A new era of cancer immunotherapy: combining revolutionary technologies for enhanced CAR-M therapy.

Significant advancements have been made in the application of chimeric antigen receptor (CAR)-T treatment for blood cancers during the previous ten years. However, its effectiveness in treating solid tumors is still lacking, necessitating the exploration of alternative immunotherapies that can overcome the significant challenges faced by current CAR-T cells. CAR-based immunotherapy against solid tumors shows promise with the emergence of macrophages, which possess robust phagocytic abilities, antigen-presenting functions, and the ability to modify the tumor microenvironment and stimulate adaptive responses. This paper presents a thorough examination of the latest progress in CAR-M therapy, covering both basic scientific studies and clinical trials. This study examines the primary obstacles hindering the realization of the complete potential of CAR-M therapy, as well as the potential strategies that can be employed to overcome these hurdles. With the emergence of revolutionary technologies like in situ genetic modification, synthetic biology techniques, and biomaterial-supported gene transfer, which provide a wider array of resources for manipulating tumor-associated macrophages, we suggest that combining these advanced methods will result in the creation of a new era of CAR-M therapy that demonstrates improved efficacy, safety, and availability.

Analysis of Variables Associated with Positive Micro-Embolic Signals Detected by Transcranial Doppler in Patients with Atrial Fibrillation and Their Predictive Value for Embolic Risk.

Objective: This study examined the factors associated with positive micro-embolic signals (MES) on transcranial Doppler monitoring in patients with atrial fibrillation (AF), as well as the predictive value of MES for the risk of embolism in AF. Methods: Sixty-six patients who had micro emboli with AF were included in the positive group, and 75 patients who did not have micro emboli with AF served as the control group. The clinical data, congestive heart failure, hypertension, age ≥ 75 (doubled), diabetes mellitus, prior stroke or transient ischemic attack (doubled), vascular disease, age 65-74, female (CHA2DS2-VASc) score, D-dimer (D-d) level, echocardiography results, and brain magnetic resonance imaging (MRI) findings were compared between the two groups. Logistic regression models were used to analyze the relationship between positive micro emboli with CHA2DS2-VASc score, D-d, left atrial anteroposterior diameter (LAD), and silent cerebral ischemia (SCI) occurrence. Results: The CHA2DS2-VASc score, D-d level, and LAD were significantly higher in the positive group than in the control group (P < 0.05) and were accompanied by a higher detection rate of SCI by brain MRI (P < 0.01). Elevated D-d levels, increased LAD, and the detection rate of SCI were all highly positively correlated with positive micro emboli. Also, CHA2DS2-VASc score ≥ 2 showed a significant positive correlation with positive micro emboli, and the higher CHA2DS2-VASc score was associated with a stronger correlation. The multivariate regression analysis demonstrated that positive micro-embolic was independently associated with SCI and a CHA2DS2-VASc score of ≥ 4. Conclusion: Positive micro emboli in patients with persistent AF are consistent with an increased risk of embolism, and are independently associated with a higher CHA2DS2-VASc score and SCI, which can be used as an indicator of individual embolic risk in patients with AF.

Efficiency Assessment of Bacterial Cellulose on Lowering Lipid Levels In Vitro and Improving Lipid Metabolism In Vivo.

Bacterial cellulose (BC) is well known as a high-performance dietary fiber. This study investigates the adsorption capacity of BC for cholesterol, sodium cholate, unsaturated oil, and heavy metal ions in vitro. Further, a hyperlipidemia mouse model was constructed to investigate the effects of BC on lipid metabolism, antioxidant levels, and intestinal microflora. The results showed that the maximum adsorption capacities of BC for cholesterol, sodium cholate, Pb2+ and Cr6+ were 11.910, 16.149, 238.337, 1.525 and 1.809 mg/g, respectively. Additionally, BC reduced the blood lipid levels, regulated the peroxide levels, and ameliorated the liver injury in hyperlipidemia mice. Analysis of the intestinal flora revealed that BC improved the bacterial community of intestinal microflora in hyperlipidemia mice. It was found that the abundance of Bacteroidetes was increased, while the abundance of Firmicutes and Proteobacteria was decreased at the phylum level. In addition, increased abundance of Lactobacillus and decreased abundance of Lachnospiraceae and Prevotellaceae were obtained at the genus level. These changes were supposed to be beneficial to the activities of intestinal microflora. To conclude, the findings prove the role of BC in improving lipid metabolism in hyperlipidemia mice and provide a theoretical basis for the utilization of BC in functional food.

