Macrophage Inflammatory Protein-1 Alpha, a Potential Biomarker for Predicting Left Atrial Remodeling in Patients With Atrial Fibrillation

Objectives: Left atrial (LA) remodeling itself is an independent risk factor for ischemic stroke and mortality, with or without atrial fibrillation (AF). Macrophage inflammatory protein-1 alpha (MIP-1α) has been reported to be involved in the induction of autoimmune myocarditis and dilated cardiomyopathy. Little is known about whether MIP-1α can be used to predict LA remodeling, especially in patients with AF.Methods: We prospectively enrolled 78 patients who had received a cardiac implantable electronic device due to sick sinus syndrome in order to define AF accurately. AF was diagnosed clinically before enrollment, according to 12-lead electrocardiography (ECG) and 24-h Holter test in 54 (69%) patients. The serum cytokine levels and the mRNA expression levels of peripheral blood leukocytes were checked and echocardiographic study was performed on the same day within 1 week after the patients were enrolled into the study. The 12-lead ECG and 24-h Holter test were performed on the same day of the patients' enrollment, and the device interrogation was performed every 3 months after enrollment. The enrolled patients were clinically followed up for 1 year.Results: There was no difference in baseline characteristics, cytokine levels and mRNA expression between patients with and without AF. Larger LA volume was positively correlated with higher levels of MIP-1α (r = 0.461, p ≤ 0.001) and the atrial high-rate episodes (AHREs) burden (r = 0.593, p < 0.001), and negatively correlated with higher levels of transforming growth factor (TGF)-β1 (r = −0.271, p = 0.047) and TGF-β3 (r = −0.279, p = 0.041). The higher AHREs burden and MIP-1α level could predict LA volume independently. The mRNA expression of RORC was negatively associated with the MIP-1α level.Conclusions: This study showed that higher MIP-1α was significantly associated with LA remodeling and may have the potentials to predict LA remodeling in terms of a larger LA volume, and that circadian gene derangement might affect the expression of MIP-1α.

Single-Cell Immunogenomic Approach Identified SARS-CoV-2 Protective Immune Signatures in Asymptomatic Direct Contacts of COVID-19 Cases

The response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely impacted by the level of virus exposure and status of the host immunity. The nature of protection shown by direct asymptomatic contacts of coronavirus disease 2019 (COVID-19)-positive patients is quite intriguing. In this study, we have characterized the antibody titer, SARS-CoV-2 surrogate virus neutralization, cytokine levels, single-cell T-cell receptor (TCR), and B-cell receptor (BCR) profiling in asymptomatic direct contacts, infected cases, and controls. We observed significant increase in antibodies with neutralizing amplitude in asymptomatic contacts along with cytokines such as Eotaxin, granulocyte-colony stimulating factor (G-CSF), interleukin 7 (IL-7), migration inhibitory factor (MIF), and macrophage inflammatory protein-1α (MIP-1α). Upon single-cell RNA (scRNA) sequencing, we explored the dynamics of the adaptive immune response in few representative asymptomatic close contacts and COVID-19-infected patients. We reported direct asymptomatic contacts to have decreased CD4+ naive T cells with concomitant increase in CD4+ memory and CD8+ Temra cells along with expanded clonotypes compared to infected patients. Noticeable proportions of class switched memory B cells were also observed in them. Overall, these findings gave an insight into the nature of protection in asymptomatic contacts.

Circulating macrophage inflammatory protein-1β/IL-12p40 ratio predicts sofosbuvir-based treatment outcome in HCV- genotype 4 patients

This study aimed to evaluate the prognostic value of baseline macrophage inflammatory protein (MIP)-1β/IL12p40 ratio for antiviral treatment outcome in HCV genotype 4 patients. METHODS: Sera of 450 treatment-naïve chronic HCV patients and 50 healthy individuals were collected. Liver transaminases, total bilirubin and albumin were biochemically tested, viral RNA was quantified, and circulating MIP-1β and IL-12p40 were estimated using human anti-MIP-1β and IL-12p40 antibodies in Sandwich ELISA. RESULTS : No difference was observed in the baseline chemokines levels between responders and relapsers, but the later had a significantly higher MIP-1β/IL-12p40 ratio (P< 0.0001). Multivariate regression analysis of baseline characteristics showed that gender, age, viral load, albumin level and chemokine ratios can significantly predict treatment outcome (P= 0.0114, 0.0095, 0.042, 0.0004 and < 0.0001; respectively). Accordingly, a predictive threshold of baseline chemokine ratio was calculated and it showed an AUC of 0.6917 (P= 0.0108; 95% CI: 0.5566 to 0.8268). The calculated threshold for predicting virologic response was 8.245, with positive and negative predictive values of 92.98% and 100%; respectively. The chemokine ratios had significant correlations with liver transaminases in treated groups whether pre or post-treatment. CONCLUSION: Baseline MIP-1β/IL-12p40 ratio represents a non-invasive prognostic biomarker that would provide shorter treatment duration and minimizes the emergence of drug-resistant variants in HCV genotype 4-patients.

