HBB contributes to individualized aconitine-induced cardiotoxicity in mice via interfering with ABHD5/AMPK/HDAC4 axis.

The root of Aconitum carmichaelii Debx. (Fuzi) is an herbal medicine used in China that exerts significant efficacy in rescuing patients from severe diseases. A key toxic compound in Fuzi, aconitine (AC), could trigger unpredictable cardiotoxicities with high-individualization, thus hinders safe application of Fuzi. In this study we investigated the individual differences of AC-induced cardiotoxicities, the biomarkers and underlying mechanisms. Diversity Outbred (DO) mice were used as a genetically heterogeneous model for mimicking individualization clinically. The mice were orally administered AC (0.3, 0.6, 0.9 mg· kg-1 ·d-1) for 7 d. We found that AC-triggered cardiotoxicities in DO mice shared similar characteristics to those observed in clinic patients. Most importantly, significant individual differences were found in DO mice (variation coefficients: 34.08%-53.17%). RNA-sequencing in AC-tolerant and AC-sensitive mice revealed that hemoglobin subunit beta (HBB), a toxic-responsive protein in blood with 89% homology to human, was specifically enriched in AC-sensitive mice. Moreover, we found that HBB overexpression could significantly exacerbate AC-induced cardiotoxicity while HBB knockdown markedly attenuated cell death of cardiomyocytes. We revealed that AC could trigger hemolysis, and specifically bind to HBB in cell-free hemoglobin (cf-Hb), which could excessively promote NO scavenge and decrease cardioprotective S-nitrosylation. Meanwhile, AC bound to HBB enhanced the binding of HBB to ABHD5 and AMPK, which correspondingly decreased HDAC-NT generation and led to cardiomyocytes death. This study not only demonstrates HBB achievement a novel target of AC in blood, but provides the first clue for HBB as a novel biomarker in determining the individual differences of Fuzi-triggered cardiotoxicity.

Corporate social responsibility, debt financing cost and enterprise innovation.

Based on the data of A-share listed companies in China from 2016 to 2020, this study empirically analyzes the relationship among corporate social responsibility, debt financing cost and enterprise innovation by constructing a regulated mediation effect model. The results show that enterprises perform social responsibility actively can enhance the level of enterprise innovation. Besides, debt financing cost plays a part of the intermediary role between corporate social responsibility and enterprise innovation. It is found that market competition degree positively regulates the relationship between corporate social responsibility and enterprise innovation, and market competition degree strengthens the part of the intermediary effect of debt financing cost. The conclusions not only help to reveal the impact mechanism of corporate social responsibility on enterprise innovation, but also provide empirical evidence for promoting enterprises to actively assume social responsibility, improve the level of innovation, and provide empirical evidence for the government to formulate corresponding policies according to the degree of competition in different markets.

Nano-enabled delivery of EGCG ameliorates silica-induced pulmonary fibrosis in rats.

Silicosis is the most serious occupational pulmonary fibrosis caused by excessive inhalation of silica particles, whereas viable therapeutic choices are constrained. Epigallocatechin gallate (EGCG) presents massive health benefits, but unfortunately with stability absence. Here, encapsulation of EGCG in poly(n-butylcyanoacrylate) nanoparticles (EGCG/PBCA-NPs) were fabricated by self-polymerization for gastrointestinal delivery in silicosis fibrosis treatment. The obtained nano-enabled delivery of EGCG was produced using a medical adhesive approved by FDA as carrier, and presented spherical particles with approximate diameter of 160 nm, a narrow PDI value of 0.2, Zeta potential value of 30 mV as well as a high EGCG incorporation (90 %) and loading efficiency (20 %). In evaluating the protect effects of nano-formulations, EGCG/PBCA-NPs shown excellent stability in gastric fluid with pH-triggered release in intestine and strong EGCG gastrointestinal retention against degradation. After daily gastrointestinal administration, EGCG/PBCA-NPs exhibited the superior anti-fibrosis efficacy in silicosis model rats induced by silica, involving lung index decline, hydroxyproline content decrease, histological improvement, collagen accumulation reduction and α-SMA down-regulation in comparison with naked EGCG. These results strongly demonstrated that PBCA-based NPs may be a promising nano-enabled delivery carrier for enhancing the gastrointestinal stability and anti-fibrotic effects of EGCG.

