ABSTRACT
Cyclopropanes are ubiquitous in medicines, yet robust synthetic access to a wide range of sterically and electronically diverse analogs remains a challenge. To address the synthetic limitations of the most direct strategy, (2+1) cycloaddition, we sought to develop a variant that employs non-stabilized carbenes. We present herein an FeCl2-catalyzed cyclopropanation that uniquely employs aliphatic (enolizable) aldehydes as carbene precursors. A remarkably broad range of alkenes may be coupled with these non-stabilized, alkyl carbenes. This extensive scope enables the synthesis of novel classes of cyclopropanes bearing alkyl, benzyl, allyl, halide, and heteroatom substituents, as well as spirocyclic and fused bicycles. Over 40 examples illustrate the broad generality, efficiency, selectivity, functional group tolerance, and practical utility of this approach. Mechanistic insights, gathered from stereochemical probes and competition experiments, are included to reveal the applicability of this non-stabilized carbene route for novel cyclopropane synthesis.
ABSTRACT
The cross-regulation of metabolism and trafficking is not well understood for the vital sphingolipids and cholesterol constituents of cellular compartments. While reports are starting to surface on how sphingolipids like sphingomyelin (SM) dysregulate cholesterol levels in different cellular compartments (Jiang et al., 2022), limited research is available on the mechanisms driving the relationship between sphingolipids and cholesterol homeostasis, or its biological implications. Previously, we have identified sphingolipid metabolism as a unique vulnerability for IDH1 mut gliomas via a rational drug design. Herein, we show how modulating sphingolipid levels affects cholesterol homeostasis in brain tumors. However, we unexpectedly discovered for the first time that C17 sphingosine and NDMS addition to cancer cells alters cholesterol homeostasis by impacting its cellular synthesis, uptake, and efflux leading to a net decrease in cholesterol levels and inducing apoptosis. Our results reflect a reverse correlation between the levels of sphingosines, NDMS, and unesterified, free cholesterol in the cells. We show that increasing sphingosine and NDMS (a sphingosine analog) levels alter not only the trafficking of cholesterol between membranes but also the efflux and synthesis of cholesterol. We also demonstrate that despite the effort to remove free cholesterol by ABCA1-mediated efflux or by suppressing machinery for the influx (LDLR) and biosynthetic pathway (HMGCR), apoptosis is inevitable for IDH1 mut glioma cells. This is the first study that shows how altering sphingosine levels directly affects cholesterol homeostasis in cancer cells and can be used to manipulate this relationship to induce apoptosis in IDH1 mut gliomas.
ABSTRACT
Wide hybridizations across species and genera have been employed to enhance agriculturally important traits in crops. Within the tribe Maleae of the Rosaceae family, different genera and species exhibit several traits useful for increasing diversity and gene pool through hybridization. This study aimed to develop and characterize intergeneric hybrid individuals between Malus and Pyrus. Through seed germination, shoot multiplication, and rooting in vitro, acclimatized seedlings showing vegetative growth on their own roots were obtained from crosses of Malus × domestica pollinated by Pyrus communis, P. bretschneideri, and the Pyrus interspecific hybrid (P. communis × P. pyrifolia). Comparative analysis of leaf morphology, flow cytometry, and molecular genotyping confirmed the hybrid status of the individuals. Genome-wide genotyping revealed that all the hybrid individuals inherited genomic fragments symmetrically from the Malus and Pyrus parents. To the best of our knowledge, this is the first report on the development of intergeneric hybrid seedlings between Malus × domestica and P. bretschneideri. Furthermore, the Pyrus interspecific hybrid individual served as a bridge plant for introducing the genetic background of P. pyrifolia into Malus × domestica. The results of this study provided a crucial foundation for breeding through intergeneric hybridization between Malus and Pyrus, facilitating the incorporation of valuable traits from diverse gene pools.