Peptidylarginine deiminases 4 as a promising target in drug discovery.

Peptidylarginine deaminase 4 (PAD4) is a crucial post-translational modifying enzyme catalyzing the conversion of arginine into citrulline residues, and mediating the formation of neutrophil extracellular traps (NETs). PAD4 plays a vital role in the occurrence and development of cardiovascular diseases, autoimmune diseases, and various tumors. Therefore, PAD4 is considered as a promising drug target for disease diagnosis and treatment. More and more efforts are devoted to developing highly efficient and selective PAD4 inhibitors via high-throughput screening, structure-based drug design and structure-activity relationship study. This article outlined the physiological and pathological functions of PAD4, and corresponding representative small molecule inhibitors reported in recent years.

A suspending-droplet mode paper-based microfluidic platform for low-cost, rapid, and convenient detection of lead(II) ions in liquid solution.

A paper-based microfluidic device based on unconventional principle was developed and used to detect lead ions through a two-step process including heated incubation and subsequent mixing. The device was made by generating a superhydrophobic pattern, which defines channel and reservoir barriers, on a water-impermeable paper substrate, followed by loading and drying the reagents in the defined reservoirs. Different from the conventional paper-based devices that are made of water-permeable paper, the as-prepared device holds water drops in discrete reservoirs, and the water drops will not move unless the device is titled along the direction of the predefined channels. In this way, the liquid samples applied onto the device are handled as individual drops and could be stored, transported, and mixed on demand. Different from the conventional paper-based devices that use capillary force to drive liquid, our new device uses wetting and gravity as driving force. We name this operation principle suspending-droplet mode paper-based device (SD-µPAD). The use of a Teflon contact-printing stamp makes the production of such devices rapid, cost efficient, and mass productive. Utilizing a G-quadruplex-based luminescence switch-on assay, we demonstrated rapid, convenient, highly sensitive, and low cost detection of lead(II) ions in water samples, using a custom made battery-powered portable device, and a smart phone as the detector.

Complete structure and variation of the chloroplast genome of Agropyron cristatum (L.) Gaertn.

Agropyron cristatum (L.) Gaertner, a perennial grass in the tribe Triticeae (Poaceae), is a wild relative of cereal crops that is suitable for genetic improvement. In this study, we first sequenced the complete chloroplast (cp) genome of Ag. cristatum using Hiseq4000 PE150. The Ag. cristatum chloroplast genome is 135,554bp in length, has a typical quadripartite structure and contains 76 protein-coding genes, 29 tRNA genes and four rRNA genes. The cp genome of Ag. cristatum was used for comparison with other seven Triticeae species. One large variable region (800bp), which primarily contained the rpl23 (non-reciprocally translocated from IRs) and accD genes, was detected between rbcL gene and psaI gene within LSC region. The deletion of the accD and translocated rpl23 genes in Ag. cristatum indicated an independent gene-loss events or an additional divergence in Triticeae. Analyses of the dn/ds ratio and K2-P's genetic distance for 76 protein-coding genes showed that genes with evolutionary divergence might suffer from the effect of sequence regional constraints or gene functional constraints in Triticeae species. Our research will generally contribute to the knowledge of plastid genome evolution in Triticeae.

Construction of a Nano Biosensor for Cyanide Anion Detection and Its Application in Environmental and Biological Systems.

We have developed a Ag@Au core-shell nanoparticle (NP)/iridium(III) complex-based sensing platform for the sensitive luminescence "turn-on" sensing of cyanide ions, an acutely toxic pollutant. The assay is based on the quenching effect of Ag@Au NPs on the emission of complex 1, but luminescence is restored after the addition of cyanide anions due to their ability to dissolve the Au shell. Our sensing platform exhibited a high sensitivity toward cyanide anions with a detection limit of 0.036 µM, and also showed high selectivity for cyanide over 10-fold excess amounts of other anions. The sensing platform was also successfully applied to monitor cyanide anions in drinking water and in living cells.

Turn-on Luminescent Probe for Hydrogen Peroxide Sensing and Imaging in Living Cells based on an Iridium(III) Complex-Silver Nanoparticle Platform.

