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Displaying publications 21 - 26 of 26 in total

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In Vivo Anti-Tumor Effects of Flavokawain A in 4T1 Breast Cancer Cell-Challenged Mice

Abu N, Mohamed NE, Yeap SK, Lim KL, Akhtar MN, Zulfadli AJ, et al.

Anticancer Agents Med Chem, 2015;15(7):905-15.
PMID: 26179368

Flavokawain A is a chalcone that can be found in the kava-kava plant (Piper methsyticum) extract. The kava-kava plant has been reported to possess anti-cancer, anti-inflammatory and antinociceptive activities. The state of the immune system, and the inflammatory process play vital roles in the progression of cancer. The immunomodulatary effects and the anti-inflammatory effects of flavokawain A in a breast cancer murine model have not been studied yet. Thus, this study aimed to elucidate the basic mechanism as to how flavokawain A regulates and enhance the immune system as well as impeding the inflammatory process in breast cancer-challenged mice. Based on our study, it is interesting to note that flavokawain A increased the T cell population; both Th1 cells and CTLs, aside from the natural killer cells. The levels of IFN-γ and IL-2 were also elevated in the serum of flavokawain A-treated mice. Apart from that, flavokawain A also decreased the weight and volume of the tumor, and managed to induce apoptosis in them. In terms of inflammation, flavokawain A-treated mice had reduced level of major pro-inflammatory mediators; NO, iNOS, NF-KB, ICAM and COX-2. Overall, flavokawain A has the potential to not only enhance antitumor immunity, but also prevents the inflammatory process in a cancer-prone microenvironment.

Matched MeSH terms: Inflammation/immunology
Fulltext Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma

Higuchi H, Yamakawa N, Imadome KI, Yahata T, Kotaki R, Ogata J, et al.

Blood, 2018 06 07;131(23):2552-2567.
PMID: 29685921 DOI: 10.1182/blood-2017-07-794529

Epstein-Barr virus (EBV) causes various diseases in the elderly, including B-cell lymphoma such as Hodgkin's lymphoma and diffuse large B-cell lymphoma. Here, we show that EBV acts in trans on noninfected macrophages in the tumor through exosome secretion and augments the development of lymphomas. In a humanized mouse model, the different formation of lymphoproliferative disease (LPD) between 2 EBV strains (Akata and B95-8) was evident. Furthermore, injection of Akata-derived exosomes affected LPD severity, possibly through the regulation of macrophage phenotype in vivo. Exosomes collected from Akata-lymphoblastoid cell lines reportedly contain EBV-derived noncoding RNAs such as BamHI fragment A rightward transcript (BART) micro-RNAs (miRNAs) and EBV-encoded RNA. We focused on the exosome-mediated delivery of BART miRNAs. In vitro, BART miRNAs could induce the immune regulatory phenotype in macrophages characterized by the gene expressions of interleukin 10, tumor necrosis factor-α, and arginase 1, suggesting the immune regulatory role of BART miRNAs. The expression level of an EBV-encoded miRNA was strongly linked to the clinical outcomes in elderly patients with diffuse large B-cell lymphoma. These results implicate BART miRNAs as 1 of the factors regulating the severity of lymphoproliferative disease and as a diagnostic marker for EBV+ B-cell lymphoma.

Matched MeSH terms: Inflammation/immunology
Fulltext Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

Tan HY, Yong YK, Shankar EM, Paukovics G, Ellegård R, Larsson M, et al.

J Immunol, 2016 05 15;196(10):4052-63.
PMID: 27076678 DOI: 10.4049/jimmunol.1502203

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) complicates combination antiretroviral therapy (cART) in up to 25% of patients with HIV/TB coinfection. Monocytes and IL-18, a signature cytokine of inflammasome activation, are implicated in TB-IRIS pathogenesis. In this study, we investigated inflammasome activation both pre- and post-cART in TB-IRIS patients. HIV/TB patients exhibited higher proportions of monocytes expressing activated caspase-1 (casp1) pre-cART, compared with HIV patients without TB, and patients who developed TB-IRIS exhibited the greatest increase in casp1 expression. CD64(+) monocytes were a marker of increased casp1 expression. Furthermore, IL-1β, another marker of inflammasome activation, was also elevated during TB-IRIS. TB-IRIS patients also exhibited greater upregulation of NLRP3 and AIM2 inflammasome mRNA, compared with controls. Analysis of plasma mitochondrial DNA levels showed that TB-IRIS patients experienced greater cell death, especially pre-cART. Plasma NO levels were lower both pre- and post-cART in TB-IRIS patients, providing evidence of inadequate inflammasome regulation. Plasma IL-18 levels pre-cART correlated inversely with NO levels but positively with monocyte casp1 expression and mitochondrial DNA levels, and expression of IL-18Rα on CD4(+) T cells and NK cells was higher in TB-IRIS patients, providing evidence that IL-18 is a marker of inflammasome activation. We propose that inflammasome activation in monocytes/macrophages of HIV/TB patients increases with ineffective T cell-dependent activation of monocytes/macrophages, priming them for an excessive inflammatory response after cART is commenced, which is greatest in patients with TB-IRIS.

