IL-13Rα2/TGF-ß bispecific CAR-T cells counter TGF-ß-mediated immune suppression and potentiate anti-tumor responses in glioblastoma.

BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapies targeting glioblastoma (GBM)-associated antigens such as interleukin-13 receptor subunit alpha-2 (IL-13Rα2) have achieved limited clinical efficacy to date, in part due to an immunosuppressive tumor microenvironment (TME) characterized by inhibitory molecules such as transforming growth factor-beta (TGF-ß). The aim of this study was to engineer more potent GBM-targeting CAR-T cells by countering TGF-ß-mediated immune suppression in the TME. METHODS: We engineered a single-chain, bispecific CAR targeting IL-13Rα2 and TGF-ß, which programs tumor-specific T cells to convert TGF-ß from an immunosuppressant to an immunostimulant. Bispecific IL-13Rα2/TGF-ß CAR-T cells were evaluated for efficacy and safety against both patient-derived GBM xenografts and syngeneic models of murine glioma. RESULTS: Treatment with IL-13Rα2/TGF-ß CAR-T cells leads to greater T-cell infiltration and reduced suppressive myeloid cell presence in the tumor-bearing brain compared to treatment with conventional IL-13Rα2 CAR-T cells, resulting in improved survival in both patient-derived GBM xenografts and syngeneic models of murine glioma. CONCLUSION: Our findings demonstrate that by reprogramming tumor-specific T-cell responses to TGF-ß, bispecific IL-13Rα2/TGF-ß CAR-T cells resist and remodel the immunosuppressive TME to drive potent anti-tumor responses in GBM.

Computational Simulation Study of Potential Inhibition of c-Met Kinase Receptor by Phenoxy pyridine Derivatives: Based on QSAR, Molecular Docking, Molecular Dynamics.

The mesenchymal-epithelial transition factor (c-Met) is a tyrosine kinase receptor protein, and excessive cell transformation can lead to cancer. Therefore, there is an urgent need to develop novel receptor tyrosine kinase inhibitors by inhibiting the activity of c-Met protein. In this study, 41 compounds are selected from the reported literature, and the interactions between phenoxy pyridine derivatives and tumor-associated proteins are systematically investigated using a series of computer-assisted drug design (CADD) methods, aiming to predict potential c-Met inhibitors with high activity. The Topomer CoMFA (q2=0.620, R2=0.837) and HQSAR (q2=0.684, R2=0.877) models demonstrate a high level of robustness. Further internal and external validation assessments show high applicability and accuracy. Based on the results of the Topomer CoMFA model, structural fragments with higher contribution values are identified and randomly combined using a fragment splice technique, result in a total of 20 compounds with predicted activities higher than the template molecules. Molecular docking results show that these compounds have good interactions and van der Waals forces with the target proteins. The results of molecular dynamics and ADMET predictions indicate that compounds Y4, Y5, and Y14 have potential as c-Met inhibitors. Among them, compound Y14 exhibits superior stability with a binding free energy of -165.18 KJ/mol. These studies provide a reference for the future design and development of novel compounds with c-Met inhibitory activity.

Evidence for genetic causality between iron homeostasis and Parkinson's disease: A two-sample Mendelian randomization study.

BACKGROUND: Parkinson's disease (PD) is a degenerative disease of the central nervous system, and its specific etiology is still unclear. At present, it is believed that the main pathological basis is the reduction of dopamine concentration in the brain striatum. Although many previous studies have believed that iron as an important nutrient element participates in the occurrence and development of PD, whether there is a causal correlation between total iron binding capacity(TIBC), transferring saturation(TSAT), ferritin and serum iron in iron homeostasis indicators and PD, there has been a lack of effective genetic evidence. METHODS: We used Mendelian randomization (MR) as an analytical method to effectively evaluate the genetic association between exposure and outcome, based on the largest genome-wide association study (GWAS) data to date. By using randomly assigned genetic instrumental variables (SNPs, Single Nucleotide Polymorphisms) that are not affected by any causal relationship, we effectively evaluated the causal relationship between iron homeostasis indicators and PD while controlling for confounding factors. RESULTS: By coordinated analysis of 86 SNPs associated with iron homeostasis markers and 12,858,066 SNPs associated with PD, a total of 56 SNPs were finally screened for genome-wide significance of iron homeostasis associated with PD. The results of inverse variance weighting(IVW) analysis suggested that iron（ ß = - 0.524; 95%cl=-0.046 to -0.002; P=0.032) was considered to have a genetic causal relationship with PD. Cochran's Q, Egger intercept and MR-PRESSO global tests did not detect the existence of heterogeneity and pleiotropy (P>0.05). Mr Steiger directionality test further confirmed our estimation of the potential causal direction of iron and PD (P=0.001). In addition, TIBC (ß=-0.142; 95%Cl=-0.197-0.481; P=0.414), TSAT (ß=-0.316; 95%Cl=-0.861-0.229; P=0.255), and ferritin (ß=-0.387; 95%Cl=-1.179-0.405; P=0.338) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). In addition, TIBC (ß=-0.142; 95%Cl=-0.197-0.481; P=0.414), TSAT (ß=-0.316; 95%Cl=-0.861-0.229; P=0.255), and ferritin (ß=-0.101; 95%Cl=--0.987 to -0.405; P=0.823) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). TIBC (P=0.008), TSAT (P=0.000) and ferritin (P=0.013) were all consistent with the estimation of MR Steiger directivity test. CONCLUSION: Our study found that among the four iron homeostasis markers, there was a genetic causal association between serum iron and PD, and the serum iron level was negatively correlated with the risk of PD. In addition, TIBC, TSAT, ferritin had no genetic causal relationship with PD.

