NK-92 cells labeled with Fe3O4-PEG-CD56/Avastin@Ce6 nanoprobes for the targeted treatment and noninvasive therapeutic evaluation of breast cancer.

Adoptive cellular immunotherapy as a promising and alternative cancer therapy platform is critical for future clinical applications. Natural killer (NK) cells have attracted attention as an important type of innate immune regulatory cells that can rapidly kill multiple adjacent cancer cells. However, these cells are significantly less effective in treating solid tumors than in treating hematological tumors. Herein, we report the synthesis of a Fe3O4-PEG-CD56/Avastin@Ce6 nanoprobe labeled with NK-92 cells that can be used for adoptive cellular immunotherapy, photodynamic therapy and dual-modality imaging-based in vivo fate tracking. The labeled NK-92 cells specifically target the tumor cells, which increases the amount of cancer cell apoptosis in vitro. Furthermore, the in vivo results indicate that the labeled NK-92 cells can be used for tumor magnetic resonance imaging and fluorescence imaging, adoptive cellular immunotherapy, and photodynamic therapy after tail vein injection. These data show that the developed multifunctional nanostructure is a promising platform for efficient innate immunotherapy, photodynamic treatment and noninvasive therapeutic evaluation of breast cancer.

Why •CF2H is nucleophilic but •CF3 is electrophilic in reactions with heterocycles.

Radical substitution is a useful method to functionalize heterocycles, as in the venerable Minisci reaction. Empirically observed regiochemistries indicate that the CF2H radical has a nucleophilic character similar to alkyl radicals, but the CF3 radical is electrophilic. While the difference between •CH3 and •CF3 is well understood, the reason that one and two Fs make little difference but the third has a large effect is puzzling. DFT calculations with M06-2X both reproduce experimental selectivities and also lead to an explanation of this difference. Theoretical methods reveal how the F inductive withdrawal and conjugative donation alter radical properties, but only CF3 becomes decidedly electrophilic toward heterocycles. Here, we show a simple model to explain the radical orbital energy trends and resulting nucleophilicity or electrophilicity of fluorinated radicals.

Tumor Microenvironment Specific Regulation Ca-Fe-Nanospheres for Ferroptosis-Promoted Domino Synergistic Therapy and Tumor Immune Response.

Reactive oxygen species (ROS)-mediated emerging treatments exhibit unique advantages in cancer therapy in recent years. While the efficacy of ROS-involved tumor therapy is greatly restricted by complex tumor microenvironment (TME). Herein, a dual-metal CaO2@CDs-Fe (CCF) nanosphere, with TME response and regulation capabilities, are proposed to improve ROS lethal power by a multiple cascade synergistic therapeutic strategy with domino effect. In response to weak acidic TME, CCF will decompose, accompanied with intracellular Ca2+ upregulated and abundant H2O2 and O2 produced to reverse antitherapeutic TME. Then the exposed CF cores can act as both Fenton agent and sonosensitizer to generate excessive ROS in the regulated TME for enhanced synergistic CDT/SDT. In combination with calcium overloading, the augmented ROS induced oxidative stress will cause more severe mitochondrial damage and cellular apoptosis. Furthermore, CCF can also reduce GPX4 expression and enlarge the lipid peroxidation, causing ferroptosis and apoptosis in parallel. These signals of damage will finally initiate damage-associated molecular patterns to activate immune response and to realize excellent antitumor effect. This outstanding domino ROS/calcium loading synergistic effect endows CCF with excellent anticancer effect to efficiently eliminate tumor by apoptosis/ferroptosis/ICD both in vitro and in vivo.

Boosting the Faradaic Efficiency of Br--Mediated Photoelectrochemical Epoxidation by Local Acidity on α-Fe2O3.

