Overactivation Of Macrophages Research Articles

Diverse pro-inflammatory ability of mutated spike protein derived from variant strains of SARS-CoV-2

The severity of COVID-19 has been reported to differ among SARS-CoV-2 mutant variants. The overactivation of macrophages is involved in severe COVID-19, yet the effects of SARS-CoV-2 mutations on macrophages remain poorly understood. To clarify the effects, we examined whether mutations of spike proteins (S-proteins) affect macrophage activation. CD14+ monocyte-derived macrophages were stimulated with the recombinant S-protein of the wild-type, Delta, and Omicron strains or live viral particles of individual strains. Regarding IL-6 and TNF-α, Delta or Omicron S-protein had stronger or weaker pro‑inflammatory ability, respectively, than the wild-type. Similar trends were observed between S-proteins and viral particles. S-protein mutations could be related to the diversity in macrophage activation and severity rates in COVID-19 caused by various SARS-CoV-2 strains.

Detection of a novel gross deletion in the UNC13D gene ends the diagnostic odyssey for a family with familial hemophagocytic lymphohistiocytosis 3

BackgroundFamilial hemophagocytic lymphohistiocytosis (FHL) is an immunological disorder characterized by overactivation of macrophages and T lymphocytes. This autosomal recessive condition has been characterized into multiple types depending on the genetic etiology. FHL type 3 is associated with bi-allelic pathogenic variants in the UNC13D gene.Case presentationWe present a 12-year diagnostic odyssey for a family with FHL that signifies the advances of FHL genetic testing in a clinical genetic diagnostic laboratory setting. We describe the first case of a large UNC13D gross deletion in trans to a nonsense variant in a family with FHL3, which may have been mediated by Alu elements within introns 12 and 25 of the UNC13D gene.ConclusionsThis case highlights the importance of re-evaluating past genetic testing for a patient and family as test technology evolves in order to end a diagnostic odyssey.

Inhibitory Effect of Cinobufotalin on Macrophage Inflammatory Factor Storm and Its Mechanism

To investigate the inflammatory effects of Cinobufotalin on monocytes in resting state and macrophages in activated state and its molecular mechanism. THP-1 cells were stimulated with Phorbol 12-myristate 13-acetate to induce differentiation into macrophages. Lipopolysaccharides was added to activate macrophages in order to establish macrophage activation model. Cinobufotalin was added to the inflammatory cell model for 24 h as a treatment. CCK-8 was used to detect cell proliferation, Annexin V /PI double staining flow cytometry was used to detect cell apoptosis, flow cytometry was used to detect macrophage activation, and cytometric bead array was used to detect cytokines. Transcriptome sequencing was used to explore the gene expression profile regulated by Cinobufotalin. Changes in the significantly regulated molecules were verified by real-time quantitative polymerase chain reaction and Western blot. 1∶25 concentration of Cinobufotalin significantly inhibited the proliferation of resting monocytes(P<0.01), and induced apoptosis(P<0.01), especially the activated macrophages(P<0.001, P<0.001). Cinobufotalin significantly inhibited the activation of macrophages, and significantly down-regulated the inflammatory cytokines(IL-6, TNF-α, IL-1β, IL-8) released by activated macrophages(P＜0.001). Its mechanism was achieved by inhibiting TLR4/MYD88/P-IκBa signaling pathway. Cinobufotalin can inhibit the inflammatory factors produced by the over-activation of macrophages through TLR4/MYD88/P-IκBa pathway, which is expected to be applied to the treatment and research of diseases related to the over-release of inflammatory factors.

Investigation of Anti-inflammatory and Anti-oxidative Activities of Lonicerae Flos, &lt;i&gt;Citri&lt;/i&gt; Pericarpium and &lt;i&gt;Violae&lt;/i&gt; Herba Complex (LCVC)