Matched MeSH terms: Inflammation/immunology*
LPS-induced Apoptosis is Partially Mediated by Hydrogen Sulphide in RAW 264.7 Murine Macrophages

George L, Ramasamy T, Sirajudeen K, Manickam V

Immunol Invest, 2019 Jul;48(5):451-465.
PMID: 30689461 DOI: 10.1080/08820139.2019.1566355

Lipopolysaccharide (LPS) induces apoptosis in murine macrophages through the autocrine secretion of tumor necrosis factor (TNF)-α and nitric oxide (NO). LPS-induced inflammation in murine macrophages is associated with hydrogen sulfide (H2S) production. In this present study, we reported the novel role of H2S in LPS-induced apoptosis and its underlying molecular mechanism specifically at late phases in murine macrophage cells. Stimulation of RAW 264.7 macrophages with LPS resulted in a time- and dose-dependent induction of apoptosis. We observed that the LPS-induced early apoptosis (associated with TNF-α secretion) in macrophages was not inhibited in the presence of H2S inhibitor (DL-propargylglycine), whereas early apoptosis was absent in the presence of TNF receptor antibody. Interestingly, LPS-induced late apoptosis paralleled with H2S production was reduced in the presence of H2S inhibitor but not with TNF receptor antibody. The late apoptotic events mediated by H2S and not the TNF-α induced early apoptosis correlated significantly with the induction of p53 and Bax expression in LPS-induced macrophages. Thus, it is possible that RAW 264.7 murine macrophages treated with LPS mediated early apoptosis through TNF-α and the late apoptotic events through the production of H2S.

Matched MeSH terms: Inflammation/immunology*
Fulltext Orally Administered Enoxaparin Ameliorates Acute Colitis by Reducing Macrophage-Associated Inflammatory Responses

Lean QY, Eri RD, Randall-Demllo S, Sohal SS, Stewart N, Peterson GM, et al.

PLoS One, 2015;10(7):e0134259.
PMID: 26218284 DOI: 10.1371/journal.pone.0134259

Inflammatory bowel diseases, such as ulcerative colitis, cause significant morbidity and decreased quality of life. The currently available treatments are not effective in all patients, can be expensive and have potential to cause severe side effects. This prompts the need for new treatment modalities. Enoxaparin, a widely used antithrombotic agent, is reported to possess anti-inflammatory properties and therefore we evaluated its therapeutic potential in a mouse model of colitis. Acute colitis was induced in male C57BL/6 mice by administration of dextran sulfate sodium (DSS). Mice were treated once daily with enoxaparin via oral or intraperitoneal administration and monitored for colitis activities. On termination (day 8), colons were collected for macroscopic evaluation and cytokine measurement, and processed for histology and immunohistochemistry. Oral but not intraperitoneal administration of enoxaparin significantly ameliorated DSS-induced colitis. Oral enoxaparin-treated mice retained their body weight and displayed less diarrhea and fecal blood loss compared to the untreated colitis group. Colon weight in enoxaparin-treated mice was significantly lower, indicating reduced inflammation and edema. Histological examination of untreated colitis mice showed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and the presence of edema, while all aspects of this pathology were alleviated by oral enoxaparin. Reduced number of macrophages in the colon of oral enoxaparin-treated mice was accompanied by decreased levels of pro-inflammatory cytokines. Oral enoxaparin significantly reduces the inflammatory pathology associated with DSS-induced colitis in mice and could therefore represent a novel therapeutic option for the management of ulcerative colitis.

Matched MeSH terms: Inflammation/immunology
Fulltext HIV/Human herpesvirus co-infections: Impact on tryptophan-kynurenine pathway and immune reconstitution

Yap SH, Abdullah NK, McStea M, Takayama K, Chong ML, Crisci E, et al.

PLoS One, 2017;12(10):e0186000.
PMID: 29016635 DOI: 10.1371/journal.pone.0186000

BACKGROUND: Co-infections with human herpesvirus (HHV) have been associated with residual chronic inflammation in antiretroviral (ART)-treated human immunodeficiency virus (HIV)-infected individuals. However, the role of HHV in modulating the tryptophan-kynurenine pathway and clinical outcomes in HIV-infected individuals is poorly understood. Thus, we investigated the seroprevalence of four common HHVs among treated HIV-infected participants and their impact on kynurenine/tryptophan (K/T) ratio and long-term CD4 T-cell recovery in HIV/HHV co-infected participants.
METHOD: In this cross-sectional study, HIV-infected participants receiving suppressive ART for a minimum of 12 months were recruited from the University Malaya Medical Centre (UMMC), Malaysia. Stored plasma was analyzed for CMV, VZV, HSV-1 and HSV-2 IgG antibody levels, immune activation markers (interleukin-6, interferon-γ, neopterin and sCD14), kynurenine and tryptophan concentrations. The influence of the number of HHV co-infection and K/T ratio on CD4 T-cell recovery was assessed using multivariate Poisson regression.
RESULTS: A total of 232 HIV-infected participants were recruited and all participants were seropositive for at least one HHV; 96.1% with CMV, 86.6% with VZV, 70.7% with HSV-1 and 53.9% with HSV-2. K/T ratio had a significant positive correlation with CMV (rho = 0.205, p = 0.002), VZV (rho = 0.173, p = 0.009) and a tendency with HSV-2 (rho = 0.120, p = 0.070), with CMV antibody titer demonstrating the strongest modulating effect on K/T ratio among the four HHVs assessed in SOM analysis. In multivariate analysis, higher K/T ratio (p = 0.03) and increasing number of HHV co-infections (p<0.001) were independently associated with poorer CD4 T-cell recovery following 12 months of ART initiation.
CONCLUSION: Multiple HHV co-infections are common among ART-treated HIV-infected participants in the developing country setting and associated with persistent immune activation and poorer CD4 T-cell recovery.

Matched MeSH terms: Inflammation/immunology