An update of the molecular mechanisms underlying anthracycline induced cardiotoxicity.

Anthracycline drugs mainly include doxorubicin, epirubicin, pirarubicin, and aclamycin, which are widely used to treat a variety of malignant tumors, such as breast cancer, gastrointestinal tumors, lymphoma, etc. With the accumulation of anthracycline drugs in the body, they can induce serious heart damage, limiting their clinical application. The mechanism by which anthracycline drugs cause cardiotoxicity is not yet clear. This review provides an overview of the different types of cardiac damage induced by anthracycline-class drugs and delves into the molecular mechanisms behind these injuries. Cardiac damage primarily involves alterations in myocardial cell function and pathological cell death, encompassing mitochondrial dysfunction, topoisomerase inhibition, disruptions in iron ion metabolism, myofibril degradation, and oxidative stress. Mechanisms of uptake and transport in anthracycline-induced cardiotoxicity are emphasized, as well as the role and breakthroughs of iPSC in cardiotoxicity studies. Selected novel cardioprotective therapies and mechanisms are updated. Mechanisms and protective strategies associated with anthracycline cardiotoxicity in animal experiments are examined, and the definition of drug damage in humans and animal models is discussed. Understanding these molecular mechanisms is of paramount importance in mitigating anthracycline-induced cardiac toxicity and guiding the development of safer approaches in cancer treatment.

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.

Bioinspired inhibition of aggregation in metal-organic frameworks (MOFs).

Different from traditional procedures of using solid stabilizers like polymers and surfactants, here we demonstrate that water, as a very "soft" matter, could function as a "spacer" to prevent the aggregation of metal-organic frameworks (MOFs) in aqueous dispersions. Our theoretical calculations reveal in case of an excess of positively charged metal nodes of MOFs, where water molecules are ligated to metal nodes that greatly enhance MOFs' solution dispersibility through electrostatic stabilization. This discovery has motivated us to develop a facile experimental approach for producing a category of "clean" MOF dispersions without foreign additives. Potential application has been demonstrated for the size fractionation of MOFs, which results in small-size MOFs (50-80 nm) characteristic of superior electrocatalytic oxygen evolution activities (256 mV at 10 mA cm-2, Tafel slope of 49 mV dec-1 and durability >30 h). This work would provide new clues for aqueous processing of MOFs for many emerging applications.

Battery-Driven N2 Electrolysis Enabled by High-Entropy Catalysts: From Theoretical Prediction to Prototype Model.

A small-scale standalone device of nitrogen (N2 ) splitting holds great promise for producing ammonia (NH3 ) in a decentralized manner as the compensation or replacement of centralized Haber-Bosch process. However, the design of such a device has been impeded by sluggish kinetics of its half reactions, i.e., cathodic N2 reduction reaction (NRR) and anodic oxygen evolution reaction (OER). Here, it is predicted from density function theory that high-entropy oxides (HEOs) are potential catalysts for promoting NRR and OER, and subsequently develop a facile procedure to synthesize HEOs in the morphology of sea urchin-shaped hollow nanospheres assembled from ultrathin nanosheets. The excellent electrocatalytic activities of HEOs for both NRR (NH3 yield rate: 47.58 µg h-1 mg-1 and Faradaic efficiency (FE): 10.74%) and OER (215 mV @10 mA cm-2 ) are demonstrated. Consequently, a prototype device of N2 electrolysis driven by commercial batteries is constructed, which can operate smoothly and deliver remarkable NH3 yield rate (41.11 µg h-1 mg-1 ) and FE (14.14%). Further mechanism study has attributed the excellent catalytic performances of HEOs to their unique electronic structures originated from multi-metal synergistic effects and entropy increase effects. The work will provide new clues for designing versatile catalysts and devices for large-scale industrialization.

A fast and powerful eQTL weighted method to detect genes associated with complex trait using GWAS summary data.

Although genomewide association studies (GWASs) have identified many genetic variants underlying complex traits, a large fraction of heritability still remains unexplained. Integrative analysis that incorporates additional information, such as expression quantitativetrait locus (eQTL) data into sequencing studies (denoted as transcriptomewide association study [TWAS]), can aid the discovery of trait-associated genetic variants. However, general TWAS methods only incorporate one eQTL-derived weight (e.g., cis-effect), and thus can suffer a substantial loss of power when the single estimated cis-effect is not predictive for the effect size of a genetic variant or when there are estimation errors in the estimated cis-effect, or if the data are not consistent with the model assumption. In this study, we propose an omnibus test (OT) which utilizes a Cauchy association test to integrate association evidence demonstrated by three different traditional tests (burden test, quadratic test, and adaptive test) using GWAS summary data with multiple eQTL-derived weights. The p value of the proposed test can be calculated analytically, and thus it is fast and efficient. We applied our proposed test to two schizophrenia (SCZ) GWAS summary data sets and two lipids trait (HDL) GWAS summary data sets. Compared with the three traditional tests, our proposed OT can identify more trait-associated genes.

Establishment of an embryonic cell line from the American cockroach Periplaneta americana (Blattaria: Blattidae) and a preliminary study of telomerase activity changes during the culturing process.

Despite the pest status and medicinal value of the American cockroach Periplaneta americana, few attempts have been made to establish cell lines from this insect owing to the difficulty of culturing Blattarian cells. Here, we describe the establishment of the RIRI-PA1 line from P. americana embryo tissue following primary culture in modified Grace's medium containing 20% fetal bovine serum. RIRI-PA1 was found to primarily consist of attached spindle-shaped and giant cells, which attach themselves to their container. The population-doubling time of 40th-passage cells was approximately 84.8 h. The average chromosome number at the 30th passage was 42, with 40% of cells demonstrating substantial variations, with the highest number of variations of 78 and lowest of 24. The identity of RIRI-PA1 was confirmed by comparing the COI gene of these cells to that of P. americana embryo tissue. Telomerase activity decreased in primary cells after 7 d of culture and 5th-passage cells in comparison to embryo tissues; however, compared to the other cultured cells tested, the telomerase activity significantly increased at the 20th passage. We propose that the stagnation periods and cessation of proliferation observed relate to cellular telomerase activity, but the relationship between insect cell proliferation and telomerase as well as the regulatory mechanism involved remains to be elucidated.