Objectives: The anti-inflammatory and anti-oxidative activities of LCVC (&lt;i&gt;Lonicerae&lt;/i&gt; Flos, &lt;i&gt;Citri&lt;/i&gt; Pericarpium and &lt;i&gt;Violae&lt;/i&gt; Herba Complex) have not been fully elucidated. The purpose of this study was to investigate the mechanisms underlying these effects in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages.Methods: The evaluation of the anti-oxidative activity of LCVC was completed via DPPH and ABTS radical scavenging capacity, FRAP assay, measurement of polyphenol and flavonoid, assessment of ROS and NO levels in LPS-induced RAW 264.7 cells. The anti-inflammatory activity was defined by measuring the production of biomarkers (PGE2, IL-1B, IL-6 and TNF-&lt;i&gt;α&lt;/i&gt;), proteins (ERK, JNK, P38, Nrf2, Keap1, HO-1 and NQO1) and expressions of genes (iNOS, COX-2, IL-1&lt;i&gt;β&lt;/i&gt;, IL-6, TNF-&lt;i&gt;α&lt;/i&gt;, Nrf2, Keap1, HO-1 and NQO1) in LPS-induced RAW 264.7 cells.Results: LCVC have polyphenol and flavonoid contents. The results of DPPH and ABTS free radical scavenging capacity and FRAP assay showed that the anti-oxidative activity was increased. Production of ROS, NO, IL-6, TNF-&lt;i&gt;α&lt;/i&gt;, mRNA expressions of IL-1&lt;i&gt;β&lt;/i&gt;, IL-6, TNF-&lt;i&gt;α&lt;/i&gt;, Keap1, iNOS and COX-2 were decreased, and NQO1, Nrf2, and HO-1 were increased. In protein expression, JNK and Keap1 were decreased, NQO1, Nrf2 and HO-1 were increased, and no relationships were observed with the ERK and P38 by LCVC.Conclusions: These results suggest that LCVC may offer protective effects against LPS-induced inflammatory and oxidative responses through attenuating Nrf2/HO-1 pathway and MAPKs pathway. Therefore, we propose that LCVC has anti-inflammatory and anti-oxidative activities that have therapeutic potential in the treatment of inflammatory and oxidative disorders caused by the over-activation of macrophages.

Acute Clinical Syndrome of HLH in Patients with Hematologic Malignancy and EBV Infection

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by dysregulation of the reticuloendothelial system, overactivation of macrophages and lymphocytes, hemophagocytosis, and cytokine storm collectively causing systemic inflammation and organ damage. Malignancy-associated HLH (M-HLH) is associated with poor prognosis and survival of 1-2 months (Daver N, et.al., Cancer. 2017). Viral infections such as Epstein-Barr Virus (EBV) can independently contribute to development of lymphoproliferative neoplasms and non-malignancy associated HLH. While both malignancy and EBV are recognized as independent risk factors for HLH, a syndrome of overlapping M-HLH and EBV-HLH remains underreported. The optimal long-term treatment strategy for M-HLH in EBV positive patients is unknown, with combinations of HLH and malignancy directed therapy reported in the literature without significant improvement in survival (Zhao A, et.al., Front Immunol. 2022). We report a case series of patients with EBV infection and newly diagnosed hematologic malignancies complicated by HLH demonstrating poor prognosis despite initial control of disease. Methods: Between July 2020 and July 2021, 8 patients >18 years of age hospitalized at Montefiore Medical Center were identified meeting diagnostic criteria of HLH with associated primary hematologic malignancy, and concomitant EBV infection. Data on demographics and clinical characteristics, laboratory studies, malignancy diagnosis, treatments received, and disease course were collected. HLH-04, H-Score were recorded for all patients. Data were analyzed using descriptive statistics. Results: The median age was 53.6 years old (range 29-75). Five out of 8 patients met systemic inflammatory response syndrome (SIRS) criteria on presentation. The median H-Score was 217.1 (range 183-247). All but one patient exceeded CD25 and ferritin parameters of optimized HLH inflammatory (OHI) index suggestive of high mortality risk. Classical Hodgkin Lymphoma (cHL) was seen in 4/8 patients; other diagnoses included large B cell lymphoma, angioimmunoblastic T cell lymphoma, intravascular large B cell lymphoma, and anaplastic large cell lymphoma. Dexamethasone was the backbone of treatment and the initial HLH directed therapy in all patients, starting on average 9 days after presentation (range 2-17) and preceding treatment with other HLH directed therapies by median of 7.2 days (range 0-33). Four out of 8 patients received dexamethasone, etoposide, and rituximab; 2 patients received dexamethasone with etoposide and 2 received dexamethasone alone. The administration schedule and cumulative doses of both rituximab and etoposide varied significantly between the patients. Initiation of malignancy directed chemotherapy lagged the initiation of dexamethasone by median of 16.5 days (range 0-53). Delays were due to patients' clinical condition, organ function, and pending diagnosis of malignancy. Median overall survival from the initial presentation was 102.5 days (range 33-219). Two out of 8 patients in our case series survived. One received dexamethasone and etoposide, followed by 6 cycles of malignancy-directed chemotherapy and autologous stem cell transplant. The second patient was treated with dexamethasone, rituximab, etoposide with addition of anakinra, followed by malignancy directed therapy without rituximab or etoposide. At the time of death, 4 out of 6 patients had active HLH and 3 out of 6 patients were treated for an overwhelming polymicrobial infection. Conclusion: HLH is the setting of EBV-positive malignancy results in a syndrome with an aggressive clinical course and high early mortality rate. Here we demonstrate that HLH-directed therapy prior to or incorporated into malignancy-directed therapy extended patients' survival to median 3 months, as compared to 1-2 months reported in the literature. Nevertheless, most patients suffered HLH relapse and succumbed to infectious complications of prolonged hospitalization and immunosuppression. Long term HLH therapy with immunomodulatory agents and EBV-directed therapies is needed to achieve sustained control of systemic inflammation. Patients who survive initial HLH episode need to be closely monitored for recurrence. Preemptive strategies such as autologous stem cell transplant should be considered in eligible patients to further reduce the risk of relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Rhein ameliorates septic lung injury and intervenes in macrophage metabolic reprogramming in the inflammatory state by Sirtuin 1

