases activity. [ABSTRACT FROM AUTHOR]

Jiao Mei Gu (JMG), Cayratia albifolia C.L.Li, is a type of Dong plant widely growing in Dong autonomous counties, Hunan province, China. As a type of traditional herbal medicine, the root of JMG plant has been used to treat inflammatory-related diseases such as arthritis because of its prominent anti-inflammatory effects in Dong medicine. This work investigated the anti-inflammatory effects and mechanisms of the water extract from the root of JMG on lipopolysaccharide (LPS)-induced inflammatory models. Endotoxemia was induced in C57BL/6 mice by intraperitoneal injection of LPS (20 mg/kg), meanwhile intraperitoneal administration of safe doses of JMG. The survival curve of mice was determined. Serum inflammatory cytokines were detected by the Bio-Plex Mouse Cytokine 23-Plex Panel Kit and enzyme-linked immunosorbent assay (ELISA) at 6 h after drug treatment. Hematoxylin-eosin (HE) staining of important organs was completed at 24 h after treatment. The mechanism of inflammatory action was investigated in vitro on LPS-stimulated macrophages. Macrophage inflammation was then induced using 10 μg/mL LPS. The anti-inflammatory effect of JMG was investigated by the quantitative polymerase chain reaction (qPCR) and ELISA. The anti-inflammatory mechanism was determined using western blotting, the electrophoretic mobility shift assay, and immunocytochemistry. Finally, the antimicrobial activity of JMG was verified by survival experiments in vivo and by bacterial culture experiments in vitro. A 200 mg/kg water extract of JMG was safe for mice and had a significant protective effect on LPS-induced sepsis. Organ damage of heart, liver, lung and kidney was also significantly reduced at 24 h in the JMG group, when compared with the LPS group. The serum MIP-1α (CCL-3), MIP-1β (CCL-4), IL-1β, and TNFα cytokines were significantly decreased at 6 h in the JMG group, when compared with the LPS group. In a similar manner, 0.2μg/ml JMG significantly reduced mRNA and protein levels of MIP-1α (CCL-3), MIP-1β (CCL-4), IL-1β, and TNFα in LPS-stimulated macrophage. JMG treatment inhibited the phosphorylation of NF-κB p65 and reduced nuclear transduction, thus reducing transcriptional activity. At the same time, we showed that JMG had no protective effect on Escherichia coli -induced sepsis, as well as no antimicrobial activity. Our results showed that a water-soluble extract of JMG inhibited LPS-induced inflammation via attenuating the NF-κB signaling pathway, which provides an important rationale for the treatment of inflammation-related diseases. Image 1 [ABSTRACT FROM AUTHOR]