Clinical Utility of Melatonin in Fibromyalgia Diagnosis

       Fibromyalgia syndrome (FMS) is a chronic disease with an unknown etiology, which is characterized by reduced pain threshold (hyperallgesia) & pain with normally innocuous stimuli (allodynia).This diffuse pain is often disease associated  with wide range of  other symptoms including fatigue, sleep disturbance, stiffness& more.FMS often occur concomitantly  with other rheumatologic disease such as rheumatoid arthritis(RA), systemic lupus erthymatosus(SLE).       The pineal hormone melatonin (MT) exerts a variety of effects on the immune system. MT activates immune cells and enhances inflammatory cytokine and nitric oxide production.Methods: We were studied 75 subjects, 55 of subjects were FMS patients defined by the American Colleague of Rheumatology (ACR 2010) criteria. Patients' mean age was 32.5 ± 13.9 years. They were classified into two groups: Group I of 25  primary FMS patients . Group II of 30 secondary FMS patients with other rheumatologic disease such as RA, SLE. Twenty age and sex matched healthy individuals were included in the study as a control group.Results:Mean Melatonin titers were significantly reduced (p<0.0001) in primary FMs patients compared to the controls (21.32vs. 30.9 pg/ml), but they were significantly elevated (p<0.0001) in secondary FMS compared to controls (138.1vs.30.9 pg/ml). Our data imposed that, in 1ry FMS there were negative correlations of MT titers with tender points (r=-0.848**,p<0.0001), sleep disturbance(r=-0.963**, p< 0.0001**), Fatigue (r= -0.972**, p<0.001**), WPI (r= -0,953 **, p<0.0001) and SS (r=-0.901**, p< 0.0001). Conclusions:In primary FMS patients melatonin level is lower than melatonin level in control, but MT level is high in secondary FMS patients. There was a negative correlation between MT with tender points, sleep disturbance, fatigue, SS & WPI. But there was a positive correlation between MT & cognitive symptoms

CLINICAL SIGNIFICANCE OF PROCALCITONIN AND C-REACTIVE PROTEIN IN THE PREDICTION OF CARDIOVASCULAR COMPLICATIONS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

  Objective: This work was delineated to assess procalcitonin (PCT) and C-reactive protein (CRP) as prognostic markers for cardiovascular complication in type 2 diabetic patients.Methods: Forty diabetic patients without cardiovascular disease (CVD), 40 diabetic patients with CVD, and 20 healthy control counterparts were participated in this study. Serum PCT and CRP levels were assayed and correlated with metabolic parameters. Receiver operating characteristic (ROC) curve analysis was done for each biochemical marker.Results: The mean level of PCT was 707.17±99.19 ng/l in diabetic patients versus 881.30±123.56 ng/l for the cardio-diabetic patients (p<0.0001). The mean value of CRP was 34.43±17.27 mg/l in diabetic patients versus 50.32±20.19 mg/l for the cardio-diabetic patients (p=0.0003). PCT levels were significantly amplified in the cardio-diabetic patients with increasing CRP, triglycerides (TG), fasting blood glucose (FBG), and cholesterol (p=0.004, 0.0005, 0.002, and 0.01, respectively). CRP levels were significantly enhanced in the cardio-diabetic patients with increasing TG, FBG, cholesterol, and microalbumin (p=0.002, 0.047, 0.003, and 0.001 respectively). ROC curve analysis for PCT and CRP revealed that the area under curve (AUC) was 0.878 and 0.727, respectively. These findings indicate the good validity of the above biomarkers especially PCT as a prognostic marker for cardiovascular complication in type 2 diabetic patients.Conclusion: This study evidences the usefulness of measuring serum levels of PCT and CRP in diagnosis of cardiovascular complication in type 2 diabetic patients

Thymoquinone Inhibits Bone Metastasis of Breast Cancer Cells Through Abrogation of the CXCR4 Signaling Axis

