Inhibitory Efficacy of Main Components of Scutellaria baicalensis on the Interaction between Spike Protein of SARS-CoV-2 and Human Angiotensin-Converting Enzyme II.

Blocking the interaction between the SARS-CoV-2 spike protein and the human angiotensin-converting enzyme II (hACE2) protein serves as a therapeutic strategy for treating COVID-19. Traditional Chinese medicine (TCM) treatments containing bioactive products could alleviate the symptoms of severe COVID-19. However, the emergence of SARS-CoV-2 variants has complicated the process of developing broad-spectrum drugs. As such, the aim of this study was to explore the efficacy of TCM treatments against SARS-CoV-2 variants through targeting the interaction of the viral spike protein with the hACE2 receptor. Antiviral activity was systematically evaluated using a pseudovirus system. Scutellaria baicalensis (S. baicalensis) was found to be effective against SARS-CoV-2 infection, as it mediated the interaction between the viral spike protein and the hACE2 protein. Moreover, the active molecules of S. baicalensis were identified and analyzed. Baicalein and baicalin, a flavone and a flavone glycoside found in S. baicalensis, respectively, exhibited strong inhibitory activities targeting the viral spike protein and the hACE2 protein, respectively. Under optimized conditions, virus infection was inhibited by 98% via baicalein-treated pseudovirus and baicalin-treated hACE2. In summary, we identified the potential SARS-CoV-2 inhibitors from S. baicalensis that mediate the interaction between the Omicron spike protein and the hACE2 receptor. Future studies on the therapeutic application of baicalein and baicalin against SARS-CoV-2 variants are needed.

ACE2 and a Traditional Chinese Medicine Formula NRICM101 Could Alleviate the Inflammation and Pathogenic Process of Acute Lung Injury.

COVID-19 is a highly transmittable respiratory illness caused by SARS-CoV-2, and acute lung injury (ALI) is the major complication of COVID-19. The challenge in studying SARS-CoV-2 pathogenicity is the limited availability of animal models. Therefore, it is necessary to establish animal models that can reproduce multiple characteristics of ALI to study therapeutic applications. The present study established a mouse model that has features of ALI that are similar to COVID-19 syndrome to investigate the role of ACE2 and the administration of the Chinese herbal prescription NRICM101 in ALI. Mice with genetic modifications, including overexpression of human ACE2 (K18-hACE2 TG) and absence of ACE2 (mACE2 KO), were intratracheally instillated with hydrochloric acid. The acid intratracheal instillation induced severe immune cell infiltration, cytokine storms, and pulmonary disease in mice. Compared with K18-hACE2 TG mice, mACE2 KO mice exhibited dramatically increased levels of multiple inflammatory cytokines (IL-6 and TNF-α) in bronchoalveolar lavage fluid, histological evidence of lung injury, and dysregulation of MAPK and MMP activation. In mACE2 KO mice, NRICM101 could ameliorate the disease progression of acid-induced ALI. In conclusion, the established mouse model provided an effective platform for researchers to investigate pathological mechanisms and develop therapeutic strategies for ALI, including COVID-19-related ALI.

Engineering PD-L1 Cellular Nanovesicles Encapsulating Epidermal Growth Factor for Deep Second-Degree Scald Treatment.

Scars are common and intractable consequences after scalded wound healing, while monotherapy of epidermal growth factors does not solve this problem. Maintaining the stability of epidermal growth factors and promoting scarless healing of wounds is paramount. In this study, engineering cellular nanovesicles overexpressing PD-L1 proteins, biomimetic nanocarriers with immunosuppressive efficacy, were successfully prepared to encapsulate epidermal growth factors for maintaining its bioactivity. Remarkably, PD-L1 cellular nanovesicles encapsulating epidermal growth factors (EGF@PDL1 NVs) exerted desired therapeutic effect by attenuating the overactivation of T cell immune response and promoting skin cells migration and proliferation. Hence, EGF@PD-L1 NVs promoted wound healing and prevented scarring in deep second-degree scald treatment, demonstrating a better effect than using individual PD-L1 NVs or EGF. This research proved that EGF@PD-L1 NVs is considered an innovative and thorough therapy of deep second-degree scald.

Immunohistochemical analysis of PD-L1 and tumor-infiltrating immune cells expression in the tumor microenvironment of primary signet ring cell carcinoma of the prostate.

