Nanointegrative In Situ Reprogramming of Tumor-Intrinsic Lipid Droplet Biogenesis for Low-Dose Radiation-Activated Ferroptosis Immunotherapy.

Low-dose radiotherapy (LDR) has shown significant implications for inflaming the immunosuppressive tumor microenvironment (TME). Surprisingly, we identify that FABP-dependent lipid droplet biogenesis in tumor cells is a key determinant of LDR-evoked cytotoxic and immunostimulatory effects and developed a nanointegrated strategy to promote the antitumor efficacy of LDR through cooperative ferroptosis immunotherapy. Specifically, TCPP-TK-PEG-PAMAM-FA, a nanoscale multicomponent functional polymer with self-assembly capability, was synthesized for cooperatively entrapping hafnium ions (Hf4+) and HIF-1α-inhibiting siRNAs (siHIF-1α). The TCPP@Hf-TK-PEG-PAMAM-FA@siHIF-1α nanoassemblies are specifically taken in by folate receptor-overexpressing tumor cells and activated by the elevated cellular ROS stress. siHIF-1α could readily inhibit the FABP3/7 expression in tumor cells via HIF-1α-FABP3/7 signaling and abolish lipid droplet biogenesis for enhancing the peroxidation susceptibility of membrane lipids, which synergizes with the elevated ROS stress in the context of Hf4+-enhanced radiation exposure and evokes pronounced ferroptotic damage in vital membrane structures. Interestingly, TCPP@Hf-TK-PEG-PAMAM-FA@siHIF-1α-enhanced ferroptotic biomembrane damage also facilitates the exposure of tumor-associated antigens (TAAs) to promote post-LDR immunotherapeutic effects, leading to robust tumor regression in vivo. This study offers a nanointegrative approach to boost the antitumor effects of LDR through the utilization of tumor-intrinsic lipid metabolism.

Using Highly Electronegative Zn to Regulate the Superlattice Structure for the Na-Ion Layered Oxide Cathode with Superior Electrochemical Performance.

The introduction of a superlattice structure into layered oxide cathode materials is a novel strategy to improve the structural stability of sodium-ion batteries (SIBs). However, the superlattice structure gradually disappears during cycling, which shortens the long life of SIBs. Here, the highly electronegative Zn is introduced into a P2-type layered oxide to regulate the superlattice structure. The obtained P2-Na0.80Li0.13Ni0.20Zn0.03Mn0.64O2 exhibits excellent cycling performance (the capacity retention is 96.7% after 100 cycles at 0.5C) and rate capability (95.8 mAh g-1 at 5C). Zn effectively inhibits the Li migration and the Mn dissolution, which ensures the integrity of the Li/Mn superlattice structure during long cycling, thus achieving an ultralong cycling life of SIBs. The introduction of Zn dramatically increases the length of the c-axis, leading to a faster de-embedding rate of Na+ and a better diffusion kinetics. Meanwhile, the larger pristine volume can withstand more stress/strain due to the sharp increase in the level of O-O repulsion during the desodiation process. In addition, Raman test results show that Zn can inhibit the Na+/vacancy ordering transition and improve the structural stability. This study confirms the feasibility of a Zn-regulated superlattice structure. It provides inspiration for the construction of stable layered oxide cathode materials for SIBs.

Corrigendum: Interferon-induced transmembrane protein 3 in the hippocampus: a potential novel target for the therapeutic effects of recombinant human brain natriuretic peptide on sepsis-associated encephalopathy.

[This corrects the article DOI: 10.3389/fnmol.2023.1182005.].

Mechanotransduction in response to ECM stiffening impairs cGAS immune signaling in tumor cells.