AimsSepsis is an organ dysfunction syndrome caused by the maladjustment of response to infection. Acute lung injury (ALI) appears the earliest, with urgent onset and limited treatments. Previous pharmacological studies have found that rhein (RH), an active ingredient rich in rhubarb, has multiple pharmacological activities such as anti-inflammatory, anti-infection and metabolic regulation. This research aimed to explore whether RH alleviates septic acute lung injury and probe possible mechanisms. Main methodsIn this study, the septic ALI mouse model was established by cecal ligation and perforation (CLP). LPS-induced RAW264.7 model was selected to further explore the protective mechanism of RH. H&E staining, Western blot, qRT-PCR, and 1H NMR analysis were used to verify the protective effect of RH on ALI in vivo and vitro. Key findingsRH could relieve pathological lung injury and pulmonary edema, reduce the serum LPS and inhibit inflammatory response in CLP mice. Further studies displayed that RH affected the metabolism in vivo, with significant changes in serum and lung metabolomics. In vitro results demonstrated that RH inhibited the expression of inflammatory mediators and factors in macrophages by affecting metabolic reprogramming and upregulating the expression of Sirtuin 1. SignificanceRH improved the overall metabolic condition of sepsis mice by up-regulating and activating SIRT1, and inhibited the over activation of macrophages by regulating metabolism. These findings reveal the therapeutic mechanism of RH on sepsis ALI from the perspective of metabolism.

TRIM64 promotes ox-LDL-induced foam cell formation, pyroptosis, and inflammation in THP-1-derived macrophages by activating a feedback loop with NF-κB via IκBα ubiquitination

Atherosclerosis is a chronic inflammatory disease and the main pathology behind most cardiovascular diseases and the overactivation of macrophages initiates the development of atherosclerosis. However, the specific functions of oxidized low-density lipoprotein (ox-LDL) in macrophages remain elusive. Macrophages derived from monocyte (THP-1) were treated with ox-LDL and were used to generate atherosclerosis in an in vitro model. NLRP3 inflammasome markers were examined using quantitative RT-PCR and Western blotting. Cytokines were measured using ELISA. Chromatin immunoprecipitation (ChIP) was utilized to detect nuclear factor kappa B (NF-κB) and TRIM64 interactions. A fat-rich diet was applied to ApoE-/- mice for in vivo studies. ox-LDL promoted TRIM64 expression in a time-dependent manner. According to loss- and gain-of-function analyses, TRIM64 enhanced the activation of NLRP3 inflammasomes and the expression of downstream molecules. TRIM64 directly interacted with IκBα and promoted IκBα ubiquitination at K67 to activate NF-κB signaling. We detected direct binding between NF-κB and the TRIM64 promoter, as well as enhanced TRIM64 expression. Our study revealed an interaction between TRIM64 and NF-κB in the development of atherosclerosis. TRIM64 and NF-κB formed a positive feedback to activate NF-κB pathway.Graphical abstractox-LDL induces foam cell formation and TRIM64 expressionTRIM64 regulates ox-LDL-induced foam cell formation, pyroptosis and inflammation via the NF-κB signalingTRIM64 activates NF-κB signaling by ubiquitination of IκBαNF-κB inhibition attenuates atherosclerosis in HFD-induced ApoE (-/-) mice