Subject(s)
Malus , Pyrus , Rosaceae , Humans , Malus/genetics , Pyrus/genetics , Pyrus/metabolism , Plant Breeding , Rosaceae/genetics , Hybridization, GeneticABSTRACT
Immune checkpoint inhibitors, particularly PD-1/PD-L1 blockades, have been approved for unresectable hepatocellular carcinoma (HCC). However, high resistance rates still limit their efficacy, highlighting the urgent need to understand the underlying mechanisms and develop strategies for overcoming the resistance. In this study, we demonstrate that HCC with high MER proto-oncogene tyrosine kinase (MerTK) expression exhibits anti-PD-1/PD-L1 resistance in two syngeneic mouse models and in patients who received anti-PD-1/PD-L1 therapy. Mechanistically, MerTK renders HCC resistant to anti-PD-1/PD-L1 by limiting ferroptosis with the upregulation of SLC7A11 via the ERK/SP1 pathway and facilitating the development of an immunosuppressive tumor microenvironment (TME) with the recruitment of myeloid-derived suppressor cells (MDSCs). Sitravatinib, an inhibitor of MerTK, sensitizes resistant HCC to anti-PD-L1 therapy by promoting tumor ferroptosis and decreasing MDSC infiltration into the TME. In conclusion, we find that MerTK could serve as a predictive biomarker for patient stratification and as a promising target to overcome anti-PD-1/PD-L1 resistance in HCC.
Subject(s)
Carcinoma, Hepatocellular , Ferroptosis , Liver Neoplasms , Animals , Humans , Mice , B7-H1 Antigen , c-Mer Tyrosine Kinase/genetics , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Immunity , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Tumor MicroenvironmentABSTRACT
Effective detection of bio-molecules relies on the precise design and preparation of materials, particularly in laser desorption/ionization mass spectrometry (LDI-MS). Despite significant advancements in substrate materials, the performance of single-structured substrates remains suboptimal for LDI-MS analysis of complex systems. Herein, designer Au@SiO2@ZrO2 core-shell substrates are developed for LDI-MS-based early diagnosis and prognosis of pancreatic cancer (PC). Through controlling Au core size and ZrO2 shell crystallization, signal amplification of metabolites up to 3 orders is not only achieved, but also the synergistic mechanism of the LDI process is revealed. The optimized Au@SiO2@ZrO2 enables a direct record of serum metabolic fingerprints (SMFs) by LDI-MS. Subsequently, SMFs are employed to distinguish early PC (stage I/II) from controls, with an accuracy of 92%. Moreover, a prognostic prediction scoring system is established with enhanced efficacy in predicting PC survival compared to CA19-9 (p < 0.05). This work contributes to material-based cancer diagnosis and prognosis.
Subject(s)
Early Detection of Cancer , Gold , Pancreatic Neoplasms , Silicon Dioxide , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Zirconium , Pancreatic Neoplasms/diagnosis , Humans , Zirconium/chemistry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods , Prognosis , Early Detection of Cancer/methods , Gold/chemistry , Silicon Dioxide/chemistryABSTRACT
Carbonyls and alkenes are versatile functional groups, whose reactivities are cornerstones of organic synthesis. The selective combination of two carbonyls to form an alkene-a carbonyl cross-metathesis-would be a valuable tool for their exchange. Yet, this important synthetic challenge remains unsolved. Although alkene/alkene and alkene/carbonyl cross-metathesis reactions are known, there is a lack of analogous methods for deoxygenative cross-coupling of two carbonyl compounds. Here we report a pair of strategies for the cross-metathesis of unbiased carbonyls, allowing an aldehyde to be chemo- and stereoselectively combined with another aldehyde or ketone. These mild, catalytic methods are promoted by earth-abundant metal salts and enable rapid access to an unprecedentedly broad range of either Z- or E-alkenes by two distinct mechanisms-entailing transiently generated (1) carbenes and ylides (via Fe catalysis) or (2) doubly nucleophilic gem-di-metallics (via Cr catalysis).
ABSTRACT
MAIN CONCLUSION: For the first time, stone cells in pear and apple pedicel were studied. The lignification of the pedicel outer part was correlated with flesh, and the secondary cell wall biosynthesis genes were activated. Fruit pedicels act as bridges between the fruit and the shoot. They have secondary thickened cell walls that presumably function in mechanical support, water and nutrient transport. Stone cells are cells with a secondary cell wall thickening. In pears, yet not in apples, the stone cells affect the flesh texture. There have been few reports on stone cell formation in pear and apple pedicels; therefore, we studied these cells for the first time. The apple pedicel had few stone cells in the cortex. The formation of stone cells in pear continued until seven weeks after flowering (WAF), and the density was significantly higher than in apple. The stone cell formation degree (SFD) of pear was 3.6-7.1 times higher than that of apple. Total lignin and lignin non-condensed structure (G and S units) content in the pear pedicle outer part was 1.5-2.7 times higher than that of the apple at harvest. The SFD of the pedicel outer part had a positive correlation with the G and S units content of the flesh. The total lignin and G and S units content between flesh and the pedicel outer part were positively correlated. Correlation analysis revealed a positive relationship between fruit and pedicel formation of the stone cells. The WGCNA showed that NST3 was linked to NAC028, MYB46, CESA, POD, LAC, and VSR6. These genes were highly expressed in the outer part of the pear pedicel, while they were suppressed in that issue of the apple at 4 WAF.
