Isoquercitrin alleviates pirarubicin-induced cardiotoxicity in vivo and in vitro by inhibiting apoptosis through Phlpp1/AKT/Bcl-2 signaling pathway

Introduction: Due to the cardiotoxicity of pirarubicin (THP), it is necessary to investigate new compounds for the treatment of THP-induced cardiotoxicity. Isoquercitrin (IQC) is a natural flavonoid with anti-oxidant and anti-apoptosis properties. Thus, the present study aimed to investigate the influence of IQC on preventing the THP-induced cardiotoxicity in vivo and in vitro.Methods: The optimal concentration and time required for IQC to prevent THP-induced cardiomyocyte damage were determined by an MTT assay. The protective effect was further verified in H9c2 and HCM cells using dichlorodihydrofluorescein diacetate fluorescent probes, MitoTracker Red probe, enzyme-linked immunosorbent assay, JC-1 probe, and real time-quantitative polymerase chain reaction (RT-qPCR). Rats were administered THP to establish cardiotoxicity. An electrocardiogram (ECG) was performed, and cardiac hemodynamics, myocardial enzymes, oxidative stress indicators, and hematoxylin-eosin staining were studied. Voltage-dependent anion channel 1 (VDAC1), adenine nucleotide translocase 1 (ANT1), and cyclophilin D (CYPD) were detected by qRT-PCR, and the Phlpp1/AKT/Bcl-2 axis proteins were detected by western blot, confirming that IQC markedly increased cell viability and superoxide dismutase (SOD) levels, diminished the levels of ROS and MDA, and elevated mitochondrial function and apoptosis in vivo and in vitro.Results: Results showed that IQC reduced THP-induced myocardial histopathological injury, electrocardiogram (ECG) abnormalities, and cardiac dysfunction in vivo. IQC also decreased serum levels of MDA, BNP, CK-MB, c-TnT, and LDH, while increasing levels of SOD and GSH. We also found that IQC significantly reduced VDAC1, ANT1, and CYPD mRNA expression. In addition, IQC controlled apoptosis by modulating Phlpp1/AKT/Bcl-2 signaling pathways. IQC markedly increased H9c2 and HCM cell viability and SOD levels, diminished the levels of ROS and MDA, and elevated mitochondrial function in H9c2 and HCM cells to defend against THP-induced cardiomyocyte apoptosis in vitro. The AKT inhibitor IMQ demonstrated that IQC lacked antioxidant and anti-apoptotic properties. Moreover, our data showed that IQC regulates Phlpp1 expression, thereby influencing the expression levels of p-AKT, cytochrome c, caspase-3, caspase-9, Bcl-2, and Bax.Discussion: In conclusion, our results indicate that IQC protects the changes in mitochondrial membrane permeability in cardiomyocytes by regulating the Phlpp1/AKT/Bcl-2 signaling pathway, inhibits the release of cytc from the mitochondrial inner membrane to the cytoplasm, forms apoptotic bodies, induces cell apoptosis, and reduces THP induced cardiotoxicity

Full Size Two-Layer Steel Frame–Exterior Wall Panel Shaking-Table Test

A cantilever block wall-panel attachment strip (CBW) flexible connection node was designed to connect precast concrete (PC) exterior wall panels to steel frames. To investigate the performance of the CBW flexible connection node and PC exterior wall panels during earthquakes, a partial two-storey steel frame was extracted from an actual engineering structure, and a full-scale steel frame–exterior wall panel shaking-table model was designed. Two sets of shaking-table tests were conducted under seismic intensity 7, 8, and 9 (Chinese Seismic Intensity Scale) earthquakes. The acceleration and displacement responses of the composite wall panel, open window panel, and integral wall panel along the in-plane and out-of-plane motions were analysed. The acceleration amplification factors of the PC exterior wall panels ranged from 0.753 to 1.400 (in-plane) and from 0.998 to 2.199 (out-of-plane). The CBW flexible connection node had a deformation capacity that could coordinate the deformation of the exterior wall panel and prevent severe damage. The surfaces of the PC exterior wall panels remained intact during a very strong seismic intensity 9 earthquake

