Enantiospecific Analysis of Carboxylic Acids Using Cinchona Alkaloid Dimers as Chiral Solvating Agents.

Cinchona alkaloid derivatives as Brønsted base catalysts have attracted considerable attention in the field of asymmetric catalysis. However, their potential application as chiral solvating agents has not been described. In this research, we investigated the use of the Cinchona alkaloid dimer, namely, (DHQ)2PHAL, as a chiral solvating agent for discerning various mandelic acid derivatives through 1H NMR spectroscopy. The addition of catalytic amounts of DMAP facilitated this process. Our experimental results demonstrate that dimeric (DHQ)2PHAL exhibits remarkable chiral discrimination properties regarding the diagnostic split protons of 1H NMR signals (including 24 examples, up to 0.321 ppm). Furthermore, it serves as an excellent chiral discriminating agent and provides good resolution for racemic chiral phosphoric acid as determined by 31P NMR spectroscopy. The quality of enantiodifferentiation has also been evaluated by means of the parameter "resolution (Rs)". Significantly, this class of CSAs based on (alkaloid)2linker systems with an azaaromatic linker can be directly employed, which is commercially available in an enantiopure form at very low cost and exhibits promising potential in determining the enantiopurity of α-hydroxy acids by chemoselective and biocatalytic reactions.

Polyarylisocyanides Derived from an Alkyne-Pd(II) Catalyst as Robust Alignment Media with Excellent Enantiodiscimination.

The development of chiral alignment media for measuring anisotropic NMR parameters provides an opportunity to determine the absolute configuration of chiral molecules without the need for derivatization. However, chiral alignment media with a high and robust enantiodiscriminating property for a wide range of chiral molecules are still scarce. In this study, we synthesized cholesterol-end-functionalized helical polyisocyanides from a chiral monomer using a cholesterol-based alkyne-Pd(II) initiator. These stereoregular polyisocyanides form stable and weak anisotropic lyotropic liquid crystals (LLCs) in dichloromethane systems, exhibiting highly optical activities in both single left- and right-handed helices. The preparation process of the media was straightforward, and the aligning property of the LLCs could be controlled by adjusting the concentration and temperature. Using the chiral polyisocyanides, we extracted the residual dipolar coupling for an enantiomeric pair of isopinocampheol (IPC), as well as a number of pharmaceutical molecules, demonstrating excellent enantiodiscriminating properties for a broad range of chiral compounds.

Formulation and Performance of NBR/CR-Based High-Damping Rubber Composites for Soundproof Using Orthogonal Test.

Multiple functional-material-filled nitrile butadiene rubber/chloroprene rubber (NBR/CR) acoustic composites were extensively studied and prepared. According to the orthogonal test table L25 (56), 25 groups of samples were prepared by using a low-temperature one-time rubber mixing process. With tensile strength, average transmission loss, and damping peak as indexes, the influence degree of different factors and levels on the properties of acoustic composites was quantitatively discussed and analyzed. The matrix weight analysis was employed to optimize the material formula of rubber composites, and the corresponding influence weight was given. Results showed that the acoustic composite with blending ratio of 70/30 for NBR/CR matrix had preferable mechanical and acoustic properties; adding mica powder (MP) and montmorillonite (MMT) in matrix contributed to improve all above three indexes owing to their specific lamellar structures; hollow glass beads (HGB) had a positive influence on improving acoustic property due to its hollow microcavities, however, it had a negative impact on damping property because of the smooth spherical surfaces. Accordingly, the optimal formulation was found to be NBR/CR blending ratio of 70/30, MP of 10 phr (per hundred rubber), HGB of 4 phr, and MMT of 10 phr.

Metformin Alleviates Delayed Hydrocephalus after Intraventricular Hemorrhage by Inhibiting Inflammation and Fibrosis.

