Construction of Highly Porous and Robust Hydrogen-Bonded Organic Framework for High-Capacity Clean Energy Gas Storage.

Development of highly porous and robust HOFs for high-pressure methane and hydrogen storage remains a grand challenge due to the fragile nature of hydrogen bonds. Herein, we report a strategy of constructing double-walled framework to target highly porous and robust HOF (ZJU-HOF-5a) for extraordinary CH4 and H2 storage. ZJU-HOF-5a features a minimized twofold interpenetration with double-walled structure, in which multiple supramolecular interactions are existed between the interpenetrated walls. This structural configuration can notably enhance the framework robustness while maintaining its high porosity, affording one of the highest gravimetric and volumetric surface areas of 3102 m2 g-1 and 1976 m2 cm-3 among the reported HOFs so far. ZJU-HOF-5a exhibits an extremely high volumetric H2 uptake of 43.6 g L-1 at 77 K/100 bar and working capacity of 41.3 g L-1 under combined swing conditions, and also impressive methane storage performance with a 5-100 bar working capacity of 187 (or 159) cm3 cm-3 at 270 K (or 296 K). SCXRD studies on CH4-loaded ZJU-HOF-5a reveal that abundant supramolecular binding sites combined with ultrahigh porosities account for its high CH4 storage capacities. Combined with high stability, super-hydrophobicity, and easy-recovery, ZJU-HOF-5a is placed among the most promising materials for H2 and CH4 storage applications.

Inhibition of the p62-Nrf2-GPX4 Pathway Confers Sensitivity to Butachlor-Induced Splenic Macrophage Ferroptosis.

Butachlor is widely used in agriculture around the world and therefore poses environmental and public health hazards due to persistent and poor biodegradability. Ferroptosis is a type of iron-mediated cell death controlled by glutathione (GSH) and GPX4 inhibition. P62 is an essential autophagy adaptor that regulates Keap1 to activate nuclear factor erythroid 2-related factor 2 (Nrf2), which effectively suppresses lipid peroxidation, thereby relieving ferroptosis. Here, we found that butachlor caused changes in splenic macrophage structure, especially impaired mitochondrial morphology with disordered structure, which is suggestive of the occurrence of ferroptosis. This was further confirmed by the detection of iron metabolism, the GSH system, and lipid peroxidation. Mechanistically, butachlor suppressed the protein level of p62 and promoted Keap1-mediated degradation of Nrf2, which results in decreased GPX4 expression and accelerated splenic macrophage ferroptosis. These findings suggest that targeting the p62-Nrf2-GPX4 signaling axis may be a promising strategy for treating inflammatory diseases.

AQP1 Deficiency Drives Phthalate-Induced Epithelial Barrier Disruption through Intestinal Inflammation.

Di-2-ethylhexyl phthalate (DEHP) is frequently used as a plasticizer to enhance the plasticity and durability of agricultural products, which pose adverse effects to human health and the environment. Aquaporin 1 (AQP1) is a main water transport channel protein and is involved in the maintenance of intestinal integrity. However, the impact of DEHP exposure on gut health and its potential mechanisms remain elusive. Here, we determined that DEHP exposure induced a compromised duodenum structure, which was concomitant with mitochondrial structural injury of epithelial cells. Importantly, DEHP exposure caused duodenum inflammatory epithelial cell damage and strong inflammatory response accompanied by activating the TLR4/MyD88/NF-κB signaling pathway. Mechanistically, DEHP exposure directly inhibits the expression of AQP1 and thus leads to an inflammatory response, ultimately disrupting duodenum integrity and barrier function. Collectively, our findings uncover the role of AQP1 in phthalate-induced intestinal disorders, and AQP1 could be a promising therapeutic approach for treating patients with intestinal disorders or inflammatory diseases.

Novel quinoxaline analogs as telomeric G-quadruplex ligands exert antitumor effects related to enhanced immunomodulation.

