Visible-Light-Promoted Deoxygenative Alkylation of Quinoxalin-2(1H)-ones with Activated Alcohols.

A one-pot strategy for deoxygenative alkylation of alcohols with quinoxalin-2(1H)-ones was developed by using xanthate salts as alcohol-activating groups for radical generation in the presence of tricyclohexylphosphine under visible-light-promoted conditions. The remarkable features of this reaction include a broad substrate scope, excellent functional group tolerance, mild conditions, and simple operation. Moreover, the synthetic utility of this reaction was validated by the success of two-step one-pot reactions, scale-up synthesis, and chemoselective radical monodeoxygenation of diols.

Unveiling aging dynamics in the hematopoietic system insights from single-cell technologies.

As the demographic structure shifts towards an aging society, strategies aimed at slowing down or reversing the aging process become increasingly essential. Aging is a major predisposing factor for many chronic diseases in humans. The hematopoietic system, comprising blood cells and their associated bone marrow microenvironment, intricately participates in hematopoiesis, coagulation, immune regulation and other physiological phenomena. The aging process triggers various alterations within the hematopoietic system, serving as a spectrum of risk factors for hematopoietic disorders, including clonal hematopoiesis, immune senescence, myeloproliferative neoplasms and leukemia. The emerging single-cell technologies provide novel insights into age-related changes in the hematopoietic system. In this review, we summarize recent studies dissecting hematopoietic system aging using single-cell technologies. We discuss cellular changes occurring during aging in the hematopoietic system at the levels of the genomics, transcriptomics, epigenomics, proteomics, metabolomics and spatial multi-omics. Finally, we contemplate the future prospects of single-cell technologies, emphasizing the impact they may bring to the field of hematopoietic system aging research.

Micropeptide MIAC inhibits the tumor progression by interacting with AQP2 and inhibiting EREG/EGFR signaling in renal cell carcinoma.

BACKGROUND: Although, micropeptides encoded by non-coding RNA have been shown to have an important role in a variety of tumors processes, there have been no reports on micropeptide in renal cell carcinoma (RCC). Based on the micropeptide MIAC (micropeptide inhibiting actin cytoskeleton) discovered and named in the previous work, this study screened its tumor spectrum, and explored its mechanism of action and potential diagnosis and treatment value in the occurrence and development of renal carcinoma. METHODS: The clinical significance of MIAC in RCC was explored by bioinformatics analysis through high-throughput RNA-seq data from 530 patients with kidney renal clear cell carcinoma (KIRC) in the TCGA database, and the detection of clinical samples of 70 cases of kidney cancer. In vitro and in vivo experiments to determine the role of MIAC in renal carcinoma cell growth and metastasis; High-throughput transcriptomics, western blotting, immunoprecipitation, molecular docking, affinity experiments, and Streptavidin pulldown experiments identify MIAC direct binding protein and key regulatory pathways. RESULTS: The analysis of 600 renal carcinoma samples from different sources revealed that the expression level of MIAC is significantly decreased, and corelated with the prognosis and clinical stage of tumors in patients with renal carcinoma. Overexpression of MIAC in renal carcinoma cells can significantly inhibit the proliferation and migration ability, promote apoptosis of renal carcinoma cells, and affect the distribution of cells at various stages. After knocking down MIAC, the trend is reversed. In vivo experiments have found that MIAC overexpression inhibit the growth and metastasis of RCC, while the synthetized MIAC peptides can significantly inhibit the occurrence and development of RCC in vitro and in vivo. Further mechanistic studies have demonstrated that MIAC directly bind to AQP2 protein, inhibit EREG/EGFR expression and activate downstream pathways PI3K/AKT and MAPK to achieve anti-tumor effects. CONCLUSIONS: This study revealed for the first time the tumor suppressor potential of the lncRNA-encoded micropeptide MIAC in RCC, which inhibits the activation of the EREG/EGFR signaling pathway by direct binding to AQP2 protein, thereby inhibiting renal carcinoma progression and metastasis. This result emphasizes that the micropeptide MIAC can provide a new strategy for the diagnosis and treatment of RCC.

Gram-scale synthesis of nitrogen-doped carbon dots from locusts for selective determination of sunset yellow in food samples.

