Epstein-Barr virus-positive CD30+ B-cell lymphoproliferative disease with histologic features resembling grade III lymphomatoid granulomatosis induced by methotrexate.

Methotrexate (MTX) is a first-line systemic medication used to treat rheumatoid arthritis because of its immunomodulatory effects. However, MTX has also been linked to the development of lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis. We describe a patient with long-standing rheumatoid arthritis treated with MTX who developed cutaneous Epstein-Barr virus (EBV)-positive B cell lymphoproliferative disease resembling grade III lymphomatoid granulomatosis localized to the right leg. The lymphomatoid process resolved with withdrawal of the MTX. The pathogenesis of iatrogenic lymphoproliferative disorder was most likely triggered by the rheumatoid inflammation and the immunosuppressing effects of MTX, which led to EBV reactivation. We recommend a trial of MTX discontinuation prior to considering chemotherapy in patients with rheumatoid arthritis treated with MTX who develop EBV-positive B cell lymphoproliferative disease resembling a high grade B-cell lymphoma.

Multifunctional mesoporous curcumin encapsulated iron-phenanthroline nanocluster: A new Anti-HIV agent.

A new strategy to encapsulating the drug curcumin into the hydrophobic core of the iron-phenanthroline nanocomplex (NIP) and eventually its release is signified. NIP was prepared via coordinate interaction between Fe2+ and the lone pairs present on the N atoms of the bidentate phenanthroline ligand (spherical morphology, diameter 18.8 nm, mesoporous with pore size 2.443 nm, amorphous). Thereafter, curcumin was successfully encapsulated (NCIP) in NIP, resulting in its enhanced stability (spherical morphology, diameter 46.8 nm). The nanocomplex NIP was used for drug delivery applications. We evaluated the anti-HIV effects of NCIP in vitro on cultures of HIV infected human microglia. The treatment of HIV-1 infected microglia with NCIP significantly decreased the expression of HIV-p24 by 41% and pro-inflammatory mediators TNF-α, IL-8 and NO by 61.2%, 41% and 50.2%, respectively, compared to NIP. Flow cytometry data also support the decrease in TNF-α and IL-8 expression in case of NCIP. NCIP induced antioxidative effects by increasing the gene expression of catalase (CAT) and simulatenously decreasing hemeoxygenase-1 (HMOX-1) gene expression, thereby maintaining homeostasis which reduces neuroinflammation. These results support our premise that NCIP may be a significant adjuvant when used with traditional anti-retroviral regimens and may ameliorate HIV-1 associated neurotoxicity.

Methamphetamine Induces Apoptosis of Microglia via the Intrinsic Mitochondrial-Dependent Pathway.

Methamphetamine (METH) is a drug of abuse, the acute and chronic use of which induces neurotoxic responses in the human brain, ultimately leading to neurocognitive disorders. Our goals were to understand the impact of METH on microglial mitochondrial respiration and to determine whether METH induces the activation of the mitochondrial-dependent intrinsic apoptosis pathway in microglia. We assessed the expression of pro- apoptosis genes using qPCR of RNA extracted from a human microglial cell line (HTHU). We examined the apoptosis-inducing effects of METH on microglial cells using digital holographic microscopy (DHM) to quantify real-time apoptotic volume decrease (AVD) in microglia in a noninvasive manner. METH treatment significantly increased AVD, activated Caspase 3/7, increased the gene expression levels of the pro- apoptosis proteins, APAF-1 and BAX, and decreased mitochondrial DNA content. Using immunofluorescence analysis, we found that METH increased the expression of the mitochondrial proteins cytochrome c and MCL-1, supporting the activation of mitochondrion-dependent (intrinsic) apoptosis pathway. Cellular bio-energetic flux analysis by Agilent Seahorse XF Analyzer revealed that METH treatment increased both oxidative and glycolytic respiration after 3 h, which was sustained for at least 24 h. Several events, such as oxidative stress, neuro-inflammatory responses, and mitochondrial dysfunction, may converge to mediate METH-induced apoptosis of microglia that may contribute to neurotoxicity of the CNS. Our study has important implications for therapeutic strategies aimed at preserving mitochondrial function in METH abusing patients.

Immunomodulatory activities of curcumin-stabilized silver nanoparticles: Efficacy as an antiretroviral therapeutic.

We synthesized and characterized curcumin-stabilized silver nanoparticles (Cur-AgNP) and found them to be 45 nm by dynamic light scattering with a maximum absorbance at 406 nm. We evaluated Cur-AgNP for immunomodulatory activities and their potential as an antiretroviral agent. The antiretroviral effects of Cur-AgNP were determined in ACH-2 cells latently infected with human immunodeficiency virus (HIV)-1. ACH-2 cells, 200,000/ml, were treated with Cur-AgNP for 24-48 h. Expression of HIV-1 LTR and p24, the pro-inflammatory cytokines, IL-1ß, TNF-α, and NF-κB was quantitated. Treatment of ACH-2 cells latently infected with HIV-1 with Cur-AgNP produced no toxic effects but significantly inhibited the expression of HIV-1 LTR (-73%, P < 0.01) and p24 (-57%, P < 0.05), IL-1ßα (-61%, P < 0.01), TNF-αα (-54%, P < 0.05), IL-6 (-68%, P < 0.01), and NF-κB (-79%, P < 0.0001) as compared to untreated controls. Thus, Cur-AgNP have therapeutic potential as direct antiretroviral agents, as well as having immunomodulatory activities inhibiting the expression of pro-inflammatory mediators induced by infection with HIV-1. Experimental controls, such as curcumin alone, and conventional silver nanoparticles capped with citric acid, produced no similar biological effects. We conclude that treatment of HIV-1 infected cells with Cur-AgNP significantly reduced replication of HIV by inhibition of NF-κB nuclear translocation and the downstream expression of the pro-inflammatory cytokines IL-1ß, TNF-α, and IL-6. Subsequent in vivo studies with Cur-AgNP using a humanized mouse model of HIV infection are underway.