In Vitro Targeted Delivery of Simvastatin and Niacin to Macrophages Using Mannan-Grafted Magnetite Nanoparticles.

Atherosclerosis, a leading cause of mortality worldwide, involves various subsets of macrophages that contribute to its initiation and progression. Current treatment approaches focus on systemic, long-term administration of cholesterol-lowering antioxidants such as statins and certain vitamins, which unfortunately come with prolonged side effects. To overcome these drawbacks, a mannose-containing magnetic nanoparticle (NP) is introduced as a drug delivery system to specifically target macrophages in vitro using simvastatin or niacin and a combinational therapy approach that reduces local inflammation while avoiding unwanted side effects. The synthesized NPs exhibited superparamagnetic behavior, neutrally charged thin coating with a hydrodynamic size of 77.23 ± 13.90 nm, and a metallic core ranging from 15 to 25 nm. Efficient loading of niacin (87.21%) and simvastatin (75.36%) on the NPs was achieved at respective weights of 20.13 and 5.03 (w/w). In the presence of a mannan hydrolyzing enzyme, 79.51% of simvastatin and 67.23% of niacin were released from the NPs within 90 min, with a leakage rate below 19.22%. Additionally, the coated NPs showed no destructive effect on J774A macrophages up to a concentration of 200 µg/mL. Simvastatin-loaded NPs exhibited a minimal increase in IL-6 expression. The low dosage of simvastatin decreased both IL-6 and ARG1 expressions, while niacin and combined simvastatin/niacin increased the level of ARG1 expression significantly. Toxicity evaluations on human umbilical vein endothelial cells and murine liver cells revealed that free simvastatin administration caused significant toxicity, whereas the encapsulated forms of simvastatin, niacin, and a combination of simvastatin/niacin at equivalent concentrations exhibited no significant toxicity. Hence, the controlled release of the encapsulated form of simvastatin and niacin resulted in the effective modulation of macrophage polarization. The delivery system showed suitability for targeting macrophages to atherosclerotic plaque.

Th-1, Th-2, Th-9, Th-17, Th-22 type cytokine concentrations of critical COVID-19 patients after treatment with Remdesivir.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread around the world causing a pandemic known as coronavirus disease 2019 (COVID-19). Cytokine storm was directly correlated with severity of COVID-19 syndromes. We evaluated the levels of 13 cytokines in ICU hospitalized COVID-19 patients (n = 29) before, and after treatment with Remdesivir as well as in healthy controls (n = 29). Blood samples were obtained from ICU patients during ICU admission (before treatment) and 5 days after treatment with Remdesivir. A group of 29 age- and gender-matched healthy controls was also studied. Cytokine levels were evaluated by multiplex immunoassay method using a fluorescence labeled cytokine panel. In comparison to cytokine levels measured at ICU admission, serum levels were reduced of IL-6 (134.75 pg/mL vs. 20.73 pg/mL, P < 0.0001), TNF-α (121.67 pg/mL vs. 10.15 pg/mL, P < 0.0001) and IFN-γ (29.69 pg/mL vs. 22.27 pg/mL, P = 0.005), whereas serum level was increased of IL-4 (8.47 pg/mL vs. 12.44 pg/mL, P = 0.002) within 5 days after Remdesivir treatment. Comparing with before treatment, Remdesivir significantly reduced the levels of inflammatory (258.98 pg/mL vs. 37.43 pg/mL, P < 0.0001), Th1-type (31.24 pg/mL vs. 24.46 pg/mL, P = 0.007), and Th17-type (36.79 pg/mL vs. 26.22 pg/mL, P < 0.0001) cytokines in critical COVID-19 patients. However, after Remdesivir treatment, the concentrations of Th2-type cytokines were significantly higher than before treatment (52.69 pg/mL vs. 37.09 pg/mL, P < 0.0001). In conclusion, Remdesivir led to decrease levels of Th1-type and Th17-type cytokines and increase Th2-type cytokines in critical COVID-19 patients 5 days after treatment.

Immunosenescence in atherosclerosis: A role for chronic viral infections.

