Aging and comprehensive molecular profiling in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.

S-Shaped Helical Singlet Diradicaloid and Its Transformation to Circumchrysene via a Two-Stage Cyclization.

Polycyclic hydrocarbons with diradical and polyradical characters usually display unique reactivities in ring-cyclization reactions. However, such reactions are rarely used to construct π-extended polycyclic aromatic hydrocarbons. Here, we describe the synthesis of an S-shaped doubly helical singlet diradicaloid compound and its facile transformation into an unprecedented circumchrysene via a two-stage ring cyclization, which includes: (1) an eletrocylization from diradicaloid precursor and (2) a Scholl reaction. The reaction mechanism was investigated through in situ spectroscopic studies, assisted by theoretical calculations. This reaction sequence yields an optically resolved π-extended [5]helicene derivative with a fluorescence quantum yield up to 85% and a circularly polarized luminescence brightness up to 6.05 M-1 cm-1 in the far-red to near-infrared regions. This sequence also yielded a highly delocalized circumchrysene molecule, exhibiting large electron delocalization, moderate fluorescence quantum yield, and multistage redox properties.

Separable Microneedle for Integrated Hyperglycemia Sensing and Photothermal Responsive Metformin Release.

Microdevices that offer hyperglycemia monitoring and controllable drug delivery are urgently needed for daily diabetes management. Herein, a theranostic separable double-layer microneedle (DLMN) patch consisting of a swellable GelMA supporting base layer for glycemia sensing and a phase-change material (PCM) arrowhead layer for hyperglycemia regulation has been fabricated. The Cu-TCPP(Fe)/glucose oxidase composite and 3,3',5,5'-tetramethylbenzidine coembedded in the supporting base layer permit a visible color shift at the base surface in the presence of glucose via a cascade reaction, allowing for the in situ detection of glucose in interstitial fluid. The PCM arrowhead layer is encapsulated with water monodispersity melanin nanoparticles from Sepia officinalis and metformin that is imparted with a near-infrared ray photothermal response feature, which is beneficial to the controllable release of metformin for suppression of hyperglycemia. By applying the DLMN patch to the streptozotocin-induced type 2 diabetic Sprague-Dawley rat model, the results demonstrated that it can effectively extract dermal interstitial fluid, read out glucose levels, and regulate hyperglycemia. This DLMN-integrated portable colorimetric sensor and self-regulated glucose level hold great promise for daily diabetes management.

Analysis of risk factors associated with diffuse alveolar haemorrhage in patients with ANCA-associated vasculitis and construction of a risk prediction model using line graph.

OBJECTIVES: This study aims to analyse the risk factors associated with diffuse alveolar haemorrhage (DAH) in patients with ANCA-associated vasculitis (AAV) and construct a risk prediction model using line graph. METHODS: A retrospective study was conducted from January 2012 to May 2023 at the First Clinical College of Three Gorges University, focusing on patients diagnosed with AAV. Clinical and laboratory data were collected from these patients. The potential predictors subsets of high-risk AAV combined with DAH were screened by LASSO regression and 10-fold cross-validation method, and determined by using multivariate Logistic regression analysis, then were used for developing a prediction nomogram for high-risk AAV combined with DAH using the R software. ROC curve analysis was used to validate the model's stability. Internal validation was performed using a bootstrap method. The discrimination of the nomogram was determined by calculating the average consistency index(C-index). The calibration curve was used to assess the calibration of the nomogram. RESULTS: A total of 234 patients with AAV were included, among whom 85 developed DAH, with an incidence rate of 36%, and the average age was 63±12. Multivariable logistic regression analysis showed that Age [OR=1.037 (95%CI: 1.006, 1.071), p=0.019], platelet count (PLT) [OR=0.996 (95%CI: 0.992, 0.999), p=0.029], ESR [OR=1.028 (95%CI: 1.015, 1.042), p<0.01], HB [OR=0.978 (95%CI: 0.959, 0.996), p=0.024], and haematuria [OR=3.77 (95%CI: 1.677, 8.976), p=0.001] were found to be independent predictors of AAV combined with DAH and were used to construct a nomogram. The AUCROC values of the nomogram for DAH in AAV patients was 0.852 (95%CI: 0.801, 0.903), and the C-index could reach 0.824 after internal verification, showing good differentiation and consistency. CONCLUSIONS: The new nomogram, which included age, Hb, ESR, PLT and haematuria as variables, had the potential to predict the risk of AAV patients complicated with DAH.

