Contribution of FOS in neutrophils to venous thromboembolism via miR-144 based on bioinformatic prediction and validation.

The Finkel-Biskis-Jinkins Osteosarcoma (c-Fos; encoded by FOS) plays an important role in several cardiovascular diseases, including atherosclerosis and stroke. However, the relationship between FOS and venous thromboembolism (VTE) remains unknown. We identified differentially expressed genes in Gene Expression Omnibus dataset, GSE48000, comprising VTE patients and healthy individuals, and analysed them using CIBERSORT and weighted co-expression network analysis (WGCNA). FOS and CD46 expressions were significantly downregulated (FOS p = 2.26E-05, CD64 p = 8.83E-05) and strongly linked to neutrophil activity in VTE. We used GSE19151 and performed PCR to confirm that FOS and CD46 had diagnostic potential for VTE; however, only FOS showed differential expression by PCR and ELISA in whole blood samples. Moreover, we found that hsa-miR-144 which regulates FOS expression was significantly upregulated in VTE. Furthermore, FOS expression was significantly downregulated in neutrophils of VTE patients (p = 0.03). RNA sequencing performed on whole blood samples of VTE patients showed that FOS exerted its effects in VTE via the leptin-mediated adipokine signalling pathway. Our results suggest that FOS and related genes or proteins can outperform traditional clinical markers and may be used as diagnostic biomarkers for VTE.

Nobiletin alleviates atherosclerosis by inhibiting lipid uptake via the PPARG/CD36 pathway.

BACKGROUND: Atherosclerosis (AS) is a persistent inflammatory condition triggered and exacerbated by several factors including lipid accumulation, endothelial dysfunction and macrophages infiltration. Nobiletin (NOB) has been reported to alleviate atherosclerosis; however, the underlying mechanism remains incompletely understood. METHODS: This study involved comprehensive bioinformatic analysis, including multidatabase target prediction; GO and KEGG enrichment analyses for function and pathway exploration; DeepSite and AutoDock for drug binding site prediction; and CIBERSORT for immune cell involvement. In addition, target intervention was verified via cell scratch assays, oil red O staining, ELISA, flow cytometry, qRT‒PCR and Western blotting. In addition, by establishing a mouse model of AS, it was demonstrated that NOB attenuated lipid accumulation and the extent of atherosclerotic lesions. RESULTS: (1) Altogether, 141 potentially targetable genes were identified through which NOB could intervene in atherosclerosis. (2) Lipid and atherosclerosis, fluid shear stress and atherosclerosis may be the dominant pathways and potential mechanisms. (3) ALB, AKT1, CASP3 and 7 other genes were identified as the top 10 target genes. (4) Six genes, including PPARG, MMP9, SRC and 3 other genes, were related to the M0 fraction. (5) CD36 and PPARG were upregulated in atherosclerosis samples compared to the normal control. (6) By inhibiting lipid uptake in RAW264.7 cells, NOB prevents the formation of foam cell. (7) In RAW264.7 cells, the inhibitory effect of oxidized low-density lipoprotein on foam cells formation and lipid accumulation was closely associated with the PPARG signaling pathway. (8) In vivo validation showed that NOB significantly attenuated intra-arterial lipid accumulation and macrophage infiltration and reduced CD36 expression. CONCLUSIONS: Nobiletin alleviates atherosclerosis by inhibiting lipid uptake via the PPARG/CD36 pathway.

Oxidized low-density lipoprotein induces M2-type differentiation of macrophages to promote the protracted progression of atherosclerotic inflammation in high-fat diet-fed ApoE -/- mice.