Immune system is a versatile and dynamic body organ which offers survival and endurance of human beings in their hostile living environment. However, similar to other cells, immune cells are hijacked by senescence. The ageing immune cells lose their beneficial functions but continue to produce inflammatory mediators which draw other immune and non-immune cells to the senescence loop. Immunosenescence has been shown to be associated with different pathological conditions and diseases, among which atherosclerosis has recently come to light. There are common drivers of both immunosenescence and atherosclerosis; e.g. inflammation, reactive oxygen species (ROS), chronic viral infections, genomic damage, oxidized-LDL, hypertension, cigarette smoke, hyperglycaemia, and mitochondrial failure. Chronic viral infections induce inflammaging, sustained cytokine signaling, ROS generation and DNA damage which are associated with atherogenesis. Accumulating evidence shows that several DNA and RNA viruses are stimulators of immunosenescence and atherosclerosis in an interrelated network. DNA viruses such as CMV, EBV and HBV upregulate p16, p21 and p53 senescence-associated molecules; induce inflammaging, metabolic reprogramming of infected cells, replicative senescence and telomere shortening. RNA viruses such as HCV and HIV induce ROS generation, DNA damage, induction of senescence-associated secretory phenotype (SASP), metabolic reprogramming of infected cells, G1 cell cycle arrest, telomere shortening, as well as epigenetic modifications of DNA and histones. The newly emerged SARS-CoV-2 virus is also a potent inducer of cytokine storm and SASP. The spike protein of SARS-CoV-2 promotes senescence phenotype in endothelial cells by augmenting p16, p21, senescence-associated ß-galactosidase (SA-ß-Gal) and adhesion molecules expression. The impact of SARS-CoV-2 mega-inflammation on atherogenesis, however, remains to be investigated. In this review we focus on the common processes in immunosenescence and atherogenesis caused by chronic viral infections and discuss the current knowledge on this topic.

Comparison of the Antibody Responses Following Vaccination with AstraZeneca and Sinopharm.

BACKGROUND: Vaccines are the most effective way to prevent Coronavirus 2 severe acute respiratory syndrome (SARS-CoV-2). OBJECTIVES: To compare the antibody response of healthy individuals vaccinated with either the AstraZeneca (ChAdOx1 nCoV-19) or the Sinopharm (BBIBP-CorV) vaccine, in those who had no prior infection with SARS-CoV-2. METHODS: Thirty seven participants were included, of which 17 were administered the AstraZeneca (ChAdOx1 nCoV-19) vaccine, while 20 were given the Sinopharm (BBIBP-CorV) vaccine. SARS-CoV-2 neutralizing antibody and anti-receptor-binding domain (RBD) IgG levels were checked 4 weeks after giving the first and the second dose of either vaccine using the enzyme-linked immunosorbent assay (ELISA) technique. RESULTS: The AstraZeneca (ChAdOx1 nCoV-19) vaccine exhibited a higher levels of anti-(RBD) IgG compared with the Sinopharm (BBIBP-CorV) in both the first (14.51 µg/ml vs. 1.160 µg/ml) and the second (46.68 µg/ml vs. 11.43 µg/ml) doses. About neutralizing Abs, the titer of the antibody was higher in the AstraZeneca (ChAdOx1 nCoV-19) recipients than in the Sinopharm (BBIBP-CorV) subjects after the first (7.77 µg/ml vs. 1.79 µg/ml, p < 0.0001) and the second dose (10. 36 µg/ml vs. 4.88 µg/ml, p < 0.0001). CONCLUSIONS: Recipients vaccinated with two doses of the AstraZeneca (ChAdOx1 nCoV-19) had superior quantitative antibody levels than Sinopharm (BBIBP-CorV)-vaccinated subjects. These data suggest that a booster dose may be needed for the Sinopharm (BBIBP-CorV) recipients, to control the COVID-19 pandemic.

Partial recovery of senescence in circulating follicular helper T cells after Dasatinib treatment.