TsCl promoted deoxygenative phosphorothiolation of quinoline N-oxides towards S-quinolyl phosphorothioates.

A convenient, efficient and practical approach for the synthesis of S-quinolyl phosphorothioates via cheap TsCl promoted deoxygenative C2-H phosphorothiolation of quinoline N-oxides with readily available triethylammonium O,O-dialkylphosphorothioates was developed. The reaction performed well under transition-metal-free conditions at room temperature with a very short reaction time (10-20 min). Preliminary studies showed that the current transformation underwent a nucleophilic substitution process.

KNSTRN Is a Prognostic Biomarker That Is Correlated with Immune Infiltration in Breast Cancer and Promotes Cell Cycle and Proliferation.

Kinetochore-localized astrin/SPAG5-binding protein (KNSTRN) promotes the progression of bladder cancer and lung adenocarcinoma. However, its expression and biological function in breast cancer remain largely unknown. Therefore, this study aimed to analyze KNSTRN expression, prognoses, correlation with immune infiltration, expression-associated genes, and regulated signaling pathways to characterize its role in regulating the cell cycle using both bioinformatics and in vitro functional experiments. Analyses of The Cancer Genome Atlas, Gene Expression Omnibus, TIMER, and The Human Protein Atlas databases revealed a significant upregulation of KNSTRN transcript and protein levels in breast cancer. Kaplan-Meier survival analyses demonstrated a significant association between high expression of KNSTRN and poor overall survival, relapse-free survival, post-progression survival, and distant metastases-free survival in patients with breast cancer. Furthermore, multivariate Cox regression analyses confirmed that KNSTRN is an independent prognostic factor for breast cancer. Immune infiltration analysis indicated a positive correlation between KNSTRN expression and T regulatory cell infiltration while showing a negative correlation with Tgd and natural killer cell infiltration. Gene set enrichment analysis along with single-cell transcriptome data analysis suggested that KNSTRN promoted cell cycle progression by regulating the expression of key cell cycle proteins. The overexpression and silencing of KNSTRN in vitro, respectively, promoted and inhibited the proliferation of breast cancer cells. The overexpression of KNSTRN enhanced the expression of key cell cycle regulators, including CDK4, CDK6, and cyclin D3, thereby accelerating the G1/S phase transition and leading to aberrant proliferation of breast cancer cells. In conclusion, our study demonstrates that KNSTRN functions as an oncogene in breast cancer by regulating immune response, promoting G1/S transition, and facilitating breast cancer cell proliferation. Moreover, KNSTRN has potential as a molecular biomarker for diagnostic and prognostic prediction in breast cancer.

[Effect of Zuogui Jiangtang Qinggan Formula on lipid metabolism in db/db mouse model of type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease].

This study aims to explore the effect of Zuogui Jiangtang Qinggan Formula(ZGJTQGF) on the lipid metabolism in the db/db mouse model of type 2 diabetes mellitus(T2DM) complicated with non-alcoholic fatty liver disease(NAFLD) via the insulin receptor(INSR)/adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)/sterol-regulatory element-binding protein 2(SREBP-2) signaling pathway. Twenty-four db/db mice were randomized into positive drug(metformin, 0.067 g·kg~(-1)) and low-(7.5 g·kg~(-1)) and high-dose(15 g·kg~(-1)) ZGJTQGF groups. Six C57 mice were used as the blank group and administrated with an equal volume of distilled water. The mice in other groups except the blank group were administrated with corresponding drugs by gavage for 6 consecutive weeks. At the end of drug administration, fasting blood glucose(FBG) and blood lipid levels were measured, and oral glucose tolerance test was performed. Compared with the blank group, the mice treated with ZGJTQGF showed decreased body mass and liver weight coefficient, lowered levels of FBG, total cholesterol(TC), triglyceride(TG), and low-density lipoprotein(LDL), and weakened liver function. The pathological changes and lipid accumulation in the liver tissue were examined. Western blot was employed to measure the protein levels of INSR, AMPK, p-AMPK, and SREBP-2. Compared with the blank group, the model group showed down-regulated protein levels of INSR and p-AMPK/AMPK and up-regulated protein level of SREBP-2. Compared with the model group, high-dose ZGJTQGF up-regulated the protein levels of INSR and p-AMPK/AMPK and down-regulated the protein level of SREBP-2. Low-dose ZGJTQGF slightly up-regulated the protein levels of INSR and p-AMPK/AMPK and down-regulated the protein level of SREBP-2, without significant differences. The results suggested that ZGJTQGF may alleviate insulin resistance and improve lipid metabolism in db/db mice by activating the INSR/AMPK/SREBP-2 signaling pathway.