In this study, the significance of oxidized low-density lipoprotein (ox-LDL) in promoting the progression of atherosclerosis was investigated by inducing the differentiation of macrophages into the M2 subtype within a high-fat diet-induced ApoE -/- mouse model. The study also evaluated the effects of ß2-AR agonists and blockers on this process. Ox-LDL was found to have significantly promoted the differentiation of macrophages into the M2 type and induced related functional alterations. Furthermore, it activated the pyroptosis pathway and encouraged the release of lactate dehydrogenase. The administration of ß2-AR agonists intensified these processes, while ß2-AR blockers had the opposite effect. In animal experiments, the model group displayed elevated numbers of M2-type macrophages beneath the aortic root intima, an increased rate of plaque destruction, and the formation of atherosclerotic plaques compared to the control group. The SAL (Salbutamol) group exhibited even more severe plaque development than the model group. Conversely, the ICI (ICI118551) group demonstrated M2-type macrophage levels comparable to the control group, with a higher plaque destruction rate than controls but significantly lower than the model group, and no atherosclerotic plaques. These findings suggest that ox-LDL promoted the differentiation of recruited monocytes into M2-type macrophages, leading to a shift in the inflammatory response from M1 to M2 macrophages. This alteration resulted in the persistence of atherosclerotic inflammation, as M2-type macrophages were prone to cell membrane rupture (such as pyroptosis), contributing to the continuous recruitment of circulating monocytes and heightened inflammatory reactions within atherosclerotic plaques. Consequently, this process fueled the progression of atherosclerosis.

Structure-regulated mitochondrial-targeted fluorescent probe for sensing and imaging SO2in vivo.

SO2 and its derivatives play an important role in the antioxidation and anticorrosion of food and medicine. In biological systems, abnormal levels of SO2 lead to the occurrence of many biological diseases. Hence, the development of suitable tools for monitoring SO2 in mitochondria is beneficial for studying the biological effect of SO2 in subcellular organelles. In this research, DHX-1 and DHX-2 are fluorescent probes designed on the basis of dihydroxanthene skeletons. Importantly, DHX-1 (650 nm) and DHX-2 (748 nm) show near-infrared fluorescence response toward endogenous and exogenous SO2, which showed advantages of great selectivity, good sensitivity and low cytotoxicity, and the detection limit is 5.6 µM and 4.08 µM of SO2, respectively. Moreover, DHX-1 and DHX-2 realized SO2 sensing in HeLa cells and zebrafish. Moreover, cell imaging demonstrated that DHX-2 with a thiazole salt structure possesses good mitochondria-targeting ability. Additionally, DHX-2 was perfectly achieved by in situ imaging of SO2 in mice.

Activatable endoplasmic reticulum-targeted NIR fluorescent probe with a large Stokes shift for detecting and imaging chymotrypsin.

In this work, the first endoplasmic reticulum-targeted near-infrared fluorescent probe, ISO-Chy, with a dicyanoisophorone derivative as a fluorophore is reported by introducing the recognition group of 4-bromobutyl for chymotrypsin detection. The probe can be easily synthesized and has shown satisfactory sensitivity and selectivity to chymotrypsin. Meanwhile, ISO-Chy has a large Stokes shift (135 nm) to minimize self-absorption and interference from autofluorescence and then generate significant fluorescence enhancement upon incubation with chymotrypsin. Additionally, ISO-Chy has an excellent ability to target the endoplasmic reticulum, along with preferable Pearson's correlation coefficients (Rr) of 0.9411 and 0.9522 in P815 cells and HepG2 cells, respectively. Moreover, ISO-Chy was successfully utilized to visualize endogenous chymotrypsin in P815 cells and HepG2 cells and was first used to detect chymotrypsin activity in HepG2 tumor-bearing mice. These findings indicate that ISO-Chy could be an effective tool for detecting endogenous chymotrypsin activity, supporting its use for investigating chymotrypsin function in pathologic processes.

Butyrate protects endothelial function through PPARδ/miR-181b signaling.