The tumor microenvironment (TME) plays decisive roles in disabling T cell-mediated antitumor immunity, but the immunoregulatory functions of its biophysical properties remain elusive. Extracellular matrix (ECM) stiffening is a hallmark of solid tumors. Here, we report that the stiffened ECM contributes to the immunosuppression in TME via activating the Rho-associated coiled-coil-containing protein kinase (ROCK)-myosin IIA-filamentous actin (F-actin) mechanosignaling pathway in tumor cells to promote the generation of TRIM14-scavenging nonmuscle myosin heavy chain IIA (NMHC-IIA)-F-actin stress fibers, thus accelerating the autophagic degradation of cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) to deprive tumor cyclic GMP-AMP (cGAMP) and further attenuating tumor immunogenicity. Pharmacological inhibition of myosin IIA effector molecules with blebbistatin (BLEB) or the RhoA upstream regulator of this pathway with simvastatin (SIM) restored tumor-intrinsic cGAS-mediated cGAMP production and enhanced antitumor immunity. Our work identifies that ECM stiffness is an important biophysical cue to regulate tumor immunogenicity via the ROCK-myosin IIA-F-actin axis and that inhibiting this mechanosignaling pathway could boost immunotherapeutic efficacy for effective solid tumor treatment.

DFT Studies on the Mechanisms of Carboamination/Diamination of Unactivated Alkenes Mediated by Pd(IV) Intermediates.

Density functional theory (DFT) calculations have been employed to investigate the mechanism of carboamination and diamination of unactivated alkenes mediated by Pd(IV) intermediates. Both reactions share a common Pd(IV) intermediate, serving as the starting point for either the carboamination or the diamination pathway. The formation of this Pd(IV) intermediate encompasses a transition state that substantially impacts the turnover frequency (TOF) of catalytic cycles, with an apparent activation free-energy barrier of 26.1 kcal mol-1. Carboamination of unactivated alkenes proceeds through the coordination of a toluene molecule, C-H activation, inner reductive elimination, and the separation of the carboamination product from this intermediate, while diamination of unactivated alkenes involves the formation of the ion nucleophile, SN2 attack, and the separation of the diamination product. A comparison of the free-energy profiles for carboamination and diamination of unactivated alkenes can elucidate the origin of the chemoselectivity, and Bader's atoms in molecules (AIM) wave function analyses have been performed to analyze the contributions of the outer C-N bonding in the diamination process.

Interferon-induced transmembrane protein 3 in the hippocampus: a potential novel target for the therapeutic effects of recombinant human brain natriuretic peptide on sepsis-associated encephalopathy.

Objective: This study aims to explore whether interferon-induced transmembrane protein 3 (IFITM3) is involved in recombinant human brain natriuretic peptide (rhBNP)-mediated effects on sepsis-induced cognitive dysfunction in mice. Methods: The cellular localization and expression level of IFITM3 in the hippocampus were detected. The IFITM3 overexpression was achieved using an intracranial stereotactic system to inject an adeno-associated virus into the hippocampal CA1 region of mice. Field experiments, an elevated plus maze, and conditioned fear memory tests assessed the cognitive impairment in rhBNP-treated septic mice. Finally, in the hippocampus of septic mice, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining and Immunoblot were used to detect changes in the protein expression of cleaved Caspase-8 and cleaved Caspase-3 in apoptosis-related pathways, and toll-like receptor 4 (TLR4) and nuclear factor κB (NF-κB) p65 in inflammatory pathways. Results: Fourteen days after cecal ligation and puncture (CLP) surgery, IFITM3 localized in the plasma membrane and cytoplasm of the astrocytes in the hippocampus of septic mice, partially attached to the perivascular and neuronal surfaces, but not expressed in the microglia. The expression of IFITM3 was increased in the astrocytes and neurons in the hippocampus of septic mice, which was selectively inhibited by the administration of rhBNP. Overexpression of IFITM3 resulted in elevated anxiety levels and long-term learning and memory dysfunction, completely abolished the therapeutic effect of rhBNP on cognitive impairment in septic mice, and induced an increase in the number of neuronal apoptosis in the hippocampal CA1 region. The expression levels of cleaved Caspase-3 and cleaved Caspase-8 proteins were significantly increased in the hippocampus, but the expression levels of TLR4 and NF-κB p65 were not increased. Conclusion: The activation of IFITM3 may be a potential new target for treating sepsis-associated encephalopathy (SAE), and it may be one of the key anti-apoptotic mechanisms in rhBNP exerting its therapeutic effect, providing new insight into the clinical treatment of SAE patients.

