Anti-Coronaviral Nanocluster Restrain Infections of SARS-CoV-2 and Associated Mutants through Virucidal Inhibition and 3CL Protease Inactivation.

Antivirals that can combat coronaviruses, including SARS-CoV-2 and associated mutants, are urgently needed but lacking. Simultaneously targeting the viral physical structure and replication cycle can endow antivirals with sustainable and broad-spectrum anti-coronavirus efficacy, which is difficult to achieve using a single small-molecule antiviral. Thus, a library of nanomaterials on GX_P2V, a SARS-CoV-2-like coronavirus of pangolin origin, is screened and a surface-functionalized gold nanocluster (TMA-GNC) is identified as the top hit. TMA-GNC inhibits transcription- and replication-competent SARS-CoV-2 virus-like particles and all tested pseudoviruses of SARS-CoV-2 variants. TMA-GNC prevents viral dissemination through destroying membrane integrity physically to enable a virucidal effect, interfering with viral replication by inactivating 3CL protease and priming the innate immune system against coronavirus infection. TMA-GNC exhibits biocompatibility and significantly reduces viral titers, inflammation, and pathological injury in lungs and tracheas of GX_P2V-infected hamsters. TMA-GNC may have a role in controlling the COVID-19 pandemic and inhibiting future emerging coronaviruses or variants.

Microfluidics-enabled Serial Assembly of Lipid-siRNA-sorafenib Nanoparticles for Synergetic Hepatocellular Carcinoma Therapy.

Multi-component nanoparticles (mNPs) hold great potential for disease prevention and treatment. However, a major barrier is the lack of versatile platforms to accommodate steps of assembly processes of mNPs. Here the microfluidics-enabled serial assembly (MESA) of mNPs is presented. The microfluidic chip, as a mini-conveyor of initial materials, sequentially enables the assembly of sorafenib supramolecule, electrostatic adsorption of siRNA, and surface assembly of protective lipids. The produced lipid-siRNA-sorafenib nanoparticles (LSS NPs) have ultrahigh encapsulation efficiencies for sorafenib (≈100%) and siRNA (≈95%), which benefit from the accommodation of both fast and slow processes on the chip. Although carrying negative charges, LSS NPs enable cytosolic delivery of agents and high gene silencing efficiency within tumor cells. In vivo, the LSS NPs delivering hypoxia-induced factor (HIF1α)-targeted siRNA efficiently regress tumors of Hep3B xenograft and hepatocellular carcinoma patient-derived primary cells xenograft (PDCX) and finally extend the average survival of PDCX mice to 68 days. Thus, this strategy is promising as a sorafenib/siRNA combination therapy, and MESA can be a universal platform for fabricating complex nanosystems.

Effects of a functional fatty acid blend on growth performance, intestinal morphology, and serum profiles in weaned piglets.

OBJECTIVE: The objective of this study was to determine whether dietary supplementation with a functional fatty acid blend (FA) that contains 31.4% butyric acid and 4.99% medium-chain FA improve growth performance, antioxidant capacity, immunity status, and anti-inflammatory ability in weaned piglets. METHODS: One hundred and forty-four healthy piglets (Duroc×Landrace×Yorkshire) with an average body weight (BW) of 7.98±3.43 kg were randomly divided into three groups with six replicate pens and eight piglets per pen: Normal control (NC): a corn-soybean basal diet; FA1: a basal diet supplemented with 1,000 mg/kg of a functional FA; FA2: a basal diet supplemented with 2,000 mg/kg of a functional FA. The experiment lasted for 28 d. On d 14 and 28, one piglet in each pen from NC and FA2 groups was randomly selected for antioxidative index and immunoglobulins. On d 28, one piglet in each pen from NC and FA2 groups was randomly selected for intestinal morphology and inflammatory factor. RESULTS: We observed that FA supplementation linearly increased (p<0.05) average daily gain and the final BW. There was higher (p<0.05) catalase on d 14, and immunoglobulin (Ig) A and IgM on d 28 in piglets supplemented with FA2 than in the NC group. Moreover, dietary FA2 reduced (p<0.05) crypt depth of ileum in piglets. The concentrations of tumor necrosis factor-α, interleukin (IL)-1ß, IL-8, and IL-10 in jejunum were lower (p<0.05) in the FA2 group compared with the NC group. CONCLUSION: Therefore, the overall results suggests that the FA may help to improve gut health, antioxidant status, and immune parameters resulting in the improvement of growth performance.