Reports of the beneficial roles of butyrate in cardiovascular diseases, such as atherosclerosis and ischemic stroke, are becoming increasingly abundant. However, the mechanisms of its bioactivities remain largely unknown. In this study, we explored the effects of butyrate on endothelial dysfunction and its potential underlying mechanism. In our study, ApoE-/- mice were fed with high-fat diet (HFD) for ten weeks to produce atherosclerosis models and concurrently treated with or without sodium butyrate daily. Thoracic aortas were subsequently isolated from C57BL/6 wild-type (WT), PPARδ-/-, endothelial-specific PPARδ wild-type (EC-specific PPARδ WT) and endothelial-specific PPARδ knockout (EC-specific PPARδ KO) mice were stimulated with interleukin (IL)-1ß with or without butyrate ex vivo. Our results demonstrated that butyrate treatment rescued the impaired endothelium-dependent relaxations (EDRs) in thoracic aortas of HFD-fed ApoE-/- mice. Butyrate also rescued impaired EDRs in IL-1ß-treated thoracic aorta ring ex vivo. Global and endothelial-specific knockout of PPARδ eliminated the protective effects of butyrate against IL-1ß-induced impairment to EDRs. Butyrate abolished IL-1ß-induced reactive oxygen species (ROS) production in endothelial cells while the inhibitory effect was incapacitated by genetic deletion of PPARδ or pharmacological inhibition of PPARδ. IL-1ß increased NADPH oxidase 2 (NOX2) mRNA and protein expressions in endothelial cells, which were prevented by butyrate treatment, and the effects of butyrate were blunted following pharmacological inhibition of PPARδ. Importantly, butyrate treatment upregulated the miR-181b expression in atherosclerotic aortas and IL-1ß-treated endothelial cells. Moreover, transfection of endothelial cells with miR-181b inhibitor abolished the suppressive effects of butyrate on NOX2 expressions and ROS generation in endothelial cells. To conclude, butyrate prevents endothelial dysfunction in atherosclerosis by reducing endothelial NOX2 expression and ROS production via the PPARδ/miR-181b pathway.

Aminolactonization of Unactivated Alkenes Catalyzed by Aryl Iodine.

A one-step protocol of the aryl iodine-catalyzed aminolactonization of unactivated alkenes under oxidation conditions was first reported to efficiently construct diverse amino lactones in a short time using HNTs2 as the compatible nitrogen source. In addition, we investigated the influence of the reaction rate based on the structure of the iodoarene precatalyst, which revealed the selective adjustment effect on aminolactonization and oxylactonization. Finally, preliminary experiments verified the feasibility of asymmetric aminolactonization catalyzed by a chiral iodoarene precatalyst.

The Natural Compound Myricetin Effectively Represses the Malignant Progression of Prostate Cancer by Inhibiting PIM1 and Disrupting the PIM1/CXCR4 Interaction.

BACKGROUND/AIMS: Natural compounds are a promising resource for anti-tumor drugs. Myricetin, an abundant flavonoid found in the bark and leaves of bayberry, shows multiple promising anti-tumor functions in various cancers. METHODS: The cytotoxic, pro-apoptotic, and anti-metastatic effects of myricetin on prostate cancer cells were investigated in both in vitro and in vivo studies. Short-hairpin RNA knockdown of the proviral integration site for Moloney murine leukemia virus-1 (PIM1), pull-down and co-immunoprecipitation assays, and an intracellular Ca2+ flux assay were used to investigate the potential underlying mechanism of myricetin. ONCOMINE database data mining and immunohistochemical analysis of prostate cancer tissues were used to evaluate the expression of PIM1 and CXCR4, as well as the correlation between PIM1 and CXCR4 expression and the clinicopathologic characteristics and prognoses of prostate cancer patients. RESULTS: Myricetin exerted selective cytotoxic, pro-apoptotic, and anti-metastatic effects on prostate cancer cells by inhibiting PIM1 and disrupting the PIM1/CXCR4 interaction. Moreover, PIM1 and CXCR4 were coexpressed and associated with aggressive clinicopathologic traits and poor prognosis in prostate cancer patients. CONCLUSION: These results offer preclinical evidence for myricetin as a potential chemopreventive and therapeutic agent for precision medicine tailored to prostate cancer patients characterized by concomitant elevated expression of PIM1 and CXCR4.