Intraventricular hemorrhage (IVH) is a subtype of intracerebral hemorrhage (ICH) with high morbidity and mortality. Posthemorrhagic hydrocephalus (PHH) is a common and major complication that affects prognosis, but the mechanism is still unclear. Inflammation and fibrosis have been well established as the major causes of PHH after IVH. In this study, we aimed to investigate the effects of metformin on IVH in adult male mice and further explored the underlying molecular mechanisms of these effects. In the acute phase, metformin treatment exerted dose-dependent neuroprotective effects by reducing periependymal apoptosis and neuronal degeneration and decreasing brain edema. Moreover, high-dose metformin reduced inflammatory cell infiltration and the release of proinflammatory factors, thus protecting ependymal structure integrity and subependymal neurons. In the chronic phase, metformin administration improved neurocognitive function and reduced delayed hydrocephalus. Additionally, metformin significantly inhibited basal subarachnoid fibrosis and ependymal glial scarring. The ependymal structures partially restored. Mechanically, IVH reduced phospho-AMPK (p-AMPK) and SIRT1 expression and activated the phospho-NF-κB (p-NF-κB) inflammatory signaling pathway. However, metformin treatment increased AMPK/SIRT1 expression and lowered the protein expression of p-NF-κB and its downstream inflammation. Compound C and EX527 administration reversed the anti-inflammatory effect of metformin. In conclusion, metformin attenuated neuroinflammation and subsequent fibrosis after IVH by regulating AMPK /SIRT1/ NF-κB pathways, thereby reducing delayed hydrocephalus. Metformin may be a promising therapeutic agent to prevent delayed hydrocephalus following IVH.

Necrostatin-1 decreases necroptosis and inflammatory markers after intraventricular hemorrhage in mice.

Necrostatin-1, an inhibitor of necroptosis, can effectively inhibit necrotic apoptosis in neurological diseases, which results in the inhibition of inflammation, endoplasmic reticulum stress, and reactive oxygen species production and substantial improvement of neurological function. However, the effects of necrostatin-1 on intraventricular hemorrhage (IVH) remain unknown. In this study, we established a mouse model of IVH by injecting autologous blood into the lateral ventricle of the brain. We also injected necrostatin-1 into the lateral ventricle one hour prior to IVH induction. We found that necrostatin-1 effectively reduced the expression levels of the necroptosis markers receptor-interacting protein kinase (RIP)1, RIP3, mixed lineage kinase domain-like protein (MLKL), phosphorylated (p)-RIP3, and p-MLKL and the levels of interleukin-1ß , interleukin-6, and tumor necrosis factor-α in the surrounding areas of the lateral ventricle. However, necrostatin-1 did not reduce ependymal ciliary injury or brain water content. These findings suggest that necrostatin-1 can prevent local inflammation and microglial activation induced by IVH but does not greatly improve prognosis.

The meningeal lymphatic vessels and the glymphatic system: Potential therapeutic targets in neurological disorders.

The recent discovery of the meningeal lymphatic vessels (mLVs) and glymphatic pathways has challenged the long-lasting dogma that the central nervous system (CNS) lacks a lymphatic system and therefore does not interact with peripheral immunity. This discovery has reshaped our understanding of mechanisms underlying CNS drainage. Under normal conditions, a close connection between mLVs and the glymphatic system enables metabolic waste removal, immune cell trafficking, and CNS immune surveillance. Dysfunction of the glymphatic-mLV system can lead to toxic protein accumulation in the brain, and it contributes to the development of a series of neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. The identification of precise cerebral transport routes is based mainly on indirect, invasive imaging of animals, and the results cannot always be applied to humans. Here we review the functions of the glymphatic-mLV system and evidence for its involvement in some CNS diseases. We focus on emerging noninvasive imaging techniques to evaluate the human glymphatic-mLV system and their potential for preclinical diagnosis and prevention of neurodegenerative diseases. Potential strategies that target the glymphatic-mLV system in order to treat and prevent neurological disorders are also discussed.

Design and Synthesis of Dipeptidomimetic Isocyanonaphthalene as Enhanced-Fluorescent Chemodosimeter for Sensing Mercury Ion and Living Cells.