Effects of essential oil coated with glycerol monolaurate on growth performance, intestinal morphology, and serum profiles in weaned piglets.

OBJECTIVE: This study aimed to investigate the effects of essential oil coated with glycerol monolaurate (GML) on the growth performance, intestinal morphology, and serum profiles of weaned piglets. METHODS: A total of 144 weaned piglets (Duroc×[Landrace×Yorkshire], average weight 8.07±3.33 kg) were randomly assigned to three groups with six replicate pens and eight piglets per pen: i) CON: a corn-soybean basal diet; ii) LEG: with 1,000 mg/kg essential oil coated with GML; and iii) HEG: with 2,000 mg/kg essential oil coated with GML. RESULTS: Results showed that average daily gain was increased (p<0.05) linearly by essential oil coated with GML supplementation on day 14 to 28 and day 0 to 28 compared with the CON group. Dietary supplementation with HEG increased (p<0.05) total antioxidant capacity and catalase activity on day 14, and immunoglobulin A (IgA) and IgM concentration on day 28 and tended to increase IgG on day 28. In addition, the crypt depth in the jejunum was reduced (p<0.05), and villus height and villus height/crypt depth in the ileum were increased (p<0.05) in the HEG group compared with the CON group. Moreover, lower (p<0.05) concentrations of tumor necrosis factor-α, interferon-γ, interleukin-1ß (IL-1ß), IL-8, and IL-10 were observed in the jejunum of piglets supplemented with HEG compared with the CON group. In addition, dietary HEG tended to decrease IL-6 level in the jejunum of piglets compared with the CON group. CONCLUSION: Dietary essential oil coated with GML can improve growth performance of weaned piglets. Moreover, supplementing 2,000 mg/kg essential oil coated with GML was demonstrated to improve antioxidant ability, and intestinal morphology, and reduce jejunal inflammatory factor levels.

Study on lifestyle habits affecting sleep disorders at the undergraduate education stage in Xuzhou City, China.

Background: In China, undergraduate students face both academic and career selection pressures, sleep is an important physiological process for them. Investigate the physical exercise, sleep quality of undergraduate students in the education stage in Xuzhou City, and analyze the factors affecting their sleep quality, to promote the health education and psychological health of undergraduate students. Materials and methods: The Physical Activity Rating Scale-3 (PARS-3), the Pittsburgh Sleep Quality Index (PSQI), and the demographic information questionnaire were used to survey a whole-group sample of four undergraduate colleges and universities (Xuzhou Institute of Engineering, Xuzhou Medical University, China University of Mining and Technology, Jiangsu Normal University) in Xuzhou by cluster sampling, the general characteristics including gender, grade, height, weight, domicile, race, economic income, etc., were collected, and the data were analyzed and processed using chi-square tests and multi-factor logistic regression. Results: 3,366 valid questionnaires were collected from four undergraduate colleges and universities, including 1,355 males and 2,011 females. The detection rate of exercise in Jiangsu Normal University was lower than that in other universities, and the detection rate of sleep disorders was higher than that in other universities. Xuzhou Medical University, the highest detection rate of large exercise, Xuzhou Institute of Technology, the lowest detection rate of sleep disorders. There were significant differences in the detection rate of large amount of exercise among college students of different genders, grades, body types, and majors (χ2 = 259.172, P < 0.001; χ2 = 34.473, P < 0.001; χ2 = 36.026, P < 0.001; χ2 = 57.908, P < 0.001). There were significant differences in the detection rate of sleep disorders among college students with different gender, grade, family economic status, daily cell phone use time, cell phone purposeless usage, and exercise level (χ2 = 5.806, P = 0.016; χ2 = 47.5, P < 0.001; χ2 = 28.949, P < 0.001; χ2 = 55.866, P < 0.001; χ2 = 147.101, P < 0.001; χ2 = 9.129, P = 0.010). Multivariate logistic regression analysis showed that grade, family economic status, cell phone use time, cell phone purposeless usage is the main influencing factors of sleep disorders in college students. Conclusion: The sleep problems of undergraduates are serious, especially in Jiangsu Normal University. Scientific and appropriate exercise is an important measure to solve the sleep problems of undergraduates. Colleges and universities should actively carry out health education, college students living habits such as cell phone use should be guided training.

