RGD and Scutellarin Conjugate (WK001) Targeting Platelet Glycoprotein IIb/IIIa Receptor Protects from Myocardial Ischemia/Reperfusion Injury: Synthesis, Characterization, and Bioactivity Evaluation.

Myocardial ischemia/reperfusion (MI/R) injury is an unresolved clinical challenge. The blockade of binding fibrinogen by glycoprotein IIb/IIIa (GPIIb-IIIa) inhibitors has become a new therapeutic approach against MI/R injury. In this study, we modified the RGD structure to combine with scutellarin and synthesized a novel peptide, scutellarin-HomoArg-Gly-Asp-Trp-NH2 (WK001). Herein, reported experimental and docking evidence indicates that WK001 provides immediate and potent platelet inhibition, with stronger inhibition of platelet aggregation than eptifibatide and scutellarin. In particular, it is administered intravenously to prevent thrombus formation and attenuate myocardial fibrosis progression in vivo. Therefore, WK001 could be developed as an antiplatelet drug to treat thrombosis-associated diseases, such as stroke and myocardial infarction.

Effect of combination antiviral therapy on hematological profiles in 151 adults hospitalized with severe coronavirus disease 2019.

OBJECTIVES: The current diagnosis and medicines approach in coronavirus disease 2019 (COVID-19) does not reflect the heterogeneous characteristics of this disease. This study aims to find a new antiviral combination regimen by investigating the frequency of clinically relevant and objectively identified comorbidities, and the clustering of these clinical syndromes and varying results of treatment with antiviral drugs in patients hospitalized with severe COVID-19. METHODS: This study recruited 151 severe COVID-19 infection cases diagnosed in our hospital examination and illustrated the clinical potential during a consecutive 25-day medication period. Potential differences in disease severity and clinical characteristics, hematological profile, and current pharmacologic treatments (single agent, double or triple combinations, and the combined antiviral drugs plus Lianhua Qingwen) among comorbidity clusters were explored. RESULTS: Although disease severity was comparable among three clusters, it was markedly different in terms of laboratory test status. Coagulable abnormality was mainly present in cluster 1 and cluster 2. Other indicators were normal, except for a significant increase of neutrophils presented in cluster 2. Patients showed the most complicated haematological results in cluster 3, including severe coagulation abnormalities, leukocytosis, neutrophilic granulocytosis, and lymphopenia. Our results for the first time suggest that a quadruple combination therapy (Ribavirin, Lopinavir/ritonavir, Umifenovir, and Lianhua Qingwen) can be considered as a preferred treatment approach to severe COVID-19 patients. After treatment, abnormal coagulation and leukocyte had markedly improved with a better prognosis. CONCLUSION: This study expands the understanding of the co-occurrence of combination therapy in patients with COVID-19, which provides the probability of developing novel combined therapy. Furthermore, explore clinical trials of variable antivirus treatments based on subgroup analyses or on using subgroups in the selection criteria would be the next step.

Surface hydrolysis-designed AuNPs-zwitterionic-glucose as a novel tool for targeting macrophage visualization and delivery into infarcted hearts.

Macrophages, innate immune cells, are key players in the maintenance of myocardial homeostasis under normal conditions and tissue repair after injury. The infiltration of macrophages into the injured heart makes them a potentially appealing vehicle for noninvasive imaging and targeted drug delivery of myocardial infarction (MI). In this study, we demonstrated the use of surface hydrolysis-designed AuNPs-zwitterionic-glucose to label macrophages and track their infiltration into isoproterenol hydrochloride (ISO)-induced MI sites noninvasively using CT. The AuNPs-zwitterionic-glucose did not affect the viability or cytokine release of macrophages and were highly taken up by these cells. The in vivo CT images were obtained on Day 4, Day 6, Day 7, and Day 9, and the attenuation was seen to increase in the heart over time compared to the Day 4 scan. In vitro analysis also confirmed the presence of macrophages around injured cardiomyocytes. Additionally, we also addressed the concern of cell tracking or merely AuNP tracking, which is the inherent problem for any form of nanoparticle-labeled cell tracking by using zwitterionic and glucose-functionalized AuNPs. The glucose coated on the surface of AuNPs-zwit-glucose will be hydrolyzed in macrophages, forming only zwitterionic protected AuNPs that cannot be taken up again by endogenous cells in vivo. This will greatly improve the accuracy and precision of imaging and target delivery. We believe this is the first study to noninvasively visualize the infiltration of macrophages into MI hearts using CT, which could be used for imaging and evaluating the possibility of macrophage-mediated delivery in infarcted hearts.

Noninvasive Prognosis of Postmyocardial Infarction Using Urinary miRNA Ultratrace Detection Based on Single-Target DNA-Functionalized AuNPs.