Subject(s)
Malus , Pyrus , Lignin , Malus/genetics , Pyrus/genetics , Fruit/geneticsABSTRACT
BACKGROUND: Identifying a metastasis-correlated immune cell composition within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) will help to develop promising and innovative therapeutic strategies. However, the dynamics of immune cell lineages in the TME of advanced PDAC remains elusive. METHODS: Twenty-six samples from 11 patients (including 11 primary tumor tissues, 10 blood, and 5 lymph nodes) with different stages were used to develop a multiscale immune profile. High-dimensional single-cell analysis with mass cytometry was performed to search for metastasis-correlated immune changes in the microenvironment. The findings were further validated by published single-cell RNA sequencing (scRNA-seq) data and multiplex fluorescent immunohistochemistry. FINDINGS: High-dimensional single-cell profiling revealed that the three immune-relevant sites formed a distinct immune atlas. Interestingly, the PDAC microenvironment with the potential for metastatic spread to the liver was characterized by a decreased proportion of CD103+PD-1+CD39+ T cells with cytotoxic and exhausted functional status and an increased proportion of CD73+ macrophages. Analysis of scRNA-seq data of PDAC further confirmed the identified subsets and revealed strong potential interactions via various ligand-receptor pairs between the identified T subsets and the macrophages. Moreover, stratified patients with different immune compositions correlated with clinical outcomes of PDAC. CONCLUSIONS: Our study uncovered metastasis-correlated immune changes, suggesting that ecosystem-based patient classification in PDAC will facilitate the identification of candidates likely to benefit from immunotherapy. FUNDING: This work was supported by the National Key Research and Development Program of China, the Shanghai International Science and Technology Collaboration Program, the Shanghai Sailing Program, and the Key Laboratory of diagnosis and treatment of severe hepato-pancreatic diseases of Zhejiang Province.
Subject(s)
Carcinoma, Pancreatic Ductal , Liver Neoplasms , Pancreatic Neoplasms , Humans , Ecosystem , China , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/drug therapy , Tumor Microenvironment , Pancreatic NeoplasmsABSTRACT
Tobacco belongs to the family Solanaceae, which easily forms continuous cropping obstacles. Continuous cropping exacerbates the accumulation of autotoxins in tobacco rhizospheric soil, affects the normal metabolism and growth of plants, changes soil microecology, and severely reduces the yield and quality of tobacco. In this study, the types and composition of tobacco autotoxins under continuous cropping systems are summarized, and a model is proposed, suggesting that autotoxins can cause toxicity to tobacco plants at the cell level, plant-growth level, and physiological process level, negatively affecting soil microbial life activities, population number, and community structure and disrupting soil microecology. A combined strategy for managing tobacco autotoxicity is proposed based on the breeding of superior varieties, and this approach can be combined with adjustments to cropping systems, the induction of plant immunity, and the optimization of cultivation and biological control measures. Additionally, future research directions are suggested and challenges associated with autotoxicity are provided. This study aims to serve as a reference and provide inspirations needed to develop green and sustainable strategies and alleviate the continuous cropping obstacles of tobacco. It also acts as a reference for resolving continuous cropping challenges in other crops.
ABSTRACT
Gastric cancer (GC) is one of the most common causes of cancer-related deaths worldwide, and chemotherapy is still a standard strategy for treating patients with advanced GC. Lipid metabolism has been reported to play an important role in the carcinogenesis and development of GC. However, the potential values of lipid-metabolism-related genes (LMRGs) concerning prognostic value and the prediction of chemotherapy responsiveness in GC remains unclear. A total of 714 stomach adenocarcinoma patients were enrolled from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Using univariate Cox and LASSO regression analyses, we developed a risk signature based on LMRGs that can distinguish high-GC-risk patients from low-risk patients with significant differences in overall survival. We further validated this signature prognostic value using the GEO database. The R package "pRRophetic" was applied to calculate the sensitivity of each sample from high- and low-risk groups to chemotherapy drugs. The expression of two LMRGs, AGT and ENPP7, can predict the prognosis and response to chemotherapy in GC. Furthermore, AGT significantly promoted GC growth and migration, and the downregulation of AGT enhanced the chemotherapy response of GC both in vitro and in vivo. Mechanistically, AGT induced significant levels of epithelial-mesenchymal transition (EMT) through the PI3K/AKT pathway. The PI3K/AKT pathway agonist 740 Y-P can restore the EMT of GC cells impaired by AGT knockdown and treatment with 5-fluorouracil. Our findings suggest that AGT plays a key role in the development of GC, and targeting AGT may help to improve the chemotherapy response of GC patients.