G-quadruplexes (G4s) are commonly formed in the G-rich strand of telomeric DNA. Ligands targeting telomeric G4 induce DNA damage and telomere dysfunction, which makes them potential antitumor drugs. New telomeric G4 ligands with drug-likeness are still needed to be exploited, especially with their antitumor mechanisms thoroughly discussed. In this study, a novel series of quinoxaline analogs were rationally designed and synthesized. Among them, R1 was the most promising ligand for its cytotoxic effects on tumor cells and stabilizing ability with telomeric G4. Cellular assays illustrated that R1 stabilized G4 and induced R-loop accumulation in the telomeric regions, subsequently triggering DNA damage responses, cell cycle arrest in G2/M phase, apoptosis and antiproliferation. Moreover, R1 evoked immunogenic cell death (ICD) in tumor cells, which promoted the maturation of bone marrow derived dendritic cells (BMDCs). In breast cancer mouse model, R1 exhibited a significant decrease in tumor burden through the immunomodulatory effects, including the increase of CD4+ and CD8+ T cells in tumors and cytokine levels in sera. Our research provides a new idea that targeting telomeric G4 induces DNA damage responses, causing antitumor effects both in vitro and in vivo, partially due to the enhancement of immunomodulation.

Xylarkarynone A and B: Two Bioactive Eremophilane Sesquiterpenes from Xylaria sp. HHY-2.

A new compound xylarkarynone A (1), a first reported natural product compound xylarkarynone B (2) and eight known compounds (3-10) were isolated from Xylaria sp. HHY-2. Their structures were elucidated by spectroscopic methods, DP4+ probability analyses and electronic circular dichroism (ECD) calculations. The bioactivities of isolated compounds were assayed. Compound 1 exhibited obvious activity against A549 cells with an IC50 value of 6.12±0.28 µM. Additionally, compound 1 showed moderate antifungal activities against Plectosphaerella cucumerina and Aspergillus niger with minimum inhibitory concentrations (MICs) of both 16 µg/mL, which was at the same grade with positive control nystatin. Most compounds exhibited varying degrees of inhibitory activity against P. cucumerina, indicating that Xylaria sp. has potential as inhibitors against P. cucumerina.

Supramolecular Entanglement in a Hydrogen-Bonded Organic Framework Enables Flexible-Robust Porosity for Highly Efficient Purification of Natural Gas.

The development of porous materials with flexible-robust characteristics shows some unique advantages to target high performance for gas separation, but remains a daunting challenge to achieve so far. Herein, we report a carboxyl-based hydrogen-bonded organic framework (ZJU-HOF-8a) with flexible-robust porosity for efficient purification of natural gas. ZJU-HOF-8a features a four-fold interpenetrated structure with dia topology, wherein abundant supramolecular entanglements are formed between the adjacent subnetworks through weak intermolecular hydrogen bonds. This structural configuration could not only stabilize the whole framework to establish the permanent porosity, but also enable the framework to show some flexibility due to its weak intermolecular interactions (so-called flexible-robust framework). The flexible-robust porosity of ZJU-HOF-8a was exclusively confirmed by gas sorption isotherms and single-crystal X-ray diffraction studies, showing that the flexible pore pockets can be opened by C3H8 and n-C4H10 molecules rather by C2H6 and CH4. This leads to notably higher C3H8 and n-C4H10 uptakes with enhanced selectivities than C2H6 over CH4 under ambient conditions, affording one of the highest n-C4H10/CH4 selectivities. The gas-loaded single-crystal structures coupled with theoretical simulations reveal that the loading of n-C4H10 can induce an obvious framework expansion along with pore pocket opening to improve n-C4H10 uptake and selectivity, while not for C2H6 adsorption. This work suggests an effective strategy of designing flexible-robust HOFs for improving gas separation properties.

Prognostic value of GLIM-defined malnutrition in combination with hand-grip strength or gait speed for the prediction of postoperative outcomes in gastric cancer patients with cachexia.

BACKGROUND: Cancer cachexia is associated with impaired functional and nutritional status and worse clinical outcomes. Global Leadership Initiative in Malnutrition (GLIM) consensus recommended the application of GLIM criteria to diagnose malnutrition in patients with cachexia. However, few previous study has applied the GLIM criteria in patients with cancer cachexia. METHODS: From July 2014 to May 2019, patients who were diagnosed with cancer cachexia and underwent radical gastrectomy for gastric cancer were included in this study. Malnutrition was diagnosed using the GLIM criteria. Skeletal muscle index was measured using abdominal computed tomography (CT) images at the third lumbar vertebra (L3) level. Hand-grip strength and 6-meters gait speed were measured before surgery. RESULTS: A total of 356 patients with cancer cachexia were included in the present study, in which 269 (75.56%) were identified as having malnutrition based on the GLIM criteria. GLIM-defined malnutrition alone did not show significant association with short-term postoperative outcomes, including complications, costs or length of postoperative hospital stays. The combination of low hand-grip strength or low gait speed with GLIM-defined malnutrition led to a significant predictive value for these outcomes. Moreover, low hand-grip strength plus GLIM-defined malnutrition was independently associated with postoperative complications (OR 1.912, 95% CI 1.151-3.178, P = 0.012). GLIM-defined malnutrition was an independent predictive factor for worse OS (HR 2.310, 95% CI 1.421-3.754, P = 0.001) and DFS (HR 1.815, 95% CI 1.186-2.779, P = 0.006) after surgery. The addition of low hand-grip strength or low gait speed to GLIM-defined malnutrition did not increase its predictive value for survival. CONCLUSION: GLIM-defined malnutrition predicted worse long-term survival in gastric cancer patients with cachexia. Gait speed and hand-grip strength added prognostic value to GLIM-defined malnutrition for the prediction of short-term postoperative outcomes, which could be incorporated into preoperative assessment protocols in patients with cancer cachexia.