Urine is the most appropriate body fluid for analysis because it is easily and less-invasively obtained than blood; thus, urinary miRNAs can better represent the local stage of the disease and might grow up to be a new class of noninvasive biomarkers of postmyocardial infarction (MI). Monofunctionalized Au nanoparticles (AuNPs) with only one selective DNA at a specific location are more promising in nanotechnology. This study developed a urinary miRNA ultratrace detection strategy based on single-target DNA-functionalized AuNPs for the noninvasive prognosis of post-MI. The AuNPs were designed with only single-stranded biotinylated DNA complementary to the target miRNA through a ratio-optimized stoichiometric method for the first time. Combined with the duplex specific nuclease-assisted target recycling amplification, the single-target DNA-functionalized AuNPs for the first time were used in inductively coupled plasma-mass spectrometry for the determination of urinary miRNA with high sensitivity. After optimizing the reaction conditions, a linear detection range between 1 fM and 10 pM for miR-155 and a detection limit of 0.47 fM were obtained. Finally, the target miR-155 in urine samples collected from MI rats was quantified and the level of miR-155 in MI groups was 30 times higher than in the control groups. The results suggest that urinary miR-155 could be a novel biomarker for the noninvasive diagnosis of MI.

Application of serum exosomal hypoxia-inducible factor-1 alpha (HIF-1α) as potential circulating biomarker for bacterial peritonitis.

Bacterial peritonitis is a severe disease that diagnosis remains challenging for clinicians. Measuring biomarkers might be a rapid diagnostic method. The objective of this study was to analyze and evaluate the dynamic changes in HIF-1α concentration in serum exosomes during bacterial peritonitis. The pre-clinical application value of serum exosomal HIF-1α was evaluated via imipenem and cilastatin sodium (ICS) intervention in the bacterial peritonitis model. The new colorimetric method to quantitate dynamic expression changes of HIF-1α in serum exosomes during bacterial peritonitis was established by our team via using the gold seed-coated with aptamer-functionalized Au @ Au core-shell peroxidase mimic. The typical inflammatory cytokines of bacterial peritonitis were also measured. Following intramuscular administration with ICS, In-Vivo Xtreme imaging system was used to visualize abdominal infection extent. Meanwhile, HIF-1α concentration in rat serum exosomes and pro-inflammatory factors levels in serum were detected. The serum typical inflammatory cytokines levels were elevated in GFP-labeled E.coli induced bacterial peritonitis. The serum exosomal HIF-1α levels clearly increased at 12 h, reached the peak during 24-48 h, and then gradually decreased at 72 h. Following intramuscular administration with ICS, the abdominal infection extent, HIF-1α concentration in serum exosomes, and the serum pro-inflammatory factors levels were reduced at 24 h in GFP-labeled E. coli induced bacterial peritonitis model. The serum exosomal HIF-1α can be used as a biomarker in the early stage of bacterial peritonitis, which might provide the basic research in the pre-clinical for further predicting and monitoring the pathological process of bacterial peritonitis.

Gender-associated difference following COVID-19 virus infection: Implications for thymosin alpha-1 therapy.

Gender influences clinical presentations, duration and severity of symptoms, and therapy outcome in coronavirus disease 2019 (COVID-19) infection. Whether the immune response to Tα1 treatment for SARS-CoV-2 differs between the sexes, and whether this difference explains the male susceptibility to COVID-19, is unclear. This study aimed to investigate the efficiency and safety of Tα1 treatment and provide a basis for practically identifying gender differences characteristics and features of COVID-19. One hundred twenty-seven patients had COVID-19 symptoms and tested COVID19-positive (female 42.52%) in Wuhan union hospital were enrolled for medication. They were randomly divided into groups Control and Tα1 intervention. Seventy-eight patients received a subcutaneous injection of 1.6 mg Tα1, based on supportive treatment for 15 days. The control group included untreated 49 COVID19 patients closely matched for gender and age and received regular supportive treatment. In this retrospective analysis, we found that COVID-19-infected males reported more symptoms than COVID-19-infected females. A high degree of gender differences-related variability was observed in CRP and PCT levels and the cell counts of many lymphocyte subpopulations in the COVID-19 patients after Tα1 intervention. Levels of CRP and IL-6 were higher in Tα1-treated male group than Tα1-treated female group, while the level of PCT was significantly lower in Tα1-treated male group. Gender differences may be a factor in sustaining COVID-19 immunity responded to Tα1, male and female show statistically significant differences in relevance to cytokine production associated with the development of a more significant number of symptoms. This leaves the question of identifying gender-specific risk factors to explain these differences.