The redox mediated photoelectrochemical (PEC) or electrochemical (EC) alkene oxidation process is a promising method to produce high value-added epoxides. However, due to the competitive reaction of water oxidation and overoxidation of the mediator, the utilization of the electricity is far below the ideal value, where the loss of epoxidation's faradaic efficiency (FE) is ≈50%. In this study, a Br-/HOBr-mediated method is developed to achieve a near-quantitative selectivity and ≈100% FE of styrene oxide on α-Fe2O3, in which low concentration of Br- as mediator and locally generated acidic micro-environment work together to produce the higher active HOBr species. A variety of styrene derivatives are investigated with satisfied epoxidation performance. Based on the analysis of local pH-dependent epoxidation FE and products distribution, the study further verified that HOBr serves as the true active mediator to generate the bromohydrin intermediate. It is believed that this strategy can greatly overcome the limitation of epoxidation FE to enable future industrial applications.

Differentiation of confluent hepatic fibrosis and infiltrative hepatocellular carcinoma on MR imaging.

BACKGROUND: To identify reliable magnetic resonance imaging (MRI) features that can differentiate confluent fibrosis (CF) from infiltrative hepatocellular carcinoma (HCC). METHODS: A retrospective analysis was conducted on Twenty CF patients and 28 infiltrative HCC patients who underwent upper abdomen MRI scans. The imaging features of lesions were analyzed, and the apparent diffusion coefficient (ADC) of lesions were measured. Accuracy, sensitivity and specificity for the diagnosis of CF were calculated for each category individually and combined. RESULTS: Compared to infiltrative HCC, hepatic capsular retraction at the site of lesion, hepatic volume loss at the site of lesion and "nodular surround sign" were more common in patients with CF (all P < 0.001). Hepatic volume loss at the site of lesion, no or mild enhancement in arterial phase, and hyper-enhancing in delayed phase to the background parenchyma showed superior diagnostic accuracy (83.3%, 85.4%, 97.9%, respectively). When the lesion exhibited hepatic volume loss at the site of lesion or no or mild enhancement in arterial phase or hyper-enhancing in delayed phase, a sensitivity of 100.0% for the diagnosis of CF was achieved. When the lesion was positive for any two of three categories, or positive for all three categories, a specificity of 100.0% was achieved. The ADC values of CF were higher than those of infiltrative HCC (P < 0.001). CONCLUSION: The combination of the hepatic volume loss at the site of lesion, no or mild enhancement in arterial phase, and hyper-enhancing in delayed phase to the background parenchyma can be considered reliable MR features for the diagnosis of CF, as they allow differentiation from infiltrative HCC.

Nanomaterials-Involved Tumor-Associated Macrophages' Reprogramming for Antitumor Therapy.

Tumor-associated macrophages (TAMs) play pivotal roles in tumor development. As primary contents of tumor environment (TME), TAMs secrete inflammation-related substances to regulate tumoral occurrence and development. There are two kinds of TAMs: the tumoricidal M1-like TAMs and protumoral M2-like TAMs. Reprogramming TAMs from immunosuppressive M2 to immunocompetent M1 phenotype is considered a feasible way to improve immunotherapeutic efficiency. Notably, nanomaterials show great potential for biomedical fields due to their controllable structures and properties. There are many types of nanomaterials that exhibit great regulatory activities for TAMs' reprogramming. In this review, the recent progress of nanomaterials-involved TAMs' reprogramming is comprehensively discussed. The various nanomaterials for TAMs' reprogramming and the reprogramming strategies are summarized and introduced. Additionally, the challenges and perspectives of TAMs' reprogramming for efficient therapy are discussed, aiming to provide inspiration for TAMs' regulator design and promote the development of TAMs-mediated immunotherapy.

Organocatalytic aromatization-promoted umpolung reaction of imines.

The umpolung functionalization of imines bears vast synthetic potential, but polarity inversion is less efficient compared with the carbonyl counterparts. Strong nucleophiles are often required to react with the N-electrophiles without catalytic and stereochemical control. Here we show an effective strategy to realize umpolung of imines promoted by organocatalytic aromatization. The attachment of strongly electron-withdrawing groups to imines could enhance the umpolung reactivity by both electronegativity and aromatic character, enabling the direct amination of (hetero)arenes with good efficiencies and stereoselectivities. Additionally, the application of chiral Brønsted acid catalyst furnishes (hetero)aryl C-N atropisomers or enantioenriched aliphatic amines via dearomative amination from N-electrophilic aromatic precursors. Control experiments and density functional theory calculations suggest an ionic mechanism for the umpolung reaction of imines. This disconnection expands the options to forge C-N bonds stereoselectively on (hetero)arenes, which represents an important synthetic pursuit, especially in medicinal chemistry.

