Triple Frustrated Lewis Pair-Type Reactivity on a Single Rare-Earth Metal Center.

Rare-earth metal cations have been used rarely as Lewis-acidic components in the chemistry of frustrated Lewis pairs (FLPs). Herein, we report the first cerium/phosphorus system (2) employing a heptadentate N4 P3 ligand, which exhibits triple FLP-type reactivity towards a series of organic substrates, including isocyanates, isothiocyanates, diazomethane, and azides on a single rare-earth Lewis acidic Ce center. This result shows that the Ce center and three P atoms in 2 could simultaneously activate three equivalents of small molecules under mild conditions. This study broadens the diversity of FLPs and demonstrates that rare earth based FLP exhibit unique properties compared with other FLP systems.

An Unprecedented Ga/P Frustrated Lewis Pair: Synthesis, Characterization, and Reactivity.

Frustrated Lewis pairs (FLPs) represent a new paradigm of main-group chemistry. The Lewis acidic centers in FLP chemistry are typically B and Al atoms in the studies reported over the past decade, and most of them are tri-coordinated with strong electron-withdrawing groups. Herein, a Ga/P system is reported which contains an unprecedented four-coordinated Lewis acidic Ga center. This Ga/P species performs classical addition reactions toward heterocumulenes, alkyne, diazomethane, and transition metal complex. Regioselective formation of the products can be rationalized by DFT calculations. The penta-coordinated gallium atom center in these products is rare in the FLP chemistry. This study enriches the diversity of FLPs and demonstrates that a four-coordinated Lewis acidic site with a donor-acceptor bond can also be FLP active.

TDMPP activation of estrogen receptor 2a regulates smc2 and p53 signaling to interfere with liver development in zebrafish (Danio rerio).

Tris (2,6-dimethylphenyl) phosphate (TDMPP), a novel organic phosphorus flame retardant (OPFR), has been found to have estrogenic activity. Estrogens are critical in regulating various biological responses during liver development. However, the effects of TDMPP on zebrafish liver development remain largely unexplored. Here, we utilized a chemical genetic screening approach to assess the estrogenic effects of TDMPP on liver development and to elucidate the underlying molecular mechanism. Our findings revealed that zebrafish larvae exposed to environmentally relevant concentrations of TDMPP (0.05 and 0.5 µM) exhibited concentration-dependent liver impairments, including reduced liver size, histopathological changes, and hepatocyte apoptosis. In addition, E2 caused similar adverse effects to TDMPP, but the pharmacological blockade of estrogen synthesis alleviated the effects on liver development. Chemical inhibitors and morpholino knockdown assays indicated that the reduction of esr2a blocked TDMPP-induced liver impairments, which was further confirmed in the esr2a-/- mutant line. Subsequently, transcriptomic analysis showed that the estrogen receptor activated by TDMPP inhibited the expression of smc2, which was linked to the suppression of liver development through p53 activation. Consistently, overexpression of smc2 and inhibition of p53 evidently rescued hepatic damages induced by TDMPP. Taken together, the above findings identified esr2a, downstream smc2, and p53 as important regulators for the estrogenic effects of TDMPP on liver development. Our work fills crucial gaps in the current knowledge of TDMPP's hepatotoxicity, providing new insights into the adverse effects of TDMPP and the molecular mechanisms of action. These findings underscore the need for further ecological risk assessment and regulatory considerations.

Prospects and challenges of CAR-T cell therapy combined with ICIs.

Immune checkpoint molecules are a group of molecules expressed on the surface of immune cells that primarily regulate their immune homeostasis. Chimeric antigen receptor (CAR) T cell therapy is an immunotherapeutic technology that realizes tumor-targeted killing by constructing synthetic T cells expressing specific antigens through biotechnology. Currently, CAR-T cell therapy has achieved good efficacy in non-solid tumors, but its treatment of solid tumors has not yielded the desired results. Immune checkpoint inhibitors (ICIs) combined with CAR-T cell therapy is a novel combination therapy with high expectations to defeat solid tumors. This review addresses the challenges and expectations of this combination therapy in the treatment of solid tumors.

Application value of whole exome sequencing in screening and identifying novel mutations of hypopharyngeal cancer.