Ras inhibitor farnesylthiosalicylic acid conjugated with IR783 dye exhibits improved tumor-targeting and altered anti-breast cancer mechanisms in mice.

Ras has long been viewed as a promising target for cancer therapy. Farnesylthiosalicylic acid (FTS), as the only Ras inhibitor has ever entered phase II clinical trials, has yielded disappointing results due to its strong hydrophobicity, poor tumor-targeting capacity, and low therapeutic efficiency. Thus, enhancing hydrophilicity and tumor-targeting capacity of FTS for improving its therapeutic efficacy is of great significance. In this study we conjugated FTS with a cancer-targeting small molecule dye IR783 and characterized the anticancer properties of the conjugate FTS-IR783. We showed that IR783 conjugation greatly improved the hydrophilicity, tumor-targeting and therapeutic potential of FTS. After a single oral administration in Balb/c mice, the relative bioavailability of FTS-IR783 was increased by 90.7% compared with FTS. We demonstrated that organic anion transporting polypeptide (OATP) and endocytosis synergistically drove the uptake of the FTS-IR783 conjugate in breast cancer MDA-MB-231 cells, resulting in superior tumor-targeting ability of the conjugate both in vitro and in vivo. We further revealed that FTS-IR783 conjugate could bind with and directly activate AMPK rather than affecting Ras, and subsequently regulate the TSC2/mTOR signaling pathway, thus achieving 2-10-fold increased anti-cancer therapeutic efficacy against 6 human breast cancer cell lines compared to FTS both in vivo and in vitro. Overall, our data highlights a promising approach for the modification of the anti-tumor drug FTS using IR783 and makes it possible to return FTS back to the clinic with a better efficacy.

Efficacy and potential mechanisms of Chinese herbal compounds in coronavirus disease 2019: advances of laboratory and clinical studies.

The Coronavirus disease 2019 (COVID-19) pandemic is still spread and has made a severe public health threat around the world. To improve disease progression, emerging Chinese herbal compounds were used in clinical practice and some agents have proven beneficial in treating COVID-19. Here, the relevant literature from basic researches to clinical application were identified and comprehensively assessed. A variety of Chinese herbal compounds have been reported to be effective in improving symptoms and outcomes in patients with COVID-19, particularly together with routine treatment strategy. The pharmacological activities were mainly attributed to the relief of clinical symptoms, inhibition of cytokine storm, and improvement of organ function. Besides, the development of novel antiviral drugs from medicinal herbs were further discussed. The updated laboratory and clinical studies provided the evidence of Chinese herbal compounds such as Lianhua Qingwen prescription, Shufeng Jiedu prescription, and Qingfei Paidu Tang for the relief of COVID-19. However, both of the randomized controlled trials and real world researches need to be done for supporting the evidence including the efficacy and safety in fighting COVID-19.

Removal of Cr (VI) by Biochar Derived from Six Kinds of Garden Wastes: Isotherms and Kinetics.

Garden waste is one of the main components of urban solid waste which affects the urban environment. In this study, garden waste of Morus alba L. (SS), Ulmus pumila L. (BY), Salix matsudana Koidz (LS), Populus tomentosa (YS), Sophora japonica Linn (GH) and Platycladus orientalis (L.) Franco (CB) was pyrolyzed at 300 °C, 500 °C, 700 °C to obtain different types of biochar, coded as SSB300, SSB500, SSB700, BYB300, etc., which were tested for their Cr (VI) adsorption capacity. The results demonstrated that the removal efficiency of Cr by biochar pyrolyzed from multiple raw materials at different temperatures was variable, and the pH had a great influence on the adsorption capacity and removal efficiency. GHB700 had the best removal efficiency (89.44%) at a pH of 2 of the solution containing Cr (VI). The pseudo second-order kinetics model showed that Cr (VI) adsorption by biochar was chemisorption. The Langmuir model showed that the adsorption capacity of SSB300 was the largest (51.39 mg·g-1), BYB500 was 40.91 mg·g-1, GHB700, CBB700, LSB700, YSB700 were 36.85 mg·g-1, 36.54 mg·g-1, 34.53 mg·g-1 and 32.66 mg·g-1, respectively. This research, for the first time, used a variety of garden wastes to prepare biochar, and explored the corresponding raw material and pyrolysis temperature for the treatment of Cr (VI). It is hoped to provide a theoretical basis for the research and utilization of garden wastes and the production and application of biochar.