Synthesis, Characterization and X-Ray Crystal Structures of Oxidovanadium(V) Complexes Derived from N'-(2-Hydroxy-5-methylbenzylidene)-4-methylbenzohydrazide with Antibacterial Activity.

A dinuclear oxidovanadium(V) complex [V2O2L2(OMe)2] (1) was synthesized from N'-(2-hydroxy-5-methylbenzylidene)-4-methylbenzohydrazide (H2L) and VO(acac)2 in MeOH. Reaction of complex 1 with 3-hydroxy-2-methyl-4-pyrone (HL') afforded a mononuclear oxidovanadium(V) complex [VOLL'] (2). The hydrazone and both complexes were characterized by IR, UV and 1H NMR spectroscopy, as well as X-ray single crystal determination. X-ray powder diffraction of the complexes was performed. The V atoms in the two complexes are in octahedral coordination. The molecules of complex 2 are linked through non-classical hydrogen bonds of type C-H∙∙∙O to form one-dimensional chains running along the a axis. The biological assay indicates that the complexes have good antimicrobial activities on the bacteria strains P. aeroginosa, S. aureus, B. subtilis and E. coli.

Visible-light optical coherence tomography platform for the characterization of the skin barrier.

We demonstrate a free-space, trolley-mountable Fourier domain visible-light optical coherence tomography (OCT) system for studying the stratum corneum in non-palmar human skin. An axial resolution of 1 µm in tissue and at least -75 dB sensitivity have been achieved. High-quality B-scans, containing 1600 A-scans, are acquired at a rate of 39 Hz. Images from the dorsal hand, ventral wrist and ventral forearm areas are obtained, with a clearly resolved stratum corneum layer (typically 5-15 µm thick) presenting as a hypoechogenic dark layer below the bright entrance signal, similar to that found in palmar skin with traditional OCT systems. We find that the appearance of the stratum corneum layer strongly depends on its water content, becoming brighter after occlusive hydration.

Novel assays for quality evaluation of XueBiJing: Quality variability of a Chinese herbal injection for sepsis management.

XueBiJing is an intravenous five-herb injection used to treat sepsis in China. The study aimed to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS)- or liquid chromatography-ultraviolet (LC-UV)-based assay for quality evaluation of XueBiJing. Assay development involved identifying marker constituents to make the assay therapeutically relevant and building a reliable one-point calibrator for monitoring the various analytes in parallel. Nine marker constituents from the five herbs were selected based on XueBiJing's chemical composition, pharmacokinetics, and pharmacodynamics. A selectivity test (for "similarity of response") was developed to identify and minimize interference by non-target constituents. Then, an intercept test was developed to fulfill "linearity through zero" for each analyte (absolute ratio of intercept to C response, <2%). Using the newly developed assays, we analyzed samples from 33 batches of XueBiJing, manufactured over three years, and found small batch-to-batch variability in contents of the marker constituents (4.1%-14.8%), except for senkyunolide I (26.5%).

Discovery of a Thioxanthone-TfOH Complex as a Photoredox Catalyst for Hydrogenation of Alkenes Using p-Xylene as both Electron and Hydrogen Sources.

Hydrogenation of alkenes is one of the most fundamental transformations in organic synthesis, and widely used in the petrochemical, pharmaceutical, and food industries. Although numerous hydrogenation methods have been developed, novel types of catalysis with new mechanisms and new hydrogen sources are still desirable. Thioxanthone (TX) is widely used in energy-transfer photoreactions, but rarely in photoredox processes. Herein we show that a catalytic amount of TfOH as a co-catalyst can tune the properties of TX to make it a photoredox catalyst with highly enhanced oxidative capability in the hydrogenation of carbonylated alkenes with the cheap petroleum industrial product p-xylene serving as the hydrogen source. Deuterium can also be introduced by this method by using D2 O as the D source. To the best of our knowledge, this is the first example of using p-xylene as a hydrogen source.