Relationship between ADAMTS4 and carotid atherosclerotic plaque vulnerability in humans.

BACKGROUND: Rupture of atherosclerotic plaques and the resulting thrombosis are vital causes of clinical ischemic events. Recent studies have shown that ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) is a pathogenic factor of plaque vulnerability in mice. However, the relationship between ADAMTS4 and carotid atherosclerotic vulnerable plaques in humans remains unclear. METHODS: Forty-eight carotid atherosclerotic plaque specimens were obtained from 48 carotid artery stenosis inpatients undergoing carotid endarterectomy. We performed hematoxylin and eosin and Movat pentachrome staining for histologic characteristics; immunohistochemical staining for ADAMTS4, versican, and macrophages; and serologic tests for ADAMTS4. Patients were divided into stable and vulnerable groups on the basis of histologic characterization according to the classification criteria of the American Heart Association. Comparison between the groups was carried out using SPSS 17.0 (SPSS Inc, Chicago, Ill). RESULTS: Expression of ADAMTS4 in the plaque and its serum concentration were significantly higher in the vulnerable group compared with the stable one (P = .004 and P = .021, respectively), whereas the expression of versican was lower in the vulnerable group than in the stable group (P = .015). Univariate analysis revealed that the incidence of symptomatic cerebral ischemic events and ADAMTS4 serum levels were statistically higher in the vulnerable group compared with the stable group (P = .021 and P = .029, respectively). Multivariate analysis showed that ADAMTS4 was an independent risk factor (odds ratio, 1.14; P = .038). CONCLUSIONS: Our study revealed that ADAMTS4 expression was upregulated during carotid atherosclerotic plaque development. Serum levels of ADAMTS4 were associated with increased plaque vulnerability in both symptomatic and asymptomatic patients with carotid artery stenosis. ADAMTS4 may be a potential biomarker for plaque vulnerability.

Activation of GPR55 Ameliorates Maternal Separation-Induced Learning and Memory Deficits by Augmenting 5-HT Synthesis in the Dorsal Raphe Nucleus of Juvenile Mice.

Maternal separation (MS) represents a profound early life stressor with enduring impacts on neuronal development and adult cognitive function in both humans and rodents. MS is associated with persistent dysregulations in neurotransmitter systems, including the serotonin (5-HT) pathway, which is pivotal for mood stabilization and stress-coping mechanisms. Although the novel cannabinoid receptor, GPR55, is recognized for its influence on learning and memory, its implications on the function and synaptic dynamics of 5-HT neurons within the dorsal raphe nucleus (DRN) remain to be elucidated. In this study, we sought to discern the repercussions of GPR55 activation on 5-HT synthesis within the DRN of adult C57BL/6J mice that experienced MS. Concurrently, we analyzed potential alterations in excitatory synaptic transmission, long-term synaptic plasticity, and relevant learning and memory outcomes. Our behavioral assessments indicated a marked amelioration in MS-induced learning and memory deficits following GPR55 activation. In conjunction with this, we noted a substantial decrease in 5-HT levels in the MS model, while GPR55 activation stimulated tryptophan hydroxylase 2 synthesis and fostered the release of 5-HT. Electrophysiological patch-clamp analyses highlighted the ability of GPR55 activation to alleviate MS-induced cognitive deficits by modulating the frequency and magnitude of miniature excitatory postsynaptic currents within the DRN. Notably, this cognitive enhancement was underpinned by the phosphorylation of both NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In summary, our findings underscore the capacity of GPR55 to elevate 5-HT synthesis and modify synaptic transmissions within the DRN of juvenile mice, positing GPR55 as a promising therapeutic avenue for ameliorating MS-induced cognitive impairment.

An edoplasmic reticulum-targeted NIR fluorescent probe with a large Stokes shift for hypoxia imaging.

