The dynamic role of nucleoprotein SHCBP1 in the cancer cell cycle and its potential as a synergistic target for DNA-damaging agents in cancer therapy.

BACKGROUND: Malignant tumours seriously threaten human life and health, and effective treatments for cancer are still being explored. The ability of SHC SH2 domain-binding protein 1 (SHCBP1) to induce cell cycle disturbance and inhibit tumour growth has been increasingly studied, but its dynamic role in the tumour cell cycle and corresponding effects leading to mitotic catastrophe and DNA damage have rarely been studied. RESULTS: In this paper, we found that the nucleoprotein SHCBP1 exhibits dynamic spatiotemporal expression during the tumour cell cycle, and SHCBP1 knockdown slowed cell cycle progression by inducing spindle disorder, as reflected by premature mitotic entry and multipolar spindle formation. This dysfunction was caused by G2/M checkpoint impairment mediated by downregulated WEE1 kinase and NEK7 (a member of the mammalian NIMA-related kinase family) expression and upregulated centromere/kinetochore protein Zeste White 10 (ZW10) expression. Moreover, both in vivo and in vitro experiments confirmed the significant inhibitory effects of SHCBP1 knockdown on tumour growth. Based on these findings, SHCBP1 knockdown in combination with low-dose DNA-damaging agents had synergistic tumouricidal effects on tumour cells. In response to this treatment, tumour cells were forced into the mitotic phase with considerable unrepaired DNA lesions, inducing mitotic catastrophe. These synergistic effects were attributed not only to the abrogation of the G2/M checkpoint and disrupted spindle function but also to the impairment of the DNA damage repair system, as demonstrated by mass spectrometry-based proteomic and western blotting analyses. Consistently, patients with low SHCBP1 expression in tumour tissue were more sensitive to radiotherapy. However, SHCBP1 knockdown combined with tubulin-toxic drugs weakened the killing effect of the drugs on tumour cells, which may guide the choice of chemotherapeutic agents in clinical practice. CONCLUSION: In summary, we elucidated the role of the nucleoprotein SHCBP1 in tumour cell cycle progression and described a novel mechanism by which SHCBP1 regulates tumour progression and through which targeting SHCBP1 increases sensitivity to DNA-damaging agent therapy, indicating its potential as a cancer treatment.

Insight into melting point differences of dinitroimidazoles and dinitropyrazoles from the perspective of intermolecular interactions.

Dinitroimidazole (DNI) and dinitropyrazole (DNP), along with their congeners, possess similar molecular structures but exhibit distinct melting points. To analyse and elucidate the fundamental reasons for property differences from the perspective of intermolecular interactions, we proposed a simplified approach named binding energy in clusters (BEC) in computing weak interactions within complex crystal systems. Based on the results of the symmetry-adapted perturbation theory (SAPT) calculations, an approximate estimation of the melting point range can be derived by taking into account the cumulative effect (energy of electrostatic, dispersion and induction terms) and repulsive effect (energy of exchange term) values. We have also proposed a formula for calculating the specific melting point, which indicates that stronger intermolecular interactions have a major impact on the melting point, while the distribution of weak interactions also affects the melting point. This work would provide an effective reference for molecular design and structure-performance analysis.

Multiple Hydrogen-Bond Modification of [1,2,5]Oxadiazolo[3,4-b]pyridine 1-Oxide Framework Enables Access to Low-Sensitivity High-Energy Materials.

In this work, a fused-ring [1,2,5]oxadiazolo[3,4-b]pyridine 1-oxide framework with multiple modifiable sites was utilized to develop novel energetic materials with multiple hydrogen bonds. The prepared materials were characterized, and their energetic properties were extensively investigated. Among those studied, compound 3 exhibited high densities of 1.925 g cm-3 at 295 K and 1.964 g cm-3 at 170 K, with high detonation performances (Dv: 8793 m s-1 and P: 32.8 GPa), low sensitivities (IS: 20 J, FS: 288 N), and good thermal stability (Td: 223 °C). N-Oxide compound 4 had higher-energy explosive (Dv: 8854 m s-1 and P: 34.4 GPa) and low sensitivities (IS: 15 J and FS: 240 N). Compound 7 with a high enthalpy group (tetrazole) was determined as a high-energy explosive (Dv: 8851 m s-1, P: 32.4 GPa). Notably, the detonation properties of compounds 3, 4, and 7 were similar to high-energy explosive RDX (Dv: 8801 m s-1 and P: 33.6 GPa). The results indicated that compounds 3 and 4 were potential low-sensitivity high-energy materials.

