The widespread coronavirus SARS-CoV-2 has already infected over 4 million people worldwide, with a death toll over 280,000. Current treatment of COVID-19 patients relies mainly on antiviral drugs lopinavir/ritonavir, arbidol, and remdesivir, the anti-malarial drugs hydroxychloroquine and chloroquine, and traditional Chinese medicine. There are over 2,118 on-going clinical trials underway, but to date none of these drugs have consistently proven effective. Cathepsin L (CatL) is an endosomal cysteine protease. It mediates the cleavage of the S1 subunit of the coronavirus surface spike glycoprotein. This cleavage is necessary for coronavirus entry into human host cells, virus and host cell endosome membrane fusion, and viral RNA release for next round of replication. Here we summarize data regarding seven CatL-selective inhibitors that block coronavirus entry into cultured host cells and provide a mechanism to block SARS-CoV-2 infection in humans. Given the rapid growth of the SARS-CoV-2-positive population worldwide, ready-to-use CatL inhibitors should be explored as a treatment option. We identify ten US FDA-approved drugs that have CatL inhibitory activity. We provide evidence that supports the combined use of serine protease and CatL inhibitors as a possibly safer and more effective therapy than other available therapeutics to block coronavirus host cell entry and intracellular replication, without compromising the immune system.

18F-FPPRGD2, which was approved for clinical study recently, has favorable properties for integrin targeting and showed potential for antiangiogenic therapy and early response monitoring. However, the time-consuming multiple-step synthesis may limit its widespread applications in the clinic. In this study, we developed a simple lyophilized kit for labeling PRGD2 peptide (18F-AlF-NOTA-PRGD2, denoted as 18F-alfatide) using a fluo-ride–aluminum complex that significantly simplified the labeling procedure. Methods Nine patients with a primary diagnosis of lung cancer were examined by both static and dynamic PET imaging with 18F-alfatide, and 1 tuberculosis patient was investigated using both 18F-alfatide and 18F-FDG imaging. Standardized uptake values were measured in tumors and other main organs at 30 min and 1 h after injection. Kinetic parameters were calculated by Logan graphical analysis. Immunohisto-chemistry and staining intensity quantification were performed to confirm the expression of integrin αvβ3. Results Under the optimal conditions, the whole radiosynthesis including purifica-tion was accomplished within 20 min with a decay-corrected yield of 42.1% ± 2.0% and radiochemical purity of more than 95%. 18F-alfatide PET imaging identified all tumors, with mean standardized uptake values of 2.90 ± 0.10. Tumor-to-muscle and tumor-to-blood ratios were 5.87 ± 2.02 and 2.71 ± 0.92, respectively. Conclusion 18F-alfatide can be produced with excellent radiochemical yield and purity via a simple, 1-step, lyophilized kit. PET scanning with 18F-alfatide allows specific imaging of αvβ3 expression with good contrast in lung cancer patients. This technique might be used for the assessment of angiogene-sis and for planning and response evaluation of cancer therapies that would affect angiogenesis status and integrin expression levels.

NOTA-MAL-FSH1 could be labeled rapidly and efficiently with (18)F using one step method. Favorable preclinical data suggest that (18)F-Al-NOTA-MAL-FSH1 may be a suitable radiotracer for the non-invasive visualization of FSHR positive tumor in vivo.

Herein, we report the development of a new “smart” radioactive probe (i.e., 1) which can undergo furin-controlled condensation and self-assembly of radioactive nanoparticles (i.e., 1-NPs) in tumor cells and its application for enhanced microPET imaging of tumors in nude mice co-injected with its cold analog (i.e., 1-Cold). Furin-controlled condensation of 1-Cold and self-assembly of its nanoparticles (i.e., 1-Cold-NPs) in vitro were validated and characterized with HPLC, mass spectra, SEM, and TEM analyses. Cell uptake studies showed that both 1 and 1-Cold have good cell permeability. TEM images of 1-Cold-treated MDA-MB-468 cells directly uncovered that the intracellular 1-Cold-NPs were at/near the location of furin (i.e., Golgi bodies). MTT results indicated that 50 µM 1-Cold did not impose cytotoxicity to MDA-MB-468 cells up to 12 hours. MicroPET imaging of MDA-MB-468 tumor-bearing mice indicated that mice co-injected with 1 and 1-Cold showed higher uptake and longer attenuation of the radioactivity in tumors than those mice only injected with same dosage of 1. Tumor uptake ratios of 1 between these two groups of mice reached the maximum of 8.2 folds at 240 min post injection. Biodistribution study indicated that the uptake ratios of 1 in kidneys between these two groups continuously increased and reached 81.9 folds at 240 min post injection, suggesting the formation of radioactive NPs (i.e., 1-NPs) in MDA-MB-468 tumors of mice co-injected with 1 and 1-Cold. And the nanoparticles were slowly digested and secreted from the tumors, accumulating in the kidneys. Our ''smart'' probe (i.e., 1), together with the strategy of co-injection, might help researchers trace the biomarkers of interest within a longer time window.