A novel valine-based isocyanonaphthalene (NpI) was designed and synthesized by using an easy method and enabled the selective fluorescence detection of Hg2+. The chemodosimeter can display an immediate turn-on fluorescence response (500-fold) towards target metal ions upon the Hg2+-mediated conversion of isocyano to amino within NpI. Based on this specific reaction, the fluorescence-enhancement probe revealed a high sensitivity toward Hg2+ over other common metal ions and exhibited excellent aqueous solubility, good antijamming capability, high sensitivity (detection limit: 14.2 nM), and real-time detection. The response mechanism of NpI was supported by NMR spectroscopy, MS analysis and DFT theoretical calculation using various techniques. Moreover, a dipeptidomimetic NpI probe was successfully applied to visualize intracellular Hg2+ in living cells and monitor Hg2+ in real water samples with good recoveries and small relative standard deviations.

A palladium-catalyzed sequential Heck coupling/C-C bond activation approach to oxindoles with all-carbon-quaternary centers.

Catalytic construction of oxindoles bearing all-carbon-quaternary centers attracts wide attention from the synthetic chemistry community. Herein, we report a palladium-catalyzed sequential Heck coupling/C-C bond activation of aryl halide-tethered alkenes with benzocyclobutenols affording a series of oxindole-derived compounds in good to excellent yields, as well as the preliminary enantioselectivity results.

Self-Assembly of Helical Polymers and Oligomers to Create Liquid Crystalline Alignment for Anisotropic NMR Parameters.

The measurement of anisotropic residual dipolar couplings (RDCs) parameters for the structure elucidation of organic molecules relies on suitable alignment media. Employment of self-assembled liquid crystalline systems to create anisotropic alignment can be an effective way to realize aligned samples and acquire RDCs. This Mini-review highlights the recent advances on amino acid-based helical polymers and supramolecular oligomers forming rigid, rod-like structures that aggregate into ordered liquid crystalline phases, including amino acid-based helical polyisocyanides, polyacetylenes, polypeptides, and oligopeptides assembled alignment media. The methodology for the determination of anisotropic liquid crystals is briefly discussed, and a summary of recent research progress in the enantiodifferentiation of helical polymers aligned media is followed. In addition, the self-assembled mechanism of oligopeptides and their RDCs structural analysis are also described.

B7-H3 as a Target for CAR-T Cell Therapy in Skull Base Chordoma.

OBJECTIVE: chordomas are rare bone tumors with few therapeutic options. Skull base and sacrum are the two most common origin sites. Immunotherapies are emerging as the most promising approaches to fight various cancers. This study tends to identify new cell surface targets for immunotherapeutic options of skull base chordomas. METHODS: we profiled 45 skull base chordoma clinical samples by immunohistochemistry for the expression of six CAR-Targets (PD-L1, B7-H3, B7-H4, VISTA, HER2 and HER3). In addition, we generated B7-H3 targeted CAR-T-cells and evaluated their antitumor activities in vitro. RESULTS: We found that B7-H3 was positively stained in 7 out of 45 (16%) chordoma samples and established an expression hierarchy for these antigens (B7-H3 > HER3 > PD-L1 > HER2 = VISTA = B7-H4). We then generated a B7-H3 targeted CAR vector and demonstrated that B7-H3-CAR-T-cells recognized antigen positive cells and exhibited significant antitumor effects, including suppression of tumor spheroid formation, CAR-T-cell activation and cytokine secretion. CONCLUSIONS: Our results support B7-H3 might serve as a promising target for CAR-T-cell therapies against chordomas.

Fn14-targeted BiTE and CAR-T cells demonstrate potent preclinical activity against glioblastoma.