Fabrication of Energetic Metal-Organic Frameworks: Potassium 5-Carboxylato-3,4-Dinitropyrazole and Potassium 5-(Hydrazinecarbonyl)-3,4-Dinitropyrazole.

Energetic materials have been widely applied in civil and military fields, whose thermostability is a key indicator to evaluate their safety levels under severe conditions. Herein, two novel energetic metal-organic frameworks (EMOFs), namely, 4 and 6, were experimentally obtained and comprehensively characterized. The two EMOFs both possess unique three-dimensional (3D) coordination structures. With a high crystal density of 2.184 g·cm-3, EMOF 4 exhibits outstandingly superior thermostability (onset: 290 °C; peak: 303 °C), while EMOF 6 features onset and peak decomposition temperatures of 220 and 230 °C. The calculated energetic parameters of 4 and 6 are as follows: detonation velocity: 8731 m·s-1 and 8294 m·s-1; detonation pressure: 26.5 and 26.4 GPa. Compared to EMOF 6, EMOF 4 features high energy, excellent thermostability, and low mechanical sensitivities, which should be partly attributed to more plentiful coordination interactions. More coordination bonds are conducive to strengthening the EMOF framework, which needs much more energy to collapse, thereby maintaining higher thermal stability. The above favorable characteristics not only indicate EMOF 4 has a promising future in applications as a thermostable explosive but also provide an effective and feasible strategy for developing novel heat-resistant energetic materials via reinforced frame structures of EMOFs.

Predicting the Melting Point of Energetic Molecules Using a Learnable Graph Neural Fingerprint Model.

Melting point prediction for organic molecules has drawn widespread attention from both academic and industrial communities. In this work, a learnable graph neural fingerprint (GNF) was employed to develop a melting point prediction model using a dataset of over 90,000 organic molecules. The GNF model exhibited a significant advantage, with a mean absolute error (MAE) of 25.0 K, when compared to other featurization methods. Furthermore, by integrating prior knowledge through a customized descriptor set (i.e., CDS) into GNF, the accuracy of the resulting model, GNF_CDS, improved to 24.7 K, surpassing the performance of previously reported models for a wide range of structurally diverse organic compounds. Moreover, the generalizability of the GNF_CDS model was significantly improved with a decreased MAE of 17 K for an independent dataset containing melt-castable energetic molecules. This work clearly demonstrates that prior knowledge is still beneficial for modeling molecular properties despite the powerful learning capability of graph neural networks, especially in specific fields where chemical data are lacking.

Enabling Quick Response to Nitrogen Dioxide at Room Temperature and Limit of Detection to Ppb Level by Heavily n-Doped Graphene Hybrid Transistor.

Sensitive detection of nitrogen dioxide (NO2) is of significance in many areas for health and environmental protections. In this work, we developed an efficient NO2 sensor that can respond within seconds at room temperature, and the limit of detection (LOD) is as low as 100 ppb. Coating cyano-substituted poly(p-phenylene vinylene) (CN-PPV) films on graphene (G) layers can dope G sheets effectively to a heavy n state. The influences of solution concentrations and annealing temperatures on the n-doping effect were investigated in detail. The CN-PPV-G transistors fabricated with the optimized parameters demonstrate active sensing abilities toward NO2. The n-doping state of CN-PPV-G is reduced dramatically by NO2, which is a strong p-doping compound. Upon exposure to 25 ppm of NO2, our CN-PPV-G sensors react in 10 s, indicating it is almost an immediate response. LOD is determined as low as 100 ppb. The ultrahigh responding speed and low LOD are not affected in dry air. Furthermore, cycling use of our sensors can be realized through simple annealing. The superior features shown by our CN-PPV-G sensors are highly desired in the applications of monitoring the level of NO2 in situ and setting immediate alarms. Our results also suggest that transfer curves of transistors can react very promptly to the stimulus of target gas and, thus, are very promising in the development of fast-response sensing devices although the response values may not reach maximum as a tradeoff.

