Endothelium Activation during Severe Yellow Fever Triggers an Intense Cytokine-Mediated Inflammatory Response in the Liver Parenchyma

Yellow fever (YF) is a pansystemic disease caused by the yellow fever virus (YFV), the prototype species of the family Flaviviridae and genus Flavivirus, and has a highly complex host-pathogen relationship, in which endothelial dysfunction reflects viral disease tropism. In this study, the in situ endothelial response was evaluated. Liver tissue samples were collected from 21 YFV-positive patients who died due to the disease and five flavivirus-negative controls who died of other causes and whose hepatic parenchyma architecture was preserved. Immunohistochemical analysis of tissues in the hepatic parenchyma of YF cases showed significantly higher expression of E-selectin, P-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and very late antigen-4 in YFV-positive cases than in flavivirus-negative controls. These results indicate that endothelium activation aggravates the inflammatory response by inducing the expression of adhesion molecules that contribute to the rolling, recruitment, migration, and construction of the inflammatory process in the hepatic parenchyma in fatal YF cases.

Thymosin beta-4 improves endothelial function and reparative potency of diabetic endothelial cells differentiated from patient induced pluripotent stem cells

Background Prior studies show that signature phenotypes of diabetic human induced pluripotent stem cells derived endothelial cells (dia-hiPSC-ECs) are disrupted glycine homeostasis, increased senescence, impaired mitochondrial function and angiogenic potential as compared with healthy hiPSC-ECs. In the current study, we aimed to assess the role of thymosin β-4 (Tb-4) on endothelial function using dia-hiPSC-ECs as disease model of endothelial dysfunction. Methods and results Using dia-hiPSC-ECs as models of endothelial dysfunction, we determined the effect of Tb-4 on cell proliferation, senescence, cyto-protection, protein expression of intercellular adhesion molecule-1 (ICAM-1), secretion of endothelin-1 and MMP-1, mitochondrial membrane potential, and cyto-protection in vitro and angiogenic potential for treatment of ischemic limb disease in a mouse model of type 2 diabetes mellitus (T2DM) in vivo. We found that 600 ng/mL Tb4 significantly up-regulated AKT activity and Bcl-XL protein expression, enhanced dia-hiPSC-EC viability and proliferation, limited senescence, reduced endothelin-1 and MMP-1 secretion, and improved reparative potency of dia-hiPSC-ECs for treatment of ischemic limb disease in mice with T2DM. However, Tb4 had no effect on improving mitochondrial membrane potential and glycine homeostasis and reducing intercellular adhesion molecule-1 protein expression in dia-hiPSC-ECs. Conclusions Tb-4 improves endothelial dysfunction through enhancing hiPSC-EC viability, reducing senescence and endothelin-1 production, and improves angiogenic potency in diabetes.

Effects of Sevoflurane on Apoptosis of Myocardial Cells in IRI Rats

Background. Cardiomyocyte apoptosis functions essentially in ischemia/reperfusion- (I/R-) induced myocardial injury. It is suggested that autophagy is widely implicated in the regulation of cell survival and death. Sevoflurane, as a largely used inhalational general anesthetic, has been shown to have a protective effect on cardiomyocytes. However, it was yet elusive on the underlying mechanisms. Aim. The objective of this study is to investigate the association of sevoflurane-mediated cardioprotective effects with autophagy regulation. Methods. An in vitro hypoxia model was established in primary cardiomyocytes from fresh myocardial tissue of the rats. The apoptosis rate of myocardial cells treated with hypoxia and treated with sevoflurane was measured. Western blot and immunocytochemical assay were used to measure the protein expression. The cell proliferation rate and cell apoptosis were measured using the MTT assay and flow cytometry, respectively. Results. The expression of apoptotic proteins including B cell lymphoma-2 (Bcl-2), CCAAT/enhancer-binding protein homologous protein (CHOP), glucose-regulated protein 78 (GRP78), and Bcl-2-associated X protein (BAX) in myocardium treated with sevoflurane was significantly lower than that in myocardium treated with hypoxia. The expression of adhesion proteins such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in myocardium treated with sevoflurane was higher than that in myocardium treated with hypoxia, suggesting better connectivity of the myocardium. Conclusion. Sevoflurane treatment reduced the apoptosis of myocardial cells after hypoxia treatment.