Overexpression of chemokine receptor type 4 (CXCR4) has been found to be associated with increased cell proliferation, metastasis and also act as an indicator of poor prognosis in patients with breast cancer. Therefore, new agents that can abrogate CXCR4 expression have potential against breast cancer metastasis. In this study, we examined the potential effect of thymoquinone (TQ), derived from the seeds of Nigella sativa, on the expression and regulation of CXCR4 in breast cancer cells. TQ was found to inhibit the expression of CXCR4 in MDA-MB-231 triple negative breast cancer (TNBC) cells in a dose- and time-dependent manner. It was noted that suppression of CXCR4 by TQ was possibly transcriptionally regulated, as treatment with this drug caused down-regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation and suppression of NF-kB binding to the CXCR4 promoter. Pretreatment with a proteasome inhibitor and/or lysosomal stabilization did not affect TQ induced suppression of CXCR4. Down-regulation of CXCR4 was further correlated with the inhibition of CXCL12-mediated migration and invasion of MDA-MB-231 cells. Interestingly, it was observed that the deletion of p65 could reverse the observed antiinvasive/ anti-migratory effects of TQ in breast cancer cells. TQ also dose-dependently inhibited MDA-MB-231 tumor growth and tumor vascularity in a chick chorioallantoic membrane assay model. We also observed TQ (2 and 4 mg/kg) treatment significantly suppressed multiple lung, brain, and bone metastases in a dose-dependent manner in a metastasis breast cancer mouse model. Interestingly, H&E and immunohistochemical analysis of bone isolated from TQ treated mice indicated a reduction in number of osteolytic lesions and the expression of metastatic biomarkers. In conclusion, the results indicate that TQ primarily exerts its anti-metastatic effects by down-regulation of NF-kB regulated CXCR4 expression and thus has potential for the treatment of breast cancer

TREM-1 Protects HIV-1-Infected Macrophages from Apoptosis through Maintenance of Mitochondrial Function.

Macrophages are a reservoir for latent human immunodeficiency type 1 (HIV) infection and a barrier to HIV eradication. In contrast to CD4+ T cells, macrophages are resistant to the cytopathic effects of acute HIV infection. Emerging data suggest a role for TREM1 (triggering receptor expressed on myeloid cells 1) in this resistance to HIV-mediated cytopathogenesis. Here, we show that upon HIV infection, macrophages increase the expression of BCL2, BCLXL, TREM1, mitofusin 1 (MFN1), and MFN2 and the translocation of BCL2L11 (BIM) to the mitochondria and decrease the expression of BCL2-associated agonist of cell death (BAD) and BAX while maintaining a 95% survival rate over 28 days. The HIV proteins Tat and gp120 and the GU-rich single-stranded RNA (ssRNA) (RNA40) from the HIV long terminal repeat region (and a natural Toll-like receptor 8 [TLR8] agonist) induced similar effects. TREM1 silencing in HIV-infected macrophages led to decreased expression of BCL2, BCLXL, MFN1, and MFN2 and increased expression of BAD and BAX. This correlated with a significant increase in apoptosis mediated by a disruption of the mitochondrial membrane potential (Δψm), leading to the release of cytochrome c and caspase 9 cleavage. Exposure of TREM1-silenced macrophages to Tat, gp120, or RNA40 similarly resulted in the disruption of Δψm, cytochrome c release, caspase 9 cleavage, and apoptosis. Thus, our findings identify a mechanism whereby HIV promotes macrophage survival through TREM1-dependent upregulation of BCL2 family proteins and mitofusins that inhibits BCL2L11-mediated disruption of Δψm and subsequent apoptosis. These findings indicate that TREM1 can be a useful target for elimination of the HIV reservoir in macrophages.IMPORTANCE The major challenge to human immunodeficiency virus (HIV) treatment is the development of strategies that lead to viral eradication. A roadblock to accomplishing this goal is the lack of an approach that would safely eliminate HIV from all resting/latent reservoirs, including macrophages. Macrophages are a key part of the innate immune system and are responsible for recognizing invading microbes and sending appropriate signals to other immune cells. Here, we found that HIV induces the upregulation of the protein TREM1 (triggering receptor expressed on myeloid cells 1), which signals an increase in the expression of antiapoptotic proteins, thus promoting survival of HIV-infected macrophages