The treatment of dispersion terms for solution systems.

DFT calculations of reaction mechanisms in solution have always been a hot topic, especially for transition-metal-catalyzed reactions, in which the traditional DFT-D3 method has been extensively employed. The overestimation of the dispersion from the traditional DFT-D3 method leads to a quite low activation free-energy barrier, so it is worth finding a proper way to deal with the dispersion for solution systems. The solvent-solute dispersion is also important for solution systems, and thus it should be calculated together with the solute dispersion. The newly generated solute-solute dispersion energy should be shared equally with the newly formed cavity between two interacting species; therefore, only half of the solute-solute and solvent-solute dispersion terms belong to the solute molecule. The detailed treatment of dispersion correction for solution systems has been fully addressed, and this method has been confirmed with the examples of ligand exchange reactions and catalytic reactions.

High-efficient capture and degradation of formaldehyde based on the electric-field-enhanced catalytic effect.

Enhancing the generation of active groups is of great significance for alleviating the catalyst deactivation of formaldehyde (HCHO) by accelerating the decomposition of intermediate products. Herein, an electric-field-enhanced catalytic effect was proposed for the efficient capture and degradation of HCHO base on carbon cloth loaded manganese oxide catalyst (MnOx-CC). Under the action of electric field, MnOx can generate more hydroxyl radicals (•OH) and superoxide radicals (•O2-), thus accelerating the degradation of HCHO and intermediates at room temperature. After the introduction electric field (∼1 ×104 V/m), •O2- and •OH radical on the surface of MnOx-CC catalyst can be increased by 8 times and 23 times, respectively. At weight hourly space velocity of 300,000 mL/(gcat h) for ∼15 ppm HCHO, MnOx-CC-Electric Field catalyst reached the removal efficiency of 99.4%, and the CO2 conversion efficiency of 81.2%, without decrease significantly within 80 h. Theoretical calculation shows that the electric field can increase the electron state density of Mn atom at the Fermi level and reduce the adsorption energy of HCHO, O2 and H2O, thus promoting the generation of active groups and degradation of intermediate products. The electric-field-enhancement catalytic effect provides a new approach for the degradation of Volatile Organic Compounds.

α-Stereoselective 3-Deoxy-d-manno-oct-2-ulosonoic Acid (Kdo) O-Glycosylation with a p-Toluenethioglycoside Donor by the (p-Tol)2SO/Tf2O Preactivation Strategy.

A convenient and efficient approach was developed to synthesize α-Kdo O-glycosides based on the Tf2O/(p-Tol)2SO preactivation strategy using peracetylated Kdo thioglycoside as a donor. Under the optimized reaction conditions, several O-glycoside products, including α-(2 → 1)-, α-(2 → 2)-, α-(2 → 3)-, and α-(2 → 6)-Kdo products, were stereoselectively synthesized in high yields. Remarkably, a series of aromatic α-Kdo O-glycosides were first and successfully constructed in high yields. An SN2-like mechanism was revealed by DFT calculations and experimental results.

Catalytic removal of toluene using MnO2-based catalysts: A review.

Volatile organic compounds (VOCs) have serious hazard to human health and ecological environment. Due to its low cost and high activity, the catalytic oxidation technology considered to be the most effective method to remove VOCs. Toluene is one of the typical VOCs, hence its catalytic elimination is crucial for the regulation of VOCs. Manganese dioxide (MnO2) has been extensively studied for its excellent redox performance and low-temperature operation conditions. In this review, we summarize the research progresses in the toluene catalytic oxidation of MnO2-based catalysts, which contain single MnO2, metal-doped MnO2 and supported MnO2 catalyst. In particular, we pay much attention on the relationship between the chemical properties and toluene oxidation performance over MnO2 catalyst, as well as the catalytic reaction mechanisms. Moreover, the effects of different crystal forms and morphologies on the catalytic toluene reaction were discussed. And the perspective on MnO2 catalysts for the catalytic oxidation of toluene has been proposed. We expect that the summary of these important findings can serve as an important reference for the catalytic treatment of VOCs.