Unusual Enantiodivergence in Chiral Brønsted Acid-Catalyzed Asymmetric Allylation with ß-Alkenyl Allylic Boronates.

We report herein a rare example of enantiodivergent aldehyde addition with ß-alkenyl allylic boronates via chiral Brønsted acid catalysis. 2,6-Di-9-anthracenyl-substituted chiral phosphoric acid-catalyzed asymmetric allylation using ß-vinyl substituted allylic boronate gave alcohols with R absolute configuration. The sense of asymmetric induction of the catalyst in these reactions is opposite to those in prior reports. Moreover, in the presence of the same acid catalyst, the reactions with ß-2-propenyl substituted allylic boronate generated homoallylic alcohol products with S absolute configuration. Unusual substrate-catalyst C-H⋅⋅⋅π interactions in the favoured reaction transition state were identified as the origins of observed enantiodivergence through DFT computational studies.

LncRNA and mRNA expression profiles in brown adipose tissue of obesity-prone and obesity-resistant mice.

Obesity-prone or obesity-resistant phenotypes can exist in individuals who consume the same diet type. Brown adipose tissue functions to dissipate energy in response to cold exposure or overfeeding. Long noncoding RNAs play important roles in a wide range of biological processes. However, systematic examination of lncRNAs in phenotypically divergent mice has not yet been reported. Here, the lncRNA expression profiles in BAT of HFD-induced C57BL/6J mice were investigated by high-throughput RNA sequencing. Genes that play roles in thermogenesis and related pathways were identified. We found lncRNA (Gm44502) may play a thermogenic role in obesity resistance by interacting with six mRNAs. Our results also indicated that seven differentially expressed lncRNAs (4930528G23Rik, Gm39490, Gm5627, Gm15551, Gm16083, Gm36860, Gm42002) may play roles in reducing heat production in obesity susceptibility by interacting with seven differentially expressed mRNAs. The screened lncRNAs may participate in the pathogenesis of weight regulation and provide insight into obesity therapy.

Organocatalytic discrimination of non-directing aryl and heteroaryl groups: enantioselective synthesis of bioactive indole-containing triarylmethanes.

Despite the enormous developments in asymmetric catalysis, the basis for asymmetric induction is largely limited to the spatial interaction between the substrate and catalyst. Consequently, asymmetric discrimination between two sterically similar groups remains a challenge. This is particularly formidable for enantiodifferentiation between two aryl groups without a directing group or electronic manipulation. Here we address this challenge by using a robust organocatalytic system leading to excellent enantioselection between aryl and heteroaryl groups. With versatile 2-indole imine methide as the platform, an excellent combination of a superb chiral phosphoric acid and the optimal hydride source provided efficient access to a range of highly enantioenriched indole-containing triarylmethanes. Control experiments and kinetic studies provided important insights into the mechanism. DFT calculations also indicated that while hydrogen bonding is important for activation, the key interaction for discrimination of the two aryl groups is mainly π-π stacking. Preliminary biological studies also demonstrated the great potential of these triarylmethanes for anticancer and antiviral drug development.

Mitochondrial apolipoprotein A-I binding protein alleviates atherosclerosis by regulating mitophagy and macrophage polarization.

Apolipoprotein A-I binding protein (AIBP), a secreted protein, has been shown to play a pivotal role in the development of atherosclerosis. The function of intracellular AIBP, however, is not yet well characterized. Here, we found that AIBP is abundantly expressed within human and mouse atherosclerotic lesions and exhibits a distinct localization in the inner membrane of mitochondria in macrophages. Bone marrow-specific AIBP deficiency promotes the progression of atherosclerosis and increases macrophage infiltration and inflammation in low-density lipoprotein receptor-deficient (LDLR-/-) mice. Specifically, the lack of mitochondrial AIBP leads to mitochondrial metabolic disorders, thereby reducing the formation of mitophagy by promoting the cleavage of PTEN-induced putative kinase 1 (PINK1). With the reduction in mitochondrial autophagy, macrophages polarize to the M1 proinflammatory phenotype, which further promotes the development of atherosclerosis. Based on these results, mitochondrial AIBP in macrophages performs an antiatherosclerotic role by regulating of PINK1-dependent mitophagy and M1/M2 polarization. Video Abstract.