A sensitive turn-on luminescent sensor for H2O2 based on the silver nanoparticle (AgNP)-mediated quenching of an luminescent Ir(III) complex (Ir-1) has been designed. In the absence of H2O2, the luminescence intensity of Ir-1 can be quenched by AgNPs via non-radiative energy transfer. However, H2O2 can oxidize AgNPs to soluble Ag+ cations, which restores the luminescence of Ir-1. The sensing platform displayed a sensitive response to H2O2 in the range of 0-17 µM, with a detection limit of 0.3 µM. Importantly, the probe was successfully applied to monitor intracellular H2O2 in living cells, and it also showed high selectivity for H2O2 over other interfering substances.

A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells.

The JAK2/STAT3 signaling pathway plays a critical role in tumorigenesis, and has been suggested as a potential molecular target for anti-melanoma therapeutics. However, few JAK2 inhibitors were being tested for melanoma therapy. In this study, eight amentoflavone analogues were evaluated for their activity against human malignant melanoma cells. The most potent analogue, compound 1, inhibited the phosphorylation of JAK2 and STAT3 in human melanoma cells, but had no discernible effect on total JAK2 and STAT3 levels. A cellular thermal shift assay was performed to identify that JAK2 is engaged by 1 in cell lysates. Moreover, compound 1 showed higher antiproliferative activity against human melanoma A375 cells compared to a panel of cancer and normal cell lines. Compound 1 also activated caspase-3 and cleaved PARP, which are markers of apoptosis, and suppressed the anti-apoptotic Bcl-2 level. Finally, compound 1 induced apoptosis in 80% of treated melanoma cells. To our knowledge, compound 1 is the first amentoflavone-based JAK2 inhibitor to be investigated for use as an anti-melanoma agent.

The Development of G-Quadruplex-Based Assays for the Detection of Small Molecules and Toxic Substances.

G-Quadruplexes can be induced to form guanine-rich DNA sequences by certain small molecules or metal ions. In concert with an appropriate signal transducer, such as a fluorescent dye or a phosphorescent metal complex, the ligand-recognition event can be transduced into a luminescent response. This focus review aims to highlight recent examples of aptamer-based and metal-mediated G-quadruplex assays for the detection of small molecules and toxic substances in the last three years. We discuss the mechanisms and features of the different assays and present an outlook and a perspective for the future of this field.

Luminescent Strategies for Label-Free G-Quadruplex-Based Enzyme Activity Sensing.

By catalyzing highly specific and tightly controlled chemical reactions, enzymes are essential to maintaining normal cellular physiology. However, aberrant enzymatic activity can be linked to the pathogenesis of various diseases. Therefore, the unusual activity of particular enzymes can represent testable biomarkers for the diagnosis or screening of certain diseases. In recent years, G-quadruplex-based platforms have attracted wide attention for the monitoring of enzymatic activities. In this Personal Account, we discuss our group's works on the development of G-quadruplex-based sensing system for enzyme activities by using mainly iridium(III) complexes as luminescent label-free probes. These studies showcase the versatility of the G-quadruplex for developing assays for a variety of different enzymes.

A reaction-based luminescent switch-on sensor for the detection of OH- ions in simulated wastewater.

A series of luminescent iridium(iii) complexes were synthesized and evaluated for their ability to interact with hydroxide ions in semi-aqueous media at ambient temperature. Upon the addition of OH-, a nucleophilic aromatic substitution reaction takes place at the bromine groups of the N^N ligand of complex 1, resulting in the generation of a yellow-green luminescence. Complex 1 showed a 35-fold enhanced emission at pH 14 when compared to neutral pH, and the detection limit for OH- ions was 4.96 µM. Complex 1 exhibited high sensitivity and selectivity, long-lived luminescence and impressive stability. Additionally, we have demonstrated the practical application of complex 1 to detect OH- ions in simulated wastewater.

An anti-prostate cancer benzofuran-conjugated iridium(III) complex as a dual inhibitor of STAT3 and NF-κB.