Atropisomeric 9,10-dihydrophenanthrene/bibenzyl trimers with anti-inflammatory and PTP1B inhibitory activities from Bletilla striata.

Two pairs of novel trimeric dihydrophenanthrene-bibenzyl-dihydrophenanthrene enantiomers (1 and2), the first examples of a dihydrophenanthrene dimer linked to a bibenzyl or dihydrophenanthrene through a C-O-C bond (3 and4), and a pair of rare polymers with a bibenzyl connected to C-8' of the dihydrophenanthro[b]furan moiety via a methylene (5), together with four known compounds (6-9) were isolated from the tubers of Bletilla striata. Their structures including the absolute configurations were determined using spectroscopic data analysis and ECD and NMR calculations, combined with the exciton chirality method or the reversed helicity rule. The atropisomerism of dihydrophenanthrenes and related polymers was considered based on their chiral optical properties, and QM torsion profile calculations, which revealed the racemic mixture form of the polymers. Compounds 4, 5b, 6a and 7b significantly inhibited the production of NO in LPS-induced BV-2 cells, with IC50 values ranging from 0.78 to 5.52 µM. Further mechanistic study revealed that 7b suppressed the expression of iNOS, and suppressed the phosphorylation of the p65 subunit to regulate the NF-κB signaling pathway. Furthermore, compounds 2b, 5a, 5b, 7a and 7b displayed significant protein tyrosine phosphatase 1B (PTP1B) inhibitory activities with IC50 values of 3.43-12.30 µM.

Dual functions of STAT3 in LPS-induced angiogenesis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a long-term consequence of chronic inflammatory liver injury. Hepatic injury is associated with a defective intestinal barrier and increased hepatic exposure to bacterial products including lipopolysaccharide (LPS), which promotes hepatocarcinogenesis. Despite its clinical significance, the molecular mediator linking chronic inflammation with HCC development remains to be clarified. In this study, we explored the significant dual functions of active signal transducer and activator of transcription 3 (STAT3) in LPS-induced angiogenesis of HCC. The in vitro effects of active STAT3 in tumor cells and endothelial cells were assessed using angiogenesis assay, ELISA, confocal assay, flow cytometry and western blot. The in vivo role of active STAT3 was assessed in xenografts model in nude mice. Here we report a novel mechanism by which LPS/STAT3 signaling promotes the angiogenesis of HCC both in vitro and in vivo. STAT3 activated by LPS increases the production of vascular endothelial growth factor (VEGF) by tumor cells, which not only promotes the proliferation of HCC cells but also stimulates the migration and tubulogenesis of endothelial cells through STAT3 activation and hence promotes angiogenesis in HCC. Our findings not only provide a potential mechanism by which bacterial infection enhances HCC oncogenesis through promoting the angiogenesis in liver, but also suggest that targeting STAT3 might be an effective therapeutic strategy in HCC treatment considering the dual roles of STAT3 in angiogenesis.

The STAT3 inhibitor S3I-201 suppresses fibrogenesis and angiogenesis in liver fibrosis.

Liver fibrosis is a common pathological response to chronic hepatic injury. STAT3 is actively involved in the fibrogenesis and angiogenesis seen in liver fibrosis. S3I-201 (NSC 74859) is a chemical inhibitor of STAT3 activity, which blocks the dimerization of STAT3, STAT3-DNA binding and transcription activity. This study evaluated the effects of S3I-201 against liver fibrosis. S3I-201 inhibited the proliferation, migration, and actin filament formation in primary human hepatic stellate cells (HSCs), as well as the expression of α-SMA, collagen I and TIMP1 in both primary HSC and in a CCl4-induced fibrosis mouse model. S3I-201 induced both apoptosis and cell cycle arrest in the HSC cell line (LX-2). S3I-201 inhibited the expression of fibrogenesis factors TGFß1 and TGFßRII, as well as the downstream phosphorylation of Smad2, Smad3, Akt and ERK induced by TGFß1. In addition to fibrogenesis, both in vitro and in vivo assays showed that S3I-201 inhibited angiogenesis through expression suppression of VEGF and VEGFR2. Moreover, S3I-201 also had a synergistic effect with sorafenib, an FDA approved liver cancer drug, in the proliferation, apoptosis, angiogenesis and fibrogenesis of HSC. S3I-201 suppressed liver fibrosis through multiple mechanisms, and combined with sorafenib, S3I-201 could be a potentially effective antifibrotic agent.