Hypoxia is closely linked to various diseases, including solid tumors. The level of nitroreductase (NTR) is usually abnormally upregulated in hypoxic conditions, which can be a biomarker of hypoxia. Herein, the first endoplasmic reticulum-targeting NIR fluorescent probe, ISO-NTR, was developed for highly selective and sensitive detection of NTR. It shows a large Stokes shift (185 nm) and a 5-fold increases in fluorescence intensity. Meanwhile, the ISO-NTR probe with a dicyanoisophorone derivative has excellent endoplasmic reticulum targeting in living systems with high Pearson's correlation coefficients (Rr = 0.9489). Molecular docking calculations and high binding energy between the probe and NTR (-10.78 kcal·mol-1) may explain the high selectivity of ISO-NTR. Additionally, it has been successfully applied to NTR imaging in vitro and vivo due to its good sensitivity, high selectivity and large Stokes shift, which may provide an effective method for studying the physiological and pathological functions of NTR in living systems. This probe could be developed as a potential imaging tool to further explore the pathogenesis of hypoxia-related diseases in endoplasmic reticulum stress.

Photoinduced Borylation of the Inert C(sp3)-O Bond of Alkyl Heteroaryl Ethers.

A photoinduced reductive Calkyl-O borylation of alkyl heteroaryl ethers with very negative reduction potential in the presence of 4-dimethylaminopyridine (DMAP) and bis(catecholato)diborane(B2cat2) was developed. Despite the high reducing power, various substrates with liable functional groups were well-tolerated as well as ethers derived from natural products and medicinal-relevant compounds. Mechanistic investigation implied that an intra-single electron transfer process in an electron donor-acceptor complex formed from ethers with the adduct of B2cat2 and DMAP should be involved.

LINC01936 inhibits the proliferation and metastasis of lung squamous cell carcinoma probably by EMT signaling and immune infiltration.

Purpose: To discover the biological function and potential mechanism of LINC01936 in the development of lung squamous cell carcinoma (LUSC). Methods: Transcriptome data of LUSC from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to analyze the differentially expressed lncRNAs in LUSC and normal tissues by R "DEseq2", "edgeR" and "limma" packages. The subcellular localization of LINC01936 was predicted by lncLocator. Cell proliferation and apoptosis were measured by CCK-8, MTT assay and Hoechst fluorescence staining. The migration and invasion were detected by Transwell assay. The function and pathway enrichment analysis were performed by Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and gene set variation analysis (GSVA). The downstream targets of LINC01936 were predicted using RNA-Protein Interaction Prediction (RPISeq) program. The effect of LINC01936 on tumor immune infiltration was analyzed using Pearson Correlation Analysis using R "ggpubr" package. Results: Based on the gene expression data of LUSC from TCGA database, 1,603, 1,702 and 529 upregulated and 536, 436 and 630 downregulated lncRNAs were obtained by DEseq2, edgeR and limma programs, respectively. For GSE88862 dataset, we acquired 341 differentially expressed lncRNAs (206 upregulated and 135 downregulated). Venn plot for the intersection of above differential expressed lncRNAs showed that there were 29 upregulated and 23 downregulated genes. LINC01936 was one of downregulated lncRNAs in LUSC tissues. The biological analysis showed that the overexpression of LINC01936 significantly reduced proliferation, migration and invasion of LUSC cells, and promoted cell apoptosis. The knockdown of LINC01936 promoted cell proliferation and metastasis. Pathway and GSVA analysis indicated that LINC01936 might participated in DNA repair, complement, cell adhesion and EMT, etc. LINC01936 was predicted to interact with TCF21, AOC3, RASL12, MEOX2 or HSPB7, which are involved in EMT and PI3K-AKT-MTOR pathway, etc. The expression of LINC01936 was also positively correlated with the infiltrating immune cells in LUSC. Conclusions: LINC01936 is downregulated in LUSC. LINC01936 affected proliferation, migration and invasion of LUSC cells probably by EMT and immune infiltration, which might serve as a new target for the treatment of LUSC.