Combination Therapy with a TLR7 Agonist and a BRD4 Inhibitor Suppresses Tumor Growth via Enhanced Immunomodulation.

JQ-1 is a typical BRD4 inhibitor with the ability to directly fight tumor cells and evoke antitumor immunity via reducing the expression of PD-L1. However, problems arise with the development of JQ-1 in clinical trials, such as marked lymphoid and hematopoietic toxicity, leading to the investigation of combination therapy. SZU-101 is a TLR7 agonist designed and synthesized by our group with potent immunostimulatory activity. Therefore, we hypothesized that combination therapy of SZU-101 and JQ-1 would target innate immunity and adaptive immunity simultaneously, to achieve a better antitumor efficacy than monotherapy. In this study, the repressive effects of the combination administration on tumor growth and metastasis were demonstrated in both murine breast cancer and melanoma models. In 4T1 tumor-bearing mice, i.t. treatment with SZU-101 in combination with i.p. treatment with JQ-1 suppressed the growth of tumors at both injected and uninjected sites. Combination therapy increased M1/M2 ratio in TAMs, decreased PD-L1 expression and promoted the recruitment of activated CD8+ T cells in the TME. In summary, the improved therapeutic efficacy of the novel combination therapy appears to be feasible for the treatment of a diversity of cancers.

Programmed fluorine binding engineering in anion-pillared metal-organic framework for record trace acetylene capture from ethylene.

Porous physisorbents are attractive candidates for selective capture of trace gas or volatile compounds due to their low energy footprints. However, many physisorbents suffer from insufficient sorbate-sorbent interactions, resulting in low uptake or inadequate selectivity when gases are present at trace levels. Here, we report a strategy of programmed fluorine binding engineering in anion-pillared metal-organic frameworks to maximize C2H2 binding affinity for benchmark trace C2H2 capture from C2H4. A robust material (ZJU-300a) was elaborately designed to provide multiple-site fluorine binding model, resulting in an ultrastrong C2H2 binding affinity. ZJU-300a exhibits a record-high C2H2 uptake of 3.23 millimoles per gram (at 0.01 bar and 296 kelvin) and one of the highest C2H2/C2H4 selectivity (1672). The adsorption binding of C2H2 and C2H4 was visualized by gas-loaded ZJU-300a structures. The separation capacity was confirmed by breakthrough experiments for 1/99 C2H2/C2H4 mixtures, affording the maximal dynamic selectivity (264) and C2H4 productivity of 436.7 millimoles per gram.

Novel phenanthrene imidazoles as telomeric G-quadruplex ligands trigger potent immunogenic cell death in triple-negative breast cancer.

Immunogenic cell death (ICD) is a typical type of regulated cell demise, and ICD inducers stimulate the immune responses against dead-cell antigens and exert specific antitumor effects. G-quadruplex (G4) binders targeting the telomeres lead to DNA damage response (DDR) and the potential of harnessing the immune system for cancer therapy. However, the immunostimulatory effects of G4 ligands in cancer cells are still seldomly determined. In this study, we rationally designed and synthesized a series of novel phenanthrene imidazoles targeting telomeric G4. Among them, PI-2 was identified as the most promising ligand with high cytotoxicity, cellular uptake efficiency and G4-interacting ability. Cellular studies indicated that PI-2 inhibited the proliferation and migration of both human and mouse triple-negative breast cancer (TNBC) cells. PI-2 triggered the occurrence of DDR and ICD, where the related pathways were further decided. In vivo experiments displayed that PI-2-treated dying cells could be an effective vaccination to reduce tumor burden and promote the infiltration of CD8+ and CD4+ T cells to the tumor microenvironment (TME). To our knowledge, it is the first time to report a DDR-targeted G4 ligand with ICD-inducing ability in immunocompetent animals, which may provide new insights for the development of promising G4-based immunochemotherapeutic agents.