Primary signet ring cell carcinoma (SRCC) of the prostate is a rare neoplasm. However, its potential tumorigenic mechanism, clinicopathological features, and prognostic outcome have not been systematically described. To determine the pathogenic mechanism, we detected distributions of programmed cell death-ligand 1 (PD-L1), programmed death 1 (PD-1), and cellular components in the tumor microenvironment, including tumor-infiltrating lymphocytes (CD4 and CD8), tumor-associated macrophages (TAMs; CD163 and CD68), and tumor-associated fibroblasts (vimentin and alpha-smooth muscle actin [α-SMA]), in tumor tissues from four patients with primary prostatic SRCC compared with corresponding adjacent tissues and tumor tissues from 30 patients with prostate adenocarcinoma (PCa) by immunohistochemical staining. We found higher expression of PD-L1, CD163, and CD68 in primary SRCC specimens than that in both corresponding adjacent nontumor specimens and PCa specimens with different Gleason scores, indicating that TAMs may participate in the malignant biological behavior of primary SRCC of the prostate. For further analysis, we searched electronic journal databases and Surveillance, Epidemiology, and End Results (SEER) to identify 200 eligible patients including our four cases. According to Kaplan-Meier survival curve analysis, patients <68 years old, with radical prostatectomy (RP), Gleason score of 7-8, and lower clinical stage had longer overall survival (OS). Moreover, Cox multivariate analysis indicated that race (hazard ratio [HR] = 1.422), surgical approach (HR = 1.654), and Gleason score (HR = 2.162) were independent prognostic factors for OS. Therefore, primary SRCC of the prostate represents a distinct and aggressive subtype of prostate cancer associated with a higher distribution of PD-L1 and TAMs, which warrants further clinical investigation.

Anthelmintic niclosamide attenuates pressure-overload induced heart failure in mice.

The heart is a high energy demand organ and enhancing mitochondrial function is proposed as the next-generation therapeutics for heart failure. Our previous study found that anthelmintic drug niclosamide enhanced mitochondrial respiration and increased adenosine triphosphate (ATP) production in cardiomyocytes, therefore, this study aimed to determine the effect of niclosamide on heart failure in mice and the potential molecular mechanisms. The heart failure model was induced by transverse aortic constriction (TAC) in mice. Oral administration of niclosamide improved TAC-induced cardiac hypertrophy, cardiac fibrosis, and cardiac dysfunction in mice. Oral administration of niclosamide reduced TAC-induced increase of serum IL-6 in heart failure mice. In vitro, niclosamide within 0.1 µM increased mitochondrial respiration and ATP production in mice heart tissues. At the concentrations more than 0.1 µM, niclosamide reduced the increased interleukin- 6 (IL-6) mRNA expression in lipopolysaccharide (LPS)-stimulated RAW264.7 and THP-1 derived macrophages. In cultured primary cardiomyocytes and cardiac fibroblasts, niclosamide (more than 0.1 µM) suppressed IL-6- and phenylephrine-induced cardiomyocyte hypertrophy, and inhibited collagen secretion from cardiac fibroblasts. In conclusion, niclosamide attenuates heart failure in mice and the underlying mechanisms include enhancing mitochondrial respiration of cardiomyocytes, inhibiting collagen secretion from cardiac fibroblasts, and reducing the elevated serum inflammatory mediator IL-6. The present study suggests that niclosamide might be therapeutic for heart failure.

Chemical mitochondrial uncouplers share common inhibitory effect on NLRP3 inflammasome activation through inhibiting NFκB nuclear translocation.

Activation of NLRP3 inflammasome is implicated in varieties of pathologies, the aim of the present study is to characterize the effect and mechanism of mitochondrial uncouplers on NLRP3 inflammasome activation by using three types of uncouplers, niclosamide, CCCP and BAM15. Niclosamide, CCCP and BAM15 inhibited LPS plus ATP-induced increases of NLRP3 protein and IL-1ß mRNA levels in RAW264.7 macrophages and THP-1 derived macrophages. Niclosamide, CCCP and BAM15 inhibited LPS plus ATP-induced increase of NFκB (P65) phosphorylation, and inhibited NFκB (P65) nuclear translocation in RAW264.7 macrophages. Niclosamide and BAM15 inhibited LPS-induced increase of IκBα phosphorylation in RAW264.7 macrophages, and the inhibitory effect was dependent on increased intracellular [Ca2+]i; however, CCCP showed no significant effect on IκBα phosphorylation in RAW264.7 macrophages stimulated with LPS. In conclusion, chemical mitochondrial uncouplers niclosamide, CCCP and BAM15 share common inhibitory effect on NLRP3 inflammasome activation through inhibiting NFκB nuclear translocation.

Solid-State Nonlinear Optical Switch with the Widest Switching Temperature Range Owing to Its Continuously Tunable Tc.

Interest on the nonlinear optical (NLO) switches that turn on/off the second-harmonic generation (SHG) triggered by the external stimulus (such as heat) have continuously grown, especially on the solid-state NLO switches showing superior stability, reversibility, and reproducibility. Herein, we discover (NH4)2PO3F, as an entirely new solid-state NLO switch showing outstanding switch contrast and reversibility as well as strong SHG intensity (1.1 × KH2PO4 (KDP)) and high laser-induced damage threshold (2.0 × KDP), undergoes a unique first-order phase transition that originates from a reversible hydrogen-bond rearrangement and needs to overcome an energy barrier. Accordingly, we put forward a strategy to continuously modify such an energy barrier by reducing the number of hydrogen bonds per unit cell via an isoelectronic replacement of NH4+ by K+ with a similar size yet incapability of providing any hydrogen bond. Consequently, Kx(NH4)2-xPO3F (x = 0-0.3) exhibiting excellent switching performance are obtained. Remarkably, Kx(NH4)2-xPO3F not only realizes a continuously tunable Tc spanning from 270 to 150 K, representing the widest NLO switching temperature range ever known but also indicates the first solid-state NLO switch example with continuous Tc. Intrinsically, such a Tc decline depends on the weakening degree of the hydrogen-bonding interactions in the unit cell. These new insights will shed useful light on the future material design and open new application possibilities.