[Screening of bioactive components endowing hawthorn with turbidity-eliminating and lipid-lowering functions and development of quality control method of hawthorn].

Hawthorn has the efficacy of eliminating turbidity and lowering the blood lipid level, and it is used for treating hyperlipidemia in clinic. However, the bioactive components of hawthorn are still unclear. In this study, the spectrum-effect relationship was employed to screen the bioactive components of hawthorn in the treatment of hyperlipidemia, and then the bioactive components screened out were verified in vivo. Furthermore, the quality control method for hawthorn was developed based on liquid chromatography-mass spectrometry(LC-MS). The hyperlipidemia model of rats was built, and different polar fractions of hawthorn extracts and their combinations were administrated by gavage. The effects of different hawthorn extract fractions on the total cholesterol(TC), triglycerides(TG), and low-density lipoprotein-cholesterol(LDL-C) in the serum of model rats were studied. The orthogonal projections to latent structures(OPLS) algorithm was used to establish the spectrum-effect relationship model between the 24 chemical components of hawthorn and the pharmacodynamic indexes, and the bioactive components were screened out and verified in vivo. Finally, 10 chemical components of hawthorn, including citric acid and quinic acid, were selected to establish the method for evaluating hawthorn quality based on LC-MS. The results showed that different polar fractions of hawthorn extracts and their combinations regulated the TG, TC, and LDL-C levels in the serum of the model rats. The bioactive components of hawthorn screened by the OPLS model were vitexin-4″-O-glucoside, vitexin-2″-O-rhamnoside, rutin, citric acid, malic acid, and quinic acid. The 10 chemical components of hawthorn, i.e., citric acid, quinic acid, rutin, gallic acid, vitexin-4″-O-glucoside, vitexin-2″-O-rhamnoside, malic acid, vanillic acid, neochlorogenic acid, and fumaric acid were determined, with the average content of 38, 11, 0.018, 0.009 5, 0.037, 0.017, 8.1, 0.009 5, 0.073, and 0.98 mg·g~(-1), respectively. This study provided a scientific basis for elucidating the material basis of hawthorn in treating hyperlipidemia and developed a content determination method for evaluating the quality of hawthorn.

KCNN1 promotes proliferation and metastasis of breast cancer via ERLIN2-mediated stabilization and K63-dependent ubiquitination of Cyclin B1.

Potassium Calcium-Activated Channel Subfamily N1 (KCNN1), an integral membrane protein, is thought to regulate neuronal excitability by contributing to the slow component of synaptic after hyperpolarization. However, the role of KCNN1 in tumorigenesis has been rarely reported, and the underlying molecular mechanism remains unclear. Here, we report that KCNN1 functions as an oncogene in promoting breast cancer cell proliferation and metastasis. KCNN1 was overexpressed in breast cancer tissues and cells. The pro-proliferative and pro-metastatic effects of KCNN1 were demonstrated by CCK8, clone formation, Edu assay, wound healing assay and transwell experiments. Transcriptomic analysis using KCNN1 overexpressing cells revealed that KCNN1 could regulate key signaling pathways affecting the survival of breast cancer cells. KCNN1 interacts with ERLIN2 and enhances the effect of ERLIN2 on Cyclin B1 stability. Overexpression of KCNN1 promoted the protein expression of Cyclin B1, enhanced its stability and promoted its K63 dependent ubiquitination, while knockdown of KCNN1 had the opposite effects on Cyclin B1. Knockdown (or overexpression) ERLNI2 partially restored Cyclin B1 stability and K63 dependent ubiquitination induced by overexpression (or knockdown) of KCNN1. Knockdown (or overexpression) ERLIN2 also partially neutralizes the effects of overexpression (or knockdown) KCNN1-induced breast cancer cell proliferation, migration and invasion. In paired breast cancer clinical samples, we found a positive expression correlations between KCNN1 and ERLIN2, KCNN1 and Cyclin B1, as well as ERLIN2 and Cyclin B1. In conclusion, this study reveals, for the first time, the role of KCNN1 in tumorigenesis and emphasizes the importance of KCNN1/ERLIN2/Cyclin B1 axis in the development and metastasis of breast cancer.

DNA Assembly of Plasmonic Nanostructures Enables In Vivo SERS-Based MicroRNA Detection and Tumor Photoacoustic Imaging.