Microencapsulation of Lead-Halide Perovskites in an Oil-in-Fluorine Emulsion for Cell Imaging.

The superior optical properties of lead-halide perovskites (LHPs) inspired significant research in cell imaging applications; many encapsulating processes have improved perovskite stabilities with comparable biosafety. Herein, facile solvent evaporation encapsulation based on an oil-in-fluorine emulsion for aqueous-stable and extremely nontoxic LHP microcapsules is described. Perfluorooctane dispersed the emulsifier fluorocarbon surfactant to form a continuous fluorine phase, while LHPs and polymethylmethacrylate (PMMA) were dispersed in 1,2-dichloroethane, then emulsified in the fluorine phase to form an oil-in-fluorine emulsion. CsPbBr3 microcapsules with a dense PMMA shell that protect fragile CsPbBr3 from the external environment and inhibit lead ion release were obtained after solvent evaporation. The CsPbBr3 microcapsules not only retained 91% of fluorescence intensity after exposure to water for 30 d but also possess extremely low cytotoxicity for MCF-7 cells. After exposure to 2 mg/mL of CsPbBr3 microcapsules for 48 h, the cell viability remained >90%. The intracellular uptake of CsPbBr3 microcapsules indicates its potential use in cell imaging.

Non-fused imidazole-biphenyl analogs repress triple-negative breast cancer growth by mainly stabilizing the c-MYC G-quadruplex via a multi-site binding mode.

As oncogene c-MYC is abnormally expressed during TNBC pathogenesis, stabilizing its promoter G-quadruplex (G4), which may thus inhibit c-MYC expression and promote DNA damage, may be a potential anti-TNBC strategy. However, large quantities of potential G4-forming sites exist in the human genome, which represents a potential drug selectivity problem. In order to achieve better recognition for c-MYC G4, we herein presented a new approach of designing small-molecule ligands by linking tandem aromatic rings with the c-MYC G4 selective binding motifs. Thus, a series of non-fused, conformation-tunable imidazole-biphenyl analogs were designed and synthesized. Among them, the optimal ligand appeared more effective on stabilizing c-MYC G4 than other types of G4s possibly through an adaptive, multi-site binding mode involved of end-stacking, groove-binding and loop-interacting. Then, the optimal ligand exerted good inhibitory activity on c-MYC expression and induced remarkable DNA damage, leading to the occurrence of G2/M phase arrest, apoptosis and autophagy. Furthermore, the optimal ligand exhibited potent antitumor effects in a TNBC xenograft tumor model. To sum up, this work offers new insights for the development of selective c-MYC G4 ligands against TNBC.

Hexavalent chromium causes centrosome amplification by inhibiting the binding between TMOD2 and NPM2.

BACKGROUND: Hexavalent chromium can promote centrosome amplification (CA) as well as tumorigenesis. Since CA can lead to tumorigenesis, it is plausible that the chromium promotes the development of cancer via CA. In the present study, we investigated the signaling pathways of the chromium-induced CA. RESULTS: Our results showed that sub-toxic concentration of chromium was able to cause CA in HCT116 cells, and decrease the expression of TMOD2 and NPM2. Furthermore, TMOD2 and NPM2 interacted to each other via their C-terminal and the N-terminal, respectively, which was inhibited by the chromium. Overexpression of TMOD2 and NPM2 increased their binding and significantly attenuated the CA. Moreover, TMOD2 and NPM2 were co-localized with the centrosomes. The chromium inhibited the centrosomeal localization of NPM2, which was reversed by the overexpression of TMOD2, C-terminal of TMOD2, but not the N-terminal of NPM2. CONCLUSION: Our results suggest that the chromium induces CA via inhibiting the binding between TMOD2 and NPM2 as well as the dissociation of NPM2 from centrosomes.

Complete mitochondrial genome of a Eurytopic midge, Polypedilum nubifer (Diptera: Chironomidae).