Locust powder was converted into water-soluble fluorescent nitrogen-doped carbon dots (N-CDs) with gram-scale yield through a self-exothermic reaction between nitric acid and diethylenetriamine (DETA) within 10 min. The morphology, elemental information, and optical properties of the N-CDs were characterized using high-resolution transmission electron microscopy, X-ray photoelectron spectroscopy, and Fourier-transform infrared, ultraviolet-visible and fluorescence spectroscopy. Spectroscopic investigation indicated that the fluorescence emission behaviour of N-CDs is excitation wavelength dependent, with the strongest emission peak at 470 nm using a 390 nm excitation wavelength. The strong absorption peak of sunset yellow (SY) at 482 nm overlaps substantially with the blue emission peak (470 nm) of N-CDs. This enables the fluorescence emission of N-CDs to be obviously quenched by SY through the inner filter effect. There was a good linear relationship between the fluorescence quenching degree and the concentrations of SY within the range 0.5-40 µM. The detection limit of developed fluorescence assay for SY is 28 nM, and the relative standard deviation is 2.3% (c = 10 µM). The N-CDs derived from locusts by the self-exothermic reaction are highly selective and sensitive fluorescent probes for SY, which were applied to the fluorescence sensing of SY in different food samples with satisfactory results.

Lack of Association between rs4680 Polymorphism in Catechol-O-Methyltransferase Gene and Alcohol Use Disorder: A Meta-Analysis.

BACKGROUND: The underlying mechanisms of alcohol use disorder (AUD) are regarded to be strongly associated with genetic factors. Although great efforts have been made to identify the association of rs4680 polymorphism in the catechol-o-methyltransferase gene and risk to AUD, the outcomes were still inconsistent. This study is aimed at exploring the association of rs4680 polymorphism and AUD by using a meta-analysis approach. METHODS: Literature searching was undertaken across PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases. We set the search period before February 20, 2020. We used the Review Manager 5.3 (RevMan 5.3) software to estimate the effect sizes in five genetic models. RESULTS: In total, eighteen case-control studies and two cohort studies were included in this study. The merged results of overall population indicated there was no significant association between rs4680 polymorphism and AUD: V vs. M, OR = 1.02, 95% CI 0.93-1.12, P = 0.70; VV vs. MM, OR = 0.99, 95% CI 0.79-1.23, P = 0.92; VM vs. MM, OR = 0.91, 95% CI 0.81-1.03, P = 0.15; VV+VM vs. MM, OR = 0.95, 95% CI 0.80-1.13, P = 0.65; VV vs. VM+MM, OR = 1.04, 95% CI 0.91-1.18, P = 0.57. Subgroup analysis by gender suggested rs4680 polymorphism was marginally associated with an elevated risk to AUD among males (VM vs. MM, OR = 0.81, 95% CI 0.67-0.98, P = 0.03). However, subgroup analysis by race and diagnosis did not support any significant association. CONCLUSIONS: The present study suggests that rs4680 polymorphism has no association with AUD in the overall population, but it has a weak association with AUD in males. Carriers of VM genotype in males appear to have an increased risk to AUD.

NK cell-derived exosomes carry miR-207 and alleviate depression-like symptoms in mice.

BACKGROUND: Depression is a common mental disease that mainly manifests as bad mood, decreased interest, pessimism, slow thinking, lack of initiative, poor diet and sleep. Patients with severe depression have suicidal tendencies. Exosomes are small vesicles released by the fusion of a multivesicular body and membranes, and they contain specific proteins, nucleic acids, and lipids related to the cells from which they originate. MicroRNAs (miRNAs) are 20-24 nt RNAs that can be packaged into exosomes and can play important regulatory roles. Astrocytes are the most abundant cell population in the central nervous system and have a close link to depression. Astrocyte activation could result in the release of inflammatory cytokines, including IL-1ß, IL-6, and TNF-α, which could promote the symptoms of depression. In previous research, our team confirmed that NK cells regulate depression in mice. Here, we propose that miRNA in the exosomes from NK cells performs this antidepressant function. METHODS: Exosomes from NK cells were shown by in vivo and in vitro experiments to alleviate symptoms of chronic mild stress in mice and decrease pro-inflammatory cytokines release from astrocytes. The production of pro-inflammatory cytokines was assessed by ELISA. Microarray analysis was used to identify critical miRNAs. Luciferase reporter assays, qPCR, and other experiments were used to prove that exosomal miR-207 has an important role in alleviating the symptoms of stress in mice. RESULTS: MiRNA-containing exosomes from NK cells could alleviate symptoms of chronic mild stress in mice. In vivo experiments showed that these exosomes decreased the levels of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) released by astrocytes. By microarray analysis of exosome miRNA profiles, miR-207 was found to be overexpressed in exosomes derived from unstressed mice. Experiments confirmed that miR-207 directly targets TLR4 interactor with leucine-rich repeats (Tril) and inhibits NF-κB signaling in astrocytes. MiR-207 could decrease the release of pro-inflammatory cytokines and inhibit expression of Tril in vitro. In vivo experiments revealed that exosomes with low miR-207 levels showed decreased antidepressant activity. CONCLUSION: Collectively, our findings revealed that exosomal miR-207 alleviated symptoms of depression in stressed mice by targeting Tril to inhibit NF-κB signaling in astrocytes.