Rationale: Blood eosinophil (EOS) count and EOS cationic protein (ECP) associate with human cardiovascular diseases (CVD). Yet, whether EOS play a role in CVD remains untested. The current study detected EOS accumulation in human and murine abdominal aortic aneurysm (AAA) lesions, suggesting EOS participation in this aortic disease. Objective: To test whether and how EOS affect AAA growth. Methods and Results: Population-based randomized clinically controlled screening trials revealed higher blood EOS count in 579 male AAA patients than in 5,063 non-AAA control (0.236{plus minus}0.182 vs 0.211{plus minus}0.154, 109/L, P<0.001). Univariate (OR=1.381, P<0.001) and multivariate (OR=1.237, P=0.031) logistic regression analyses indicated that increased blood EOS count in AAA patients served as an independent risk factor of human AAA. Immunostaining and immunoblot analyses detected EOS accumulation and EOS cationic protein expression in human and murine AAA lesions. Results showed that EOS deficiency exacerbated AAA growth with increased lesion inflammatory cell contents, matrix-degrading protease activity, angiogenesis, cell proliferation and apoptosis, and smooth muscle cell (SMC) loss using angiotensin-II perfusion-induced AAA in Apoe -/- and EOS-deficient Apoe -/- ;∆dblGATA mice. EOS deficiency increased lesion chemokine expression, muted lesion expression of IL4 and EOS-associated-ribonuclease-1 (mEar1, human ECP homolog), and slanted M1 macrophage polarization. In cultured macrophages and monocytes, EOS-derived IL4 and mEar1 polarized M2 macrophages, suppressed CD11b+Ly6Chi monocytes, and increased CD11b + Ly6C lo monocytes. mEar1 treatment or adoptive transfer of EOS from WT and Il13 -/- mice, but not EOS from Il4 -/- mice, blocked AAA growth in Apoe -/- ∆dblGATA mice. Immunofluorescent staining and immunoblot analyses demonstrated a role for EOS IL4 and mEar1 in blocking NF-κB activation in macrophages, SMCs, and endothelial cells. Conclusions: EOS play a protective role in AAA by releasing IL4 and cationic proteins such as mEar1 to regulate macrophage and monocyte polarization and to block NF-κB activation in aortic inflammatory and vascular cells.

Abstract Aims Obesity is a risk factor of abdominal aortic aneurysm (AAA). Inflammatory cytokine interleukin-18 (IL18) has two receptors: IL18 receptor (IL18r) and Na-Cl co-transporter (NCC). In human and mouse AAA lesions, IL18 colocalizes to its receptors at regions rich in adipocytes, suggesting a role of adipocytes in promoting IL18 actions in AAA development. Methods and results We localized both IL18r and NCC in human and mouse AAA lesions. Murine AAA development required both receptors. In mouse AAA lesions, IL18 binding to these receptors increased at regions enriched in adipocytes or adjacent to perivascular adipose tissue. 3T3-L1 adipocytes enhanced IL18 binding to macrophages, aortic smooth muscle cells (SMCs), and endothelial cells by inducing the expression of both IL18 receptors on these cells. Adipocytes also enhanced IL18r and IL18 expression from T cells and macrophages, AAA-pertinent protease expression from macrophages, and SMC apoptosis. Perivascular implantation of adipose tissue from either diet-induced obese mice or lean mice but not that from leptin-deficient ob/ob mice exacerbated AAA development in recipient mice. Further experiments established an essential role of adipocyte leptin and fatty acid-binding protein 4 (FABP4) in promoting IL18 binding to macrophages and possibly other inflammatory and vascular cells by inducing their expression of IL18, IL18r, and NCC. Conclusion Interleukin-18 uses both IL18r and NCC to promote AAA formation. Lesion adipocyte and perivascular adipose tissue contribute to AAA pathogenesis by releasing leptin and FABP4 that induce IL18, IL18r, and NCC expression and promote IL18 actions.

[(18)F]AlF-NOTA-MAL-Cys(39)-exendin-4 shows favorable characteristics for insulinoma imaging and may be translated to clinical studies.

Objective: By binding to its high-affinity receptor FcεR1, IgE activates mast cells, macrophages, and other inflammatory and vascular cells. Recent studies support an essential role of IgE in cardiometabolic diseases. Plasma IgE level is an independent predictor of human coronary heart disease. Yet, a direct role of IgE and its mechanisms in cardiometabolic diseases remain incompletely understood. Approach and Results: Using atherosclerosis prone Apoe −/− mice and IgE-deficient Ige −/− mice, we demonstrated that IgE deficiency reduced atherosclerosis lesion burden, lesion lipid deposition, smooth muscle cell and endothelial cell contents, chemokine MCP (monocyte chemoattractant protein)-1 expression and macrophage accumulation. IgE deficiency also reduced bodyweight gain and increased glucose and insulin sensitivities with significantly reduced plasma cholesterol, triglyceride, insulin, and inflammatory cytokines and chemokines, including IL (interleukin)-6, IFN (interferon)-γ, and MCP-1. From atherosclerotic lesions and peritoneal macrophages from Apoe −/− Ige −/− mice that consumed an atherogenic diet, we detected reduced expression of M1 macrophage markers (CD68, MCP-1, TNF [tumor necrosis factor]-α, IL-6, and iNOS [inducible nitric oxide synthase]) but increased expression of M2 macrophage markers (Arg [arginase]-1 and IL-10) and macrophage-sterol-responsive-network molecules (complement C3, lipoprotein lipase, LDLR [low-density lipoprotein receptor]-related protein 1, and TFR [transferrin]) that suppress macrophage foam cell formation. These IgE activities can be reproduced in bone marrow-derived macrophages from wild-type mice, but muted in cells from FcεR1-deficient mice, or blocked by anti-IgE antibody or complement C3 deficiency. Conclusions: IgE deficiency protects mice from diet-induced atherosclerosis, obesity, glucose tolerance, and insulin resistance by regulating macrophage polarization, macrophage-sterol-responsive-network gene expression, and foam cell formation.