Probiotic modulation of dendritic cell function is influenced by ageing

Dendritic cells (DCs) are critical for the generation of T-cell responses. DC function may be modulated by probiotics, which confer health benefits in immunocompromised individuals, such as the elderly. This study investigated the effects of four probiotics, Bifidobacterium longum bv. infantis CCUG 52486, B. longum SP 07/3, L. rhamnosus GG (L.GG) and L. casei Shirota (LcS) on DC function in an allogeneic mixed leucocyte reaction (MLR) model, using DCs and T-cells from young and older donors in different combinations. All four probiotics enhanced expression of CD40, CD80 and CCR7 on both young and older DCs, but enhanced cytokine production (TGF-β, TNF-α) by old DCs only. LcS induced IL-12 and IFNγ production by DC to a greater degree than other strains, while Bifidobacterium longum bv. infantis CCUG 52486 favoured IL-10 production. Stimulation of young T cells in an allogeneic MLR with DC was enhanced by probiotic pretreatment of old DCs, which demonstrated greater activation (CD25) than untreated controls. However, pretreatment of young or old DCs with LPS or probiotics failed to enhance the proliferation of T-cells derived from older donors. In conclusion, this study demonstrates that ageing increases the responsiveness of DCs to probiotics, but this is not sufficient to overcome the impact of immunosenescence in the MLR

An intranasal selective antisense oligonucleotide impairs lung cyclooxygenase-2 production and improves inflammation, but worsens airway function, in house dust mite sensitive mice

<p>Abstract</p> <p>Background</p> <p>Despite its reported pro-inflammatory activity, cyclooxygenase (COX)-2 has been proposed to play a protective role in asthma. Accordingly, COX-2 might be down-regulated in the airway cells of asthmatics. This, together with results of experiments to assess the impact of COX-2 blockade in ovalbumin (OVA)-sensitized mice in vivo, led us to propose a novel experimental approach using house dust mite (HDM)-sensitized mice in which we mimicked altered regulation of COX-2.</p> <p>Methods</p> <p>Allergic inflammation was induced in BALBc mice by intranasal exposure to HDM for 10 consecutive days. This model reproduces spontaneous exposure to aeroallergens by asthmatic patients. In order to impair, but not fully block, COX-2 production in the airways, some of the animals received an intranasal antisense oligonucleotide. Lung COX-2 expression and activity were measured along with bronchovascular inflammation, airway reactivity, and prostaglandin production.</p> <p>Results</p> <p>We observed impaired COX-2 mRNA and protein expression in the lung tissue of selective oligonucleotide-treated sensitized mice. This was accompanied by diminished production of mPGE synthase and PGE₂in the airways. In sensitized mice, the oligonucleotide induced increased airway hyperreactivity (AHR) to methacholine, but a substantially reduced bronchovascular inflammation. Finally, mRNA levels of hPGD synthase remained unchanged.</p> <p>Conclusion</p> <p>Intranasal antisense therapy against COX-2 in vivo mimicked the reported impairment of COX-2 regulation in the airway cells of asthmatic patients. This strategy revealed an unexpected novel dual effect: inflammation was improved but AHR worsened. This approach will provide insights into the differential regulation of inflammation and lung function in asthma, and will help identify pharmacological targets within the COX-2/PG system.</p

Gut mucosal DAMPs in IBD: From mechanisms to therapeutic implications

Endogenous damage-associated molecular patterns (DAMPs) are released during tissue damage and have increasingly recognized roles in the etiology of many human diseases. The inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease (CD), are immune-mediated conditions where high levels of DAMPs are observed. DAMPs such as calprotectin (S100A8/9) have an established clinical role as a biomarker in IBD. In this review, we use IBD as an archetypal common chronic inflammatory disease to focus on the conceptual and evidential importance of DAMPs in pathogenesis and why DAMPs represent an entirely new class of targets for clinical translation. </p

The role of flavor and fragrance chemicals in TRPA1 (transient receptor potential cation channel, member A1) activity associated with allergies

TRPA1 has been proposed to be associated with diverse sensory allergic reactions, including thermal (cold) nociception, hearing and allergic inflammatory conditions. Some naturally occurring compounds are known to activate TRPA1 by forming a Michael addition product with a cysteine residue of TRPA1 through covalent protein modification and, in consequence, to cause allergic reactions. The anti-allergic property of TRPA1 agonists may be due to the activation and subsequent desensitization of TRPA1 expressed in sensory neurons. In this review, naturally occurring TRPA1 antagonists, such as camphor, 1,8-cineole, menthol, borneol, fenchyl alcohol and 2-methylisoborneol, and TRPA1 agonists, including thymol, carvacrol, 1’S-1’- acetoxychavicol acetate, cinnamaldehyde, α-n-hexyl cinnamic aldehyde and thymoquinone as well as isothiocyanates and sulfides are discussed