DFT calculations in solution systems: solvation energy, dispersion energy and entropy.

DFT calculations of reaction mechanisms in solution have always been a hot topic, especially for transition-metal-catalyzed reactions. The calculation of solvation energy is performed using either the polarizable continuum model (PCM) or the universal solvation model SMD. The PCM calculation is very sensitive to the choice of atomic radii to form a cavity, where the self-consistent isodensity PCM (SCI-PCM) has been recognized as the best choice and our IDSCRF radii can provide a similar cavity. Moving from a gas-phase case to a solution case, dispersion energy and entropy should be carefully treated. The solvent-solute dispersion is also important in solution systems, and it should be calculated together with the solute dispersion. Only half of the solvent-solute dispersion energy from the PCM calculation belongs to the solute molecules to maintain a thermal equilibrium between a solute molecule and its cavity, similar to the treatment of electrostatic energy. Relative solute dispersion energy should also be shared equally with the newly formed cavity. The entropy change from a gas phase to a liquid phase is quite large, but the modern quantum chemistry programs can only calculate the gas-phase translational entropy based on the idea-gas equation. In this review, we will provide an operable method to calculate the solution translational entropy, which has been coded in our THERMO program.

Machine Learning for Predicting Distant Metastasis of Medullary Thyroid Carcinoma Using the SEER Database.

Objectives: We aimed to establish an effective machine learning (ML) model for predicting the risk of distant metastasis (DM) in medullary thyroid carcinoma (MTC). Methods: Demographic data of MTC patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database of the National Institutes of Health between 2004 and 2015 to develop six ML algorithm models. Models were evaluated based on accuracy, precision, recall rate, F1-score, and area under the receiver operating characteristic curve (AUC). The association between clinicopathological characteristics and target variables was interpreted. Analyses were performed using traditional logistic regression (LR). Results: In total, 2049 patients were included and 138 developed DM. Multivariable LR showed that age, sex, tumor size, extrathyroidal extension, and lymph node metastasis were predictive features for DM in MTC. Among the six ML models, the random forest (RF) had the best predictability in assessing the risk of DM in MTC, with an accuracy, precision, recall rate, F1-score, and AUC higher than those of the traditional binary LR model. Conclusion: RF was superior to traditional LR in predicting the risk of DM in MTC and can provide a valuable reference for clinicians in decision-making.

Modulating tumor physical microenvironment for fueling CAR-T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy has achieved unprecedented clinical success against hematologic malignancies. However, the transition of CAR-T cell therapies for solid tumors is limited by heterogenous antigen expression, immunosuppressive microenvironment (TME), immune adaptation of tumor cells and impeded CAR-T-cell infiltration/transportation. Recent studies increasingly reveal that tumor physical microenvironment could affect various aspects of tumor biology and impose profound impacts on the antitumor efficacy of CAR-T therapy. In this review, we discuss the critical roles of four physical cues in solid tumors for regulating the immune responses of CAR-T cells, which include solid stress, interstitial fluid pressure, stiffness and microarchitecture. We highlight new strategies exploiting these features to enhance the therapeutic potency of CAR-T cells in solid tumors by correlating with the state-of-the-art technologies in this field. A perspective on the future directions for developing new CAR-T therapies for solid tumor treatment is also provided.

YTHDF1 upregulation mediates hypoxia-dependent breast cancer growth and metastasis through regulating PKM2 to affect glycolysis.

N6-methyladenosine modification is the most common RNA modification mechanism in mammals. YTHDF1, a m6A reader, can recognize the m6A of mRNAs to facilitate the interaction with the mRNA ribosome assembly and recruitment of translation initiators to promote translation. From a clinical perspective, YTHDF1 upregulation is frequently observed in breast cancer, but its involvement in those cancer-related events is still unclear. Here we report that YTHDF1 is a cancer driver capable of facilitating the proliferation and invasion of breast cancer cells as well as enhancing tumorigenicity and metastasis through promoting glycolysis. We found that tumor hypoxia can transcriptionally induce HIF1α and post-transcriptionally inhibit the expression of miR-16-5p to promote YTHDF1 expression, which could sequentially enhance tumor glycolysis by upregulating PKM2 and eventually increase the tumorigenesis and metastasis potential of breast cancer cells. Inhibiting YTHDF1 via gene knockdown or miR-16-5p would significantly abolish YTHDF1-dependent tumor growth and metastasis. In summary, we identified the role of the YTHDF1-PKM2 signal axis in the occurrence and development of breast cancer, which can be used as a potential target for breast cancer treatment.