The potential applications of microparticles in the diagnosis, treatment, and prognosis of lung cancer.

Microparticles (MPs) are 100-1000 nm heterogeneous submicron membranous vesicles derived from various cell types that express surface proteins and antigenic profiles suggestive of their cellular origin. MPs contain a diverse array of bioactive chemicals and surface receptors, including lipids, nucleic acids, and proteins, which are essential for cell-to-cell communication. The tumour microenvironment (TME) is enriched with MPs that can directly affect tumour progression through their interactions with receptors. Liquid biopsy, a minimally invasive test, is a promising alternative to tissue biopsy for the early screening of lung cancer (LC). The diverse biomolecular information from MPs provides a number of potential biomarkers for LC risk assessment, early detection, diagnosis, prognosis, and surveillance. Remodelling the TME, which profoundly influences immunotherapy and clinical outcomes, is an emerging strategy to improve immunotherapy. Tumour-derived MPs can reverse drug resistance and are ideal candidates for the creation of innovative and effective cancer vaccines. This review described the biogenesis and components of MPs and further summarised their main isolation and quantification methods. More importantly, the review presented the clinical application of MPs as predictive biomarkers in cancer diagnosis and prognosis, their role as therapeutic drug carriers, particularly in anti-tumour drug resistance, and their utility as cancer vaccines. Finally, we discussed current challenges that could impede the clinical use of MPs and determined that further studies on the functional roles of MPs in LC are required.

Hunting for Energetic Complexes as Hypergolic Promoters for Green Propellants Using Hydrogen Peroxide as Oxidizer.

The development of hypergolic materials has aroused great interest due to their important applications in aerospace technology. In this work, six new energetic complexes were prepared and comprehensively characterized. All energetic complexes had isostructural characteristics, which made them ideal candidates for studying their structure-performance relationships. These energetic complexes had good thermal stabilities and excellent specific impulses. The vacuum-specific impulses were in the range 264.0-271.9 s, which was greater than most reported solid hypergolic materials. Moreover, the hypergolic performance of these compounds was examined by using 100% HNO3 as the oxidizer, and their catalytic performance in the hypergolic reaction of typical energetic ionic liquids and 90% H2O2 was comprehensively studied. All compounds displayed excellent hypergolic performance with the shortest ignition delay time of 4 ms. The examined copper-containing energetic complexes displayed excellent catalytic activities for the hypergolic reaction between energetic ionic liquids and 90% H2O2. The shortest ignition delay time of the examined hypergolic reactions was 31 ms. The suitable physicochemical properties, excellent energetic properties, and high catalytic activity of the hypergolic reactions have demonstrated the great potential of these energetic complexes as promoters for the development of green hypergolic bipropellants.

Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes: a multi-centre retrospective study.

AIMS/HYPOTHESIS: Hyperglycaemia is associated with an elevated risk of mortality in community-acquired pneumonia, stroke, acute myocardial infarction, trauma and surgery, among other conditions. In this study, we examined the relationship between fasting blood glucose (FBG) and 28-day mortality in coronavirus disease 2019 (COVID-19) patients not previously diagnosed as having diabetes. METHODS: We conducted a retrospective study involving all consecutive COVID-19 patients with a definitive 28-day outcome and FBG measurement at admission from 24 January 2020 to 10 February 2020 in two hospitals based in Wuhan, China. Demographic and clinical data, 28-day outcomes, in-hospital complications and CRB-65 scores of COVID-19 patients in the two hospitals were analysed. CRB-65 is an effective measure for assessing the severity of pneumonia and is based on four indicators, i.e. confusion, respiratory rate (>30/min), systolic blood pressure (≤90 mmHg) or diastolic blood pressure (≤60 mmHg), and age (≥65 years). RESULTS: Six hundred and five COVID-19 patients were enrolled, including 114 who died in hospital. Multivariable Cox regression analysis showed that age (HR 1.02 [95% CI 1.00, 1.04]), male sex (HR 1.75 [95% CI 1.17, 2.60]), CRB-65 score 1-2 (HR 2.68 [95% CI 1.56, 4.59]), CRB-65 score 3-4 (HR 5.25 [95% CI 2.05, 13.43]) and FBG ≥7.0 mmol/l (HR 2.30 [95% CI 1.49, 3.55]) were independent predictors for 28-day mortality. The OR for 28-day in-hospital complications in those with FBG ≥7.0 mmol/l and 6.1-6.9 mmol/l vs <6.1 mmol/l was 3.99 (95% CI 2.71, 5.88) or 2.61 (95% CI 1.64, 4.41), respectively. CONCLUSIONS/INTERPRETATION: FBG ≥7.0 mmol/l at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes. Glycaemic testing and control are important to all COVID-19 patients even where they have no pre-existing diabetes, as most COVID-19 patients are prone to glucose metabolic disorders. Graphical abstract.