Micropeptide MIAC Inhibits HNSCC Progression by Interacting with Aquaporin 2.

Several important micropeptides encoded by noncoding RNAs have been identified in recent years; however, there have never been any reports of micropeptides in head and neck squamous cell carcinoma (HNSCC). Here we report the discovery and characterization of a human endogenous peptide named micropeptide inhibiting actin cytoskeleton (MIAC). Comprehensive analysis of the TCGA (The Cancer Genome Atlas) database (n = 500), clinical fresh samples (n = 94), and tissue microarrays (n = 60) revealed that lower MIAC expression is correlated with poor overall survival of HNSCC patients. Meanwhile, RNA-sequencing analysis of 9657 human tissues across 32 cancer types from TCGA cohorts found that MIAC is significantly associated with the progression of 5 other different tumors. Mechanistically, MIAC directly interacts with AQP2 (Aquaporin 2) to inhibit the actin cytoskeleton by regulating SEPT2 (Septin 2)/ITGB4 (Integrin Beta 4) and ultimately suppressing the tumor growth and metastasis of HNSCC. Collectively, the mechanism investigation and evaluation of MIAC activity in vivo and in vitro highlights that MIAC plays an important role in HNSCC tumorigenesis.

CD200-CD200R1 signalling attenuates imiquimod-induced psoriatic inflammation by inhibiting the activation of skin inflammatory macrophages.

Psoriasis is an autoimmune skin disease caused by interactions between keratinocytes and immune cells, such as macrophages. CD200 is expressed on the surface of various cell types, and its receptor, CD200R1, belongs to a family of immunosuppressive receptors that are mainly expressed on myeloid cells. CD200/CD200R1 signalling is associated with the prevention of autoimmune diseases; however, the role of CD200/CD200R1 signalling in the pathogenesis of psoriasis remains unknown. In this study, we detected in vivo effect of the CD200 protein on psoriasis and in vitro effects of CD200 on macrophages and keratinocytes co-cultured with macrophages were also evaluated. Our data showed that the expression of CD200 and CD200R1 was decreased and the expression of macrophage-related pro-inflammatory factors (IL-6, IL-1ß, TNF-α) was increased in IMQ-induced psoriasis-like skin of mice. After subcutaneous injection of CD200, the symptoms were alleviated, local expression of CD200R1 was markedly induced, infiltrated CD68+ cells were significantly reduced and the expression levels of IL-6, IL-1ß, and TNF-α were strongly downregulated. In in vitro experiments, CD200 suppressed the migration of macrophages, induced CD200R1 expression on the surface of macrophages, and decreased the levels of pro-inflammatory factors. Western blot (WB) data showed that the CD200-CD200R1 reaction controlled the activation of inflammatory macrophages by inhibiting the NF-κB signalling pathway. These results demonstrate that CD200-CD200R1 signalling can reduce IMQ-induced psoriasis-like skin inflammation by inhibiting the activation of macrophages.

Development of novel 5-fluorouracil carrier erythrocyte with pharmacokinetics and potent antitumor activity in mice bearing malignant ascites.

BACKGROUND: To investigate pharmacokinetics and potency of antitumor activity of a novel 5-fluorouracil carrier erythrocyte (RBC-FU) in mice bearing malignant ascites. METHODS: RBC-FU was synthesized with a hyperosmotic technique. The entrapment efficiency of targeted carrier erythrocytes was determined by reverse dialysis method with high-performance liquid chromatography (HPLC) for analyzing the quantity of 5-fluorouracil (5-FU). After a H22 hepatocarcinoma malignant ascites model was established in Kunming mice, 5-FU encapsulated by carrier erythrocytes (for Group A) and 5-FU solution (for Group B) at 20 mg per kg were injected into the peritoneal cavity of the mice, respectively. Blood and ascites samples were collected at different times to detect 5-FU quantity by HPLC. Body weight and survival time of mice were recorded in Group A, B and the Control Group in which mice were injected with normal saline only. RESULTS: 5-FU was effectively encapsulated into erythrocytes, with an encapsulating effect as 55 +/- 0.50%. In Group A, the maximum concentration (Cmax) and the area under curve (AUC) in peritoneal exudates were significantly higher than those of Group B (P < 0.05). On the other hand, 5-FU level in serum was significantly lower than that in peritoneal exudates of Group A and B (P < 0.05). High drug levels in the abdominal cavity in Group A were maintained longer than those in Group B. Compared with that in Group B and the control, the quantity of malignant ascites in Group A had significant regression and the survival time was prolonged. CONCLUSION: The hyperosmotic method described here could be suitable for producing this novel RBC-FU as a liposomal drug of potential value for treating malignant ascites by intraperitoneal administration.