Controllable self-assembly of the DNA-linked gold nanoparticle (AuNP) architecture for in vivo biomedical applications remains a key challenge. Here, we describe the use of the programmed DNA tetrahedral structure to control the assembly of three different types of AuNPs (∼20, 10, and 5 nm) by organizing them into defined positioning and arrangement. A DNA-assembled "core-satellite" architecture is built by DNA sequencing where satellite AuNPs (10 and 5 nm) surround a central core AuNP (20 nm). The density and arrangement of the AuNP satellites around the core AuNP were controlled by tuning the size and amount of the DNA tetrahedron functionalized on the core AuNPs, resulting in strong electromagnetic field enhancement derived from hybridized plasmonic coupling effects. By conjugating with the Raman molecule, strong surface-enhanced Raman scattering photoacoustic imaging signals could be generated, which were able to image microRNA-21 and tumor tissues in vivo. These results provided an efficient strategy to build precision plasmonic superstructures in plasmonic-based bioanalysis and imaging.

Phylogenomic insights into the origin and evolutionary history of evergreen broadleaved forests in East Asia under Cenozoic climate change.

The evergreen versus deciduous leaf habit is an important functional trait for adaptation of forest trees and has been hypothesized to be related to the evolutionary processes of the component species under paleoclimatic change, and potentially reflected in the dynamic history of evergreen broadleaved forests (EBLFs) in East Asia. However, knowledge about the shift of evergreen versus deciduous leaf with the impact of paleoclimatic change using genomic data remains rare. Here, we focus on the Litsea complex (Lauraceae), a key lineage with dominant species of EBLFs, to gain insights into how evergreen versus deciduous trait shifted, providing insights into the origin and historical dynamics of EBLFs in East Asia under Cenozoic climate change. We reconstructed a robust phylogeny of the Litsea complex using genome-wide single-nucleotide variants (SNVs) with eight clades resolved. Fossil-calibrated analyses, diversification rate shifts, ancestral habit, ecological niche modelling and climate niche reconstruction were employed to estimate its origin and diversification pattern. Taking into account studies on other plant lineages dominating EBLFs of East Asia, it was revealed that the prototype of EBLFs in East Asia probably emerged in the Early Eocene (55-50 million years ago [Ma]), facilitated by the greenhouse warming. As a response to the cooling and drying climate in the Middle to Late Eocene (48-38 Ma), deciduous habits were evolved in the dominant lineages of the EBLFs in East Asia. Up to the Early Miocene (23 Ma), the prevailing of East Asian monsoon increased the extreme seasonal precipitation and accelerated the emergence of evergreen habits of the dominant lineages, and ultimately shaped the vegetation resembling that of today.

Phylotranscriptomic analyses reveal deep gene tree discordance in Camellia (Theaceae).

Gene tree discordance is a significant legacy of biological evolution. Multiple factors can result in incongruence among genes, such as introgression, incomplete lineage sorting (ILS), gene duplication or loss. Resolving the background of gene tree discordance is a critical way to uncover the process of species diversification. Camellia, the largest genus in Theaceae, has controversial taxonomy and systematics due in part to a complex evolutionary history. We used 60 transcriptomes of 55 species, which represented 15 sections of Camellia to investigate its phylogeny and the possible causes of gene tree discordance. We conducted gene tree discordance analysis based on 1,617 orthologous low-copy nuclear genes, primarily using coalescent species trees and polytomy tests to distinguish hard and soft conflict. A selective pressure analysis was also performed to assess the impact of selection on phylogenetic topology reconstruction. Our results detected different levels of gene tree discordance in the backbone of Camellia, and recovered rapid diversification as one of the possible causes of gene tree discordance. Furthermore, we confirmed that none of the currently proposed sections of Camellia was monophyletic. Comparisons among datasets partitioned under different selective pressure regimes showed that integrating all orthologous genes provided the best phylogenetic resolution of the species tree of Camellia. The findings of this study reveal rapid diversification as a major source of gene tree discordance in Camellia and will facilitate future investigation of reticulate relationships at the species level in this important plant genus.

ZBTB28 inhibits breast cancer by activating IFNAR and dual blocking CD24 and CD47 to enhance macrophages phagocytosis.