ICAM-1 Targeted Drug Combination Nanoparticles Enhanced Gemcitabine-Paclitaxel Exposure and Breast Cancer Suppression in Mouse Models

Despite the availability of molecularly targeted treatments such as antibodies and small molecules for human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and programmed death-ligand 1 (PD-L1), limited treatment options are available for advanced metastatic breast cancer (MBC), which constitutes ~90% mortality. Many of these monotherapies often lead to drug resistance. Novel MBC-targeted drug-combination therapeutic approaches that may reduce resistance are urgently needed. We investigated intercellular adhesion molecule-1 (ICAM-1), which is abundant in MBC, as a potential target to co-localize two current drug combinations, gemcitabine (G) and paclitaxel (T), assembled in a novel drug-combination nanoparticle (GT DcNP) form. With an ICAM-1-binding peptide (referred to as LFA1-P) coated on GT DcNPs, we evaluated the role of the LFA1-P density in breast cancer cell localization in vitro and in vivo. We found that 1–2% LFA1-P peptide incorporated on GT DcNPs provided optimal cancer cell binding in vitro with ~4× enhancement compared to non-peptide GT DcNPs. The in vivo probing of GT DcNPs labeled with a near-infrared marker, indocyanine green, in mice by bio-imaging and G and T analyses indicated LFA1-P enhanced drug and GT DcNP localization in breast cancer cells. The target/healthy tissue (lung/gastrointestinal (GI)) ratio of particles increased by ~60× compared to the non-ligand control. Collectively, these data indicated that LFA1 on GT DcNPs may provide ICAM-1-targeted G and T drug combination delivery to advancing MBC cells found in lung tissues. As ICAM-1 is generally expressed even in breast cancers that are triple-negative phenotypes, which are unresponsive to inhibitors of nuclear receptors or HER2/estrogen receptor (ER) agents, ICAM-1-targeted LFA1-P-coated GT DcNPs should be considered for clinical development to improve therapeutic outcomes of MBCs.

Are Markers of Allergic Inflammation in Grass Pollen Allergy Influenced by H1 Antihistamines?

Soluble intercellular adhesion molecule-1 (ICAM-1) and soluble vascular adhesion molecule-1 (VCAM-1) play important roles in allergic rhinitis (AR). Treatment with H1 antihistamines improves AR symptoms and in vitro reduces the levels of adhesion molecules. The aim of the study was to evaluate serum levels of ICAM-1 and VCAM-1 in patients with AR to grass pollen and their response to different H1 antihistamines. Material and methods: A total of 50 patients with grass pollen AR were clinically and biologically evaluated. ICAM-1 and VCAM-1 serum levels were evaluated during pollen season before and after treatment with levocetirizine and desloratadine through the ELISA method. Results: ICAM-1, VCAM-1, eosinophils, and total IgE were elevated in patients with AR, compared with healthy subjects. Both antihistamines improved specific symptoms of AR and increased patients’ quality of life during pollen season after one month of treatment. H1 antihistamines reduced VCAM-1, ICAM-1, and total IgE after one-month treatment but not significantly. Patients with increased baseline values tend to remain with increased values after one-month AH1 treatment. Conclusions: ICAM-1 and sVCAM-1 levels are higher in patients with grass pollen-induced AR than healthy controls during pollen exposure. Their serum levels tend to remain at high values during pollen season despite antihistaminic therapy.

Endothelium Activation during Severe Yellow Fever Triggers an Intense Cytokine-Mediated Inflammatory Response in the Liver Parenchyma

Yellow fever (YF) is a pansystemic disease caused by the yellow fever virus (YFV), the prototype species of the family Flaviviridae and genus Flavivirus, and has a highly complex host-pathogen relationship, in which endothelial dysfunction reflects viral disease tropism. In this study, the in situ endothelial response was evaluated. Liver tissue samples were collected from 21 YFV-positive patients who died due to the disease and five flavivirus-negative controls who died of other causes and whose hepatic parenchyma architecture was preserved. Immunohistochemical analysis of tissues in the hepatic parenchyma of YF cases showed significantly higher expression of E-selectin, P-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and very late antigen-4 in YFV-positive cases than in flavivirus-negative controls. These results indicate that endothelium activation aggravates the inflammatory response by inducing the expression of adhesion molecules that contribute to the rolling, recruitment, migration, and construction of the inflammatory process in the hepatic parenchyma in fatal YF cases.