T cell-engaging therapies involving bispecific T cell engager (BiTE) and chimeric antigen receptor T (CAR-T) cells have achieved great success in the treatment of hematological tumors. However, the paucity of ideal cell surface molecules that can be targeted on glioblastoma (GBM) partially reduces the immunotherapeutic efficacy. Recently, high expression of Fn14 has been reported in several solid tumors, so the strategy of exploiting this specific antigen for GBM immunotherapy is worth studying. Consequently, we constructed Fn14× CD3 BiTE and Fn14-specific CAR-T cells and investigated their cytotoxic activity against GBM in vitro and in vivo. First, expression of Fn14 was confirmed in glioma tissues and GBM cells. Then, we designed Fn14-specific BiTE and CAR-T cells and tested their cytotoxicity in GBM cell cultures and mouse models of GBM. Fn14 was highly expressed in GBM tissues and cell lines, while it was undetectable in normal brain samples. Fn14× CD3 BiTE, Fn14 CAR-T cells and Fn14 CAR-T/IL-15 cells were antigen-specific and highly cytotoxic, showing good antitumor activity in vitro and causing significant regression of established solid tumors in xenograft models. However, the xenografts treated with Fn14 CAR-T cells regrew, whereas xenografts treated with Fn14 CAR-T/IL-15 cells did not. IL-15 engineering augmented the antitumor activity of Fn14 CAR-T cells and resulted in significant antitumor effects similar to those of Fn14× CD3 BiTE. Our results suggest that Fn14 is an appropriate target for GBM. Anti-Fn14 BiTE and Fn14-specific CAR-T/IL-15 cells may be exciting immunotherapeutic options for malignant brain cancer.

Screening for genes and subnetworks associated with atypical teratoid/rhabdoid tumors using bioinformatics analysis.

Objectives: Atypical teratoid/rhabdoid tumors (AT/RTs) are rare, fast-growing lesions of central nervous system and their prognosis is poor. Nowadays, multimodal managements, including surgery, chemotherapy and radiation therapy are advocated; however, low survival rate and severe neurocognitive toxicity of chemotherapy as well as the irreversible long-term sequelae of irradiation in infants and young children with AT/RTs are alarming. The aim of our study is to provide valid biological information for more tailored advance therapy for these lesions.Methods: Gene expression profile of GSE94349 was downloaded from GEO database and was analyzed using limma R package. Function and enrichment analyses of DEGs were performed based on DAVID database. PPI network construction, hub gene selection and module analysis were conducted in Cytoscape software.Results: In this study, 224 up-regulated genes and 572 down-regulated genes were selected as DEGs. The up-regulated genes were mainly enriched in molecular function and cell component, which mainly included protein binding and nucleus, respectively. The down-regulated DEGs were significantly involved in cell component such as plasma membrane and integral component of membrane. Cell cycle and retrograde endocannabinoid signaling were the main KEGG pathway of up and down DEGs, respectively. CDK1, CCNA2, CDC20, TOP2A were identified as hub genes and two significant network modules were also obtained.Conclusions: Our study may help to further understand the molecular characteristics and provide more tailored targets for future treatment of AT/RTs. Hub genes CDK1, CCNA2, CDC20, TOP2A as well as cell cycle signaling pathway may be new more tailored targets for future treatment of AT/RTs.

Bioactivity and safety of B7-H3-targeted chimeric antigen receptor T cells against anaplastic meningioma.

OBJECTIVE: We conducted a first-in-human study to evaluate the bioactivity and safety of B7-H3-targeted chimeric antigen receptor (CAR) autologous T cells for treating recurrent anaplastic meningioma. METHODS: Tumor tissues from a patient with recurrent anaplastic meningioma were evaluated for B7-H3 expression. B7-H3-targeted CAR-T cells were delivered into the intracranial tumor resection cavity using an Ommaya device at a maximum dose of 1.5 × 107 cells. Magnetic resonance imaging (MRI) screening and multiple serum indexes were regularly monitored. The patient received surgical intervention after three-cycle infusions, allowing analysis for CAR-T-cell infiltration and target antigen expression in post-CAR-T therapy tumor tissues. RESULTS: Immunochemical analysis demonstrated high and homogeneous B7-H3 expression in tumor samples. MRI results indicated that the tumor near the delivery device was relatively stable compared with the rapid progression of tumors distant from the device. We found CAR-T-cell trafficking to regions of B7-H3+ tumor tissues near the device, but not to tumor tissues distant from the device. Decreased B7-H3 expression was observed near the region of CAR-T-cell infiltration after therapy. The intracavitary delivery of B7-H3-targeted CAR-T cells was well-tolerated and not associated with any toxic effects of grade 3 or higher. CONCLUSION: Our results suggested that although intracavitary administration of B7-H3-targeted CAR-T cells was safe and resulted in local bioactivity, addressing antigen loss and CAR-T-cell trafficking may further enhance the applications of B7-H3-targeted CAR-T-cell therapy.