Cellular senescence is an irreversible arrest of cell proliferation triggered by different stimuli, including DNA damage, telomere shortening and oncogenic stress. Senescent cells, by releasing the senescence-associated-secretory-phenotype (SASP), contribute to various diseases pathogenesis. Human atherosclerotic plaque contains cells with multiple markers of senescence that associate with disease severity. We characterized the frequency of senescent cTfh cells and genes expressions before and after treatment with Dasatinib in patients with different degrees of stenosis. Twelve high (≥50%), and twelve low (<50%) stenosis patients and six healthy controls were enrolled. The percentage of senescent CD3+CD4+CXCR5+CD153+CD57+ cells was significantly decreased in Dasatinib treated cells from individuals with low and high stenosis (P = 0.0007 and P = 0.0002, respectively). However, the frequency of total lymphocytes, CD3+ and CD4+ T cells were not significantly different between the groups before and after treatment. The expression levels of P53 (P = 0.0003 and P = 0.0001), P16 (P = 0.0005 and P = 0.0002), p21 (P = 0.0002 and P < 0.0001), SENEX (P = 0.0005 and P < 0.0001) and BCL-2 (P = 0.0005 and P = 0.0002) were decreased in PBMCs of low and high stenosis groups after treatment with Dasatinib, respectively. The percentage of senescent cTfh cells positively correlated with cholesterol (P = 0.034; r = 0.671), C-reactive protein (CRP) (P = 0.029; r = 0.707), Erythrocyte sedimentation rate (ESR) levels (P = 0.030; r = 0.598) and neutrophil counts (P = 0.021; r = 0.799) in patients with high stenosis. The decreased frequency of senescent cTfh cells and the expression levels of senescence genes after Dasatinib treatment in patients with atherosclerosis suggest a role for Dasatinib in partial clearance or rejuvenation of senescent cTfh cells, which may decrease inflammatory mediators and attenuate disease progression.

Frequency of Efficient Circulating Follicular Helper T Cells Correlates with Dyslipidemia and WBC Count in Atherosclerosis.

Background: The significance of cTfh cells and their subsets in atherosclerosis is not well understood. We measured the frequency of cTfh subsets in patients with different degrees of stenosis using flow-cytometry. Methods: Participants included high (≥50%; n = 12) and low (<50%; n = 12) stenosis groups, as well as healthy controls (n = 6). Results: The frequency of CCR7loPD-1hiefficient-cTfh was significantly higher in patients with high stenosis compared to healthy controls (p = 0.003) and correlated with low-density lipoprotein (LDL; p = 0.043), cholesterol (p = 0.043), triglyceride (p = 0.019), neutrophil count (p = 0.032), platelet count (p = 0.024), neutrophil/lymphocyte ratio (NLR; p = 0.046), and platelet/lymphocyte ratio (PLR; p = 0.025) in high stenosis group. The frequency of CCR7hiPD-1lo quiescent-cTfh was higher in healthy controls compared to the high-stenosis group (p = 0.001) and positively correlated with high-density lipoprotein (p = 0.046). The frequency of efficient-cTfh cells was correlated with platelet count (p = 0.043), NLR (p = 0.036), and PLR (p P = 0.035) in low-stenosis group, while that of quiescent-cTfh cells was negatively correlated with LDL (p = 0.034), cholesterol (p = 0.047), platelet count (p = 0.032), and PLR (p = 0.041). Conclusion: High percentages of cTfh and efficient-cTfh cells in patients with advanced atherosclerosis and their correlation with dyslipidemia and white blood cell counts suggest an ongoing cTfh subset deviation, towards efficient phenotype in the milieu of inflammation and altered lipid profile. Efficient cTfh cells have an effector phenotype and could in turn contribute to atherosclerosis progression.

Potential Immune Indicators for Predicting the Prognosis of COVID-19 and Trauma: Similarities and Disparities.

Although cellular and molecular mediators of the immune system have the potential to be prognostic indicators of disease outcomes, temporal interference between diseases might affect the immune mediators, and make them difficult to predict disease complications. Today one of the most important challenges is predicting the prognosis of COVID-19 in the context of other inflammatory diseases such as traumatic injuries. Many diseases with inflammatory properties are usually polyphasic and the kinetics of inflammatory mediators in various inflammatory diseases might be different. To find the most appropriate evaluation time of immune mediators to accurately predict COVID-19 prognosis in the trauma environment, researchers must investigate and compare cellular and molecular alterations based on their kinetics after the start of COVID-19 symptoms and traumatic injuries. The current review aimed to investigate the similarities and differences of common inflammatory mediators (C-reactive protein, procalcitonin, ferritin, and serum amyloid A), cytokine/chemokine levels (IFNs, IL-1, IL-6, TNF-α, IL-10, and IL-4), and immune cell subtypes (neutrophil, monocyte, Th1, Th2, Th17, Treg and CTL) based on the kinetics between patients with COVID-19 and trauma. The mediators may help us to accurately predict the severity of COVID-19 complications and follow up subsequent clinical interventions. These findings could potentially help in a better understanding of COVID-19 and trauma pathogenesis.