Tuning the Trade-Off between Ethane/Ethylene Selectivity and Adsorption Capacity within Isoreticular Microporous Metal-Organic Frameworks by Linker Fine-Fluorination.

The pore dimension and surface property directly dictate the transport of guests, endowing diverse gas selective adsorptions to porous materials. It is highly relevant to construct metal-organic frameworks (MOFs) with designable functional groups that can achieve feasible pore regulation to improve their separation performances. However, the role of functionalization in different positions or degrees within framework on the separation of light hydrocarbon has rarely been emphasized. In this context, four isoreticular MOFs (TKL-104-107) bearing dissimilar fluorination are rationally screened out and afforded intriguing differences in the adsorption behavior of C2 H6 and C2 H4 . Ortho-fluoridation of carboxyl allows TKL-105-107 to exhibit enhanced structural stabilities, impressive C2 H6 adsorption capacities (>125 cm3 g-1 ) and desirable inverse selectivities (C2 H6 over C2 H4 ). The more modified ortho-fluorine group and meta-fluorine group of carboxyl have improved the C2 H6 /C2 H4 selectivity and adsorption capacity, respectively, and the C2 H6 /C2 H4 separation potential can be well optimized via linker fine-fluorination. Meanwhile, dynamic breakthrough experiments proved that TKL-105-107 can be used as highly efficient C2 H6 -selective adsorbents for C2 H4 purification. This work highlights that the purposeful functionalization of pore surfaces facilitates the assembly of highly efficient MOF adsorbents for specific gas separation.

Construction of CeRNA regulatory network based on WGCNA reveals diagnosis biomarkers for colorectal cancer.

BACKGROUND: Colorectal cancer is the third most common cause of death among cancers in the world. Although improvements in various treatments have greatly improved the survival time of colorectal cancer patients, since colorectal cancer is often at an advanced stage when diagnosed, the prognosis of patients is still very poor. Since the ceRNA regulatory network was proposed in 2011, it has greatly promoted the study of the molecular mechanism of colorectal cancer occurrence and development. OBJECTIVE: Exploring the new molecular mechanism of colorectal cancer occurrence and development and providing new targets for the diagnosis and treatment of colorectal cancer. METHOD: We analyzed the RNA-seq data of CRC from TCGA, such as differential expression analysis, weighted gene co-expression network analysis (WGCNA) and construction of ceRNA regulatory network. RESULTS: We constructed a ceRNA network using RNA-seq data of CRC from TCGA. In the ceRNA regulatory network, 19 hub molecules with significant prognostic effects were ultimately identified, including 8 lncRNAs, 2 mRNAs and 9 miRNAs. These hub molecules constitute the lncRNA-miRNA, miRNA-mRNA or lncRNA-miRNA-mRNA axis. CONCLUSION: In this article, some new ceRNA regulatory axes have been discovered, which may potentially disclose new molecular mechanisms for the occurrence and development of colorectal cancer, thereby providing an important blueprint for the treatment and prognosis assessment of CRC patients.

Trace removal of benzene vapour using double-walled metal-dipyrazolate frameworks.