Wogonin inhibits in vitro herpes simplex virus type 1 and 2 infection by modulating cellular NF-κB and MAPK pathways.

BACKGROUND: Wogonin, a natural flavonoid-like chemical compound, exhibits anti-inflammatory, antitumor, antiviral, neuroprotective, and anxiolytic effects by modulating a variety of cellular signaling pathways including PI3K-Akt, p53, nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK) pathways. In this study, its antiviral effect against herpes simplex virus (HSV) type 1 and 2 (HSV-1 and HSV-2) replication was investigated. RESULTS: Wogonin suppressed HSV-2-induced cytopathic effect (CPE) and reduced viral mRNA transcription, viral protein synthesis, and infectious virion particle titers in a dose-dependent manner. A time-of-drug-addition assay demonstrated that wogonin acted as a postentry viral inhibitor. Wogonin also significantly reduced HSV-induced NF-κB and MAPK pathway activation, which has previously been demonstrated to be important for viral replication. CONCLUSIONS: Our results suggest that the anti-herpes effect of wogonin may be mediated by modulation of cellular NF-κB and JNK/p38 MAPK pathways and imply that wogonin may be useful as an anti-HSV agent.

Is oseltamivir suitable for fighting against COVID-19: In silico assessment, in vitro and retrospective study.

BACKGROUND: Oseltamivir is a first-line antiviral drug, especially in primary hospitals. During the ongoing outbreak of coronavirus disease 2019 (COVID-19), most patients with COVID-19 who are symptomatic have used oseltamivir. Considering its popular and important role as an antiviral drug, it is necessary to evaluate oseltamivir in the treatment of COVID-19. OBJECTIVE: To evaluate the effect of oseltamivir against COVID-19. METHODS: Swiss-model was used to construct the structure of the N-terminal RNA-binding domain (NRBD) of the nucleoprotein (NC), papain-like protease (PLpro), and RNA-directed RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). TM-align program was performed to compare the structure of the viral proteins with the structure of the neuraminidase of influenza A. Molecular docking was used to analyze the theoretical possibility of effective binding of oseltamivir with the active centers of the viral proteins. In vitro study was used to evaluate the antiviral efficiency of oseltamivir against SARS-CoV-2. By clinical case analysis, we statistically evaluated whether the history of oseltamivir use influenced the progression of the disease. RESULTS: The structures of NRBD, PLpro, and RdRp were built successfully. The results from TM-align suggested that the S protein, NRBD, 3C-like protease (3CLpro), PLPrO, and RdRp were structurally similar to the influenza A neuraminidase, with TM-scores of 0.30077, 0.19254, 0.28766, 0.30666, and 0.34047, respectively. Interestingly, the active center of 3CL pro was found to be similar to the active center from the neuraminidase of influenza A. Through an analysis of molecular docking, we discovered that oseltamivir carboxylic acid was more favorable to bind to the active site of 3CLpro effectively, but its inhibitory effect was not strong compared with the positive group. Finally, we used in vitro study and retrospective case analysis to verify our speculations. We found that oseltamivir is ineffective against SARS-CoV-2 in vitro study and the clinical use of oseltamivir did not improve the patients' symptoms and signs and did not slow the disease progression. CONCLUSIONS: We consider that oseltamivir isn't suitable for the treatment of COVID-19. During the outbreak of novel coronavirus, when oseltamivir is not effective for the patients after they take it, health workers should be highly vigilant about the possibility of COVID-19.

Stabilization of the Pentazolate Anion in a Zeolitic Architecture with Na20 N60 and Na24 N60 Nanocages.