Metformin Sensitizes Leukemic Cells to Cytotoxic Lymphocytes by Increasing Expression of Intercellular Adhesion Molecule-1 (ICAM-1)

Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The antidiabetic drug metformin modifies tumor cell metabolism and several clinical trials are testing its effectiveness for the treatment of solid cancers. The use of metformin in hematologic cancers has received much less attention, although allogeneic cytotoxic lymphocytes are very effective against these tumors. We show here that metformin induces expression of Natural Killer G2-D (NKG2D) ligands (NKG2DL) and intercellular adhesion molecule-1 (ICAM-1), a ligand of the lymphocyte function-associated antigen 1 (LFA-1). This leads to enhance sensitivity to cytotoxic lymphocytes. Overexpression of antiapoptotic Bcl-2 family members decrease both metformin effects. The sensitization to activated cytotoxic lymphocytes is mainly mediated by the increase on ICAM-1 levels, which favors cytotoxic lymphocytes binding to tumor cells. Finally, metformin decreases the growth of human hematological tumor cells in xenograft models, mainly in presence of monoclonal antibodies that recognize tumor antigens. Our results suggest that metformin could improve cytotoxic lymphocyte-mediated therapy.

The Differential Effects of Propylthiouracil and Methimazole as Graves’ Disease Treatment on Vascular Atherosclerosis Markers: A Randomized Clinical Trial

BackgroundHyperthyroidism is related to vascular atherosclerosis. Propylthiouracil (PTU) and methimazole, other than their antithyroid effects, may have different mechanisms in preventing atherogenesis in Graves’ disease.ObjectiveThis study aimed to investigate the effect of antithyroid drugs on markers of vascular atherosclerosis in Graves’ hyperthyroidism.MethodsThis study was a single-blind, randomized clinical trial conducted on 36 patients with Graves’ disease in Cipto Mangunkusumo General Hospital, Jakarta, Indonesia, from June 2019 until July 2020. Graves’ disease was diagnosed from clinical manifestation of hyperthyroidism with diffuse goiter and then confirmed by thyroid stimulation hormone (TSH), free T4 (fT4), and TSH-receptor antibody (TRAb) measurements. Participants were randomly assigned to either a PTU or a methimazole treatment group and followed up for 3 months. Markers of vascular atherosclerosis were represented by adhesion molecules [intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin], carotid artery stiffness [pulse wave velocity (PWV)], and thickness [carotid intima media thickness (cIMT)].ResultsBy the end of the study, 24 participants reached euthyroid condition (13 from the PTU group and 11 from the methimazole group). After 3 months of follow-up, in the PTU group, we noticed an improvement of ICAM-1 [pretreatment: 204.1 (61.3) vs. posttreatment: 141.6 (58.4) ng/ml; p = 0.001], VCAM-1 [837 (707–977) vs. 510 (402–630) ng/ml; p < 0.001] and E-selectin [32.1 (24.1–42.7) vs. 28.2 (21.6–36.8) ng/ml; p = 0.045] in the PTU group. In the methimazole group, only VCAM-1 improvement [725 (565–904) vs. 472 (367–590); p = 0.001] was observed. Meanwhile, we found no significant changes in PWV or cIMT in either group.ConclusionAntithyroid treatment in Graves’ disease leads to improvement in adhesion molecules, with a lesser effect on methimazole, whereas there were no significant changes in PWV or cIMT. PTU may have a better mechanism compared with methimazole in terms of improving adhesion molecules.

Dysregulation of Angiogenesis and Inflammatory Genes in Endometrial Mesenchymal Stem Cells and Their Contribution to Endometriosis

Endometriosis is a common, chronic, inflammatory disorder in women, characterized by the presence of endometrial tissue outside the uterus cavity. The disease affects ~10% of women during their reproductive age. There are some debates on the pathogenesis of endometriosis and its mechanism among scientists; therefore, different hypotheses have been suggested. According to Sampson's theory, a possible mechanism for seeding ectopic endometriotic lesions is a dysregulation of endometrial mesenchymal stem cells (eMSCs). In the present study, we evaluated the expression of candidate genes in eMSCs obtained from endometriosis patients and compared them with non-endometriosis female patients. In addition, bioinformatic analysis was conducted to uncover the genes in the list of our co-expression gene network in endometriosis. According to our results, the expression of vascular endothelial growth factor A, C-X-C-motif chemokine ligand 8, interleukin-6, and intercellular adhesion molecule-1 genes were up-regulated in the eMSCs isolated from endometriosis patients. There was no significant difference in the expression of the LaminB1 gene between the endometriosis and non-endometriosis patients. On the other hand, our bioinformatics analysis demonstrated that co-expressed genes were enriched in the cytokine signaling pathway. Our study provides valuable insights into the gene expression dysregulation in eMSCs derived from endometriosis patients and suggests a possible function for co-expressed networks in the pathogenesis of endometriosis. To confirm the results, more investigations are required.