ABSTRACT
Carbenes are highly enabling reactive intermediates that facilitate a diverse range of otherwise inaccessible chemistry, including small-ring formation and insertion into strong σ bonds. To access such valuable reactivity, reagents with high entropic or enthalpic driving forces are often used, including explosive (diazo) or unstable (gem-dihalo) compounds. Here, we report that common aldehydes are readily converted (via stable α-acyloxy halide intermediates) to electronically diverse (donor or neutral) carbenes to facilitate >10 reaction classes. This strategy enables safe reactivity of nonstabilized carbenes from alkyl, aryl, and formyl aldehydes via zinc carbenoids. Earth-abundant metal salts [iron(II) chloride (FeCl2), cobalt(II) chloride (CoCl2), copper(I) chloride (CuCl)] are effective catalysts for these chemoselective carbene additions to σ and π bonds.
ABSTRACT
This study was aimed at exploring the application value of electroacupuncture in the treatment of peripheral facial palsy using surface nerve electromyogram (EMG) image data based on deep learning. The surface nerve EMG recognition model was constructed based on multiview convolutional neural network, and the differences between it and the traditional single-view convolutional neural network were analyzed. Meanwhile, the influence of the multiview aggregation method based on pooling of view and decision fusion on facial recognition accuracy was compared and analyzed. 150 patients with peripheral facial paralysis were randomly divided into the control group (n = 70, basic treatment) and treatment group (n = 80, basic treatment + electroacupuncture). After 4 weeks of treatment, the therapeutic effect was evaluated by surface EMG parameters based on Horsfall-Barratt (H-B) scale and multiview convolutional neural network. The results showed that the face recognition accuracy of multiview convolutional neural networks was significantly higher than that of all single-view convolutional neural networks. The multiview aggregation network proposed in this research had a higher accuracy in facial recognition than the pooling of the view method and decision fusion-based multiview aggregation method. According to the evaluation results of H-B scale, the number of patients who recovered, significantly effective, effective, and ineffective in the control group was 39, 17, 3, and 11, respectively. The number of patients in the treatment group who recovered, significantly effective, effective, and ineffective was 51, 15, 9, and 5, respectively. Total effective rate of patients in the control group was 84.29%, and that of the treatment group was 93.75%, which was significantly higher than the control group (P < 0.05). According to surface EMG assessment results, compared with the control group, the mean root mean square (RMS), median frequency (MF), and mean power frequency (MPF) of the buccal and frontalis muscles in the treatment group increased significantly (P < 0.05). Compared with that before treatment, the mean buccal and frontalis RMS of patients in the control and treatment groups increased significantly after treatment (P < 0.05). In conclusion, electroacupuncture treatment could significantly improve the muscle strength of patients with peripheral facial paralysis.
Subject(s)
Deep Learning , Electroacupuncture , Facial Paralysis , Telemedicine , Electromyography , Facial Paralysis/therapy , HumansABSTRACT
Gold nanoclusters (AuNCs), as a novel fluorescent material, have been extensively explored and developed for bioimaging because of their attractive advantages such as ultrasmall size, low toxicity and exceptional two-photon excitation properties. However, it still remains a challenge to produce water-soluble, biocompatible and ultrabright AuNCs. Herein, we report on a novel one-pot synthesis of highly luminescent and biocompatible AuNCs by using polyvinyl pyrrolidone (PVP), a water-soluble polymer, to rigidify the primary stabilizing layer (shell) that is composed of 6-aza-2-thiothymine (ATT) ligands bound to the particle. Such shell-rigidification resulted in a significant enhancement of the fluorescence efficiency, reaching a quantum yield of 39% under the best conditions, about 35-fold increase from the intrinsically weak fluorescence of the AuNCs stabilized by only ATT. The fluorescence enhancement mechanism was systematically characterized, and the results indicate that PVP coating rigidifies the ATT ligand shell through steric hindrance and reduces the nonradiative relaxation of the excited states. The biocompatible PVP-AuNCs were further examined for two-photon cellular and sentinel lymph node (SLN) bioimaging, and we observed pH-dependent cytoplasmic images and intense green fluorescence in SLN and lymphatic vessels.