Cytokine nanosponges suppressing overactive macrophages and dampening systematic cytokine storm for the treatment of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a highly fatal condition with the positive feedback loop between continued immune cell activation and cytokine storm as the core mechanism to mediate multiple organ dysfunction. Inspired by macrophage membranes harbor the receptors with special high affinity for proinflammation cytokines, lipopolysaccharide (LPS)-stimulated macrophage membrane-coated nanoparticles (LMNP) were developed to show strong sponge ability to both IFN-γ and IL-6 and suppressed overactivation of macrophages by inhibiting JAK/STAT signaling pathway both in vitro and in vivo. Besides, LMNP also efficiently alleviated HLH-related symptoms including cytopenia, hepatosplenomegaly and hepatorenal dysfunction and save the life of mouse models. Furthermore, its sponge effect also worked well for five human HLH samples in vitro. Altogether, it's firstly demonstrated that biocompatible LMNP could dampen HLH with high potential for clinical transformation, which also provided alternative insights for the treatment of other cytokine storm-mediated pathologic conditions such as COVID-19 infection and cytokine releasing syndrome during CAR-T therapy.

Cytotoxicity and Apoptotic Mechanism of 2-Hydroxyethyl Methacrylate via Genotoxicity and the Mitochondrial-Dependent Intrinsic Caspase Pathway and Intracellular Reactive Oxygen Species Accumulation in Macrophages.

Macrophages are mainly active cells of the immune system and play a role in the defense of pathogens. However, the overactivation of macrophages by fatal pathogens can result in toxic responses. 2-hydroxyethyl methacrylate (HEMA), which is a hydrophilic monomer, is used in dental adhesive reagents and composite resins as well as biocompatible hydrogels. The mechanisms underlying the genotoxicity engendered by HEMA-induced apoptosis that leads to cytotoxicity remain unclear. Accordingly, this study was conducted to clarify such mechanisms. The results showed that HEMA induced cell toxicity in RAW264.7 macrophages depending on the concentration. A higher HEMA concentration was associated with a higher level of apoptosis and genotoxicity. Moreover, HEMA induced a concentration-dependent increase in mitochondrial dysfunction and the intrinsic caspase pathway, including the activation of caspase-3 and caspase-9. HEMA was also found to upregulate intracellular reactive oxygen species generation and to decrease the activity of antioxidant enzymes, including superoxide dismutase and catalase. Taken together, the mitochondrial-dependent intrinsic caspase pathway and intracellular reactive oxygen species accumulation were found to mediate HEMA-induced genotoxicity and apoptosis, leading to cytotoxicity in RAW264.7 macrophages.

Fatal hemophagocytic lymphohistiocytosis, probably secondary to leishmaniasis, in an immunocompetent adult, with no response to any treatment

Hemophagocytic Lymphohistiocytosis (HLH) is a rare syndrome, attributed to genetic and acquired factors and is associated with overactivation of macrophages. There are better chances of treatment, when HLH is triggered by an infection. Herein, we describe a rare case which raises questions about this statement. A 53 year’s old, immunocompetent man, presented with relapsing fever for four months. The patient underwent a full workup with no diagnostic findings, apart from detectable IgG antibodies in the plasma and PCR positive for Leishmania in bone marrow aspirates. The patient received liposomal amphotericin B with no fever remission. Patient’s blood tests revealed thrombocytopenia, anemia, high ferritin levels and hypertriglyceridemia. Image analysis revealed splenomegaly. Diagnostic criteria of hemophagocytic syndrome were fulfilled. Genetic testing was negative. The patient received two additional cycles of liposomal amphotericin B, with no response. Finally, he received etoposide, cyclosporine and dexamethasone, according to 2004 HLH protocol. After a long hospitalization the patient passed away.