In principle, porous physisorbents are attractive candidates for the removal of volatile organic compounds such as benzene by virtue of their low energy for the capture and release of this pollutant. Unfortunately, many physisorbents exhibit weak sorbate-sorbent interactions, resulting in poor selectivity and low uptake when volatile organic compounds are present at trace concentrations. Herein, we report that a family of double-walled metal-dipyrazolate frameworks, BUT-53 to BUT-58, exhibit benzene uptakes at 298 K of 2.47-3.28 mmol g-1 at <10 Pa. Breakthrough experiments revealed that BUT-55, a supramolecular isomer of the metal-organic framework Co(BDP) (H2BDP = 1,4-di(1H-pyrazol-4-yl)benzene), captures trace levels of benzene, producing an air stream with benzene content below acceptable limits. Furthermore, BUT-55 can be regenerated with mild heating. Insight into the performance of BUT-55 comes from the crystal structure of the benzene-loaded phase (C6H6@BUT-55) and density functional theory calculations, which reveal that C-H···X interactions drive the tight binding of benzene. Our results demonstrate that BUT-55 is a recyclable physisorbent that exhibits high affinity and adsorption capacity towards benzene, making it a candidate for environmental remediation of benzene-contaminated gas mixtures.

Uncovering the mechanism of the Shenzhi Jiannao formula against vascular dementia using a combined network pharmacology approach and molecular biology.

BACKGROUND: Shenzhi Jiannao formula (SZJNF) is a herbal prescription which is used for detoxification, dredging collaterals, and activating blood circulation and Qi flow in traditional Chinese medicine. SZJNF is a clinical effective prescription for the treatment of vascular dementia (VD) first formulated based on the classical theory of traditional Chinese medicine, but its anti-VD mechanism remains ambiguous. PURPOSE: The aim of this study was to elucidate the multi-target mechanisms of SZJNF against VD using a network pharmacology approach and verify its effects through biological experiments. STUDY DESIGN AND METHODS: We utilized network pharmacology-based prediction and molecular docking techniques to uncover the potential micro-mechanism of SZJNF against VD. We identified active components and potential targets, and performed network analysis, functional annotation, and pathway enrichment analysis. Subsequently, glutamate-induced PC12 cells and VD rats were used to verify the molecular mechanisms of SZJNF. RESULTS: Seventeen active compounds were identified in SZJNF rat plasma; moreover, 773 predicted targets and 1544 VD-related targets were found. Various networks, including the PPI, herb-compound-target, and compound-target-pathway network were constructed. A total of 188 shared targets were identified by network topological analysis, which were closely associated to the anti-VD effects of SZJNF. They were also enriched in various biological processes through hypoxia reaction, promotion of cell proliferation, inhibition of apoptosis, neuroactive ligand-receptor interaction, and calcium signaling pathway, as evaluated by the analysis of advanced functions and pathways. SZJNF components docked well with the key targets. Treatment with SZJNF promoted cell proliferation, ameliorated apoptosis and oxidative stress injury, and improved neurological and cognitive abilities. CONCLUSION: This study comprehensively demonstrated the multi-target mechanisms of SZJNF in VD using network pharmacology and molecular biology experiments. This provides evidence for further mechanistic studies and for the development of SZJNF as a potential treatment for patients with VD.

HMGB1 signaling-regulated endoplasmic reticulum stress mediates intestinal ischemia/reperfusion-induced acute renal damage.

BACKGROUND: Ischemia/reperfusion of the intestine often leads to distant organ injury, but the mechanism of intestinal ischemia/reperfusion-induced renal dysfunction is still not clear. The present study aimed to investigate the mechanisms of acute renal damage after intestinal ischemia/reperfusion challenge and explore the role of released high-mobility group box-1 in this process. METHODS: Intestinal ischemia/reperfusion was induced in male Sprague-Dawley rats by clamping the superior mesenteric artery for 1.5 hours. At different reperfusion time points, anti-high-mobility group box-1 neutralizing antibodies or ethyl pyruvate were administered to neutralize or inhibit circulating high-mobility group box-1, respectively. RESULTS: Significant kidney injury was observed after 6 hours of intestinal reperfusion, as indicated by increased serum levels of urea nitrogen and creatinine, increased expression of neutrophil gelatinase-associated lipocalin, interleukin-6, and MIP-2, and enhanced cell apoptosis, as indicated by cleaved caspase 3 levels in renal tissues. The levels of phosphorylated eIF2ɑ, activating transcription factor 4, and C/EBP-homologous protein (CHOP) were markedly elevated, indicating the activation of endoplasmic reticulum stress in the impaired kidney. High-mobility group box-1 translocated to cytoplasm in the intestine and serum concentrations of high-mobility group box-1 increased notably during the reperfusion phase. Both anti-high-mobility group box-1 antibodies and ethyl pyruvate treatment significantly reduced serum high-mobility group box-1 concentrations, attenuated endoplasmic reticulum stress in renal tissue and inhibited the development of renal damage. Moreover, the elevated expression of receptor for advanced glycation end products in the kidneys after intestinal ischemia/reperfusion was abrogated after high-mobility group box-1 inhibition. CONCLUSION: These results suggested that high-mobility group box-1 signaling regulated endoplasmic reticulum stress and promoted intestinal ischemia/reperfusion-induced acute kidney injury. High-mobility group box-1 neutralization/inhibition might serve as a pharmacological intervention strategy for these pathophysiological processes.