Four benzofuran-conjugated iridium(III) or rhodium (III)-based metal complexes are synthesized to screen as an inhibitor of STAT3 activity in prostate cancer cells. All complexes show the high stability and solubility in the biological system. In this study, an iridium(III) complex engages STAT3 and NF-κB to inhibit their translocation and transcriptional activities. Moreover, complex 1 shows more potential antiproliferative activity against DU145 cells and suppresses tumor growth in a prostate cancer xenograft mouse without observable adverse effects. Complex 1 may provide the basis for developing new therapeutic strategy in vivo and in vitro for the treatment of advanced prostate cancer.

A MnO2 nanosheet-assisted GSH detection platform using an iridium(iii) complex as a switch-on luminescent probe.

A rapid and sensitive detection platform for GSH has been constructed by combining a MnO2 nanosheet with a luminescent iridium(iii) complex [Ir(Cl-phq)2(Cl-phen)]+. The MnO2 nanosheet was prepared by using a facile one-step approach and was characterized by TEM. The luminescence intensity of the detection platform responded linearly with the GSH concentration from 1 to 200 µM (R2 = 0.9951), and the detection limit for GSH was 0.13 µM. More importantly, practical application of the detection platform for visualizing the intracellular GSH distribution in living zebrafish has also been demonstrated.

Anticancer osmium complex inhibitors of the HIF-1α and p300 protein-protein interaction.

The hypoxia inducible factor (HIF) pathway has been considered to be an attractive anti-cancer target. One strategy to inhibit HIF activity is through the disruption of the HIF-1α-p300 protein-protein interaction. We report herein the identification of an osmium(II) complex as the first metal-based inhibitor of the HIF-1α-p300 interaction. We evaluated the effect of complex 1 on HIF-1α signaling pathway in vitro and in cellulo by using the dual luciferase reporter assay, co-immunoprecipitation assay, and immunoblot assay. Complex 1 exhibited a dose-dependent inhibition of HRE-driven luciferase activity, with an IC50 value of 1.22 µM. Complex 1 interfered with the HIF-1α-p300 interaction as revealed by a dose-dependent reduction of p300 co-precipitated with HIF-1α as the concentration of complex 1 was increased. Complex 1 repressed the phosphorylation of SRC, AKT and STAT3, and had no discernible effect on the activity of NF-κB. We anticipate that complex 1 could be utilized as a promising scaffold for the further development of more potent HIF-1α inhibitors for anti-cancer treatment.

Genome origin, historical hybridization and genetic differentiation in Anthosachne australasica (Triticeae; Poaceae), inferred from chloroplast rbcL, trnH-psbA and nuclear Acc1 gene sequences.

BACKGROUND AND AIMS: Anthosachne Steudel is a group of allopolyploid species that was derived from hexaploidization between the Asian StY genome Roegneria entity and the Australasia W genome Australopyrum species. Polyploidization and apomixis contribute to taxonomic complexity in Anthosachne Here, a study is presented on the phylogeny and evolutionary history of Anthosachne australasica The aims are to demonstrate the process of polyploidization events and to explore the differentiation patterns of the St genome following geographic isolation. METHODS: Chloroplast rbcL and trnH-psbA and nuclear Acc1 gene sequences of 60 Anthosachne taxa and nine Roegneria species were analysed with those of 33 diploid taxa representing 20 basic genomes in Triticeae. The phylogenetic relationships were reconstructed. A time-calibrated phylogeny was generated to estimate the evolutionary history of A. australasica Nucleotide diversity patterns were used to assess the divergence within A. australasica and between Anthosachne and its putative progenitors. KEY RESULTS: Three homoeologous copies of the Acc1 sequences from Anthosachne were grouped with the Acc1 sequences from Roegneria, Pseudoroegneria, Australopyrum, Dasypyrum and Peridictyon The chloroplast sequences of Anthosachne were clustered with those from Roegneria and Pseudoroegneria Divergence time for Anthosachne was dated to 4·66 million years ago (MYA). The level of nucleotide diversity in Australasian Anthosachne was higher than that in continental Roegneria A low level of genetic differentiation within the A. australasica complex was found. CONCLUSIONS: Anthosachne originated from historical hybridization between Australopyrum species and a Roegneria entity colonized from Asia to Australasia via South-east Asia during the late Miocene. The St lineage served as the maternal donor during the speciation of Anthosachne A contrasting pattern of population genetic structure exists in the A. australasica complex. Greater diversity in island Anthosachne compared with continental Roegneria might be associated with mutation, polyploidization, apomixis and expansion. It is reasonable to consider that A. australasica var. scabra and A. australasica var. plurinervisa should be included in the A. australasica complex.