The complete mitochondrial genome of Polypedilum nubifer was sequenced and annotated, and its general features and base composition were analyzed. The mitogenome was 15,896 bp long, comprising 13 protein-coding genes, 22 transport RNA genes, 2 ribosomal RNA genes, and 1 control region. The phylogenetic relationships based on the concatenated nucleotide sequences of 17 metagenomes from families Chironomidae, Ceratopogonidae, and Simuliidae were reconstructed. According to the phylogenetic topologies, P. nubifer was closely related to (P. unifascium + P. vanderplanki) in the maximum likelihood tree.

Immobilization of Lewis Basic Sites into a Stable Ethane-Selective MOF Enabling One-Step Separation of Ethylene from a Ternary Mixture.

Purification of C2H4 from a ternary C2H2/C2H6/C2H4 mixture by one-step adsorption separation is of prime importance but challenging in the petrochemical industry; however, effective strategies to design high-performance adsorbents are lacking. We herein report for the first time the incorporation of Lewis basic sites into a C2H6-selective MOF, enabling efficient one-step production of polymer-grade C2H4 from ternary mixtures. Introduction of amino groups into highly stable C2H6-selective UiO-67 can not only partition large pores into smaller cagelike pockets to provide suitable pore confinement but also offer additional binding sites to simultaneously enhance C2H2 and C2H6 adsorption capacities over C2H4. The amino-functionalized UiO-67-(NH2)2 thus exhibits exceptionally high C2H2 and C2H6 uptakes as well as benchmark C2H2/C2H4 and C2H6/C2H4 selectivities, surpassing all of the C2H2/C2H6-selective materials reported so far. Theoretical calculations combined with in situ infrared spectroscopy indicate that the synergetic effect of suitable pore confinement and functional surfaces decorated with amino groups provides overall stronger multipoint van der Waals interactions with C2H2 and C2H6 over C2H4. The exceptional performance of UiO-67-(NH2)2 was evidenced by breakthrough experiments for C2H2/C2H6/C2H4 mixtures under dry and wet conditions, providing a remarkable C2H4 productivity of 0.55 mmol g-1 at ambient conditions.

Tetrandrine alleviates silicosis by inhibiting canonical and non-canonical NLRP3 inflammasome activation in lung macrophages.

Silicosis caused by inhalation of silica particles leads to more than ten thousand new occupational exposure-related deaths yearly. Exacerbating this issue, there are currently few drugs reported to effectively treat silicosis. Tetrandrine is the only drug approved for silicosis treatment in China, and despite more than decades of use, its efficacy and mechanisms of action remain largely unknown. Here, in this study, we established silicosis mouse models to investigate the effectiveness of tetrandrine of early and late therapeutic administration. To this end, we used multiple cardiopulmonary function test, as well as markers for inflammation and fibrosis. Moreover, using single cell RNA sequencing and transcriptomics of lung tissue and quantitative microarray analysis of serum from silicosis and control mice, our results provide a novel description of the target pathways for tetrandrine. Specifically, we found that tetrandrine attenuated silicosis by inhibiting both the canonical and non-canonical NLRP3 inflammasome pathways in lung macrophages. Taken together, our work showed that tetrandrine yielded promising results against silicosis-associated inflammation and fibrosis and further lied the groundwork for understanding its molecular targets. Our results also facilitated the wider adoption and development of tetrandirne, potentially accelerating a globally accepted therapeutic strategy for silicosis.

A Rod-Packing Hydrogen-Bonded Organic Framework with Suitable Pore Confinement for Benchmark Ethane/Ethylene Separation.

For the separation of ethane from ethylene, it remains challenging to target both high C2 H6 adsorption and selectivity in a C2 H6 -selective material. Herein, we report a reversible solid-state transformation in a labile hydrogen-bonded organic framework to generate a new rod-packing desolvated framework (ZJU-HOF-1) with suitable cavity spaces and functional surfaces to optimally interact with C2 H6 . ZJU-HOF-1 thus exhibits simultaneously high C2 H6 uptake (88 cm3 g-1 at 0.5 bar and 298 K) and C2 H6 /C2 H4 selectivity (2.25), which are significantly higher than those of most top-performing materials. Theoretical calculations revealed that the cage-like cavities and functional sites synergistically "match" better with C2 H6 to provide stronger multipoint interactions with C2 H6 than C2 H4 . In combination with its high stability and ultralow water uptake, this material can efficiently capture C2 H6 from 50/50 C2 H6 /C2 H4 mixtures in ambient conditions under 60 % RH, providing a record polymer-grade C2 H4 productivity of 0.98 mmol g-1 .