Functional subsets of circulating follicular helper T cells in patients with atherosclerosis.

Frequencies of circulating T follicular helper (cTfh) functional subsets vary in autoimmune diseases. We evaluated the frequencies and clinical relevance of functional subsets of cTfhs in patients with different degrees of stenosis. Blood samples were collected from high (≥50%) (n = 12) and low (<50%) stenosis (n = 12) groups and healthy controls (n = 6). Three subsets of cTfh cells including cTfh1 (CXCR3+ CCR6- ), cTfh2 (CXCR3- CCX6- ), and cTfh17 (CXCR3- CCR6+ ) were detected by flow cytometry. The frequency of cTfh1 cells was higher in control (p = .0006) and low-stenosis groups (p = .005) compared to high-stenosis group. The percentages of cTfh2 and cTfh17 cells were increased in high-stenosis compared to low-stenosis (p = .002 and p = .007) and control groups (p = .0004 and p = .0005), respectively. The frequency of cTfh1 cells negatively correlated with cholesterol (p = .040; r = -.44), C-reactive protein (CRP) (p = .015; r = -.68), erythrocyte sedimentation rate (ESR) (p = .002; r = -.79), neutrophil/lymphocyte ratio (NLR) (p = .028; r = -.67), and cTfh17 (p = .017; r = -.7244) in the high-stenosis group. The percentages of cTfh2 and cTfh17 cells positively correlated with cholesterol (p = .025; r = .77 and p = .033; r = .71), CRP (p = .030; r = .61 and p = .020; r = .73), ESR (p = .027; r = .69 and p = .029; r = .70), NLR (p = .004; r = .76 and p = .005; r = .74), and with each other (p = .022; r = .7382), respectively, in the high-stenosis group. The increased frequencies of cTfh2 and cTfh17 subsets and their correlation with laboratory parameters in patients with atherosclerosis may suggest their role in promoting the inflammatory response and atherosclerosis progression.

Anti-varicella Zoster Virus IgG and hsCRP Levels Correlate with Progression of Coronary Artery Atherosclerosis.

The relationship between high levels of anti-Varicella Zoster Virus (VZV) IgG in cerebrospinal fluid (CSF) and cerebrovascular atherosclerosis commends a possible similar association in other vessels. We aimed to investigate the association of VZV-seropositivity with coronary artery atherosclerosis. We recruited 88 newly diagnosed patients with more than 50% stenosis in at least one of the main coronary arteries. As the control group, 99 age-matched individuals with normal/insignificant coronary artery findings were included. Clinical, paraclinical, and demographical data were gathered at the time of sampling. High-sensitivity C-reactive protein (hsCRP) levels were measured by nephelometry. VZV-seropositivity was determined by measuring of anti-VZV IgG level in plasma. Multivariable logistic regression was used to evaluate the correlation of data with coronary vascular atherosclerosis. The frequency of VZV-seropositivity was significantly higher in the atherosclerosis group compared to the controls (OR=1.88; 95%CI=1.03-3.44). The plasma levels of anti-VZV IgG were significantly higher in patients with atherosclerosis (Median=2.70, IQR=1.53-4.30 AU/mL) than in the controls (Median=2.10, IQR=1.70-3.10 AU/mL, p=0.034). The hsCRP levels in patients and controls were 5.19±2.00 and 1.51±1.07 mg/L, respectively. The correlation between hsCRP and anti-VZV IgG level in plasma was observed (r=0.40, p<0.001). The levels of hsCRP and anti-VZV IgG increased based on the number of diseased vessels but only the difference in hsCRP levels reached a significant level (p<0.001 and p=0.168, respectively). Our data suggest that VZV-seropositivity and hsCRP elevation jointly increase the risk of atherosclerosis. The multifactorial nature of atherosclerosis; however, leaves more options for the inflammatory milieu to be generated.