[Distribution and Ecological Risk Assessment of PPCPs in Drinking Water Sources of Henan Province].

The occurrence of emerging pollutants pharmaceuticals and personal care products (PPCPs) in aquatic environments has potential adverse effects on aquatic organisms, and the presence of PPCPs in drinking water sources is very likely to cause harm to human health. The PPCPs pollution in five typical drinking water sources in Henan province was investigated. Moreover, the source of pollutants was analyzed and the relevant ecological risks were evaluated. The results showed that the cumulative concentrations of 20 PPCPs at different sampling sites ranged from 24.2 to 317.6 ng·L-1. Caffeine (CFI) was the highest level contaminant, with the concentration up to 186.4 ng·L-1, followed by sulfamethoxazole (SMX) and ofloxacin (OFC), with detected concentrations up to 70.8 ng·L-1 and 24.2 ng·L-1, respectively. The pollution of PPCPs in Heigangkou drinking water sources was higher than those of other drinking water sources. The comparation of the labile indicator CFI and the conservative indicator carbamazepine (CBZ) concentrations implies that the pollutions from the upstream water and around scattered domestic sewage might be responsible for the PPCPs present in these drinking water sources. The risk quotient (RQ) calculation results indicated that the detected PPCPs in 5 drinking water sources have moderate to high risks to algae, while low to moderate risks to invertebrates and fish. Therefore, attention should be paid to relevant pollution control.

Novel polymeric biomaterial poly(butyl-2-cyanoacrylate) nanowires: synthesis, characterization and formation mechanism.

Poly(butyl-2-cyanoacrylate) (PBCA) nanoparticles have been widely elaborated for nearly half a century. However, PBCA nanowires (PNWs) were seldom investigated. Here, new polymeric biomaterial PNWs were prepared via emulsion polymerization based on the sodium dodecyl sulfate (SDS)-assisted emulsion process. Results indicated that SDS micelles and PBCA polymer can develop surfactant-polymer complexes by self-assembly at room temperature. SDS concentration was confirmed to be the critical parameter for the association of the surfactant and the polymer. With the addition of SDS (0-40 mM), the interaction between SDS and PBCA led to a series of transitions from nanoparticles to nanowires. These morphology transitions were triggered by changing the electrostatic repulsion in the SDS-PBCA system, confirmed by the variety of zeta potential with increasing molar contents of SDS. To overcome the electrostatic repulsion, the complexes underwent transitions from spherical, worm-like (short-cylindrical), to elongated-cylindrical form. Finally, associated with the results from scanning / transmission electron microscopy (SEM / TEM), the elongated-cylindrical PNWs acquired at 20 mM of SDS were chosen to execute cell viability assay, which showed that they had no toxicity but with good-biocompatibility at the doses ≤ 50 µg/ml. These results indicate that the PNWs prepared by this facile-green and low-toxic strategy can potentially work as promising biomaterials in the biomedicine field.

Neural correlates of future-oriented coping: Preliminary evidence from a resting-state functional connectivity study.