The Additional Effects of Clarithromycin And Pranlukast On The Cytokine Suppression By Corticosteroids Using Murine Allergic Bronchopulmonary Aspergillosis Model

Few medicines other than oral corticosteroids and anti-fungal medicines are currently known as reliable treatments for allergic bronchopulmonary aspergillosis (ABPA). The efficacies of macrolide or leukotriene receptor antagonist (LTRA) with or without corticosteroid on ABPA are unknown. Mice were sensitized to Dermatophagoides farinae (Df) allergen intranasally and infected with Aspergillus fumigatus (Af). After Af infection, corticosteroid (Dexamethasone; Dex) was administered for five days in DfAf/Dex group. The effects of macrolide (clarithromycin; CAM) or LTRA (pranlukast; PRN) with or without Dex were also evaluated. Pathologically, the combined treatment with Dex and CAM decreased the airway inflammation. The interleukin (IL)-5, IL-13 and macrophage inflammatory protein (MIP)-2 concentrations in homogenized lungs were significantly elevated in DfAf mice compared to control mice (p < 0.05, each). CAM significantly decreased the elevations of MIP-2 of DfAf mice (p < 0.05). The addition of CAM on Dex suppressed both of the MIP-2 and IL-5 elevation (p < 0.05, each, DfAf/Dex vs DfAf/Dex/CAM group), but the addition of PRN on Dex did not. It was suggested that combination of CAM and corticosteroid enhanced the suppressing effect of both eosinophilic and neutrophilic airway inflammations. This finding will give a new hope for the treatment of severe fungus-related asthma.

High-dose intravenous immunoglobulins might modulate inflammation in COVID-19 patients

The use of high-dose of intravenous immunoglobulins (IVIGs) as immunomodulators for the treatment of COVID-19–affected individuals has shown promising results. IVIG reduced inflammation in these patients, who progressively restored respiratory function. However, little is known about how they may modulate immune responses in COVID-19 individuals. Here, we have analyzed the levels of 41 inflammatory biomarkers in plasma samples obtained at day 0 (pretreatment initiation), 3, 7, and 14 from five hospitalized COVID-19 patients treated with a 5-d course of 400 mg/kg/d of IVIG. The plasmatic levels of several cytokines (Tumor Necrosis Factor, IL-10, IL-5, and IL-7), chemokines (macrophage inflammatory protein-1α), growth/tissue repairing factors (hepatic growth factor), complement activation (C5a), and intestinal damage such as Fatty acid–binding protein 2 and LPS-binding protein showed a progressive decreasing trend during the next 2 wk after treatment initiation. This trend was not observed in IVIG-untreated COVID-19 patients. Thus, the administration of high-dose IVIG to hospitalized COVID-19 patients may improve their clinical evolution by modulating their hyperinflammatory and immunosuppressive status.

Vinpocetine alleviates lung inflammation via macrophage inflammatory protein-1β inhibition in an ovalbumin-induced allergic asthma model

Asthma is a well-known bronchial disease that causes bronchial inflammation, narrowing of the bronchial tubes, and bronchial mucus secretion, leading to bronchial blockade. In this study, we investigated the association between phosphodiesterase (PDE), specifically PDE1, and asthma using 3-isobutyl-1-methylxanthine (IBMX; a non-specific PDE inhibitor) and vinpocetine (Vinp; a PDE1 inhibitor). Balb/c mice were randomized to five treatment groups: control, ovalbumin (OVA), OVA + IBMX, OVA + Vinp, and OVA + dexamethasone (Dex). All mice were sensitized and challenged with OVA, except for the control group. IBMX, Vinp, or Dex was intraperitoneally administered 1 h before the challenge. Vinp treatment significantly inhibited the increase in airway hyper-responsiveness (P<0.001) and reduced the number of inflammatory cells, particularly eosinophils, in the lungs (P<0.01). It also ameliorated the damage to the bronchi and alveoli and decreased the OVA-specific IgE levels in serum, an indicator of allergic inflammation increased by OVA (P<0.05). Furthermore, the increase in interleukin-13, a known Th2 cytokine, was significantly decreased by Vinp (P<0.05), and Vinp regulated the release and mRNA expression of macrophage inflammatory protein-1β (MIP-1β) increased by OVA (P<0.05). Taken together, these results suggest that PDE1 is associated with allergic lung inflammation induced by OVA. Thus, PDE1 inhibitors can be a promising therapeutic target for the treatment of asthma.

Modification of N-terminal α-amine of proteins via biomimetic ortho-quinone-mediated oxidation

Naturally abundant quinones are important molecules, which play essential roles in various biological processes due to their reduction potential. In contrast to their universality, the investigation of reactions between quinones and proteins remains sparse. Herein, we report the development of a convenient strategy to protein modification via a biomimetic quinone-mediated oxidation at the N-terminus. By exploiting unique reactivity of an ortho-quinone reagent, the α-amine of protein N-terminus is oxidized to generate aldo or keto handle for orthogonal conjugation. The applications have been demonstrated using a range of proteins, including myoglobin, ubiquitin and small ubiquitin-related modifier 2 (SUMO2). The effect of this method is further highlighted via the preparation of a series of 17 macrophage inflammatory protein 1β (MIP-1β) analogs, followed by preliminary anti-HIV activity and cell viability assays, respectively. This method offers an efficient and complementary approach to existing strategies for N-terminal modification of proteins.