Enhanced Gas Uptake in a Microporous Metal-Organic Framework via a Sorbate Induced-Fit Mechanism.

Physical adsorption of gas molecules in microporous materials is an exothermic process, with desorption entropy driving a decrease in uptake with temperature. Enhanced gas sorption with increasing temperature is rare in porous materials and is indicative of sorbate initiated structural change. Here, sorption of C2H6, C3H6, and C3H8 in a flexible microporous metal-organic framework (MOF) {Cu(FPBDC)]·DMF}n (NKU-FlexMOF-1) (H2FPBDC = 5-(5-fluoropyridin-3-yl)-1,3-benzenedicarboxylic acid) that increases with rising temperature over a practically useful temperature and pressure range is reported along with other small molecule and hydrocarbon sorption isotherms. Single X-ray diffraction studies, temperature-dependent gas sorption isotherms, in situ and variable temperature powder X-ray diffraction experiments, and electronic structure calculations were performed to characterize the conformation-dependent sorption behavior in NKU-FlexMOF-1. In total, the data supports that the atypical sorption behavior is a result of loading-dependent structural changes in the flexible framework of NKU-FlexMOF-1 induced by sorbate-specific guest-framework interactions. The sorbates cause subtle adaptations of the framework distinct to each sorbate providing an induced-fit separation mechanism to resolve chemically similar hydrocarbons through highly specific sorbate-sorbent interactions. The relevant intermolecular contacts are shown to be predominantly repulsion and dispersion interactions. NKU-FlexMOF-1 is also found to be stable in aqueous solutions including toleration of pH changes. These experiments demonstrate the potential of this flexible microporous MOF for cost and energy efficient industrial hydrocarbon separation and purification processes. The efficacy for the separation of C3H6/C3H8 mixtures is explicitly demonstrated using NKU-FlexMOF-1a (i.e., activated NKU-FlexMOF-1) for a particular useful temperature range.

Soft Porous Crystal Based upon Organic Cages That Exhibit Guest-Induced Breathing and Selective Gas Separation.

Soft porous crystals (SPCs) that exhibit stimuli-responsive dynamic sorption behavior are attracting interest for gas storage/separation applications. However, the design and synthesis of SPCs is challenging. Herein, we report a new type of SPC based on a [2 + 3] imide-based organic cage (NKPOC-1) and find that it exhibits guest-induced breathing behavior. Various gases were found to induce activated NKPOC-1 crystals to reversibly switch from a "closed" nonporous phase (α) to two porous "open" phases (ß and γ). The net effect is gate-opening behavior induced by CO2 and C3 hydrocarbons. Interestingly, NKPOC-1-α selectively adsorbs propyne over propylene and propane under ambient conditions. Thus, NKPOC-1-α has the potential to separate binary and ternary C3 hydrocarbon mixtures, and the performance was subsequently verified by fixed bed column breakthrough experiments. In addition, molecular dynamics calculations and in situ X-ray diffraction experiments indicate that the gate-opening effect is accompanied by reversible structural transformations. The adsorption energies from molecular dynamics simulations aid are consistent with the experimentally observed selective adsorption phenomena. The understanding gained from this study of NKPOC-1 supports the further development of SPCs for applications in gas separation/storage because SPCs do not inherently suffer from the recyclability problems often encountered with rigid materials.

Structural stabilization of a metal-organic framework for gas sorption investigation.

By inserting a ligand into a reported metal-organic framework (), the reformed aggregation of triangle grids () shows enhanced stability. In addition, owing to its structural characteristic, the also reveals a certain CO2 storage ability and CO2/CH4 adsorption selectivity as expected.

A polypyridyl-pyrene based off-on Cd²âº fluorescent sensor for aqueous phase analysis and living cell imaging.

