Bio-orthogonal click chemistry strategy for PD-L1-targeted imaging and pyroptosis-mediated chemo-immunotherapy of triple-negative breast cancer.

BACKGROUND: The combination of programmed cell death ligand-1 (PD-L1) immune checkpoint blockade (ICB) and immunogenic cell death (ICD)-inducing chemotherapy has shown promise in cancer immunotherapy. However, triple-negative breast cancer (TNBC) patients undergoing this treatment often face obstacles such as systemic toxicity and low response rates, primarily attributed to the immunosuppressive tumor microenvironment (TME). METHODS AND RESULTS: In this study, PD-L1-targeted theranostic systems were developed utilizing anti-PD-L1 peptide (APP) conjugated with a bio-orthogonal click chemistry group. Initially, TNBC was treated with azide-modified sugar to introduce azide groups onto tumor cell surfaces through metabolic glycoengineering. A PD-L1-targeted probe was developed to evaluate the PD-L1 status of TNBC using magnetic resonance/near-infrared fluorescence imaging. Subsequently, an acidic pH-responsive prodrug was employed to enhance tumor accumulation via bio-orthogonal click chemistry, which enhances PD-L1-targeted ICB, the pH-responsive DOX release and induction of pyroptosis-mediated ICD of TNBC. Combined PD-L1-targeted chemo-immunotherapy effectively reversed the immune-tolerant TME and elicited robust tumor-specific immune responses, resulting in significant inhibition of tumor progression. CONCLUSIONS: Our study has successfully engineered a bio-orthogonal multifunctional theranostic system, which employs bio-orthogonal click chemistry in conjunction with a PD-L1 targeting strategy. This innovative approach has been demonstrated to exhibit significant promise for both the targeted imaging and therapeutic intervention of TNBC.

Construction of Bridged Benzazepines via Photo-Induced Dearomatization.

Bridged benzazepine scaffolds, possessing unique structural and physicochemical activities, are widespread in various natural products and drugs. The construction of these skeletons often requires elaborate synthetic effort with low efficiency. Herein, we develop a simple and divergent approach for constructing various bridged benzazepines by a photocatalytic intermolecular dearomatization of naphthalene derivatives with readily available α-amino acids. The bridged motif is created via a cascade sequence involving photocatalytic 1,4-hydroaminoalkylation, alkene isomerization and cyclization. Interestingly, the diastereoselectivity can be regulated through different reaction modes in the cyclization step. Moreover, aminohydroxylation and its further bromination have also been demonstrated to access highly functionalized bridged benzazepines. Preliminary mechanistic studies have been performed to get insights into the mechanism. This method provides a divergent synthetic approach for construction of highly functionalized bridged benzazepines, which have been otherwise difficult to access.

Hydrated [3+2] Cyclotelomerization of Butafulvenes to Create Multiple Contiguous Fully Substituted Carbon Centers.

The construction of multiple continuous fully substituted carbon centers, which serve as unique structural motif in natural products, is a challenging topic in organic synthesis. Herein, we report a hydrated [3+2] cyclotelomerization of butafulvenes to create contiguous fully substituted carbon backbone. In the presence of scandium triflate, all-carbon skeleton with spiro fused tricyclic ring can be constructed in high diastereoselectivity by utilizing butafulvene as the synthon. Mechanistic studies suggest that this atom-economic reaction probably proceeds through a synergistic process containing butafulvenes dimerization and nucleophilic attack by water. In addition, the tricyclic product can undergo a series of synthetic derivatizations, which highlights the potential applications of this strategy. The recyclability of Sc(OTf)3 has also been demonstrated to show its robust performance in this hydrated cyclotelomerization.

CDs Regulated Sulfur-Based Flexible Electrode with Range pH Values for Efficient and Durable Hydrogen Evolution Reaction.