Pseudogene CSPG4P12 affects the biological behavior of non­small cell lung cancer by Bcl­2/Bax mitochondrial apoptosis pathway.

Increasing evidence has shown that chondroitin sulfate proteoglycan 4 (CSPG4) serve a critical role in tumor progression. However, the roles of chondroitin sulfate proteoglycan 4 pseudogene 12 (CSPG4P12) remain to be elucidated. The present study aimed to investigate the potential effects of CSPG4P12 on the physiological behaviors of non-small cell lung cancer (NSCLC) and its underlying biological mechanism. The expression levels of CSPG4P12 in NSCLC tissues and adjacent normal tissues were analyzed using the gene expression profiling interactive analysis 2 database and reverse transcription-quantitative PCR. Cell Counting Kit-8 and colony formation assays were performed to measure cell proliferation. In addition, Transwell and wound healing assays were performed to assess cell invasion and migration. Cell adhesion was measured by cell-extracellular matrix adhesion assay. Hoechst 33342 staining assay was performed to detect nucleoli of apoptotic cells, and transmission electron microscopy (TEM) was utilized for apoptosis detection. Immunofluorescence and western blot assays were performed to measure the expression levels of apoptosis-related proteins. The present results revealed that the expression levels of CSPG4P12 in NSCLC tissues were significantly lower compared with those in adjacent normal tissues. Overexpression of CSPG4P12 inhibited cell proliferation, invasion, migration and adhesion whilst promoting apoptosis. There were missing mitochondrial cristae and mitochondrial vacuoles in the CSPG4P12-overexpressed cells when observed under TEM. Overexpression of CSPG4P12 also increased the expression of Bax and p53, whereas it inhibited the expression of Bcl2. In conclusion, CSPG4P12 could inhibit NSCLC development and tumorigenesis by activating the p53/Bcl2/Bax mitochondrial apoptotic pathway.

Surgical therapy for chronic internal carotid artery occlusion: a systematic review and meta-analysis.

Chronic internal carotid artery occlusion (CICAO) significantly increases the risk of recurrent stroke. Given unfavorable outcomes, revascularization procedures are not generally recommended for CICAO. In the last several years, loads of studies reported successful surgical revascularization for CICAO with promising success rate and favorable short-term outcomes. Meanwhile, due to the lack of high-quality evidence, the safety and efficacy of revascularization procedures remain debatable. This systematic review aims to scrutinize current evidence for the applicability of revascularization for CICAO. We also investigated potential predictors of postoperative prognosis. We searched clinical studies on surgical treatment of CICAO on the Medline, Cochrane library, and Embase databases, published from Jan 1990 to Jan 2021. Surgical operation was restricted to bypass surgery, endarterectomy, endovascular therapy, and hybrid surgery. Controlled clinical studies were included for clinical outcomes. Large-sample single-arm studies were supplemented to assess complications and success rate. Co-primary endpoints were technical success rate and neurological function; secondary endpoints were recurrent stroke/cerebrovascular events, complications, and deaths within follow-up. This systematic review has been registered in PROSPERO (CRD42020181250). One RCT and 5 cohort studies with a total of 465 patients were included in this review. Seven single-arm studies were supplemented for assessing success rate and complications. Bypass surgery presented the highest graft patency of 96% and a low incidence of complications, but no benefits on neurological function, recurrent stroke, or deaths. Endovascular therapy (carotid stenting) was characterized by a relatively lower technical success rate, significant neurological function recovery, and nonsignificant reduction of cerebrovascular events and deaths. Hybrid surgery was considered as a potential treatment for CICAO because of a high technical success rate and significant neurological improvement. Endarterectomy is only suitable for short-segment occlusion. Prospective clinical trials should focus on carotid stenting and hybrid surgery for their significant capacity of improving neurologic function and potential capacity of reducing deaths and cerebrovascular events.