Intestinal Macrophage Autophagy and its Pharmacological Application in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), comprised of Crohn’s disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory disorders. IBD is regarded as a severe healthcare problem worldwide, with high morbidity and lethality. So far, despite of numerous studies on this issue, the specific mechanisms of IBD still remain unclarified and ideal treatments are not available for IBD. The intestinal mucosal barrier is vital for maintaining the function of the intestinal self-defensive system. Among all of the components, macrophage is an important one in the intestinal self-defensive system, normally protecting the gut against exotic invasion. However, the over-activation of macrophages in pathological conditions leads to the overwhelming induction of intestinal inflammatory and immune reaction, thus damaging the intestinal functions. Autophagy is an important catabolic mechanism. It has been proven to participate the regulation of various kinds of inflammation- and immune-related disorders via the regulation of inflammation in related cells. Here in this paper, we will review the role and mechanism of intestinal macrophage autophagy in IBD. In addition, several well-studied kinds of agents taking advantage of intestinal macrophage autophagy for the treatment of IBD will also be discussed. We aim to bring novel insights in the development of therapeutic strategies against IBD.

Anti-Inflammatory Activities of Captopril and Diuretics on Macrophage Activity in Mouse Humoral Immune Response

Hypertension is accompanied by the over-activation of macrophages. Diuretics administered alone or in combination with hypotensive drugs may have immunomodulatory effects. Thus, the influence of tested drugs on mouse macrophage-mediated humoral immunity was investigated. Mice were treated intraperitoneally with captopril (5 mg/kg) with or without hydrochlorothiazide (10 mg/kg) or furosemide (5 mg/kg) by 8 days. Mineral oil-induced peritoneal macrophages were harvested to assess the generation of cytokines in ELISA, and the expression of surface markers was analyzed cytometrically. Macrophages were also pulsed with sheep red blood cells (SRBC) and transferred to naive mice for evaluation of their ability to induce a humoral immune response. Tested drugs increase the expression of surface markers important for the antigen phagocytosis and presentation. SRBC-pulsed macrophages from mice treated with captopril combined with diuretics increased the secretion of antigen-specific antibodies by recipient B cells, while macrophages of mice treated with hydrochlorothiazide or furosemide with captopril increased the number of antigen-specific B cells. Tested drugs alter the macrophage secretory profile in favor of anti-inflammatory cytokines. Our results showed that diuretics with or without captopril modulate the humoral response by affecting the function of macrophages, which has significant translational potential in assessing the safety of antihypertensive therapy.

Proinflammatory Responses of 1-Nitropyrene against RAW264.7 Macrophages through Akt Phosphorylation and NF-κB Pathways

Air pollution is a major environmental and public health problem worldwide. A nitro-polycyclic aromatic hydrocarbon and the most abundant air pollutant in diesel engine exhaust, 1-nitropyrene (1-NP), is caused by the incomplete combustion of carbonaceous organic substances. Macrophages are effector cells of the innate immune cells that provide resistance in the peripheral tissue. The overactivation of macrophages results in inflammation. The generation of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumour necrosis factor alpha, is induced by 1-NP in a concentration-dependent manner in macrophages. In this study, the production of proinflammatory mediators, such as nitrogen oxide and prostaglandin E2, was induced by 1-NP in a concentration-dependent manner through the expression of iNOS and COX2. The generation of proinflammatory cytokines, iNOS, and COX2 was induced by 1-NP through nuclear factor (NF)-κB p65 phosphorylation and the degradation of its upstream factor, IκB. Finally, Akt phosphorylation was induced by 1-NP in a concentration-dependent manner. These findings suggest that 1-NP exhibits a proinflammatory response through the NF-κB pathway activation due to Akt phosphorylation.

Adult-onset still's disease masquerading as hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematological condition caused by the overactivation of macrophages leading to widespread tissue destruction and organ dysfunction. The disease has a clinical overlap with adult-onset still's disease (AOSD) and hence poses a diagnostic challenge. We report the case of a 20-year-old female who presented with prolonged febrile illness, anemia, hepatosplenomegaly, and generalized lymphadenopathy. She was diagnosed with HLH and was readmitted 6 weeks later with recurrent fever, polyarthralgia, and pharyngitis. A diagnosis of AOSD with secondary HLH was made.