The experimental detection and synthesis of pentazole (HN5 ) and its anion (cyclo-N5- ) have been actively pursued for the past hundred years. The synthesis of an aesthetic three-dimensional metal-pentazolate framework (denoted as MPF-1) is presented. It consists of sodium ions and cyclo-N5- anions in which the isolated cyclo-N5- anions are preternaturally stabilized in this inorganic open framework featuring two types of nanocages (Na20 N60 and Na24 N60 ) through strong metal coordination bonds. The compound MPF-1 is indefinitely stable at room temperature and exhibits high thermal stability relative to the reported cyclo-N5- salts. This finding offers a new approach to create metal-pentazolate frameworks (MPFs) and enables the future exploration of interesting pentazole chemistry and also related functional materials.

BX-795 inhibits HSV-1 and HSV-2 replication by blocking the JNK/p38 pathways without interfering with PDK1 activity in host cells.

BX-795 is an inhibitor of 3-phosphoinositide-dependent kinase 1 (PDK1), but also a potent inhibitor of the IKK-related kinase, TANKbinding kinase 1 (TBK1) and IKKɛ. In this study we attempted to elucidate the molecular mechanism(s) underlying the inhibition of BX-795 on Herpes simplex virus (HSV) replication. HEC-1-A or Vero cells were treated with BX-795 and infected with HSV-1 or HSV-2 for different periods. BX-795 (3.125-25 µmol/L) dose-dependently suppressed HSV-2 replication, and displayed a low cytotoxicity to the host cells. BX-795 treatment dose-dependently suppressed the expression of two HSV immediate-early (IE) genes (ICP0 and ICP27) and the late gene (gD) at 12 h postinfection. HSV-2 infection resulted in the activation of PI3K and Akt in the host cells, and BX-795 treatment inhibited HSV-2-induced Akt phosphorylation and activation. However, the blockage of PI3K/Akt/mTOR with LY294002 and rapamycin did not affect HSV-2 replication. HSV-2 infection increased the phosphorylation of JNK and p38, and reduced ERK phosphorylation at 8 h postinfection in the host cells; BX-795 treatment inhibited HSV-2-induced activation of JNK and p38 MAP kinase as well as the phosphorylation of c-Jun and ATF-2, the downstream targets of JNK and p38 MAP kinase. Furthermore, SB203580 (a p38 inhibitor) or SP600125 (a JNK inhibitor) dose-dependently inhibited the viral replication in the host cells, whereas PD98059 (an ERK inhibitor) was not effective. Moreover, BX-795 blocked PMA-stimulated c-Jun activation as well as HSV-2-mediated c-Jun nuclear translocation. BX-795 dose-dependently inhibited HSV-2, PMA, TNF-α-stimulated AP-1 activation, but not HSV-induced NF-κB activation. Overexpression of p38/JNK attenuated the inhibitory effect of BX-795 on HSV replication. BX-795 completely blocked HSV-2-induced MKK4 phosphorylation, suggesting that BX-795 acting upstream of JNK and p38 MAP kinase. In conclusion, this study identifies the anti-HSV activity of BX-795 and its targeting of the JNK/p38 MAP kinase pathways in host cells.

Downregulation of cellular c-Jun N-terminal protein kinase and NF-κB activation by berberine may result in inhibition of herpes simplex virus replication.

Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. Some reports show that berberine exhibits anti-inflammatory, antitumor, and antiviral properties by modulating multiple cellular signaling pathways, including p53, nuclear factor κB (NF-κB), and mitogen-activated protein kinase. In the present study, we investigated the antiviral effect of berberine against herpes simplex virus (HSV) infection. Current antiherpes medicines such as acyclovir can lessen the recurring activation when used early at infection but are unable to prevent or cure infections where treatment has selected for resistant mutants. In searching for new antiviral agents against herpesvirus infection, we found that berberine reduced viral RNA transcription, protein synthesis, and virus titers in a dose-dependent manner. To elucidate the mechanism of its antiviral activity, the effect of berberine on the individual steps of viral replication cycle of HSV was investigated via time-of-drug addition assay. We found that berberine acted at the early stage of HSV replication cycle, between viral attachment/entry and genomic DNA replication, probably at the immediate-early gene expression stage. We further demonstrated that berberine significantly reduced HSV-induced NF-κB activation, as well as IκB-α degradation and p65 nuclear translocation. Moreover, we found that berberine also depressed HSV-induced c-Jun N-terminal kinase (JNK) phosphorylation but had little effect on p38 phosphorylation. Our results suggest that the berberine inhibition of HSV infection may be mediated through modulating cellular JNK and NF-κB pathways.