Pyrolytic Kinetics of Polystyrene Particle in Nitrogen Atmosphere: Particle Size Effects and Application of Distributed Activation Energy Method.

This work was motivated by a study of particle size effects on pyrolysis kinetics and models of polystyrene particle. Micro-size polystyrene particles with four different diameters, 5, 10, 15, and 50 µm, were selected as experimental materials. Activation energies were obtained by isoconversional methods, and pyrolysis model of each particle size and heating rate was examined through different reaction models by the Coats-Redfern method. To identify the controlling model, the Avrami-Eroféev model was identified as the controlling pyrolysis model for polystyrene pyrolysis. Accommodation function effect was employed to modify the Avrami-Eroféev model. The model was then modified to f() = n0.39n - 1.15(1 - )[-ln(1 - )]1 - 1/n, by which the polystyrene pyrolysis with different particle sizes can be well explained. It was found that the reaction model cannot be influenced by particle geometric dimension. The reaction rate can be changed because the specific surface area will decrease with particle diameter. To separate each step reaction and identify their distributions to kinetics, distributed activation energy method was introduced to calculate the weight factor and kinetic triplets. Results showed that particle size has big impacts on both first and second step reactions. Smaller size particle can accelerate the process of pyrolysis reaction. Finally, sensitivity analysis was brought to check the sensitivity and weight of each parameter in the model.

Development and internal validation of PI-RADs v2-based model for clinically significant prostate cancer.

BACKGROUND: Our objective is to build a model based on Prostate Imaging Reporting and Data System version 2 (PI-RADs v2) and assess its accuracy by internal validation. METHODS: Patients who took prostate biopsy from 2014 to 2015 were retrospectively collected to compose training cohort according to the inclusion criteria and patients in 2016 composing validation cohort. Diagnostic performance was evaluated by analyzing the area under the curve (AUC), calibration curves, and decision curves. RESULTS: Of the 441 patients involved, the clinically significant prostate cancer (csPCa) detection rate were 40.6% (114/281) and 43.8% (70/160) in the training and validation cohort, respectively. Meanwhile, PCa detection rate were 50.2% (141/281) and 53.8% (86/160). Age, prostate-specific antigen density (PSAD)*10 and PI-RADs v2 score composed the model for PCa (model 1) and csPCa (model 2). The area under the curve of models 1 and 2 was 0.870 (95% CI 0.827-0.912) and 0.753 (95% CI 0.717-0.828) in the training cohort, while 0.845 (95% CI 0.786-0.904) and 0.834 (95% CI 0.787-0.882) in the validation cohort. Both models illustrated good calibration, and decision curve analyses showed good performance in predicting PCa or csPCa when the threshold was 0.35 or above. CONCLUSIONS: The model based on age, PSAD*10 and PI-RADs v2 score showed internally validated high predictive value for both PCa and csPCa. It could be used to improve the diagnostic performance of suspicious PCa.

In vivo MRI tracking of iron oxide nanoparticle-labeled human mesenchymal stem cells in limb ischemia.

BACKGROUND: Stem cell transplantation has been investigated for repairing damaged tissues in various injury models. Monitoring the safety and fate of transplanted cells using noninvasive methods is important to advance this technique into clinical applications. METHODS: In this study, lower-limb ischemia models were generated in nude mice by femoral artery ligation. As negative-contrast agents, positively charged magnetic iron oxide nanoparticles (aminopropyltriethoxysilane-coated Fe2O3) were investigated in terms of in vitro labeling efficiency, effects on human mesenchymal stromal cell (hMSC) proliferation, and in vivo magnetic resonance imaging (MRI) visualization. Ultimately, the mice were sacrificed for histological analysis three weeks after transplantation. RESULTS: With efficient labeling, aminopropyltriethoxysilane-modified magnetic iron oxide nanoparticles (APTS-MNPs) did not significantly affect hMSC proliferation. In vivo, APTS-MNP-labeled hMSCs could be monitored by clinical 3 Tesla MRI for at least three weeks. Histological examination detected numerous migrated Prussian blue-positive cells, which was consistent with the magnetic resonance images. Some migrated Prussian blue-positive cells were positive for mature endothelial cell markers of von Willebrand factor and anti-human proliferating cell nuclear antigen. In the test groups, Prussian blue-positive nanoparticles, which could not be found in other organs, were detected in the spleen. CONCLUSION: APTS-MNPs could efficiently label hMSCs, and clinical 3 Tesla MRI could monitor the labeled stem cells in vivo, which may provide a new approach for the in vivo monitoring of implanted cells.