Perfluorooctanoic acid (PFOA) exposure induces splenic atrophy via overactivation of macrophages in male mice

Perfluorooctanoic acid (PFOA), a synthetic and widely used chemical, has aroused wide public concern due to its persistence, bioaccumulation, and potential toxicity. To investigate splenic atrophy induced by PFOA, male mice were exposed to 0, 0.4, 2, or 10 mg/kg/d PFOA for 28 d. Results demonstrated that spleen weight and relative spleen weight (RSW) decreased in the 2 and 10 mg/kg/d PFOA exposure groups. Iron levels in the spleen and serum were also reduced in all PFOA exposure groups. Weighted gene co-expression network analysis (WGCNA) of 7 043 genes highlighted enrichment in cell cycle, autoimmunity, and anemia in the spleen. In addition, changes in the levels of hemoglobin, platelets, bilirubin, and heme oxygenase-1 were consistent with anemia. The ratio of total macrophages to M1 macrophages in the spleen, phagocytic ability of macrophages, and levels of cytokines such as TNF-α, IL-1β, and IL-6 all increased, thus suggesting the occurrence of autoimmune disorder. Therefore, we concluded that overactivation of macrophages may be an important reason for splenic atrophy induced by PFOA exposure.

Three main short-chain fatty acids inhibit the activation of THP-1 cells by Mycoplasma pneumoniae.

The overactivation of macrophages causes chronic inflammatory diseases. Short-chain fatty acids (SCFAs), potential drugs for clinical treatment, are modulators of macrophage inflammatory reaction. Therefore, the modulation of macrophage-mediated cell activity is expected to become a new therapeutic strategy for inflammatory diseases caused by Mycoplasma pneumoniae. In this study, 2 kinds of SCFAs (propionate and butyrate) were found to have anti-inflammatory effects in M. pneumoniae-stimulated THP-1 cells inflammatory. They inhibited the expressions of IL-4, IL-6, ROS, and NLRP3 inflammasome, while enhancing the expressions of IL-10 and IFN-γ. Our study revealed these 2 agents to repress transcriptional activities of NF-κB, which are important modulators of inflammation. Meanwhile, SCFAs can significantly enhance the autophagy induced by M. pneumoniae. Considering that SCFAs have few side effects, they might be the promising adjuvant therapy for the prevention and/or treatment of various inflammatory diseases.

Haemophagocytic Lymphohistiocytosis Associated with Dengue Fever - A case series

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening medical condition characterized by hyperphagocytosis secondary to an inappropriate over-activation of macrophages and lymphocytes that driven by excessive cytokines production which resulted in cellular destructions. Dengue induced hemophagocytic lymphohistiocytosis (HLH) is a serious condition and may prove fatal if not detected early and treated appropriately. Diagnosis of HLH is challenging and usually missed as clinical and laboratory findings are nonspecific. It should be suspected with prolonged fever beyond seven days associated with splenomegaly, hyperferritinemia, worsening cytopenias and development of multiorgan dysfunction. A proportion of patients recovered with supportive therapy, however most required interventions with corticosteroids, intravenous immunoglobulin or chemotherapy. We report 3 cases of dengue associated HLH . Among them 2 patients were treated with steroid with good outcome, and one died from MODS.&#x0D; J MEDICINE JUL 2020; 21 (2) : 123-126

Gaudichaudione H Inhibits Inflammatory Responses in Macrophages and Dextran Sodium Sulfate-Induced Colitis in Mice.

