Augmentative effects of leukemia inhibitory factor reveal a critical role for TYK2 signaling in vascular calcification.

Medial vascular calcification in chronic kidney disease (CKD) involves pro-inflammatory pathways induced by hyperphosphatemia. Several interleukin 6 family members have been associated with pro-calcific effects in vascular smooth muscle cells (VSMCs) and are considered as therapeutic targets. Therefore, we investigated the role of leukemia inhibitory factor (LIF) during VSMC calcification. LIF expression was found to be increased following phosphate exposure of VSMCs. LIF supplementation aggravated, while silencing of endogenous LIF or LIF receptor (LIFR) ameliorated the pro-calcific effects of phosphate in VSMCs. The soluble LIFR mediated antagonistic effects towards LIF and reduced VSMC calcification. Mechanistically, LIF induced phosphorylation of the non-receptor tyrosine-protein kinase 2 (TYK2) and signal transducer and activator of transcription-3 (STAT3) in VSMCs. TYK2 inhibition by deucravacitinib, a selective, allosteric oral immunosuppressant used in psoriasis treatment, not only blunted the effects of LIF, but also interfered with the pro-calcific effects induced by phosphate. Conversely, TYK2 overexpression aggravated VSMC calcification. Ex vivo calcification of mouse aortic rings was ameliorated by Tyk2 pharmacological inhibition and genetic deficiency. Cholecalciferol-induced vascular calcification in mice was improved by Tyk2 inhibition and in the Tyk2-deficient mice. Similarly, calcification was ameliorated in Abcc6/Tyk2-deficient mice after adenine/high phosphorus-induced CKD. Thus, our observations indicate a role for LIF in CKD-associated vascular calcification. Hence, the effects of LIF identify a central pro-calcific role of TYK2 signaling, which may be a future target to reduce the burden of vascular calcification in CKD.

Antiviral screening of four plant extracts against acyclovir resistant herpes simplex virus type-1.

Herpes simplex virus type 1 (HSV-1) causes serious infections particularly in immunocompromised patients. Methanolic extract of four plants were evaluated for their anti-viral effects against acyclovir resistant HSV-1 in HeLa cell line. The 50% cytotoxic concentration (CC50) as well as the effective minimal cytotoxic concentration of each plant extract were evaluated by MTT assay. Antiviral effects of the plant extracts on HSV-1 were examined at different concentrations of the extract. The effective minimal cytotoxic concentration was evaluated at different times of virus replication after infection. Virus titration was assessed by tissue culture infectious dose 50 (TCID50) method. Among the 4 plant extracts evaluated only Mentha pulegium L. extract was shown to exert the highest antiviral activity, with selectivity index (SI) 10.25. Direct treatment of HSV-1 with Mentha pulegium L. extract resulted in 1.7 log10 TCID50 reduction in virus titers after one hour. The highest reduction in HSV-1 infectivity was obtained 1 hour after the infection of the cells with virus resulting in 2.1 log10 TCID50 reduction as compared to the control. The antiviral effects of Mentha pulegium L. extract on HSV-1 after virus infection was more remarkable than the virucidal activity.

Accelerated calciprotein crystallization time (T50) is correlated with impaired lung diffusion capacity in systemic sclerosis.

Background: Systemic sclerosis (SSc) is a complex auto-immune disease characterized by vascular damage, inflammation, fibrosis and calcinosis, where pulmonary involvement is the leading cause of mortality. Calciprotein particles (CPPs) are increasingly formed upon disbalance of the physiological mineral buffering system and induce pro-inflammatory effects. This exploratory study investigated whether functional indicators of the endogenous mineral buffering system are dysregulated in SSc and linked to disease activity. Methods: T50 (calciprotein crystallization test or serum calcification propensity) and hydrodynamic radius of secondary CPPs (CPP2) were determined in serum samples from 78 SSc patients and 44 controls without SSc, and were associated with disease activity markers of SSc. Results: T50 was reduced and CPP2 radius was increased in SSc patients as compared to controls, indicating a deranged mineral buffering system. This was accompanied by slightly higher serum phosphate and PTH levels in SSc patients, while iFGF23 was not significantly modified. Longitudinally, all parameters remained unchanged over time in SSc patients, only iFGF23 increased. While the modified Rodnan skin score showed some inconsistent correlations with mineral buffering indicators, their association was not independent of other factors. However, lower T50 was significantly correlated to reduced lung diffusion capacity and this association remained significant in a multivariate linear regression model. Conclusion: This study provides indications for a disturbed mineral buffering system in SSc. Increased serum calcification propensity (lower T50) is correlated with impaired lung diffusion capacity, suggesting a possible role of deranged mineral buffering in disease progression. Further studies are required to confirm these observations in larger cohorts and to investigate a putative functional relevance.

