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.

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.

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.

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.

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.

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.

Phylogeny and differentiation of the St genome in Elymus L. sensu lato (Triticeae; Poaceae) based on one nuclear DNA and two chloroplast genes.

BACKGROUND: Hybridization and polyploidization can be major mechanisms for plant evolution and speciation. Thus, the process of polyploidization and evolutionary history of polyploids is of widespread interest. The species in Elymus L. sensu lato are allopolyploids that share a common St genome from Pseudoroegneria in different combinations with H, Y, P, and W genomes. But how the St genome evolved in the Elymus s. l. during the hybridization and polyploidization events remains unclear. We used nuclear and chloroplast DNA-based phylogenetic analyses to shed some light on this process. RESULTS: The Maximum likelihood (ML) tree based on nuclear ribosomal internal transcribed spacer region (nrITS) data showed that the Pseudoroegneria, Hordeum and Agropyron species served as the St, H and P genome diploid ancestors, respectively, for the Elymus s. l. polyploids. The ML tree for the chloroplast genes (matK and the intergenic region of trnH-psbA) suggests that the Pseudoroegneria served as the maternal donor of the St genome for Elymus s. l. Furthermore, it suggested that Pseudoroegneria species from Central Asia and Europe were more ancient than those from North America. The molecular evolution in the St genome appeared to be non-random following the polyploidy event with a departure from the equilibrium neutral model due to a genetic bottleneck caused by recent polyploidization. CONCLUSION: Our results suggest the ancient common maternal ancestral genome in Elymus s. l. is the St genome from Pseudoroegneria. The evolutionary differentiation of the St genome in Elymus s. l. after rise of this group may have multiple causes, including hybridization and polyploidization. They also suggest that E. tangutorum should be treated as C. dahurica var. tangutorum, and E. breviaristatus should be transferred into Campeiostachys. We hypothesized that the Elymus s. l. species origined in Central Asia and Europe, then spread to North America. Further study of intraspecific variation may help us evaluate our phylogenetic results in greater detail and with more certainty.

A label-free method for detecting biothiols based on poly(thymine)-templated copper nanoparticles.

A novel label-free nanosensor has been developed for detecting biothiols including cysteine, glutathione and homocysteine based on poly(thymine)-templated fluorescent copper nanoparticles (CuNPs), which were controlled through thymine-Hg(II)-thymine coordination. This assay provides a simple, cost-effective, and sensitive platform for the detection of biothiols. By employing this turn-on sensor, biological thiols, such as cysteine, glutathione and homocysteine, are successfully detected at concentrations as low as 12.5nM for cysteine, 15nM for glutathione, and 20nM for homocysteine. The sensing system also exhibits high selectivity against other amino acids, and the application of the sensor for biological fluids shows that the proposed method works well for real samples.

Phylogenetic relationships and Y genome origin in Elymus L. sensu lato (Triticeae; Poaceae) based on single-copy nuclear Acc1 and Pgk1 gene sequences.

To estimate the origin and genomic relationships of the polyploid species within Elymus L. sensu lato, two unlinked single-copy nuclear gene (Acc1 and Pgk1) sequences of eighteen tetraploids (StH and StY genomes) and fourteen hexaploids (StStH, StYP, StYH, and StYW genomes) were analyzed with those of 35 diploid taxa representing 18 basic genomes in Triticeae. Sequence and phylogenetic analysis suggested that: (1) the St, H, W, and P genomes were donated by Pseudoroegneria, Hordeum, Australopyrum, and Agropyron, respectively, while the Y genome is closely related to the Xp genome in Peridictyon sanctum; (2) different hexaploid Elymus s.l. species may derived their StY genome from different StY genome tetraploid species via independent origins; (3) due to incomplete lineage sorting and/or hybridization events, the genealogical conflict between the two gene trees suggest introgression involving some Elymus s.l. species, Pseudoroegneria, Agropyron and Aegilops/Triticum; (4) it is reasonable to recognize the StH genome species as Elymus sensu stricto, the StY genome species as Roegneria, the StYW genome species as Anthosachne, the StYH genome species as Campeiostachys, and the StYP genome species as Kengyilia. The occurrence of multiple origin and introgression could account for the rich diversity and ecological adaptation of Elymus s.l. species.