Macrophages-involved inflammation is considered to induce the damage in various diseases. Herein, novel therapeutics inhibiting over-activation of macrophages could prove an effective strategy to prevent inflammation-related diseases. Gaudichaudione H (GH), which is a natural small molecular compound isolated from Garcinia oligantha Merr. (Clusiaceae) has previously been demonstrated its anti-cancer effects on several cancer cell lines. However, no report has been published about the anti-inflammatory effect of GH to date. This study aims to examine the anti-inflammatory effects and potential molecular mechanism of GH, and provide new insights toward the treatment of inflammation. GH inhibited nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, cytokine interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) production, and messenger RNA (mRNA) expression to attenuate inflammatory responses in lipopolysaccharide (LPS)-induced RAW 264.7 cells or stimulated bone marrow-derived macrophages (BMDMs). GH inhibited nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, the nuclear translocation of transcription factors NF-κB and activator protein 1 (AP-1), as well as upstream signaling of the toll-like receptor 4 (TLR4)-myeloid differentiation primary response 88 (MyD88) pathway in stimulated macrophages. Furthermore, the result of the intracellular signaling array showed that the phosphorylation of adenosine 5'-monophosphate-activated protein kinase-α (AMPKα), proline-rich Akt substrate of 40 kDa (PRAS40), and p38 could be down regulated by GH in BMDMs, indicating that the mechanism by which GH inhibited inflammation may be also associated with the energy metabolism pathway, PRAS40-mediated NF-κB pathway, cell proliferation, apoptosis, and autophagy, etc. In addition, GH alleviated dextran sodium sulfate (DSS)-induced colitis in mice by ameliorating weight loss, stool consistency change, blood in the stool, and colon shortening. GH decreased the protein and mRNA levels of IL-6 and TNF-α, iNOS and COX-2 mRNA expression, the activation of NF-κB and MAPK pathways, the phosphorylation of AMPKα and PRAS40, histological damage, and infiltration of macrophages in the colons of mice with DSS-induced colitis. Taken together, our results support that GH exerts the anti-inflammatory effects in macrophages in vitro through regulation of NF-κB and MAPK pathways, and DSS-induced colitis mouse model in vivo. These findings suggest that GH may be a promising candidate in treating macrophage-related inflammatory disease.

A Rare and Fatal Complication of a Self-Limiting Infection: A Case Report on Dengue Associated Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening medical condition characterized by hyperphagocytosis secondary to an inappropriate over-activation of macrophages and lymphocytes that driven by excessive cytokines production which resulted in cellular destructions. It can arise de novo as a result of an autosomal recessive genetic disorder, or in the background of an infection, malignancy or autoimmune disease. Dengue fever is one of the uncommon causes of infection related secondary HLH. Here, we present a case of a Dengue associated HLH which was successfully treated with intravenous methylprednisolone and immunoglobulin G. In conclusion, the purpose of this case report is to illustrate the importance of early recognition and prompt initiation of the appropriate treatment for HLH suspected patient whom otherwise has high mortality rate.&#x0D; Bangladesh J Medicine July 2019; 30(2) : 93-95

Schisandrin A suppresses lipopolysaccharide-induced inflammation and oxidative stress in RAW 264.7 macrophages by suppressing the NF-κB, MAPKs and PI3K/Akt pathways and activating Nrf2/HO-1 signaling.

Schisandrin A is a bioactive lignan occurring in the fruits of plants of the Schisandra genus that have traditionally been used in Korea for treating various inflammatory diseases. Although the anti-inflammatory and antioxidant effects of lignan analogues similar to schisandrin A have been reported, the underlying molecular mechanisms have remained elusive. In the present study, schisandrin A significantly suppressed the lipopolysaccharide (LPS)-induced production of the key pro-inflammatory mediators nitric oxide (NO) and prostaglandin E2 by suppressing the expression of inducible NO synthase and cyclooxygenase-2 at the mRNA and protein levels in RAW 264.7 macrophages. Furthermore, schisandrin A was demonstrated to reduce the LPS-induced secretion of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β; this was accompanied by a simultaneous decrease in the respective mRNA and protein levels in the macrophages. In addition, the LPS- induced translocation of nuclear factor-κB (NF-κB), as well as activation of mitogen-activated protein kinases (MAPKs) and phosphatidylinositol-3 kinase (PI3K)/Akt pathways were inhibited by schisandrin A. Furthermore, schisandrin A significantly diminished the LPS-stimulated accumulation of intracellular reactive oxygen species, and effectively enhanced the expression of NF erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). These results suggested that schisandrin A has a protective effect against LPS-induced inflammatory and oxidative responses in RAW 264.7 cells by inhibiting the NF-κB, MAPK and PI3K/Akt pathways; these effects are mediated, at least in part, by the activation of the Nrf2/HO-1 pathway. Based on these results, it is concluded that schisandrin A may have therapeutic potential for treating inflammatory and oxidative disorders caused by over-activation of macrophages.