Turning anecdotal irradiation-induced anticancer immune responses into reproducible in situ cancer vaccines via disulfiram/copper-mediated enhanced immunogenic cell death of breast cancer cells.

Irradiation (IR) induces immunogenic cell death (ICD) in tumors, but it rarely leads to the abscopal effect (AE); even combining IR with immune checkpoint inhibitors has shown only anecdotal success in inducing AEs. In this study, we aimed to enhance the IR-induced immune response and generate reproducible AEs using the anti-alcoholism drug, disulfiram (DSF), complexed with copper (DSF/Cu) to induce tumor ICD. We measured ICD in vitro and in vivo. In mouse tumor models, DSF/Cu was injected intratumorally followed by localized tumor IR, creating an in situ cancer vaccine. We determined the anticancer response by primary tumor rejection and assessed systemic immune responses by tumor rechallenge and the occurrence of AEs relative to spontaneous lung metastasis. In addition, we analyzed immune cell subsets and quantified proinflammatory and immunosuppressive chemokines/cytokines in the tumor microenvironment (TME) and blood of the vaccinated mice. Immune cell depletion was investigated for its effects on the vaccine-induced anticancer response. The results showed that DSF/Cu and IR induced more potent ICD under hypoxia than normoxia in vitro. Low-dose intratumoral (i.t.) injection of DSF/Cu and IR(12Gy) demonstrated strong anti-primary and -rechallenged tumor effects and robust AEs in mouse models. These vaccinations also increased CD8+ and CD4+ cell numbers while decreasing Tregs and myeloid-derived suppressor cells in the 4T1 model, and increased CD8+, dendritic cells (DC), and decreased Treg cell numbers in the MCa-M3C model. Depleting both CD8+ and CD4+ cells abolished the vaccine's anticancer response. Moreover, vaccinated tumor-bearing mice exhibited increased TNFα levels and reduced levels of immunosuppressive chemokines/cytokines. In conclusion, our novel approach generated an anticancer immune response that results in a lack of or low tumor incidence post-rechallenge and robust AEs, i.e., absence of or decreased spontaneous lung metastasis in tumor-bearing mice. This approach is readily translatable to clinical settings and may increase IR-induced AEs in cancer patients.

Single-cell analysis of immune and stroma cell remodeling in clear cell renal cell carcinoma primary tumors and bone metastatic lesions.

BACKGROUND: Despite therapeutic advances, once a cancer has metastasized to the bone, it represents a highly morbid and lethal disease. One third of patients with advanced clear cell renal cell carcinoma (ccRCC) present with bone metastasis at the time of diagnosis. However, the bone metastatic niche in humans, including the immune and stromal microenvironments, has not been well-defined, hindering progress towards identification of therapeutic targets. METHODS: We collected fresh patient samples and performed single-cell transcriptomic profiling of solid metastatic tissue (Bone Met), liquid bone marrow at the vertebral level of spinal cord compression (Involved), and liquid bone marrow from a different vertebral body distant from the tumor site but within the surgical field (Distal), as well as bone marrow from patients undergoing hip replacement surgery (Benign). In addition, we incorporated single-cell data from primary ccRCC tumors (ccRCC Primary) for comparative analysis. RESULTS: The bone marrow of metastatic patients is immune-suppressive, featuring increased, exhausted CD8 + cytotoxic T cells, T regulatory cells, and tumor-associated macrophages (TAM) with distinct transcriptional states in metastatic lesions. Bone marrow stroma from tumor samples demonstrated a tumor-associated mesenchymal stromal cell population (TA-MSC) that appears to be supportive of epithelial-to mesenchymal transition (EMT), bone remodeling, and a cancer-associated fibroblast (CAFs) phenotype. This stromal subset is associated with poor progression-free and overall survival and also markedly upregulates bone remodeling through the dysregulation of RANK/RANKL/OPG signaling activity in bone cells, ultimately leading to bone resorption. CONCLUSIONS: These results provide a comprehensive analysis of the bone marrow niche in the setting of human metastatic cancer and highlight potential therapeutic targets for both cell populations and communication channels.

Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment.

The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumors is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquire early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogram and reverse the immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells of healthy donors or metastatic female breast cancer patients, induce robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a promising therapy for solid tumors.

Turning anecdotal irradiation-induced anti-cancer immune responses into reproducible in situ cancer vaccines via disulfiram/copper-mediated enhanced immunogenic cell death of breast cancer cells.

Irradiation (IR) induces immunogenic cell death (ICD) in tumors, but it rarely leads to the abscopal effect (AE). However, combining IR with immune checkpoint inhibitors has shown anecdotal success in inducing AEs. In this study, we aimed to enhance the IR-induced immune response and generate reproducible AEs using the anti-alcoholism drug disulfiram (DSF) and copper complex (DSF/Cu) via induction of tumor ICD. We measured ICD in vitro and in vivo. In mouse tumor models, DSF/Cu was injected intratumorally followed by localized tumor IR, creating an in situ cancer vaccine. We determined the anti-cancer response by primary tumor rejection and assessed systemic immune responses by tumor rechallenge and the occurrence of AEs, i.e., spontaneous lung metastasis. Additionally, we analyzed immune cell subsets and quantified proinflammatory and immunosuppressive chemokines/cytokines in the tumor microenvironment (TME) and blood of the vaccinated mice. Immune cell depletion was investigated for its effects on the vaccine-induced anti-cancer response. The results showed that DSF/Cu and IR induced more potent ICD under hypoxia than normoxia in vitro. Low-dose intratumoral injection of DSF/Cu and IR demonstrated strong anti-primary and -rechallenged tumor effects and robust AEs in mouse models. These vaccinations also increased CD8 + and CD4 + cell numbers while decreasing Tregs and myeloid-derived suppressor cells in the 4T1 model, and increased CD8+, DC, and decreased Treg cell numbers in the MCa-M3C model. Depleting both CD8 + and CD4 + cells abolished the vaccine's anticancer response. Moreover, vaccinated tumor-bearing mice exhibited increased TNFα levels and reduced levels of immunosuppressive chemokines/cytokines. In conclusion, our novel approach generated an anti-cancer immune response, resulting in a lack of or low tumor incidence post-rechallenge and robust AEs, i.e., the absence of or decreased spontaneous lung metastasis in tumor-bearing mice. This approach is readily translatable to clinical settings and may increase IR-induced AEs in cancer patients.

Microstructure-Based Multiscale Modeling of Deformation in MarBN Steel under Uniaxial Tension: Experiments and Finite Element Simulations.

In the current work, a multiscale model was developed coupling a macro-model with the macromechanical physically based yield strength and a crystal plasticity model with micromechanical properties and realistic grain orientation based on the representative volume element. The simulation results show that the effect of microstructure on the macromechanical properties can be considered in the macro constitutive model due to a good consistency between experimental and computed results; whereas solid strengthening, grain boundaries, and dislocation density played a more crucial role than others. Besides coupling simulation and microstructure by EBSD, the microstructure evolution can be well explained by the micromechanical model. Strain is related to the grain orientation, leading to inhomogeneous deformation, forming the various Schmid factor and slip systems. A plastic strain occurs close to the grain boundaries and declines into the grain, resulting in higher kernel average misorientation (KAM) and geometry necessary dislocations (GNDs) in the grain boundaries. The higher the loading, the higher the local strain. Shear bands with around 45 degrees can be formed, resulting in crack initiation and tensile shear failure. This work has developed the guidance of structural integrity assessment and prediction of mechanical properties for the engineering material and components.

Covalent Modification of Proteins by Osthole Reactive Metabolites using Proteomic Approaches.