Efficient Enantiodifferentiation of Carboxylic Acids Using BINOL-Based Amino Alcohol as a Chiral NMR Solvating Agent.

A new optically active BINOL-amino alcohol has been designed and synthesized in a good yield and applied as chiral nuclear magnetic resonance (NMR) solvating agent for enantioselective recognition. Analysis by 1H NMR spectroscopy demonstrated that it has excellent enantiodifferentiation properties toward carboxylic acids and non-steroidal anti-inflammatory drugs (14 examples). The non-equivalent chemical shifts (up to 0.641 ppm) of various mandelic acids were evaluated by the reliable peak of well-resolved 1H NMR signals. In addition, enantiomeric excesses of the ortho-chloro-mandelic acid with different enantiomeric ratio were calculated based on integration of proton well-separated splitting signals.

Azaheterocyclic diphenylmethanol chiral solvating agents for the NMR chiral discrimination of alpha-substituted carboxylic acids.

A series of small-membered heterocycle probes, so-called azaheterocycle-containing diphenylmethanol chiral solvating agents (CSAs), have been developed for NMR enantiodiscrimination. These chiral sensors were readily synthesized were inexpensive and efficiently used for the chiral analysis of alpha-substituted carboxylic acids. The sensing method was operationally simple and the processing was straightforward. Notably, we propose (S)-aziridinyl diphenylmethanol as a promising CSA, which has excellent chiral discriminating properties and offers multiple detectable possibilities pertaining to the 1H NMR signals of diagnostic split protons (including 25 examples, up to 0.194 ppm, 77.6 Hz). Its ability to detect the molecular recognition of fluorinated carboxylic acids were further investigated, with a good level of discrimination via the 19F NMR spectroscopic analysis. In addition, an accurate enantiomeric excess (ee) analysis of the p-methoxyl-mandelic acid with different optical compositions have been calculated based on the integration of well-separated proton signals.

Formulation, Characterization And Evaluation Of Curcumin- Loaded PLGA- TPGS Nanoparticles For Liver Cancer Treatment.

BACKGROUND: Liver cancer is a major health problem facing mankind. Currently, the focus of research is to improve the treatment of liver cancer using a variety of treatment options such as providing chemotherapy drugs through nanocarriers. PURPOSE: The aim of this study was to prepare a curcumin-loaded (PLGA/TPGS) NPs delivery system by the emulsification-solvent evaporation method in order to achieve synergistic antitumor activity against liver cancer. METHODS: Curcumin-loaded (PLGA/TPGS) NPs were prepared by the emulsification and solvent evaporation method. The physical and chemical characteristics of NPs such as size, morphology, and release profiles were discussed. In vitro and in vivo studies were carried out to evaluate its anti-tumor activity in target cells. RESULTS: Curcumin-loaded (PLGA/TPGS) NPs could be successfully internalized by HepG2 cells and play a synergistic role in inhibiting the growth of hepatocellular carcinoma cells. They exhibited high target organ accumulation, superior antitumor efficiency, and lower toxicity in vivo. CONCLUSION: The present study indicates that the curcumin-loaded (PLGA/TPGS) NPs provide a promising platform for the treatment of liver cancer.

A new strategy of applying modeling indicator determined method to high-level fusion for quantitative analysis.