Dihydroartemisinin restores the immunogenicity and enhances the anticancer immunosurveillance of cisplatin by activating the PERK/eIF2α pathway.

BACKGROUND: Immunosurveillance is pivotal in the effectiveness of anticancer therapies and tumor control. The ineffectiveness of cisplatin in activating the immunosurveillance is attributed to its lack of adjuvanticity resulting from its inability to stimulate endoplasmic reticulum stress. Dihydroartemisinin demonstrates the anti-tumor effects through various mechanisms, including the activation of the endoplasmic reticulum stress. This study aimed to develop a novel strategy to enhance the immunogenicity of dying tumor cells by combining cisplatin with dihydroartemisinin, thereby triggering effective anti-tumor immunosurveillance and improving the efficacy of cisplatin in clinical practice. METHODS: Lewis lung carcinoma (LLC) and CT26 colon cancer cell lines and subcutaneous tumor models were used in this study. The importance of immunosurveillance was validated in both immunocompetent and immunodeficient mouse models. The ability of dihydroartemisinin and cisplatin therapy to induce immunogenic cell death and tumor growth control in vivo was validated by prophylactic tumor vaccination and therapeutic tumor models. The underlying mechanism was elucidated through the pharmaceutical or genetic intervention of the PERK/eIF2α pathway in vitro and in vivo. RESULTS: Dihydroartemisinin enhanced the generation of reactive oxygen species in cisplatin-treated LLC and CT26 cancer cells. The combination treatment of dihydroartemisinin with cisplatin promoted cell death and ensured an optimal release of damage-associated molecular patterns from dying cancer cells, promoting the phagocytosis of dendritic cells. In the tumor vaccination model, we confirmed that dihydroartemisinin plus cisplatin treatment induced immunogenic cell death. Utilizing immunocompetent and immunodeficient mouse models, we further demonstrated that the combination treatment suppressed the tumor growth of CT26 colon cancer and LLC lung cancer, leading to an improved prognosis through the restoration of cytotoxic T lymphocyte responses and reinstatement of anti-cancer immunosurveillance in vivo. Mechanistically, dihydroartemisinin restored the immunogenicity of cisplatin by activating the adjuvanticity of damage-associated molecular patterns, such as calreticulin exposure, through the PERK/eIF2α pathway. Additionally, the inhibition of eIF2α phosphorylation attenuated the anti-tumor efficiency of C + D in vivo. CONCLUSIONS: We highlighted that dihydroartemisinin acts as an immunogenic cell death rescuer for cisplatin, activating anticancer immunosurveillance in a PERK/eIF2α-dependent manner and offering a strategy to enhance the anti-tumor efficacy of cisplatin in clinical practice.

Design and Synthesis of Energetic Melt-Castable Materials by Substituent-Specific Modification.

With the increase in the demand for high-performance composite explosives, the search for advanced energetic melt-castable compounds has attracted increasing attention in the field of energetic materials. Herein, two new energetic materials with nitromethyl and azidomethyl substituents (1-(nitromethyl)-3,4-dinitro-1H-pyrazole (NMDNP) and 1-(azidomethyl)-3,4-dinitro-1H-pyrazole (AMDNP) were prepared by the substituent modification of a potential melt-castable molecule ((3,4-dinitro-1H-pyrazol-1-yl) methyl nitrate, MC-4), respectively. NMDNP exhibited a suitable melting point (90 °C), good thermal stability (Td : 185 °C) and excellent detonation performance (8484 m s-1 ) and impact sensitivity (25 J), thereby demonstrating promise as an energetic melt-castable material. Simultaneously, compared with the nitrato-methyl and azidomethyl substituents, the nitromethyl substituent exhibited greater advantages in regulating performance.

Tubeimoside I Ameliorates Doxorubicin-Induced Cardiotoxicity by Upregulating SIRT3.