BACKGROUND: Osthole (OST) is a bioactive natural coumarin derived from the plant Cnidium monnieri (L.) Cusson fruit (She Chuang Zi), which has various pharmacological and biological activities. OST contains an α,ß- unsaturated lactone, which is an electrophilic group that tends to be metabolized into reactive metabolites (RMs). Then, RMs are able to covalently modify nucleophilic amino acid (AA) residues of target proteins. However, few researchers considered the contribution of the covalent modification induced by OST or its metabolites. OBJECTIVE: This study aims to investigate the metabolic profile and the metabolites-protein modification of OST. METHODS: The metabolites of OST were qualitatively identified using UHPLC-Q-TOF-MS. The RMs modification patterns and potentially modified AA residues were confirmed by UHPLC-Q-TOF-MS using rat liver microsomes (RLMs) and model AAs. Finally, the modified peptides derived from high-abundance microsomal peptides were separated via nano-LC-Orbitrap-MS, and then RM-modified proteins were identified using a proteome discoverer. RESULTS: In the presence of RLMs, OST could rapidly be metabolized within 1 h and hardly identified at 4 h. We detected 10 OST metabolites, 13 OST metabolites-NAC (N-acetyl cysteine) adducts, 3 NAL (N-acetyl lysine) adducts, and 11 GSH (glutathione) adducts. Furthermore, 16 RM-modified protein targets were identified, many of which are included in the essential biological processes of OST's anti-Alzheimer's disease (AD) and anti-tumor. CONCLUSION: This study provides a novel perspective on the molecular mechanism of OST's pharmacological activities, as well as identifies potential targets for further development and application of OST and other Natural products (NPs).

Ultrasensitive quantification of trace amines based on N-phosphorylation labeling chip 2D LC-QQQ/MS.

Trace amines (TAs) are metabolically related to catecholamine and associated with cancer and neurological disorders. Comprehensive measurement of TAs is essential for understanding pathological processes and providing proper drug intervention. However, the trace amounts and chemical instability of TAs challenge quantification. Here, diisopropyl phosphite coupled with chip two-dimensional (2D) liquid chromatography tandem triple-quadrupole mass spectrometry (LC-QQQ/MS) was developed to simultaneously determine TAs and associated metabolites. The results showed that the sensitivities of TAs increased up to 5520 times compared with those using nonderivatized LC-QQQ/MS. This sensitive method was utilized to investigate their alterations in hepatoma cells after treatment with sorafenib. The significantly altered TAs and associated metabolites suggested that phenylalanine and tyrosine metabolic pathways were related to sorafenib treatment in Hep3B cells. This sensitive method has great potential to elucidate the mechanism and diagnose diseases considering that an increasing number of physiological functions of TAs have been discovered in recent decades.

Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and tumor microenvironment, overcoming multiple obstacles of CAR T therapy for solid tumors.

The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumor is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach massively reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquired early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogrammed and reversed immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells (PBMC) of healthy or metastatic breast cancer patients, induced robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a novel therapy for solid tumor.

Modified anterior approach preserving Retzius space versus standard anterior approach robot-assisted radical prostatectomy: A matched-pair analysis.

Objective: To compare our initial perioperative and postoperative outcomes of the modified anterior approach (MA) with Retzius space preservation robot-assisted radical prostatectomy (RARP) with the standard anterior approach (SA) RARP. Materials and methods: A retrospective analysis was performed on 116 patients with RARP completed by the same surgeon between September 2019 and March 2022. They were divided into SA-RARP group (77 cases) and MA-RARP group (39 cases). Propensity score matching was performed using eight preoperative variables, including age, BMI, preoperative PSA, biopsy Gleason score, prostate volume, D'Amico risk classification, SHIM, and clinical T stage. Functional outcome was assessed by urine pad count and SHIM after surgery, and oncological outcome was assessed by statistics of postoperative pathological findings as well as follow-up postoperative PSA. The median follow-up was 13 months and 17 months for MA-RARP and SA-RARP groups respectively. Results: Propensity score matching was performed 1:1, and baseline data were comparable between the two groups after matching. Comparison of postoperative data: MA-RARP group had less mean EBL than SA-RARP group (200 vs 150 ml, p = 0.033). PSM did not differ between groups (p = 1). In terms of urinary control recovery, the MA-RARP group showed significant advantages in urinary control recovery at 24 h, 2 weeks, 1 month and 3 months after catheter removal, respectively (48.6% vs 5.7%, p < 0.001; 80% vs 22.9%, p < 0.001; 94.3% vs 51.4%, p < 0.001; 100% vs 74.3%, p = 0.002). This advantage gradually disappeared 6 months or more after surgery. The median time to recovery of sexual function was shorter in the MA-RARP group (165 vs 255 d, p = 0.001). Conclusion: MA-RARP is safe and reliable, and can achieve better early urinary control function and sexual function recovery while achieving the primary tumor control goal.