Future-oriented coping is a strategy for coping with events that may happen in the future, including efforts to ensure positive outcome and protection from potential threats. Appropriate future-oriented coping is essential for well-being and influences mental health and life satisfaction. However, little is known about the neural mechanism of future-oriented coping. We examined the neural basis of this coping strategy using resting-state functional connectivity analysis. Thirty healthy volunteers underwent resting-state functional magnetic resonance imaging scanning and completed the Future-Oriented Coping Inventory. Seed-based functional connectivity analysis was used to investigate potentially correlated regions, with 11 nodes in the default mode network defined as regions of interest. Multiple regression analysis was performed to measure the correlation between coping behavior and functional connectivity. We found that proactive coping was significantly correlated with the functional connectivity strength between the parahippocampal cortex (PHC) and the claustrum/insula. These novel findings suggest that cooperation between the PHC and the claustrum/insula plays an important role in proactive coping. Moreover, cognitive components, such as future thinking (the PHC) and sensory judgment (the claustrum/insula) could be important process factors in proactive coping.

Efficient gene delivery system mediated by cis-aconitate-modified chitosan-g-stearic acid micelles.

Cis-aconitate-modified chitosan-g-stearic acid (CA-CSO-SA) micelles were synthesized in this study to improve the gene transfection efficiency of chitosan-g-stearic acid (CSO-SA). The CA-CSO-SA micelles had a similar size, critical micelle concentration, and morphology, but their zeta potential and cytotoxicity were reduced compared with CSO-SA micelles. After modification with cis-aconitate, the CA-CSO-SA micelles could also compact plasmid DNA (pDNA) to form nanocomplexes. However, the DNA binding ability of CA-CSO-SA was slightly reduced compared with that of CSO-SA. The transfection efficiency mediated by CA-CSO-SA/pDNA against HEK-293 cells reached up to 37%, and was much higher than that of CSO-SA/pDNA (16%). Although the cis-aconitate modification reduced cellular uptake kinetics in the initial stages, the total amount of cellular uptake tended to be the same after 24 hours of incubation. An endocytosis inhibition experiment showed that the internalization mechanism of CA-CSO-SA/pDNA in HEK-293 cells was mainly via clathrin-mediated endocytosis, as well as caveolae-mediated endocytosis and macropinocytosis. Observation of intracellular trafficking indicated that the CSO-SA/pDNA complexes were trapped in endolysosomes, but CA-CSO-SA/pDNA was more widely distributed in the cytosol. This study suggests that modification with cis-aconitate improves the transfection efficiency of CSO-SA/pDNA.

[Expression of cytokine IL-1α and S100ß in different types of plaques in Alzheimer's disease].

OBJECTIVE: To study the significance of cytokine IL-1α and S100ß expression in formation and evolution of different types of plaques in Alzheimer's disease. METHODS: Thirty-four autopsy cases of Alzheimer's disease encountered during the period from 1982 to 2008 were retrieved from the archival files of Department of Pathology, Beijing Hospital. Tissue blocks were taken from hippocampus for dual immunostaining for IL-1α/Aß and S100ß/Aß. RESULTS: Immunohistochemical studied for IL-1α/Aß and S100ß/Aß delineated four different types of senile plaques: diffuse non-neuritic plaques, diffuse neuritic plaques, dense-core neuritic plaques and dense-core non-neuritic plaques. The numbers of IL-1α-positive microglias and S100ß-positive astrocytes associated with diffuse neuritic plaques were (7.29 ± 3.04) per mm(2) and (6.49 ± 2.20) per mm(2), respectively. In contrast, the numbers of IL-1α-positive microglias and S100ß-positive astrocytes associated with diffuse non-neuritic plaques, dense-core neuritic plaques and dense-core non-neuritic plaques were (3.24 ± 1.53) per mm(2) and (4.14 ± 1.77) per mm(2), (2.09 ± 1.37) per mm(2) and (2.25 ± 0.83) per mm(2), and (1.38 ± 0.90) per mm(2) and (0.58 ± 0.36) per mm(2), respectively. The numbers of IL-1α-positive microglias and S100ß-positive astrocytes associated with diffuse neuritic plaques were significantly higher than those of the other three types of plaques (P < 0.05). CONCLUSION: The IL-1α-positive microglias and S100ß-positive astrocytes may be of certain significance in transformation of diffuse non-neuritic plaques to diffuse neuritic plaques in Alzheimer's disease.