How to mildly structure a high intrinsic activity and stable catalytic electrode to realize long-term catalytic water splitting to produce hydrogen at a wide range of pH values at industrial high current is a challenge. Herein, this work creatively proposes to prepare industrial-grade catalytic electrodes with high efficiency and stability at high current density through carbon quantum dots (CDs) modification nickel sulfide on hydrophilic flexible filter paper via one-step mild chemical plating (denoted as CDs-Ni3 S2 @HFP). The intrinsic activity and surface area, electron transfer ability, and corrosion resistance of Ni3 S2 material are increased due to the regulation, homogenous, and high concentration doping of CDs. The overpotential of the flexible catalytic electrode is only 30, 35, and 87 mV in 1 m KOH, simulated seawater (1 m KOH + 0.5 m NaCl), and neutral electrolyte (0.5 m PBS) at a current density of 10 mA cm-2 . More attractively, the CDs-Ni3 S2 @HFP electrode achieves over 500 h of efficient and stable catalysis at industrial high current density (500 mA cm-2 ). Due to the advantages of mild, universal, and large-area preparation of catalytic materials, this work provides technical support for flexible catalytic electrodes in efficient catalysis toward water splitting, energy storage, and device preparation.

Potent antitumor efficacy of human dental pulp stem cells armed with YSCH-01 oncolytic adenovirus.

BACKGROUND: Systemic administration of oncolytic adenovirus for cancer therapy is still a challenge. Mesenchymal stem cells as cell carriers have gained increasing attention in drug delivery due to their excellent tumor tropism, immunosuppressive modulatory effects, and paracrine effects. However, the potential of human dental pulp stem cells (hDPSCs) loaded with oncolytic adenovirus for cancer biotherapy has not been investigated yet. METHODS: The stemness of hDPSCs was characterized by FACS analysis and Alizarin red staining, Oil Red O staining, and immunofluorescence assays. The biological fitness of hDPSCs loaded with oncolytic adenovirus YSCH-01 was confirmed by virus infection with different dosages and cell viability CCK-8 assays. Additionally, the expression of CAR receptor in hDPSCs was detected by qPCR assay. Tumor tropism of hDPSC loaded with YSCH-01 in vitro and in vivo was investigated by Transwell assays and living tumor-bearing mice imaging technology and immunohistochemistry, Panoramic scanning of frozen section slices assay analysis. Furthermore, the antitumor efficacy was observed through the different routes of YSCH-01/hPDSCs administration in SW780 and SCC152 xenograft models. The direct tumor cell-killing effect of YSCH-01/hDPSCs in the co-culture system was studied, and the supernatant of YSCH-01/hDPSCs inhibited cell growth was further analyzed by CCK-8 assays. RESULTS: hDPSCs were found to be susceptible to infection by a novel oncolytic adenovirus named YSCH-01 and were capable of transporting this virus to tumor sites at 1000 VP/cell infectious dosage in vitro and in vivo. Moreover, it was discovered that intraperitoneal injection of hDPSCs loaded with oncolytic adenovirus YSCH-01 exhibited potential anti-tumor effects in both SW780 and SCC152 xenograft models. The crucial role played by the supernatant secretome derived from hDPSCs loaded with YSCH-01 significantly exerted a specific anti-tumor effect without toxicity for normal cells, in both an active oncolytic virus and an exogenous protein-independent manner. Furthermore, the use of hDPSCs as a cell carrier significantly reduced the required dosage of virus delivery in vivo compared to other methods. CONCLUSIONS: These findings highlight the promising clinical potential of hDPSCs as a novel cell carrier in the field of oncolytic virus-based anti-cancer therapy.

Identifying the pathophysiological traits of obstructive sleep apnea during dexmedetomidine sedation.

Dexmedetomidine (DEX) has been described as a safe sedative in clinical practice, but its effects on the pathophysiological traits of obstructive sleep apnea (OSA) are unclear. We estimated the effects of DEX sedation on the four key pathophysiological traits of OSA (pharyngeal collapsibility, dilator muscle function, arousal threshold, and loop gain) in adult patients with OSA by conducting a secondary analysis of a prospective diagnostic trial. Pathophysiological traits estimated from polysomnography and the respiratory parameters under natural sleep and DEX-induced sleep were compared. Bivariate and multivariate linear regression analyses were used to estimate the relationship between pathophysiological traits and OSA severity for both sleep states. Adult patients with OSA had a significantly higher pharyngeal collapsibility (Vpassive : 44.9 [15.7 to 53.8] vs. 53.3 [34.2 to 66.3] %eupnea , p < 0.001), arousal threshold (178.5 [132.5 to 234.6] vs. 140.5 [123.2 to 192.3] %eupnea , p < 0.001), and loop gain (LG1: 0.74 ± 0.25 vs. 0.60 ± 0.17, p < 0.001; LGn: 0.52 ± 0.12 vs. 0.44 ± 0.08, p < 0.001) during DEX-induced sleep compared with natural sleep. There was no significant difference in dilator muscle function or PSG respiratory parameters between natural versus DEX-induced sleep states. Bivariate regression analysis showed varying degrees of correlation between OSA traits and severity. Multiple regression analysis indicated that collapsibility was the strongest predictor of the apnea-hypopnea index for both sleep states. Dexmedetomidine sedation in patients with OSA increased the pharyngeal collapsibility without impairing dilator muscle function, while elevating arousal threshold and increasing loop gain.