Breast cancer is the leading cause of cancer death in female. Until now, advanced breast cancer is still lack effective treatment strategies and reliable prognostic markers. In the present article, we introduced the physiologic and pathologic functions and regulation mechanisms of ZBTB28, a tumor suppressor gene, in breast cancer. ZBTB28 is frequently silenced in breast cancer due to promoter CpG methylation, and its expression is positively correlated with breast cancer patient survival. The antineoplastic effect of ZBTB28 in breast cancer was elucidated through a series of in vitro and in vivo measurements, including cell proliferation, apoptosis, cell cycle, epithelial mesenchymal transition (EMT), and growth of xenografts. Furthermore, ZBTB28 can directly regulate IFNAR to activate interferon-stimulated genes and potentiate macrophage activation. Ectopic ZBTB28 expression in breast cancer cells was sufficient to downregulate CD24 and CD47 to promote phagocytosis of macrophages, demonstrating that ZBTB28 was beneficial for the combination treatment of anti-CD24 and anti-CD47. Collectively, our results reveal a mode of action of ZBTB28 as a tumor suppressor gene and suggest that ZBTB28 is an important regulator of macrophage phagocytosis in breast cancer, holding promise for the development of novel therapy strategies for breast cancer patients.

Multidimensional study of the heterogeneity of leukemia cells in t(8;21) acute myelogenous leukemia identifies the subtype with poor outcome.

t(8;21)(q22;q22) acute myelogenous leukemia (AML) is morphologically characterized by a continuum of heterogeneous leukemia cells from myeloblasts to differentiated myeloid elements. Thus, t(8;21) AML is an excellent model for studying heterogeneous cell populations and cellular evolution during disease progression. Using integrative analyses of immunophenotype, RNA-sequencing (RNA-seq), and single-cell RNA-sequencing (scRNA-seq), we identified three distinct intrapatient leukemic cell populations that were arrested at different stages of myeloid differentiation: CD34+CD117dim blasts, CD34+CD117bri blasts, and abnormal myeloid cells with partial maturation (AM). CD117 is also known as c-KIT protein. CD34+CD117dim cells were blocked in the G0/G1 phase at disease onset, presenting with the regular morphology of myeloblasts showing features of granulocyte-monocyte progenitors (GMP), and were drug-resistant to chemotherapy. Genes associated with cell migration and adhesion (LGALS1, EMP3, and ANXA2) were highly expressed in the CD34+CD117dim population. CD34+CD117bri blasts were blocked a bit later than the CD34+CD117dim population in the hematopoietic differentiation stage and displayed high proliferation ability. AM cells, which bear abnormal myelocyte morphology, especially overexpressed granule genes AZU1, ELANE, and PRTN3 and were sensitive to chemotherapy. scRNA-seq at different time points identified CD34+CD117dim blasts as an important leukemic cluster that expanded at postrelapse refractory stage after several cycles of chemotherapy. Patients with t(8;21) AML with a higher proportion of CD34+CD117dim cells had significantly worse clinical outcomes than those with a lower CD34+CD117dim proportion. Univariate and multivariate analyses identified CD34+CD117dim proportion as an independent factor for poor disease outcome. Our study provides evidence for the multidimensional heterogeneity of t(8;21)AML and may offer new tools for future disease stratification.

RIG-I regulates myeloid differentiation by promoting TRIM25-mediated ISGylation.

Retinoic acid-inducible gene I (RIG-I) is up-regulated during granulocytic differentiation of acute promyelocytic leukemia (APL) cells induced by all-trans retinoic acid (ATRA). It has been reported that RIG-I recognizes virus-specific 5'-ppp-double-stranded RNA (dsRNA) and activates the type I interferons signaling pathways in innate immunity. However, the functions of RIG-I in hematopoiesis remain unclear, especially regarding its possible interaction with endogenous RNAs and the associated pathways that could contribute to the cellular differentiation and maturation. Herein, we identified a number of RIG-I-binding endogenous RNAs in APL cells following ATRA treatment, including the tripartite motif-containing protein 25 (TRIM25) messenger RNA (mRNA). TRIM25 encodes the protein known as an E3 ligase for ubiquitin/interferon (IFN)-induced 15-kDa protein (ISG15) that is involved in RIG-I-mediated antiviral signaling. We show that RIG-I could bind TRIM25 mRNA via its helicase domain and C-terminal regulatory domain, enhancing the stability of TRIM25 transcripts. RIG-I could increase the transcriptional expression of TRIM25 by caspase recruitment domain (CARD) domain through an IFN-stimulated response element. In addition, RIG-I activated other key genes in the ISGylation pathway by activating signal transducer and activator of transcription 1 (STAT1), including the modifier ISG15 and several enzymes responsible for the conjugation of ISG15 to protein substrates. RIG-I cooperated with STAT1/2 and interferon regulatory factor 1 (IRF1) to promote the activation of the ISGylation pathway. The integrity of ISGylation in ATRA or RIG-I-induced cell differentiation was essential given that knockdown of TRIM25 or ISG15 resulted in significant inhibition of this process. Our results provide insight into the role of the RIG-I-TRIM25-ISGylation axis in myeloid differentiation.