Subject(s)
Gold , Metal Nanoparticles , Gold/chemistry , Hydrogen-Ion Concentration , Luminescence , Metal Nanoparticles/chemistry , WaterABSTRACT
Nutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of the tumor dependence on external sources for some nutrients. However, little is known about the mechanisms that make cancer cells require certain nutrients from the microenvironment. Herein, we report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. Using several 13 C-tracers and analysis of cystathionine synthase and cystathioninase levels, we revealed that glioma cells were not able to support glutathione synthesis through the transsulfuration pathway, which allows methionine to be converted to cysteine in cysteine/cystine-deprived conditions. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine-free diet survived longer, although this increase did not attain statistical significance, with concomitant reductions in plasma glutathione and cysteine levels. At the end point, however, tumors displayed the ability to synthesize glutathione, even though higher levels of oxidative stress were detected. We observed a compensation from the nutritional intervention revealed as the recovery of cysteine-related metabolite levels in plasma. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.
Subject(s)
Cysteine , Glioma , Animals , Cell Proliferation , Cysteine/metabolism , Cystine/metabolism , Glutathione/metabolism , Humans , Mice , Tumor MicroenvironmentABSTRACT
The synthesis of highly luminescent colloidal CsSnX3 (X = halogen) perovskite nanocrystals (NCs) remains a long-standing challenge due to the lack of a fundamental understanding of how to rationally suppress the formation of structural defects that significantly influence the radiative carrier recombination processes. Here, we develop a theory-guided, general synthetic concept for highly luminescent CsSnX3 NCs. Guided by density functional theory calculations and molecular dynamics simulations, we predict that, although there is an opposing trend in the chemical potential-dependent formation energies of various defects, highly luminescent CsSnI3 NCs with narrow emission could be obtained through decreasing the density of tin vacancies. We then develop a colloidal synthesis strategy that allows for rational fine-tuning of the reactant ratio in a wide range but still leads to the formation of CsSnI3 NCs. By judiciously adopting a tin-rich reaction condition, we obtain narrow-band-emissive CsSnI3 NCs with a record emission quantum yield of 18.4%, which is over 50 times larger than those previously reported. Systematic surface-state characterizations reveal that these NCs possess a Cs/I-lean surface and are capped with a low density of organic ligands, making them an excellent candidate for optoelectronic devices without any postsynthesis ligand management. We showcase the generalizability of our concept by further demonstrating the synthesis of highly luminescent CsSnI2.5Br0.5 and CsSnI2.25Br0.75 NCs. Our findings not only highlight the value of computation in guiding the synthesis of high-quality colloidal perovskite NCs but also could stimulate intense efforts on tin-based perovskite NCs and accelerate their potential applications in a range of high-performance optoelectronic devices.
ABSTRACT
A cross-selective aza-pinacol coupling of aldehydes and imines has been developed to afford valuable ß-amino alcohols. This strategy enables chemoselective conversion of aliphatic aldehydes to ketyl radicals, in the presence of more easily reduced imines and other functional groups. Upon carbonyl-specific activation by AcI, a photoinitiated Mn catalyst selectively reduces the resulting α-oxy iodide by an atom transfer mechanism. The ensuing ketyl radical selectively couples to imines, precluding homodimerization by a classical reductive approach. In this first example of reductive, ketyl coupling by atom transfer catalysis, Zn serves as a terminal reductant to facilitate Mn catalyst turnover. This new strategy also enables ketyl radical couplings to alkenes, alkynes, aldehydes, propellanes, and chiral imines.
Subject(s)
Aza Compounds/chemistry , Oligopeptides/chemistry , Aldehydes/chemistry , Amino Alcohols/chemistry , Catalysis , Free Radicals/chemistry , Imines/chemistry , Magnesium/chemistry , Oxidation-Reduction , StereoisomerismABSTRACT
Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring a mutation in isocitrate dehydrogenase 1 mutation (IDH1mut) acquire a different tumor biology and clinical manifestation from those that are IDH1WT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we uncover increased monounsaturated fatty acids (MUFA) and their phospholipids in endoplasmic reticulum (ER), generated by IDH1 mutation, that are responsible for Golgi and ER dilation. We demonstrate a direct link between the IDH1 mutation and this organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate-limiting enzyme in MUFA biosynthesis. Inhibition of IDH1 mutation or SCD silencing restores ER and Golgi morphology, while D-2HG and oleic acid induces morphological defects in these organelles. Moreover, addition of oleic acid, which tilts the balance towards elevated levels of MUFA, produces IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the distribution of lipids in the organelles of glioma cells, providing new insight into the link between lipid metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.