N6-methyladenosine mediates Nrf2 protein expression involved in PM2.5-induced pulmonary fibrosis.

It has been reported that particulate matter with an aerodynamic diameter of <2.5 µm (PM2.5) could induce epithelial-mesenchymal transition (EMT)- and extracellular matrix (ECM)-related pulmonary fibrosis (PF). The transcription factor Nrf2 alleviated PM2.5-induced PF by antagonizing oxidative stress. The N6-methyladenosine (m6A) modification plays a significant role in the stress response. However, the effect of m6A modification on the mechanisms of Nrf2-mediated defense against PM2.5-induced PF remained unknown. Here, we explored the role and the underlying molecular mechanisms of m6A methylation of Nrf2 mRNA in PM2.5-induced PF. We established filtered air (FA), unfiltered air (UA), and concentrated PM2.5 air (CA) group mice model and 0, 50, and 100 µg/mL PM2.5-treated 16HBE cell models. The extent of lung fibrosis in mice and fibrosis indicators were detected by histopathological analysis, immunohistochemical staining and western blotting. The molecular mechanism of m6A-modified Nrf2 was demonstrated by m6A-methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), qRT-PCR and T3 ligase-based PCR. Our data showed that PM2.5 exposure for 16 weeks could induce pulmonary fibrosis and activate Nrf2 signaling pathway. m6A methyltransferase METTL3 was upregulated after PM2.5 treatment in vivo and in vitro. Moreover, METTL3 mediated m6A modification of Nrf2 mRNA and promoted Nrf2 translation in mice and 16HBE cells after PM2.5 exposure. Mechanistically, three m6A-modified sites (1317, 1376 and 935; numbered relative to the first nucleotide of 3'UTR) of Nrf2 mRNA were identified in PM2.5-treatment 16HBE cells. Furthermore, the m6A binding proteins YTHDF1/IGF2BP1 promoted Nrf2 translation by binding to m6A residues of Nrf2 mRNA. Our results revealed the mechanism of m6A mediated Nrf2 signaling pathway against oxidative stress, which affected the development of PM2.5-induced PF.

Skeleton-Reorganizing Coupling Reactions of Cycloheptatriene and Cycloalkenones with Amines.

Skeletal reorganization reactions have emerged as an intriguing tool for converting readily available compounds into complicated molecules inaccessible by traditional methods. Herein, we report a unique skeleton-reorganizing coupling reaction of cycloheptatriene and cycloalkenones with amines. In the presence of Rh/acid catalysis, cycloheptatriene can selectively couple with anilines to deliver fused 1,2-dihydroquinoline products. Mechanistic studies indicate that the retro-Mannich type ring-opening and subsequent intramolecular Povarov reaction account for the ring reorganization. Our mechanistic studies also revealed that skeleton-reorganizing amination between anilines and cycloalkenones can be achieved with acid. The synthetic utilization of this skeleton-reorganizing coupling reaction was showcased with a gram-scale reaction, synthetic derivatizations, and the late-stage modification of commercial drugs.

Nickel-Catalyzed Unsymmetrical Bis-Allylation of Alkynes.

The catalytic bis-allylation of alkynes is an important but challenging protocol to construct all-carbon tetra-substituted alkenes. Particularly, the catalytic unsymmetrical bis-allylation of alkynes remains as an underexplored task to date. We herein report an unprecedented unsymmetrical bis-allylation by simultaneously utilizing electrophilic trifluoromethyl alkene and nucleophilic allylboronate as the allylic reagents. With the aid of robust Ni0 /NHC catalysis, valuable skipped trienes can be obtained in high regio- and stereo-selectivities under mild conditions. Mechanistic studies indicate that the reaction may proceed through a ß-fluorine elimination of a nickelacycle followed by a transmetalation step with allylboronate. The present method exhibits a good tolerance of various functional groups. Besides, the skipped triene products can undergo an array of elaborate transformations, which highlights the potential applications of this strategy.