Hydrogen Abstraction by Alkoxyl Radicals: Computational Studies of Thermodynamic and Polarity Effects on Reactivities and Selectivities.

Density functional theory calculations (ωB97X-D) are reported for the reactions of methoxy, tert-butoxy, trichloroethoxy, and trifluoroethoxy radicals with a series of 26 C-H bonds in different environments characteristic of a variety of hydrocarbons and substituted derivatives. The variations in activation barriers are analyzed with modified Evans-Polanyi treatments to account for polarity and unsaturation effects. The treatments by Roberts and Steel and by Mayer have inspired the development of a simple treatment involving the thermodynamics of reactions, the difference between the reactant radical and product radical electronegativities, and the absence or presence of α-unsaturation. The three-parameter equation (ΔH⧧ = 0.52ΔHrxn(1 - d) - 0.35ΔχAB2 + 10.0, where d = 0.44 when there is α-unsaturation to the reacting C-H bond), correlates well with quantum mechanically computed barriers and shows the quantitative importance of the thermodynamics of reactions (dictated by the reactant and the product bond dissociation energies) and polar effects.

Sphingosine-1-phosphate in mitochondrial function and metabolic diseases.

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite. The past decade has witnessed exponential growth in the field of S1P research, partly attributed to drugs targeting its receptors or kinases. Accumulating evidence indicates that changes in the S1P axis (i.e., S1P production, transport, and receptors) may modify metabolism and eventually mediate metabolic diseases. Dysfunction of the mitochondria on a master monitor of cellular metabolism is considered the leading cause of metabolic diseases, with aberrations typically induced by abnormal biogenesis, respiratory chain complex disorders, reactive oxygen species overproduction, calcium deposition, and mitophagy impairment. Accordingly, we discuss decades of investigation into changes in the S1P axis and how it controls mitochondrial function. Furthermore, we summarize recent scientific advances in disorders associated with the S1P axis and their involvement in the pathogenesis of metabolic diseases in humans, including type 2 diabetes mellitus and cardiovascular disease, from the perspective of mitochondrial function. Finally, we review potential challenges and prospects for S1P axis application to the regulation of mitochondrial function and metabolic diseases; these data may provide theoretical guidance for the treatment of metabolic diseases.

Chiral Phosphoric Acid Catalyzed Conversion of Epoxides into Thiiranes: Mechanism, Stereochemical Model, and New Catalyst Design.

Computations and experiments leading to new chiral phosphoric acids (CPAs) for epoxide thionations are reported. Density functional theory calculations reveal the mechanism and origin of the enantioselectivity of such CPA-catalyzed epoxide thionations. The calculated mechanistic information was used to design new efficient CPAs that were tested experimentally and found to be highly effective. Bulky ortho-substituents on the 3,3'-aryl groups of the CPA are important to restrict the position of the epoxide in the key transition states for the enantioselectivity-determining step. Larger para-substituents significantly improve the enantioselectivity of the reaction.

Research progress on artemisinin antimalarial resistance of Plasmodium falciparum / 中国热带医学

@#Abstract: Malaria, an infectious disease caused by Plasmodium infection, is one of the most important public health problems worldwide. Artemisinin-based combination therapies (ACTs) are recommended by WHO as the first-line treatment for uncomplicated P. falciparum malaria in malaria-endemic areas. The application of artemisinin and its derivatives has played an integral role in reducing the global incidence of malaria. However, in recent years, the emergence and spread of artemisinin resistance has brought great challenges to global malaria control and elimination. At present, the mutation of K13 gene on chromosome 13 of Plasmodium falciparum is most closely related to artemisinin resistance, but in recent years, studies have shown that K13 cannot explain all artemisinin resistance. This article reviews the recent research progress in the field of artemisinin resistance in Plasmodium falciparum, including definition of artemisinin resistance, detection methods and molecular markers related to resistance. In addition, some of the issues discussed in this review remain controversial and require further study.