Subject(s)
Isocitrate Dehydrogenase/genetics , Mutation/genetics , Organelles/metabolism , Phospholipids/metabolism , Cell Line, Tumor , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/ultrastructure , Glioblastoma/pathology , Golgi Apparatus/metabolism , Golgi Apparatus/ultrastructure , Humans , Models, Biological , Oligodendroglioma/pathology , Stearoyl-CoA Desaturase/metabolismABSTRACT
In addition to providing integrity to cellular structure, the various classes of lipids participate in a multitude of functions including secondary messengers, receptor stimulation, lymphocyte trafficking, inflammation, angiogenesis, cell migration, proliferation, necrosis and apoptosis, thus highlighting the importance of understanding their role in the tumor phenotype. In the context of IDH1mut glioma, investigations focused on metabolic alterations involving lipidomics' present potential to uncover novel vulnerabilities. Herein, a detailed lipidomic analysis of the sphingolipid metabolism was conducted in patient-derived IDH1mut glioma cell lines, as well as model systems, with the of identifying points of metabolic vulnerability. We probed the effect of decreasing D-2HG levels on the sphingolipid pathway, by treating these cell lines with an IDH1mut inhibitor, AGI5198. The results revealed that N,N-dimethylsphingosine (NDMS), sphingosine C17 and sphinganine C18 were significantly downregulated, while sphingosine-1-phosphate (S1P) was significantly upregulated in glioma cultures following suppression of IDH1mut activity. We exploited the pathway using a small-scale, rational drug screen and identified a combination that was lethal to IDHmut cells. Our work revealed that further addition of N,N-dimethylsphingosine in combination with sphingosine C17 triggered a dose-dependent biostatic and apoptotic response in a panel of IDH1mut glioma cell lines specifically, while it had little effect on the IDHWT cells probed here. To our knowledge, this is the first study that shows how altering the sphingolipid pathway in IDH1mut gliomas elucidates susceptibility that can arrest proliferation and initiate subsequent cellular death.
ABSTRACT
While the interactions between HIV and various liver cell populations have been explored, the relevance of these interactions when patients are well-controlled on ART is less clear. Therefore, we focus this perspective on HIV-related alterations that may drive hepatic inflammation and fibrosis in aviremic patients, with a focus on Kupffer cells and Hepatic Stellate Cells. Persistent CD4+ T cell depletion in the gut resulting in increased gut permeability has been postulated to play a role in systemic immune activation in HIV patients. The liver, with its unique location, remains the gatekeeper between the gut and the systemic circulation. The resident liver macrophage, Kupffer cell, is responsible for clearing and responding to these products. We propose that changes in Kupffer cell biology, in the context of HIV infection, creates a mileu that drives hepatic inflammation and fibrosis in response to microbial translocation. Targeting these pathways may be helpful in improving liver-related outcomes in HIV patients.
Subject(s)
HIV Infections/complications , HIV Infections/immunology , Hepatitis/etiology , Hepatitis/immunology , Kupffer Cells/immunology , Liver Cirrhosis/etiology , Liver Cirrhosis/immunology , Gastrointestinal Microbiome/immunology , HIV-1 , Hepatic Stellate Cells/immunology , Hepatic Stellate Cells/virology , Host Microbial Interactions/immunology , Humans , Kupffer Cells/microbiology , Kupffer Cells/virology , Models, Immunological , Signal Transduction/immunology , Toll-Like Receptor 4/immunologyABSTRACT
Saturated heterocyclic acetals are useful fragments in organic synthesis and other fields. Herein, C(sp3)-H dehydrogenative cross-couplings of ethers, tetrahydrothiophenes, and pyrrolidines were achieved under visible light irradiation by using iodobenzene and an in situ-formed gold complex. The broad functional group compatibility and substrate scope indicate that our strategy is a promising way to synthesize acetal analogues. The method was successfully applied in late-stage modifications of bioactive molecules. Gram scale syntheses and mechanistic studies are also presented.