IL-17A mediates pyroptosis via the ERK pathway and contributes to steroid resistance in CRSwNP.

BACKGROUND: Pyroptosis is closely related to inflammation. However, the molecular mechanisms and pathologic contributions of pyroptotic epithelial cell are not yet fully understood. OBJECTIVE: This study aimed to explore the function and molecular mechanisms of IL-17A on human nasal epithelial cell (hNEC) pyroptosis. METHODS: The expression of pyroptosis-related biomarkers and IL-17A was assessed in sinonasal mucosa from control individuals, patients with chronic rhinosinusitis without nasal polyps, and patients with chronic rhinosinusitis with nasal polyps (CRSwNP) by using quantitative RT-PCR. Their localization was analyzed via immunohistochemistry and immunofluorescence. The ultrastructural characteristics of IL-17A-induced pyroptosis in hNECs were visualized by using electron microscopy. IL-17A functional assays were performed on hNECs and airway epithelial cell lines. Cytokine levels were quantified via ELISA. The signaling pathways involved in IL-17A-induced pyroptosis were studied via unbiased RNA sequencing and Western blotting. RESULTS: The expression of IL-17A and the pyroptotic biomarkers NOD-like receptor family, pyrin domain containing 3 (NLRP3), caspase-1, gasdermin D, and IL-1ß was increased in nasal mucosa from patients with CRSwNP compared with in those with chronic rhinosinusitis without nasal polyps and the control subjects. IL-17A was positively correlated and colocalized with the pyroptotic biomarkers. IL-17A treatment induced pyroptosis in the hNECs and cell lines analyzed, primarily through the extracellular signal-regulated kinase (ERK)-NLRP3/caspase-1 signaling pathway, and increased IL-1ß and IL-18 secretion in hNECs. Moreover, IL-17A-induced pyroptosis contributed to steroid resistance by affecting glucocorticoid receptor-α and glucocorticoid receptor-ß expression, and the inhibition of pyroptotic proteins partially abolished IL-17A-induced steroid resistance in hNECs. CONCLUSION: Elevated IL-17A level promotes pyroptosis in hNECs through the ERK-NLRP3/caspase-1 signaling pathway and contributes to glucocorticoid resistance by affecting glucocorticoid receptor homeostasis in patients with CRSwNP.

DFT Case Study on the Comparison of Ruthenium-Catalyzed C-H Allylation, C-H Alkenylation, and Hydroarylation.

Density functional calculations at the B3LYP-D3+IDSCRF/TZP-DKH(-dfg) level of theory have been performed to understand the mechanism of ruthenium-catalyzed C-H allylation reported in the literature in depth. The plausible pathway consisted of four sequential processes, including C-H activation, migratory insertion, amide extrusion, and recovery of the catalyst, in which C-H activation was identified as the rate-determining step. The amide extrusion step could be promoted kinetically by trifluoroacetic acid since its mediation lowered the free-energy barrier from 32.1 to 12.2 kcal/mol. Additional calculations have been performed to explore other common pathways between arenes and alkenes, such as C-H alkenylation and hydroarylation. A comparison of the amide extrusion and ß-H elimination steps established the following reactivity sequence of the leaving groups: protonated amide group > ß-H group > unprotonated amide group. The suppression of hydroarylation was attributed to the sluggishness of the Ru-C protonation step as compared to the amide extrusion step. This study can unveil factors favoring the C-H allylation reaction.

Tunnelling assisted hydrogen elimination mechanisms of FeCl3/TEMPO.