Methylation Regulation of TLR3 on Immune Parameters in Lung Adenocarcinoma.

This study aims to analyze the methylation regulation of TLR3 in lung adenocarcinoma (LUAD) and to explore the association of TLR3 expression with immune microenvironment. TLR3 has a decreased expression in LUAD tissues and low expression of TLR3 is not only associated with poor prognosis in patients with LUAD, but also can be used as a diagnostic marker. Bisulfite sequencing PCR (BSP) results showed that the methylation level in the promoter of TLR3 was negatively correlated with the level of TLR3 mRNA in LUAD tissues. TIMER analysis showed that TLR3 was negatively correlated with the tumor purity of LUAD and positively with immune cell infiltration to some extent. ESTIMATE analysis also suggested that TLR3 expression and its methylation had significant correlation with immune score. The lower immune scores were associated with the late stage of LUAD and poor prognosis. The high expression of TLR3 might inhibit the development of LUAD by activating apoptosis pathway. The proteins interacted with TLR3 were mainly involved in the apoptosis pathway and positively correlated with the key genes (MYD88, Caspase 8, BIRC3, PIK3R1) in this pathway. Therefore, TLR3 as a key biomarker for prognosis and diagnosis in LUAD, might be considered as a potential epigenetic and immunotherapeutic target.

Rational design of a new near-infrared fluorophore and apply to the detection and imaging study of cysteine and thiophenol.

The development of a near-infrared fluorophore with excellent fluorescence performance, a large Stokes shift, and good biocompatibility has become a focus in the field of fluorescence imaging in recent years. Based on quantum chemistry calculations and reasonable molecular design strategies, a new NIR fluorophore was developed and characterized by simple synthesis, easy structural modification, and a large Stokes shift (105 nm). Furthermore, two new "activatable" fluorescent probes QN-Cys and QN-DNP were synthesized using a simple structural modification. The probe QN-Cys can recognize Cys with high sensitivity (LOD = 128 nM) and high selectivity, and its fluorescence intensity has a good linear relationship with the Cys concentration in the range of 5-35 µM. Furthermore, probe QN-Cys can effectively distinguish Cys from Hcy and GSH, and was successfully applied to the detection and imaging of Cys in human serum, cells, and zebrafish. The probe QN-DNP showed a good specific and sensitive (LOD = 78 nM) fluorescence response to thiophenol, and its fluorescence intensity has a good linear relationship with the thiophenol concentration in the range of 5-30 µM. Furthermore, it was successfully applied to detect thiophenol in real water samples with good recoveries (97-102%), and image thiophenol in living cells, zebrafish and mice. Notebly, the QN-DNP probe could be applied to visualize the distribution of thiophenol in the mice.

Integration of transcriptomics and metabolomics reveals anlotinib-induced cytotoxicity in colon cancer cells.

BACKGROUND: Mounting evidences suggested that anlotinib exhibits effective anti-tumor activity in various cancer types, such as lung cancer, glioblastoma and medullary thyroid cancer. However, its function in colon cancer remains to be further revealed. METHODS: Colon cancer cells (HCT-116) were treated with or without anlotinib. Transcript and metabolite data were generated through RNA sequencing and liquid chromatography-tandem mass spectrometry, respectively. The integrated analysis transcriptomics and metabolomics was conducted using R programs and online tools, including ClusterProfiler R program, GSEA, Prognoscan and Cytoscape. RESULTS: We found that differentially expressed genes (DEGs) were mainly involved in metabolic pathways and ribosome pathway. Structural maintenance of chromosome 3 (SMC3), Topoisomerase II alpha (TOP2A) and Glycogen phosphorylase B (PYGB) are the most significant DEGs which bring poor clinical prognosis in colon cancer. The analysis of metabolomics presented that most of the differentially accumulated metabolites (DAMs) were amino acids, such as L-glutamine, DL-serine and aspartic acid. The joint analysis of DEGs and DAMs showed that they were mainly involved in protein digestion and absorption, ABC transporters, central carbon metabolism, choline metabolism and Gap junction. Anlotinib affected protein synthesis and energy supporting of colon cancer cells by regulating amino acid metabolism. CONCLUSIONS: Anlotinib has a significant effect on colon cancer in both transcriptome and metabolome. Our research will provide possible targets for colon cancer treatment using anlotinib.