Combination of chemical profiling and network pharmacology analysis to investigate the potential mechanism of Li-Zhong-Xiao-Pi granules in the treatment of gastric precancerous lesions.

Li-Zhong-Xiao-Pi granules (LZXP) are effective for treating gastric precancerous lesions (GPL) in traditional Chinese medicine. However, the active compounds of LZXP and their potential therapeutic mechanism in GPL remained unclarified. The purpose of this study is to investigate the chemical composition and potential targets of LZXP. Based on the accurate masses, ion fragments, and literature data, a total of 128 compounds were identified in the LZXP sample using ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) in both positive and negative ion modes, and 28 of these compounds were exactly determined by comparison with authentic reference standards. Meanwhile, 11 typical components were quantified via UPLC during a 24 min period. The linearity, accuracy, stability and recovery of the method were all proven. Through the network pharmacological analysis, six chemicals (quercetin, 4'-hydroxywogonin, sinensetin, 5, 7, 8, 3', 4'-pentamethoxyflavanone, 8-gingerdione and quercetin) were identified as the active ingredients, and five LZXP targets (AKT1, CYP1B1, PTGS2, MMP9 and EGFR) were found to be the crucial molecules in the treatment of GPL. This study provides a systematic and applicable method for the rapid screening and identification of the chemical constituents from LZXP, and an effective understanding the mechanism of LZXP in the treatment of GPL.

Development of a Novel Deep Learning-Based Prediction Model for the Prognosis of Operable Cervical Cancer.

Background: Cervical cancer ranks as the 4th most common female cancer worldwide. Early stage cervical cancer patients can be treated with operation, but clinical staging system is not a good predictor of patients' survival. We aimed to develop a novel prognostic model to predict the prognosis for operable cervical cancer patients with better accuracy than clinical staging system. Methods: A total of 13,952 operable cervical cancer patients were retrospectively enrolled in this study. The whole dataset was randomly split into a training set (n = 9,068, 65%), validation set (n = 2,442, 17.5%), and testing set (n = 2,442, 17.5%). Cox proportional hazard (CPH) model and random survival forest (RSF) model were used as baseline models for the prediction of overall survival (OS). Then, a deep survival learning model (DSLM) was developed for OS prediction. Finally, a novel prognostic model was explored based on this DSLM. Results: The C-indexes for the CPH and RSF model were 0.731 and 0.753, respectively. DSLM, which had four layers that had 50 neurons in each layer, achieved a C-index of 0.782 in the validation set and a C-index of 0.758 in the testing set. The novel prognostic model based on DSLM showed better performances than the conventional clinical staging system (area under receiver operating curves were 0.826 and 0.689, respectively). Personalized survival curves for individual patient using this novel model also showed notably different survival slopes. Conclusions: Our study developed a novel, practical, personalized prognostic model for operable cervical cancer patients. This novel prognostic model may have the potential to provide a more prognostic information to oncologists.

Monitoring Electron Flow in Nickel Single-Atom Catalysts during Nitrogen Photofixation.