Ginsenoside F1 attenuates pirarubicin-induced cardiotoxicity by modulating Nrf2 and AKT/Bcl-2 signaling pathways

Background: Pirarubicin (THP) is an anthracycline antibiotic used to treat various malignancies in humans. The clinical usefulness of THP is unfortunately limited by its dose-related cardiotoxicity. Ginsenoside F1 (GF1) is a metabolite formed when the ginsenosides Re and Rg1 are hydrolyzed. However, the protective effects and underlying mechanisms of GF1 on THP-induced cardiotoxicity remain unclear. Methods: We investigated the anti-apoptotic and anti-oxidative stress effects of GF1 on an in vitro model, using H9c2 cells stimulated by THP, plus trigonelline or AKT inhibitor imidazoquinoxaline (IMQ), as well as an in vivo model using THP-induced cardiotoxicity in rats. Using an enzyme-linked immunosorbent test, the levels of malondialdehyde (MDA), brain natriuretic peptide (BNP), creatine kinase (CK-MB), cardiac troponin (c-TnT), lactate dehydrogenase (LDH), superoxide dismutase (SOD) and glutathione (GSH) were determined. Nuclear factor (erythroid-derived2)-like 2 (Nrf2) and the expression of Nrf2 target genes, including heme oxygenase-1 (HO-1), glutathione-S-transferase (Gst), glutamate-cysteine ligase modifier subunit (GCLM), and expression levels of AKT/Bcl-2 signaling pathway proteins were detected using Western blot analysis. Results: THP-induced myocardial histopathological damage, electrocardiogram (ECG) abnormalities, and cardiac dysfunction were reduced in vivo by GF1. GF1 also decreased MDA, BNP, CK-MB, c-TnT, and LDH levels in the serum, while raising SOD and GSH levels. GF1 boosted Nrf2 nuclear translocation and Nrf2 target gene expression, including HO-1, Gst, and GCLM. Furthermore, GF1 regulated apoptosis by activating AKT/Bcl-2 signaling pathways. Employing Nrf2 inhibitor trigonelline and AKT inhibitor IMQ revealed that GF1 lacked antioxidant and anti-apoptotic effects. Conclusion: In conclusion, GF1 was found to alleviate THP-induced cardiotoxicity via modulating Nrf2 and AKT/Bcl-2 signaling pathways, ultimately alleviating myocardial oxidative stress and apoptosis

A Low-Noise and Monolithic Array Tactile Sensor Based on Incremental Delta-Sigma Analog-to-Digital Converters

A low-noise and monolithic array tactile sensor, in which a tactile sensing unit, a low-noise analog front end (AFE), and a high-resolution delta-sigma analog-to-digital converter (ΔΣ ADC) are fully integrated, is presented in this paper. In this proposed system, compared with a discrete-device-based board-level system, the parasitic effect of a long cable connection can be reduced, and results are more accurate. Furthermore, a smaller system area and a lower power consumption can be achieved in this monolithic system. A discrete-continuous mixed mode bandpass AFE is proposed to filter out low-frequency flicker noise and high-frequency white noise. In order to improve the quantization rate of the sensor readout circuit and further suppress the high-frequency noise, a two-way alternate sample-and-hold circuit scheme is adopted in this design. The proposed tactile sensor is designed and fabricated in a 0.5-μm CMOS (Complementary metal oxide semiconductor)mixed-signal process with a 16 × 16 array and a total chip area of 1.9 × 1.9 cm2. This chip consumes 33.5 mW from a 5 V supply. The measurement results showed that the signal-to-noise and distortion rate (SNDR) was 65.2894 dB and that the effective number of bits (ENoB) was 10.553 dB. Moreover, this sensor could achieve a pressure measurement range of 0.002–0.5 N with a resolution of 0.4 mN

Deinococcus radiodurans Toxin–Antitoxin MazEF-dr Mediates Cell Death in Response to DNA Damage Stress