Metal-TEMPO hybrids are a family of novel and promising catalysts for aerobic oxidation of alcohols, yet the underlying mechanisms have not been understood theoretically. Using density functional theory, we probe the hydrogen abstraction mechanisms of FeCl3/TEMPO on two characteristic substrates, 9,10-dihydroanthracene and benzyl alcohol. We found that the low spin state of FeCl3/TEMPO is more favourable, and that the N atom is the preferred hydrogen acceptor. Moreover, dispersion interactions assist the reaction, as well as nuclear tunnelling, which even at room temperature can speed up the process by almost two orders of magnitude. We also predict that pronounced kinetic isotope effects (KIE) could be observed due to tunnelling. Our findings provide insights into improving the substrate scope and the development of new transformations for the FeCl3/TEMPO system.

Changes in microglia during drug treatment of stroke.

Microglia are the main immune cells in the brain and the first defense barrier of the nervous system. Microglia play a complex role in the process of stroke. A growing number of studies focus on the mechanism of action of drugs functions and how to regulate microglia. Therefore, we talk about the pathophysiological mechanisms of stroke and elaborate on the microglia signaling pathways of drug action in stroke models and how these drugs play a role in stroke treatment in this review. Understanding how drugs modulate proinflammatory and anti-inflammatory responses of microglia may be critical to implementing therapeutic strategies using immune interventions in stroke.

Emerging Roles of Energy Metabolism in Ferroptosis Regulation of Tumor Cells.

Ferroptosis is a new form of regulated cell death, which is characterized by the iron-dependent accumulation of lethal lipid peroxides and involved in many critical diseases. Recent reports revealed that cellular energy metabolism activities such as glycolysis, pentose phosphate pathway (PPP), and tricarboxylic acid cycle are involved in the regulation of key ferroptosis markers such as reduced nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), and reactive oxygen species (ROS), therefore imposing potential regulatory roles in ferroptosis. Remarkably, tumor cells can activate adaptive metabolic responses to inhibit ferroptosis for self-preservation such as the upregulation of glycolysis and PPP. Due to the rapid proliferation of tumor cells and the intensified metabolic rate, tumor energy metabolism has become a target for disrupting the redox homeostasis and induce ferroptosis. Based on these emerging insights, regulatory impact of those-tumor specific metabolic aberrations is systematically characterized, such as rewired glucose metabolism and metabolic compensation through glutamine utilization on ferroptosis and analyzed the underlying molecular mechanisms. Additionally, those ferroptosis-based therapeutic strategies are also discussed by exploiting those metabolic vulnerabilities, which may open up new avenues for tumor treatment in a clinical context.

Drug-induced erythroderma in patients with acquired immunodeficiency syndrome.

BACKGROUND: To explore the clinical manifestations, diagnosis, and treatment of patients with acquired immunodeficiency syndrome (AIDS) complicated with drug-induced erythroderma. METHODS: The clinical data of 12 AIDS patients with drug-induced erythroderma in our hospital were retrospectively analyzed. The general information, offending medications, complications, modified severity-of-illness score for toxic epidermal necrolysis (SCORTEN) scores, and disease outcome spectrums were analyzed. RESULTS: Drug-induced erythroderma was mostly caused by antiviral drugs, antituberculosis drugs, antibiotics, traditional Chinese medicine, and immune checkpoint inhibitors. The spectrum of sensitizing drugs was broad, the clinical situation was complex, and infections were common. The affected areas were greater than 40% body surface area in all patients. The modified SCOTERN score averaged 3.01±0.99. All patients were treated with glucocorticoids, and nine patients were treated with intravenous immunoglobulin (IVIG) pulse therapy at the same time. The average time to effectiveness was 7.08±2.23 days, and the average hospital stay was 17.92±8.46 days. Eleven patients were cured, and one patient died of secondary multiple infections, who had a modified SCORTEN score of 5 points. The mortality rate in this study was 8.3%. CONCLUSIONS: The clinical situation of AIDS patients with drug-induced erythroderma in hospitalized patients is complex and the co-infection rate is high. The use of modified SCORTEN score may objectively and accurately assess the conditions, and the use of glucocorticoid combined with IVIG therapy may improve the prognosis.