By retaining the quadrapyridyl receptor of polypyridylhexaazatriphenylene (a Cd(2+) sensor reported by us) and extending its chromophoric group with pyrene, a chemical sensor (1) was designed and synthesized in this work. This sensor exhibit selective off-on fluorescence response to Cd(2+) over other metal ions, and the detection limit is as low as 0.02 µM. The Cd(2+) sensing of 1 has high water toleration and can be carried out in the media with the water content up to 70%. Additionally, 1 was successfully applied to the in vivo imaging of intracellular Cd(2+) in living HaLa cells, and showed low cytotoxicity and cell membrane permeability in these experiments. These results suggest that 1 has potential application in the Cd(2+) analysis of environmental and biological samples.

Microporous organic polymers for gas storage and separation applications.

Microporous organic polymers (MOPs), an emerging class of functional porous materials featured with the pure organic component have been widely studied in recent years. These materials have potential uses in areas such as storage, separation, and catalysis. In this Perspective, we focused on the gas storage and separation of MOPs. The targeted design and synthesis of MOPs toward the enhancement of gas capacity and selectivity are discussed. Furthermore, special emphasis is given to the post-synthesis modification of MOPs which have been proved to be effective methods to accurately tune the desired properties.

New three-dimensional porous metal organic framework with tetrazole functionalized aromatic carboxylic Acid: synthesis, structure, and gas adsorption properties.

5-(1H-Tetrazol-1-yl)isophthalic acid (H(2)L) reacts with Cu(II) ion forming a new metal-organic framework {[CuL]·DMF·H(2)O}(∞) (1) (DMF = N,N-dimethylformamide), with a rutile-related type net topology. Compound 1 possesses a 3D structure with 1D channels that can be desolvated to yield a microporous material. Adsorption properties (N(2), H(2), O(2), CO(2), and CH(4)) of the desolvated solid [CuL] (1a) have been studied, and the results exhibit that 1a possesses fairly good capability of gas sorption for N(2), H(2), O(2), and CO(2) gases, with high selectivity ratios for O(2) over H(2) at 77 K and CO(2) over CH(4) at 195, 273, and 298 K. Furthermore, 1a has excellent O(2) uptake at 77 K and a remarkably high quantity of adsorption for CO(2) at room temperature (298 K) and atmospheric pressure, suggesting its potential applications in gas separation or purification.

Copper(II), cobalt(II), and nickel(II) complexes with a bulky anthracene-based carboxylic ligand: syntheses, crystal structures, and magnetic properties.

To systematically explore the influence of the bulky aromatic ring skeleton with a large conjugated pi-system on the structures and properties of their complexes, six CuII, CoII, and NiII complexes with the anthracene-based carboxylic ligand anthracene-9-carboxylic acid (HL1), were synthesized and characterized, sometimes incorporating different auxiliary ligands: [Cu2(L1)4(CH3OH)2](CH3OH) (1), [Cu4(L1)6(L2)4](NO3)2(H2O)2 (2), {[Cu2(L1)4(L3)](CH3OH)0.25}infinity (3), [Co2(L1)4(L4)2(micro-H2O)](CH3OH) (4), {[Co(L1)2(L5)(CH3OH)2]}infinity (5), and {[Ni(L1)2(L5)(CH3OH)2]}infinity (6) (L2 = 2,2'-bipyridine, L3 = 1,4-diazabicyclo[2.2.2]octane, L4 = 1,10-phenanthroline, and L5 = 4,4'-bipyridine). 1 has a dinuclear structure that is further assembled to form a one-dimensional (1D) chain and then a two-dimensional (2D) network by the C-H...O H-bonding and pi...pi stacking interactions jointly. 2 takes a tetranuclear structure due to the existence of the chelating L2 ligand. 3 possesses a 1D chain structure by incorporating the related auxiliary ligand L3, which is further interlinked via interchain pi...pi stacking, resulting in a three-dimensional (3D) network. 4 also has a dinuclear structure and then forms a higher-dimensional supramolecular network through intermolecular pi...pi stacking and/or C-H...pi interactions. 5 and 6 are isostructural complexes, except they involve different metal ions, showing 1D chain structures, which are also assembled into 2D networks from the different crystallographic directions by interchain pi...pi stacking and C-H...pi interactions, respectively. The results reveal that the steric bulk of the anthracene ring in HL1 plays an important role in the formation of 1-6. The magnetic properties of the complexes were investigated, and the very long intermetallic distances result in weak magnetic coupling, with the exception of 1 and 3, which adopt the typical paddle-wheel structure of copper acetate and are thus strongly coupled.