Rhodium-Catalyzed Deuterated Tsuji-Wilkinson Decarbonylation of Aldehydes with Deuterium Oxide.

The recent surge in the applications of deuterated drug candidates has rendered an urgent need for diverse deuterium labeling techniques. Herein, an efficient Rh-catalyzed deuterated Tsuji-Wilkinson decarbonylation of naturally available aldehydes with D2O is developed. In this reaction, D2O not only acts as a deuterated reagent and solvent but also promotes Rh-catalyzed decarbonylation. In addition, decarbonylative strategies for the synthesis of terminal monodeuterated alkenes from α,ß-unsaturated aldehydes are within reach.

Selective C-S Bond Constructions Using Inorganic Sulfurs via Photoinduced Electron Donor-Acceptor Activation.

By complementing traditional transition metal catalysis, photoinduced catalysis has emerged as a versatile and sustainable way to achieve carbon-heteroatom bond formation. This work discloses a visible-light-induced reaction for the formation of a C-S bond from aryl halides and inorganic sulfuration agents via electron donor-acceptor (EDA) complex photocatalysis. Divergent formations of organic sulfide and disulfide have been demonstrated under mild conditions. Preliminary mechanistic studies suggest that visible-light-induced intracomplex charge transfer within the monosulfide-anion-containing EDA complex permits the C-S bond construction reactivity.

Bioinspired and Ligand-Regulated Unnatural Prenylation and Geranylation of Oxindoles with Isoprene under Pd Catalysis.

In nature, prenylation and geranylation are two important metabolic processes for the creation of hemiterpenoids and monoterpenoids under enzyme catalysis. Herein, we have demonstrated bioinspired unnatural prenylation and geranylation of oxindoles using the basic industrial feedstock isoprene through ligand regulation under Pd catalysis. Pentenylated oxindoles (with C5 added) were attained with high selectivity when using a bisphosphine ligand, whereas upon switching to a monophosphine ligand, selectivity toward geranylated oxindoles (with C10 added) was achieved. Moreover, the head-to-head product could be further isomerized to an internal skipped diene under Pd-H catalysis. No stoichiometric by-product was formed in the process.

Redox-Divergent Construction of (Dihydro)thiophenes with DMSO.

Thiophene-based rings are one of the most widely used building blocks for the synthesis of sulfur-containing molecules. Inspired by the redox diversity of these features in nature, we demonstrate herein a redox-divergent construction of dihydrothiophenes, thiophenes, and bromothiophenes from the respective readily available allylic alcohols, dimethyl sulfoxide (DMSO), and HBr. The redox-divergent selectivity could be manipulated mainly by controlling the dosage of DMSO and HBr. Mechanistic studies suggest that DMSO simultaneously acts as an oxidant and a sulfur donor. The synthetic potentials of the products as platform molecules were also demonstrated by various derivatizations, including the preparation of bioactive and functional molecules.

Visible Light Induced Bifunctional Rhodium Catalysis for Decarbonylative Coupling of Imides with Alkynes.

Transition metal catalyzed decarbonylation offers a distinct synthetic strategy for new chemical bond formation. However, the π-backbonding between CO π* orbitals and metal center d-orbitals impedes ligand dissociation to regenerate the catalyst under mild reaction conditions. Developed here is visible light induced rhodium catalysis for decarbonylative coupling of imides with alkynes under ambient conditions. Initial mechanistic studies suggest that the rhodium complex simultaneously serves as the catalytic center and photosensitizer for decarbonylation. This visible light promoted catalytic decarbonylation strategy offers new opportunities for reviewing old transformations with ligand dissociation as a rate-determining step.

Orthogonal Regulation of Nucleophilic and Electrophilic Sites in Pd-Catalyzed Regiodivergent Couplings between Indazoles and Isoprene.