An efficient catalytic system for nitrogen (N2) photofixation generally consists of light-harvesting units, active sites, and an electron-transfer bridge. In order to track photogenerated electron flow between different functional units, it is highly desired to develop in situ characterization techniques with element-specific capability, surface sensitivity, and detection of unoccupied states. In this work, we developed in situ synchrotron radiation soft X-ray absorption spectroscopy (in situ sXAS) to probe the variation of electronic structure for a reaction system during N2 photoreduction. Nickel single-atom and ceria nanoparticle comodified reduced graphene oxide (CeO2/Ni-G) was designed as a model catalyst. In situ sXAS directly reveals the dynamic interfacial charge transfer of photogenerated electrons under illumination and the consequent charge accumulation at the catalytic active sites for N2 activation. This work provides a powerful tool to monitor the electronic structure evolution of active sites under reaction conditions for photocatalysis and beyond.

Construction and validation of a prognostic model for predicting overall survival of primary adrenal malignant tumor patients: A population-based study with 1,080 patients.

Objective: Primary adrenal malignant tumor is rare. The factors affecting the prognosis remain poorly defined. This study targeted to construct and corroborate a model for predicting the overall survival of adrenal malignant tumor patients. Methods: We investigated the SEER database for patients with primary adrenal malignant tumor. 1,080 patients were divided into a construction cohort (n = 756) and a validation cohort (n = 324), randomly. The prognostic factors for overall survival were evaluated using univariate and multivariate Cox analyses. The nomogram was constructed and then validated with C-index, calibration curve, time-dependent ROC curve, and decision curve analysis in both cohorts. Then we divided the patients into 3 different risk groups according to the total points of the nomogram and analyzed their survival status by Kaplan-Meier curve with log-rank test. Results: The baseline characteristics of these two cohorts were not statistically different (P > 0.05). Using univariate and multivariate Cox analyses, 5 variables, including age, tumor size, histological type, tumor stage, and surgery of primary site, were distinguished as prognostic factors (P < 0.05). Based on these variables, we constructed a nomogram to predict the 3- year, 5- year, and 10-year overall survival. The C-indexes were 0.780 (0.760-0.800) in the construction cohort and 0.780 (0.751-0.809) in the validation cohort. In both cohorts, the AUC reached a fairly high level at all time points. The internal and external calibration curves and ROC analysis showed outstanding accuracy and discrimination. The decision curves indicated excellent clinical usefulness. The best cut-off values for the total points of the nomogram were 165.4 and 243.1, and the prognosis was significantly different for the three different risk groups (P < 0.001). Conclusion: We successfully constructed a model to predict the overall survival of primary adrenal malignant tumor patients. This model was validated to perform brilliantly internally and externally, which can assist us in individualized clinical management.

Sp1 S-Sulfhydration Induced by Hydrogen Sulfide Inhibits Inflammation via HDAC6/MyD88/NF-κB Signaling Pathway in Adjuvant-Induced Arthritis.

Histone deacetylase 6 (HDAC6) acts as a regulator of the nuclear factor kappa-B (NF-κB) signaling pathway by deacetylating the non-histone protein myeloid differentiation primary response 88 (MyD88) at lysine residues, which is an adapter protein for the Toll-like receptor (TLR) and interleukin (IL)-1ß receptor. Over-activated immune responses, induced by infiltrated immune cells, excessively trigger the NF-κB signaling pathway in other effector cells and contribute to the development of rheumatoid arthritis (RA). It has also been reported that HDAC6 can promote the activation of the NF-κB signaling pathway. In the present study, we showed that HDAC6 protein level was increased in the synovium tissues of adjuvant-induced arthritis rats. In addition, hydrogen sulfide (H2S) donor S-propargyl-cysteine (SPRC) can inhibit HDAC6 expression and alleviate inflammatory response in vivo. In vitro study revealed that HDAC6 overexpression activated the NF-κB signaling pathway by deacetylating MyD88. Meanwhile, sodium hydrosulfide (NaHS) or HDAC6 inhibitor tubastatin A (tubA) suppressed the pro-inflammatory function of HDAC6. Furthermore, the reduced expression of HDAC6 appeared to result from transcriptional inhibition by S-sulfhydrating specificity protein 1 (Sp1), which is a transcription factor of HDAC6. Our results demonstrate that Sp1 can regulate HDAC6 expression, and S-sulfhydration of Sp1 by antioxidant molecular H2S ameliorates RA progression via the HDAC6/MyD88/NF-κB signaling pathway.