The research on targeted therapy of hypopharyngeal cancer is very scarce. The discovery of new targeted driver genes will promote the progress of hypopharyngeal cancer therapy to a great extent. In our research, whole-exome sequencing in 10 patients with hypopharyngeal cancer was performed to identify single nucleotide variations (SNVs) and insertions and deletions (INDELs). American College of Medical Genetics and Genomics (ACMG) guidelines were used to evaluate the pathogenicity of the selected variants. 8113 mutation sites in 5326 genes were identified after strict screening. We identified 72 pathogenic mutations in 53 genes according to the ACMG guidelines. Gene Ontology (GO) annotation and KEGG enrichment analysis show the effect of these genes on cancer. Protein-protein interaction (PPI) was analyzed by string online software. The validation results of the ualcan database showed that 22 of the 53 genes may be related to the poor prognosis of patients with hypopharyngeal cancer. RBM20 has the most significant correlation with hypopharyngeal cancer, and it is likely to be the driver gene of hypopharyngeal cancer. In conclusion, we found possible therapeutic targets for hypopharyngeal cancer, especially RBM20 and KMT2C. Our study provides a basis for the pathogenesis and targeted therapy of hypopharyngeal cancer.

Regulating the Expression of HIF-1α or lncRNA: Potential Directions for Cancer Therapy.

Previous studies have shown that tumors under a hypoxic environment can induce an important hypoxia-responsive element, hypoxia-induced factor-1α (HIF-1α), which can increase tumor migration, invasion, and metastatic ability by promoting epithelial-to-mesenchymal transition (EMT) in tumor cells. Currently, with the deeper knowledge of long noncoding RNAs (lncRNAs), more and more functions of lncRNAs have been discovered. HIF-1α can regulate hypoxia-responsive lncRNAs under hypoxic conditions, and changes in the expression level of lncRNAs can regulate the production of EMT transcription factors and signaling pathway transduction, thus promoting EMT progress. In conclusion, this review summarizes the regulation of the EMT process by HIF-1α and lncRNAs and discusses their relationship with tumorigenesis. Since HIF-1α plays an important role in tumor progression, we also summarize the current drugs that inhibit tumor progression by modulating HIF-1α.

Research Progress and Direction of Novel Organelle-Migrasomes.

Migrasomes are organelles that are similar in structure to pomegranates, up to 3 µm in diameter, and contain small vesicles with a diameter of 50-100 nm. These membranous organelles grow at the intersections or tips of retracting fibers at the back of migrating cells. The process by which cells release migrasomes and their contents outside the cell is called migracytosis. The signal molecules are packaged in the migrasomes and released to the designated location by migrasomes to activate the surrounding cells. Finally, the migrasomes complete the entire process of information transmission. In this sense, migrasomes integrate time, space, and specific chemical information, which are essential for regulating physiological processes such as embryonic development and tumor invasion and migration. In this review, the current research progress of migrasomes, including the discovery of migrasomes and migracytosis, the structure of migrasomes, and the distribution and functions of migrasomes is discussed. The migratory marker protein TSPAN4 is highly expressed in various cancers and is associated with cancer invasion and migration. Therefore, there is still much research space for the pathogenesis of migratory bodies and cancer. This review also makes bold predictions and prospects for the research directions of the combination of migrasomes and clinical applications.

Nasal Nanovaccines for SARS-CoV-2 to Address COVID-19.

COVID-19 is still prevalent around the globe. Although some SARS-CoV-2 vaccines have been distributed to the population, the shortcomings of vaccines and the continuous emergence of SARS-CoV-2 mutant virus strains are a cause for concern. Thus, it is vital to continue to improve vaccines and vaccine delivery methods. One option is nasal vaccination, which is more convenient than injections and does not require a syringe. Additionally, stronger mucosal immunity is produced under nasal vaccination. The easy accessibility of the intranasal route is more advantageous than injection in the context of the COVID-19 pandemic. Nanoparticles have been proven to be suitable delivery vehicles and adjuvants, and different NPs have different advantages. The shortcomings of the SARS-CoV-2 vaccine may be compensated by selecting or modifying different nanoparticles. It travels along the digestive tract to the intestine, where it is presented by GALT, tissue-resident immune cells, and gastrointestinal lymph nodes. Nasal nanovaccines are easy to use, safe, multifunctional, and can be distributed quickly, demonstrating strong prospects as a vaccination method for SARS-CoV-2, SARS-CoV-2 variants, or SARS-CoV-n.

The potential, analysis and prospect of ctDNA sequencing in hepatocellular carcinoma.