Depending on the reactant property and reaction mechanism, one major regioisomer can be favored in a reaction that involves multiple active sites. Herein, an orthogonal regulation of nucleophilic and electrophilic sites in the regiodivergent hydroamination of isoprene with indazoles is demonstrated. Under Pd-hydride catalysis, the 1,2- or 4,3-insertion pathway with respect to the electrophilic sites on isoprene could be controlled by the choice of ligands. In terms of the nucleophilic sites on indazoles, the reaction occurs at either the N1 - or N2 -position of indazoles is governed by the acid co-catalysts. Preliminary experimental studies have been performed to rationalize the mechanism and regioselectivity. This study not only contributes a practical tool for selective functionalization of isoprene, but also provides a guide to manipulate the regioselectivity for the N-functionalization of indazoles.

Comparative Effects of Graphene and Molybdenum Disulfide on Human Macrophage Toxicity.

Graphene and other 2D materials, such as molybdenum disulfide, have been increasingly used in electronics, composites, and biomedicine. In particular, MoS2 and graphene hybrids have attracted a great interest for applications in the biomedical research, therefore stimulating a pertinent investigation on their safety in immune cells like macrophages, which commonly engulf these materials. In this study, M1 and M2 macrophage viability and activation are mainly found to be unaffected by few-layer graphene (FLG) and MoS2 at doses up to 50 µg mL-1 . The uptake of both materials is confirmed by transmission electron microscopy, inductively coupled plasma mass spectrometry, and inductively coupled plasma atomic emission spectroscopy. Notably, both 2D materials increase the secretion of inflammatory cytokines in M1 macrophages. At the highest dose, FLG decreases CD206 expression while MoS2 decreases CD80 expression. CathB and CathL gene expressions are dose-dependently increased by both materials. Despite a minimal impact on the autophagic pathway, FLG is found to increase the expression of Atg5 and autophagic flux, as observed by Western blotting of LC3-II, in M1 macrophages. Overall, FLG and MoS2 are of little toxicity in human macrophages even though they are found to trigger cell stress and inflammatory responses.

Ligand-Regulated Regiodivergent Hydrosilylation of Isoprene under Iron Catalysis.

A method for the regiodivergent and stereoselective hydrosilylation of the basic industrial feedstock isoprene with unactivated silanes has been developed using earth-abundant iron catalysts. The manipulation of regioselectivity relies on fine modification of the coordination geometry of the iron center. While a bidentate pyridine imine ligand promoted the formation of allylic silanes through 4,1-addition, selectivity for the 3,4-adduct homoallylic silanes was observed with a tridentate nitrogen ligand. Experimental studies and analysis were carried out to elucidate the reaction mechanism and the factors enabling manipulation of the regioselectivity. This study contributes to the art of regioselectivity control in alkene hydrofunctionalization.

Catalytic Prenylation and Reverse Prenylation of Indoles with Isoprene: Regioselectivity Manipulation through Choice of Metal Hydride.

The basic industrial feedstock isoprene was employed as a building block to install prenyl and reverse-prenyl groups onto indoles. The regioselectivity can be manipulated by the choice of metal hydride. Reverse-prenylated indoles were attained with high selectivity when using Rh-H. By switching to a Pd-H catalyst, selectivity toward prenylated indoles was achieved. This regiodivergent method also features high atom economy without stoichiometric byproduct formation.

Perylenediimide-based glycoclusters as high affinity ligands of bacterial lectins: synthesis, binding studies and anti-adhesive properties.

The synthesis of eight perylenediimide-based glycoclusters was readily performed from hexa- and tetra-propargylated cores through azide-alkyne "click" conjugation. Variations in the carbohydrate epitope (Glc, Gal, Man, Fuc) and the linker arm provided molecular diversity. Interactions with LecA and LecB, two proteins involved in the adhesion of Pseudomonas aeruginosa to host tissues, were evaluated by microcalorimetry (ITC). In both cases high affinities were obtained with Kd values in the nanomolar range. Further evaluation of their anti-adhesive properties using cultured epithelial cells demonstrated their potent anti-adhesive activities against Pseudomonas aeruginosa with only 30-40% residual adhesion observed. The fluorescence properties of the PDI core were then investigated by confocal microscopy on cell-bacteria cultures. However, the red fluorescence signal of the PDI-based glycocluster was too weak to provide significant data. The present study provides another type of anti-adhesive glycocluster against bacterial infection with a large aromatic PDI core.