Validation of a SARS-CoV-2 Surrogate Virus Neutralization Test in Recovered and Vaccinated Healthcare Workers.

Vaccination against COVID-19 is the main public health approach to fight against the pandemic. The Spike (S) glycoprotein of SARS-CoV-2 is the principal target of the neutralizing humoral response. We evaluated the analytical and clinical performances of a surrogate virus neutralization test (sVNT) compared to conventional neutralization tests (cVNTs) and anti-S eCLIA assays in recovered and/or vaccinated healthcare workers. Our results indicate that sVNTs displayed high specificity and no cross-reactivity. Both eCLIA and sVNT immunoassays were good at identifying cVNT serum dilutions ≥1:16. The optimal thresholds when identifying cVNT titers ≥1:16, were 74.5 U/mL and 49.4 IU/mL for anti-S eCLIA and sVNT, respectively. Our data show that neutralizing antibody titers (Nab) differ from one individual to another and may diminish over time. Specific assays such as sVNTs could offer a reliable complementary tool to routine anti-S serological assays.

The protection quest is a primary key to sharing the neutralizing antibody response to cover against all emerging VOCs based on BIV1-CovIran studies.

Over time, the antigenic evolution of emerging variants of SARS-CoV-2 has demanded the development of potential protective vaccines. Administration of additional doses of current vaccines based on the WT spike protein may boost immunity, but their effectiveness has dwindled for patients with more recent variants. Here, we studied the neutralization activity of post-WT strain-based vaccination and a structural simulation in-silico based on the interactions of the RBD-hACE2 as the key to initiating infection among the VOCs of SARS-CoV-2. Our data display shows that WT sera showed a markedly greater reduction in Delta and Omicron, suggesting that the Wuhan-based vaccines may be more susceptible to breakthrough and new VOCs. According to the MD simulation, mutations of Omicron result in a significant change in the variant charge distribution throughout the binding interface that consequently alters the critical interface electrostatic potential in comparison to other variants. This observation provides new insights into immunization policy and next-generation vaccine development.

Differences and similarities between mesenchymal stem cell and endothelial progenitor cell immunoregulatory properties against T cells.

Bone-marrow-derived mesenchymal stem cells and endothelial progenitor cells have some interesting biological properties that make them unique for cell therapy of degenerative and cardiovascular disorders. Although both cell populations have been already studied and used for their regenerative potentials, recently their special immunoregulatory features have brought much more attention. Mesenchymal stem cells and endothelial progenitor cells have both proangiogenic functions and have been shown to suppress the immune response, particularly T cell proliferation, activation, and cytokine production. This makes them suitable choices for allogeneic stem cell transplantation. Nevertheless, these two cells do not have equal immunoregulatory activities. Many elements including their extraction sources, age/passage, expression of different markers, secretion of bioactive mediators, and some others could change the efficiency of their immunosuppressive function. However, to our knowledge, no publication has yet compared mesenchymal stem cells and endothelial progenitor cells for their immunological interaction with T cells. This review aims to specifically compare the immunoregulatory effect of these two populations including their T cell suppression, deactivation, cytokine production, and regulatory T cells induction capacities. Moreover, it evaluates the implications of the tumor necrosis factor alpha-tumor necrosis factor receptor 2 axis as an emerging immune checkpoint signaling pathway controlling most of their immunological properties.