Background: The genome map of hepatocellular carcinoma (HCC) is complex. In order to explore whether circulating tumor cell DNA (ctDNA) can be used as the basis for sequencing and use ctDNA to find tumor related biomarkers, we analyzed the mutant genes of ctDNA in patients with liver cancer by sequencing. Methods: We used next-generation targeted sequencing technology to identify mutations in patients with liver cancer. The ctDNA from 10 patients with hepatocellular carcinoma (including eight cases of primary hepatocellular carcinoma and two cases of secondary hepatocellular carcinoma) was sequenced. We used SAMtools to detect and screen single nucleotide polymorphisms (SNPs) and insertion deletion mutations (INDELs) and ANNOVAR to annotate the structure and function of the detected mutations. Screening of pathogenic and possible pathogenic genes was performed using American College of Medical Genetics and Genomics (ACMG) guidelines. GO analysis and KEGG analysis of pathogenic and possible pathogenic genes were performed using the DAVID database, and protein-protein interaction network analysis of pathogenic and possible pathogenic genes was performed using the STRING database. Then, the Kaplan-Meier plotter database, GEPIA database and HPA database were used to analyse the relationship between pathogenic and possible pathogenic genes and patients with liver cancer. Results: Targeted capture and deep sequencing of 560 cancer-related genes in 10 liver cancer ctDNA samples revealed 8,950 single nucleotide variation (SNV) mutations and 70 INDELS. The most commonly mutated gene was PDE4DIP, followed by SYNE1, KMT2C, PKHD1 and FN1. We compared these results to the COSMIC database and determined that ctDNA could be used for sequencing. According to the ACMG guidelines, we identified 54 pathogenic and possible pathogenic mutations in 39 genes in exons and splice regions of 10 HCC patients and performed GO analysis, KEGG analysis, and PPI network analysis. Through further analysis, four genes significantly related to the prognosis of liver cancer were identified. Conclusion: In this study, our findings indicate that ctDNA can be used for sequencing. Our results provide some molecular data for the mapping of genetic variation in Chinese patients with liver cancer, which enriches the understanding of HCC pathogenesis and provides new ideas for the diagnosis and prognosis of HCC patients.

Assessment of the genotoxicity in toad Bufo raddei exposed to petrochemical contaminants in Lanzhou Region, China.

Single cell gel electrophoresis or comet assay, micronucleus (MN) test and global DNA methylation detection were used to assess the genotoxicity in toad Bufo raddei exposed to the petrochemical (mainly oil and phenol) polluted area in Lanzhou Region (LZR) comparing with a relatively unpolluted area in Liujiaxia Region (LJXR). The results from the present study indicated that DNA damage and MN frequency in toad from LZR were significantly higher than those from LJXR at the same sampling month, whereas the degree of global DNA methylation was lower, which implies that the petrochemical contaminants at environmental level in LZR were genotoxic to B. raddei. The degree of genotoxic damage was obviously related with the extent of pollution among the three sampling months in LZR. The significantly positive correlations between DNA damage and concentrations of oil and/or phenol existed in liver cells but erythrocytes, implying that liver is more suitable as a sentinel tissue for the assessment of genotoxic impact of low-level contamination. The results from both comet assay and global DNA methylation detection on liver cells showed that the genotoxicity varied significantly with oil and/or phenol concentrations, suggesting that these two methods are relatively sensitive and suitable for monitoring the genotoxicity of petrochemical pollutants on amphibians.

Cd-induced apoptosis was mediated by the release of Ca2+ from intracellular Ca storage.

Previous studies found that cadmium (Cd) could induce apoptosis via interfering with the intracellular calcium (Ca) ions homeostasis. But the detailed mechanisms remain poorly understood. In the present study two cell lines (normal human liver cell HL-7702, and tumor cell Raji cell) were exposed to Cd along or co-incubated with ethylene glycol-bis (2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) and 1,2-bis (2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM), respectively. After the incubation, the apoptosis and intracellular Ca(2+) ([Ca(2+)](i)) were measured. Excessive apoptosis was observed both in HL-7702 and Raji cells treated with Cd. Significant elevation of [Ca(2+)](i) was also detected in the cells with higher levels of apoptosis. EGTA (the extracellular Ca(2+) chelator) decreased Cd-elicited [Ca(2+)](i) (22% in HL-7702 and 41% in Raji cells; p<0.05) significantly except for apoptosis. However, BAMTA-AM (the [Ca(2+)](i) chelator) attenuated the Cd-elevated [Ca(2+)](i) (78% in HL-7702 and 59% in Raji cells; p<0.05) and inhibited Cd-induced apoptosis significantly (p<0.05). These results suggest that (1) Ca(2+) was primarily generated intracellularly and only a small portion was generated extracellularly; (2) Cd-induced apoptosis was mediated by the release of Ca(2+) from intracellular Ca storage but not an influx of extracellular Ca(2+).