Chemical profiling and antioxidants screening from natural products: using CiNingJi as an example.

Natural products with good antioxidative properties have been paid increased attention globally. However, due to its chemical complexity, it is difficult to find out its antioxidative compounds. Herein, the chemical profiling and antioxidant capacity of CiNingJi (CNJ) were analyzed, as an example. By using UHPLC-Q-TOF/MS, a total of 82 compounds were tentatively deduced. Furthermore, its free radical scavenging capacity was assessed by different in vitro spectrophotometric-based assays. The result showed that one ingredient, Rosa roxburghii, plays a critical role in its antioxidant activity. In addition, 18 potential antioxidants were screened out in CNJ by comparing the difference of it with and without DPPH reaction. They were identified mainly as catechin, ellagic acid, kajiichigoside F1, and their derivatives or isomers. With the further quantification of major found antioxidants, our results may provide some knowledge on predicting the antioxidative compounds of natural products. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-022-01049-4.

Urinary Catheterization Induces Delirium-Like Behavior Through Glucose Metabolism Impairment in Mice.

BACKGROUND: Delirium, an acute confusion status, is associated with adverse effects, including the development of Alzheimer's disease. However, the etiology and underlying mechanisms of delirium remain largely to be determined. Many patients have urinary catheterization (UC), and UC is associated with delirium. However, the cause effects of UC-associated delirium and the underlying mechanisms remain largely unknown. We, therefore, established an animal model of UC, without urinary tract infection, in mice and determined whether UC could induce delirium-like behavior in the mice and the underlying mechanism of these effects. METHODS: Adult female mice (16 weeks old) had UC placement under brief isoflurane anesthesia. The delirium-like behavior was determined using our established mice model at 3, 6, 9, and 24 hours after UC placement. We measured the amounts of glucose in both blood and brain interstitial fluid, adenosine triphosphate (ATP) concentration in the cortex, and glucose transporter 1 in the cortex of mice using western blot, immunohistochemistry imaging, reverse transcriptase-polymerase chain reaction (RT-PCR), and fluorescence at 6 hours after the UC placement. Finally, we used vascular endothelial growth factor (VEGF) in the interaction studies. RESULTS: We found that UC induced delirium-like behavior in mice at 3, 6, 9, but not 24 hours after the UC placement. UC decreased glucose amounts in brain interstitial fluid (86.38% ± 4.99% vs 100% ± 6.26%, P = .003), but not blood of mice and reduced ATP amounts (84.49% ± 8.85% vs 100% ± 10.64%, P = .031) in the cortex of mice. Finally, UC reduced both protein amount (85.49% ± 6.83% vs 100% ± 11.93%, P = .040) and messenger ribonucleic acid (mRNA) expression (41.95% ± 6.48% vs 100% ± 19.80%, P = .017) of glucose transporter 1 in the cortex of mice. VEGF attenuated these UC-induced changes. CONCLUSIONS: These data demonstrated that UC decreased brain glucose and energy amounts via impairing the glucose transport from blood to brain, leading to delirium-like behavior in mice. These findings will promote more research to identify the etiologies and underlying mechanisms of delirium.

A pH-targeted and NIR-responsive NaCl-nanocarrier for photothermal therapy and ion-interference therapy.

Transport ions into cells through nanocarrier to achieve ion-interference therapy provides new inspiration for cancer treatment. In this work, a pH-targeted and NIR-responsive NaCl-nanocarrier is prepared using surfactant Vitamin E-O(EG2-Glu) and modified with polydopamine (PDA) and pH-sensitive zwitterionic chitosan (ZWC). The NaCl-nanocarrier is decorated with NH4HCO3 and IR-780 to introduce near-infrared (NIR)-responsive performance and imaging. Once the NaCl-nanocarrier is exposed to NIR laser, the temperature rises rapidly because of the excellent photothermal conversion ability of PDA, then NH4HCO3 is decomposed into NH3 and CO2, which burst the nanocarrier, resulting in Cl- and Na+ "bomb-like" release. This pH-targeted nanocarrier accumulates more at tumor site and when irradiating the site with NIR light, the temperature rises and excessive Cl- and Na+ are released to destroy the ion homeostasis and inhibit tumor growth effectively. Through this strategy, the unique combination of ion interference therapy and photothermal therapy is achieved.