Cardiotoxicity linked to doxorubicin (DOX) is primarily caused by inflammation, oxidative stress, and apoptosis. The role of tubeimoside I (TBM) in DOX-induced cardiotoxicity remains ambiguous, despite growing evidence that it could reduce inflammation, oxidative stress, and apoptosis in various diseases. This study was designed to investigate the role of TBM in DOX-induced cardiotoxicity and uncover the underlying mechanisms. H9c2 cell line and C57BL/6 mice were used to construct an in vitro and in vivo model of DOX-induced myocardial injury, respectively. We observed that DOX treatment provoked inflammation, oxidative stress, and cardiomyocyte apoptosis, which were significantly alleviated by TBM administration. Mechanistically, TBM attenuated DOX-induced downregulation of sirtuin 3 (SIRT3), and SIRT3 inhibition abrogated the beneficial effects of TBM both in vitro and in vivo. In conclusion, TBM eased inflammation, oxidative stress, and apoptosis in DOX-induced cardiotoxicity by increasing the expression of SIRT3, suggesting that it holds great promise for treating DOX-induced cardiac injury.

Promising Energetic Melt-Castable Material with Balanced Properties.

As one of the most widely used energetic materials to date, trinitrotoluene (TNT) suffers from several generally known drawbacks such as high toxicity, oil permeability, and poor mechanical properties, which are driving researchers to explore new high-performance energetic melt-castable materials for replacing TNT. However, it still remains a great challenge to discover a promising TNT alternative due to the multidimensional requirements for practical applications. Herein, we reported a new promising energetic melt-castable molecule, 4-methoxy-1-methyl-3,5-dinitro-1H-pyrazole (named as DMDNP). Besides a reasonable melting point (Tm: 94.8 °C), good thermostability (Td: 293.2 °C), and excellent chemical compatibility, DMDNP exhibits some obvious advantages over TNT including more environmentally friendly synthesis, high yield, low toxicity, low volume shrinkage, low mechanical and electrostatic sensitivities, etc., demonstrating well-balanced properties and great promise as a TNT replacement.

Targeting Cancer Cell Ferroptosis to Reverse Immune Checkpoint Inhibitor Therapy Resistance.

In recent years, cancer therapies using immune checkpoint inhibitors (ICIs) have achieved meaningful success, with patients with advanced tumors presenting longer survival times and better quality of life. However, several patients still do not exhibit good clinical outcomes for ICI therapy due to low sensitivity. To solve this, researchers have focused on identifying the cellular and molecular mechanisms underlying resistance to ICI therapy. ICI therapy induces apoptosis, which is the most frequent regulated cell death (RCD) but lacks immunogenicity and is regarded as an "immune silent" cell death. Ferroptosis, a unique type of non-apoptotic-RCD, has been preliminarily identified as an immunogenic cell death (ICD), stimulating tumor-antigen-specific immune responses and augmenting anti-tumor immune effects. However, ferroptosis has rarely been used in clinical practice. Present evidence strongly supports that the interferon-γ signaling pathway is at the crossroads of ICI therapy and ferroptosis. TYRO3, a receptor tyrosine kinase, is highly expressed in tumors and can induce anti-programmed cell death (PD)-ligand 1/PD-1 therapy resistance by limiting tumoral ferroptosis. Therefore, in this review, we summarize the clinical practice and effects of ICI therapy in various cancers. We also provide an overview of ferroptosis and report the molecular connections between cancer cell ferroptosis and ICI therapy, and discuss the possibility to reverse ICI therapy resistance by inducing cancer cell ferroptosis.

Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid Accumulation.

Tyrosine kinase inhibitors (TKIs) resistance is a challenge in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). Here, we examined the effect of Fasudil in reversing TKIs resistance. The results of CCK8 assay, clone formation assay, cell cycle arrest analysis, and apoptosis analysis show that Fasudil treatment effectively suppressed the growth and induced apoptosis of the EGFR-mutant NSCLC cells. Furthermore, Fasudil in combination with gefitinib showed a synergistic anti-tumor effect in gefitinib-resistant NSCLC cells. RNA-seq analysis and immunoblotting indicated that Fasudil treatment significantly inhibited intracellular lipid accumulation and EGFR/PI3K/AKT pathway activation. Mechanistic investigations showed that Fasudil regulated lipogenic gene expressions via AMPK signal pathway. In vivo, Fasudil and gefitinib co-administration significantly attenuated the growth of H1975 nude mouse xenograft models, suggesting that Fasudil treatment combined with gefitinib can be applied as a therapy for gefitinib-resistant NSCLC cells.