A novel method, named as modeling indicator determined (MID) method, based on two model evaluation parameters i.e., root mean square error of prediction (RMSEP) and ratio performance deviation (RPD), is proposed to employ high-level fusion for quantitative analysis. The two MID methods of root mean square error of prediction weighted (RMSEPW) method and ratio performance deviation weighted (RPDW) method are put forward on the basis of the model evaluation indicators from the individual models. Performance of RMSEPW method and RPDW method are evaluated in terms of the predictive ability of root mean square error of prediction for fusion (RMSEPf) through the fused models. The two MID methods are applied to UV-visible (UV-vis), near infrared (NIR) and mid-infrared (MIR) spectral data of active ingredient in pesticide, and gas chromatography-mass spectrometer (GC-MS) and NIR spectral data of n-heptane in chemical complex for high-level fusion. Moreover, the results are compared with the individual methods. As a result, the overall results show that the two MID methods are promising with significant improvement of predictive performance for high-level fusion when executing quantitative analysis.

The expanding family of noncanonical regulatory cell subsets.

The overwhelming body of research on regulatory lymphocytes has focused on CD4+ CD25+ Foxp3+ T cells (regulatory T cells); however, the last 5 years have witnessed inspiring progress in our understanding of regulatory B cells, regulatory CD8+ T cells, regulatory γδ cells, and, more recently, regulatory innate lymphoid cells(ILCregs). This review focuses on these so-called noncanonical regulatory cell subsets. We primarily survey existing information on the phenotype, function, sustaining factors, and clinical value of the 4 best-characterized non-CD4 + Foxp3+ T regulatory cells. We then take a brief journey into the advances and challenges associated with next-generation sequencing technologies and the application of sequencing to the study of noncanonical regulatory cell subsets.

Microarray gene expression profiling and bioinformatics analysis reveal key differentially expressed genes in clival and sacral chordoma cell lines.

OBJECTIVE: Chordoma is a rare tumor with a certain rate of distant metastasis. Skull base and sacrum are the two most common origin sites. This study tends to identify key differentially expressed genes (DEGs) between classical clival and sacral chordomas, provide new targets for future treatment options of chordomas. METHODS: The gene expression profiles of GSE95084 and GSE68497 were downloaded from Gene Expression Omnibus database and were analyzed using the limma R package. Function and enrichment analyses of DEGs were performed based on DAVID Database. Protein-protein interaction (PPI) network was constructed using the Cytoscape based on the data collected from STRING online datasets. Hub genes selection and modules analyses of the PPI network were conducted by plugin cytoHubba and MCODE of Cytoscape software, respectively. RESULT: In total, 728 genes, including 363 up-regulated genes and 365 down-regulated genes were selected as DEGs. Notably, GO analysis showed that both up-regulated and down-regulated DEGs were mainly involved in cell component such as an integral component of the membrane, plasma membrane and extracellular exosome. DEGs were mainly enriched in pathways like Pathways in cancer, PI3K-Akt signaling pathway, Cytokine-cytokine receptor interaction. FYN, ITGB3, ACTN2 and IGF1 were identified as hub genes and they were all involved in focal adhesion signaling pathway. Furthermore, five significant network modules were obtained from the PPI network. CONCLUSION: This study helps to further understand the molecular characteristics of classic chordomas of two distinct sites. Hub genes FYN, ITGB3, ACTN2, and IGF1, as well as focal adhesion signaling pathway, would be new targets for future treatment options of chordomas.

Residual Dipolar Couplings in Structure Determination of Natural Products.

The determination of natural products stereochemistry remains a formidable task. Residual dipolar couplings (RDCs) induced by anisotropic media are a powerful tool for determination of the stereochemistry of organic molecule in solution. This review will provide a short introduction on RDCs-based methodology for the structural elucidation of natural products. Special attention is given to the current availability of alignment media in organic solvents. The applications of RDCs for structural analysis of some examples of natural products were discussed and summarized. This review provides a short introduction on RDCs-based methodology for the structural elucidation of natural products. Special attention is given to the current availability of alignment media in organic solvents. The applications of RDCs for structural analysis of some examples of natural products were discussed and summarized.