A long-lived iridium(iii) chemosensor for the real-time detection of GHB.

Gamma-hydroxybutyric acid (GHB) is a commonly used "date rape" drug in drug-facilitated sexual assaults (DFSA) due to its low price and ready availability, and it is more quickly excreted from the human body than other drugs. Therefore, the development of a real-time detection method for GHB could help facilitate law enforcement agencies in tackling DFSA. In this work, a long-lived iridium(iii) chemosensor 1 has been synthesized for the switch-off detection of GHB. Upon addition of GHB to an aqueous solution of the iridium(iii) complex 1, a significant luminescence quenching occurred that could be observed by the naked eye under UV illumination. The luminescence signal of the iridium(iii) complex 1 could also be distinguished from strongly fluorescent media using time-resolved emission spectroscopy.

An Aldol Reaction-Based Iridium(III) Chemosensor for the Visualization of Proline in Living Cells.

A long-lived aldol reaction-based iridium(III) chemosensor [Ir(ppy)2(5-CHOphen)]PF6 (1, where ppy = 2-phenylpyridine and 5-CHOphen = 1,10-phenanthroline-5-carbaldehyde) for proline detection has been synthesized. The iridium(III) complex 1, incorporating an aldehyde group in N^N donor ligand, can take part in aldol reaction with acetone mediated by proline. The transformation of the sp2-hybridized carbonyl group into a sp3-hybridized alcohol group influences the metal-to-ligand charge-transfer (MLCT) state of the iridium(III) complex, resulting in a change in luminescence in response to proline. The interaction of the iridium(III) complex 1 with proline was investigated by 1H NMR, HRMS and emission titration experiments. Upon the addition of proline to a solution of iridium(III) complex 1, a maximum 8-fold luminescence enhancement was observed. The luminescence signal of iridium(III) complex 1 could be recognized in strongly fluorescent media using time-resolved emission spectroscopy (TRES). The detection of proline in living cells was also demonstrated.

A facile label-free aptasensor for detecting ATP based on fluorescence enhancement of poly(thymine)-templated copper nanoparticles.

A label-free fluorescence assay has been developed for sensitive and selective detection of adenosine triphosphate (ATP) by using poly(thymine) (poly T)-templated copper nanoparticles (CuNPs) as fluorescent indicator. In our design, ATP aptamer was split into two fragments, both of which were elongated with poly T strands that can be utilized as efficient template for the formation of copper nanoparticles through the reduction of copper ions by sodium ascorbate. In the presence of ATP, the two split aptamers could be dragged to form aptamer-ATP aptamer complex, which drew the poly T strands close to each other and induced a remarkable fluorescence enhancement of poly T-templated CuNPs. Thus, an elevated fluorescence enhancement of poly T-templated CuNPs was obtained with the increase in ATP concentration. Under optimized conditions, a good linear range for ATP detection was realized from 100 nM to 100 µM with a detection limit of 10.29 nM. In addition, the application of this biosensing system in complex biological matrix was demonstrated with satisfactory results. This assay provided a simple, label-free, cost-effective, and sensitive platform for the detection of ATP.

A label-free assay for T4 polynucleotide kinase/phosphatase activity and its inhibitors based on poly(thymine)-templated copper nanoparticles.

DNA 3'-phosphatase takes an important role in DNA damage repair, replication and recombination. Here, we present a novel label-free fluorescent assay for T4 polynucleotide kinase/phosphatase (T4 PNKP) activity and its inhibitor screening by using poly(thymine)-templated fluorescent copper nanoparticles (CuNPs) as a fluorescent indicator. In this assay, we designed a simple T-rich hairpin primer with a 3'-phosphoryl end, which can serve as both the substrate for T4 PNKP and DNA template for the formation of fluorescent CuNPs. Once the phosphorylated hairpin primer was hydrolyzed by T4 PNKP, the resulting hairpin primer with a 3'-hydroxyl end was immediately elongated to form a long double-strand product by DNA polymerase, which prohibited the formation of fluorescent CuNPs due to the lack of poly T single-stranded DNA template. This new strategy provides a sensitive, selective, and cost-effective manner for T4 PNKP analysis, which holds a great potential in the study of DNA damage repair mechanisms.