Here we identified a functional MazEF-dr system in the exceptionally stress-resistant bacterium D. radiodurans. We showed that overexpression of the toxin MazF-dr inhibited the growth of Escherichia coli. The toxic effect of MazF-dr was due to its sequence-specific endoribonuclease activity on RNAs containing a consensus 5′ACA3′, and it could be neutralized by MazE-dr. The MazF-dr showed a special cleavage preference for the nucleotide present before the ACA sequence with the order by U>A>G>C. MazEF-dr mediated the death of D. radiodurans cells under sub-lethal dose of stresses. The characteristics of programmed cell death (PCD) including membrane blebbing, loss of membrane integrity and cytoplasm condensation occurred in a fraction of the wild-type population at sub-lethal concentration of the DNA damaging agent mitomycin C (MMC); however, a MazEF-dr mutation relieved the cell death, suggesting that MazEF-dr mediated cell death through its endoribonuclease activity in response to DNA damage stress. The MazEF-dr-mediated cell death of a fraction of the population might serve as a survival strategy for the remaining population of D. radiodurans under DNA damage stress

Nanocellulose Length Determines the Differential Cytotoxic Effects and Inflammatory Responses in Macrophages and Hepatocytes

Nanocellulose including cellulose nanocrystal (CNC) and cellulose nanofiber (CNF) has attracted much attention due to its exceptional mechanical, chemical, and rheological properties. Although considered biocompatible, recent reports have demonstrated nanocellulose can be hazardous, including serving as drug carriers that accumulate in the liver. However, the nanocellulose effects on liver cells, including Kupffer cells (KCs) and hepatocytes are unclear. Here, the toxicity of nanocellulose with different lengths is compared, including the shorter CNCs (CNC-1, CNC-2, and CNC-3) and longer CNF (CNF-1 and CNF-2), to liver cells. While all CNCs triggered significant cytotoxicity in KCs and only CNC-2 induced toxicity to hepatocytes, CNFs failed to induce significant cytotoxicity due to their minimal cellular uptake. The phagocytosis of CNCs by KCs induced mitochondria ROS generation, caspase-3/7 activation, and apoptotic cell death as well as lysosomal damage, cathepsin B release, NLRP3 inflammasome and caspase-1 activation, and IL-1β production. The cellular uptake of CNC-2 by hepatocytes is through clathrin-mediated endocytosis, and it induced the caspase-3/7-mediated apoptosis. CNC-2 shows the highest levels of uptake and cytotoxicity among CNCs. These results demonstrate the length-dependent mechanisms of toxicity on liver cells in a cell type-dependent fashion, providing information to safely use nanocellulose for biomedical applications

Manganese indicates root decomposition rates across soil layer, root order, and tree species: Evidence from a subtropical forest

http://dx.doi.org/10.13039/501100004543 China Scholarship Councilhttp://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of Chin

Dissolution of 2D Molybdenum Disulfide Generates Differential Toxicity among Liver Cell Types Compared to Non‐Toxic 2D Boron Nitride Effects

Two-dimensional (2D) boron nitride (BN) and molybdenum disulfide (MoS(2)) materials are increasingly being used for applications due to novel chemical, electronic and optical properties. Although generally considered biocompatible, recent data have shown that BN and MoS(2) could be potentially hazardous under some biological conditions, e.g., during, biodistribution of drug carriers or imaging agents to the liver. However, the effects of these 2D materials on liver cells such as Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), and hepatocytes, are unknown. Here, we compared the toxicity of BN and MoS(2), dispersed in Pluronic F87 (designated BN-PF and MoS(2)-PF) with aggregated forms of these materials (BN-Agg and MoS(2)-Agg) in liver cells. MoS(2) induced dose-dependent cytotoxicity in KCs, but not other cell types, while the BN derivatives were non-toxic. The effect of MoS(2) could be ascribed to nanosheet dissolution and the release of hexavalent Mo, capable of inducing mitochondrial ROS generation and caspases 3/7-mediated apoptosis in KUP5 cells. In addition, the phagocytosis of MoS(2)-Agg triggered an independent response pathway involving lysosomal damage, NLRP3 inflammasome activation, caspase-1 activation, IL-1β and IL-18 production. These findings demonstrate the importance of Mo release and the state of dispersion of MoS(2) in impacting Kupffer cell viability