Vitamin A supplement after neonatal Streptococcus pneumoniae pneumonia inhibits the progression of experimental asthma by altering CD4+T cell subsets.

Studies demonstrated that pneumonia can decrease vitamin A productions and vitamin A reduction/deficiency may promote asthma development. Our previous study showed that neonatal Streptococcus pneumoniae (S. pneumoniae) infection promoted asthma development. Whether neonatal S. pneumoniae pneumonia induced asthma was associated with vitamin A levels remains unclear. The aim of this study was to investigate the effects of neonatal S. pneumoniae pneumonia on vitamin A expressions, to explore the effects of vitamin A supplement after neonatal S. pneumoniae pneumonia on adulthood asthma development. Non-lethal S. pneumoniae pneumonia was established by intranasal inoculation of neonatal (1-week-old) female BALB/c mice with D39. S. pneumoniae pneumonia mice were supplemented with or without all-trans retinoic acid 24 hours after infection. Vitamin A concentrations in lung, serum and liver were measured post pneumonia until early adulthood. Four weeks after pneumonia, mice were sensitized and challenged with OVA to induce allergic airway disease (AAD). Twenty-four hours after the final challenge, the lungs and bronchoalveolar lavage fluid (BALF) were collected to assess AAD. We stated that serum vitamin A levels in neonatal S. pneumoniae pneumonia mice were lower than 0.7µmol/L from day 2-7 post infection, while pulmonary vitamin A productions were significantly lower than those in the control mice from day 7-28 post infection. Vitamin A supplement after neonatal S. pneumoniae pneumonia significantly promoted Foxp3+Treg and Th1 productions, decreased Th2 and Th17 cells expressions, alleviated airway hyperresponsiveness (AHR) and inflammatory cells infiltration during AAD. Our data suggest that neonatal S. pneumoniae pneumonia induce serum vitamin A deficiency and long-time lung vitamin A reduction, vitamin A supplement after neonatal S. pneumoniae pneumonia inhibit the progression of asthma by altering CD4+T cell subsets.

Scopoletin ameliorates anxiety-like behaviors in complete Freund's adjuvant-induced mouse model.

Anxiety disorder is highly prevalent worldwide and represents a chronic and functionally disabling condition, with high levels of psychological stress characterized by cognitive and physiological symptoms. Scopoletin (SP), a main active compound in Angelica dahurica, is traditionally used for the treatment of headache, rhinitis, pain, and other conditions. Here, we evaluated the effects of SP in a mouse model of complete Freund's adjuvant (CFA)-induced chronic inflammation anxiety. SP (2.0, 10.0, 50.0 mg/kg) administration for 2 weeks dose-dependently ameliorated CFA-induced anxiety-like behaviors in the open field test and elevated plus maze test. Moreover, we found that SP treatment inhibited microglia activation and decreased both peripheral and central IL-1ß, IL-6, and TNF-α levels in a dose-dependent manner. Additionally, the imbalance in excitatory/inhibitory receptors and neurotransmitters in the basolateral nucleus after CFA injection was also modulated by SP administration. Our findings indicate that the inhibition of the nuclear factor-kappa B and mitogen-activated protein kinase signaling pathways involving anti-inflammatory activities and regulation of the excitatory/inhibitory balance can be attributed to the anxiolytic effects of SP. Moreover, our molecular docking analyses show that SP also has good affinity for gamma-aminobutyric acid (GABA) transaminase and GABAA receptors. Therefore, these results suggest that SP could be a candidate compound for anxiolytic therapy and for use as a structural base for developing new drugs.