Compressive Strain Modulation of Single Iron Sites on Helical Carbon Support Boosts Electrocatalytic Oxygen Reduction.

Designing and modulating the local structure of metal sites is the key to gain the unique selectivity and high activity of single metal site catalysts. Herein, we report strain engineering of curved single atomic iron-nitrogen sites to boost electrocatalytic activity. First, a helical carbon structure with abundant high-curvature surface is realized by carbonization of helical polypyrrole that is templated from self-assembled chiral surfactants. The high-curvature surface introduces compressive strain on the supported Fe-N4 sites. Consequently, the curved Fe-N4 sites with 1.5 % compressed Fe-N bonds exhibit downshifted d-band center than the planar sites. Such a change can weaken the bonding strength between the oxygenated intermediates and metal sites, resulting a much smaller energy barrier for oxygen reduction. Catalytic tests further demonstrate that a kinetic current density of 7.922 mA cm-2 at 0.9 V vs. RHE is obtained in alkaline media for curved Fe-N4 sites, which is 31 times higher than that for planar ones. Our findings shed light on modulating the local three-dimensional structure of single metal sites and boosting the catalytic activity via strain engineering.

Identification and quantification of markers in Azedarach Fructus and Toosendan Fructus.

Toosendan Fructus with various pharmaceutical activities is a good source for the finding of new bioactive components, especially limonoids inside have been reported to have anticancer and antifeedant activities. To find more potential new bioactive compounds, the mass spectrometric characteristics of nimbolinin-type limonoids were first investigated. Utilizing these characteristics, totally 60 nimbolinins, including 33 new ones and at least 10 bioactive compounds, were identified by ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). Furthermore, based on UHPLC-Q-TOF/MS and statistical analysis, 9 limonoids were identified to be the differential components between Toosendan Fructus and Azedarach Fructus. Particularly, nimbolinin A and toosendanin (TSN) with higher content in Azedarach Fructus and Toosendan Fructus respectively should be good markers. Finally, an UHPLC-triple quadrupole mass spectrometry (UHPLC-QQQ/MS) quantification approach for nimbolinin A and TSN was developed for their quality control. These results provided the basis for drug development and quality control of Toosendan Fructus and Azedarach Fructus.

Spatial distribution analysis of phospholipids in rice by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry imaging.

Phospholipids are one of the main nutrients in rice, which have a positive effect on cancer, coronary heart disease and inflammation. However, phospholipids will become small molecular volatile substances during the aging process of rice, resulting in change the flavor of rice. Therefore, mapping the concentration and the spatial distribution of phospholipids in rice are of tremendous significance in its function research. In this work, we established a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) imaging method for the spatial distribution analysis of phospholipids in rice. A total of 12 phospholipid compounds were found in the range of m/z 500-1000 through a series of conditions optimization. According to the results, lysophosphatidylcholine (LPC) species spread throughout the rice tissue sections and phosphatidylcholine (PC) species distributed in the bran and embryo (particularly in the scutellum). We also compared the signal intensities of phospholipids in different parts of white rice and brown rice by region of interest (ROI) analysis, which showed the relative content of PC species was higher in the embryo and gradually decreased until disappeared with the increase of processing degree during the processing of brown rice to white rice. The PC species on the surface of rice could be used as an important indicator to identify the processing degree of rice. Our work not only establish a MALDI-TOF-MS imaging method for spatial distribution analysis of rice, but also provide the necessary reference for ensuring food security, improving the eating quality of rice and the health benefits of consumers.