LINC01806 Promotes Breast Cancer Growth and Metastasis via Sponging miR-1286 to Disinhibit ZEB1 Expression.

Breast cancer (BC) is the most abundant and aggressive cancer that impacts millions of women with poorly understood mechanisms. Here, we aimed to investigate the function of LINC01806 in BC development. Human BC tissues and nearby normal specimens were taken from diagnosed BC patients. The expression levels of LINC01806, miR-1286, ZEB1, and EMT-related markers were evaluated by qRT-PCR and western blotting. FISH was used to visualize the subcellular localization of LINC01806. The viability, proliferation, migration and invasion capacities of BC cells were assessed by MTT, colony formation, and transwell assays. Interactions among LINC01806, miR-1286 and ZEB1 were validated by dual luciferase assay. The unpaired Student t-test (for two groups) or one-way ANOVA following with Tukey post-hoc test (for more than three groups) was employed for statistical analysis. LINC01806 level was elevated in BC tissues. Knockdown of LINC01806 suppressed EMT process and BC cell proliferation, migration, and invasion. LINC01806 co-localized and directly bound with miR-1286 in the cytoplasm. MiR-1286 inhibitor blocked the effects of LINC01806 knockdown on BC cell EMT, proliferation and migration. MiR-1286 targeted ZEB1 and overexpression of ZEB1 blocked the regulatory functions of miR-1286 mimics in BC. LINC01806 facilitates EMT and accelerates BC cell proliferation, migration, and invasion via acting as miR-1286 sponge to disinhibit ZEB1 expression.

[Zuogui Jiangtang Qinggan Formula improves glucolipid metabolism in type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease by regulating FoxO1/MTP/APOB signaling pathway].

This study aimed to investigate the effect and mechanism of Zuogui Jiangtang Qinggan Formula(ZGJTQG) on the glucolipid metabolism of type 2 diabetes mellitus(T2DM) complicated with non-alcoholic fatty liver disease(NAFLD). NAFLD was induced by a high-fat diet(HFD) in MKR mice(T2DM mice), and a model of T2DM combined with NAFLD was established. Forty mice were randomly divided into a model group, a metformin group(0.067 g·kg~(-1)), and high-and low-dose ZGJTQG groups(29.64 and 14.82 g·kg~(-1)), with 10 mice in each group. Ten FVB mice of the same age were assigned to the normal group. Serum and liver tissue specimens were collected from mice except for those in the normal and model groups after four weeks of drug administration by gavage, and fasting blood glucose(FBG) and fasting insulin(FINS) levels were measured. The levels of total cholesterol(TC), triglyceride(TG), and low-density lipoprotein(LDL) were detected by the single reagent GPO-PAP method. Very low-density lipoprotein(VLDL) was detected by enzyme-linked immunosorbent assay(ELISA). Alanine aminotransferase(ALT) and aspartate ami-notransferase(AST) were determined by the Reitman-Frankel assay. The pathological changes in the liver were observed by hematoxylin-eosin(HE) staining and oil red O staining. Real-time fluorescence-based quantitative polymerase chain reaction(real-time PCR) and Western blot were adopted to detect the mRNA and protein expression of forkhead transcription factor O1(FoxO1), microsomal triglyceride transfer protein(MTP), and apolipoprotein B(APOB) in the liver. The results showed that high-dose ZGJTQG could signi-ficantly reduce the FBG and FINS levels(P<0.05, P<0.01), improve glucose tolerance and insulin resistance(P<0.05, P<0.01), alleviate the liver damage caused by HFD which was reflected in improving liver steatosis, and reduce the serum levels of TC, TG, LDL, VLDL, ALT, and AST(P<0.05, P<0.01) in T2DM mice combined with NAFLD. The findings also revealed that the mRNA and protein expression of FoxO1, MTP, and APOB in the liver was significantly down-regulated after the intervention of high-dose ZGJTQG(P<0.05, P<0.01). The above study showed that ZGJTQG could effectively improve glucolipid metabolism in T2DM combined with NAFLD, and the mechanism was closely related to the regulation of the FoxO1/MTP/APOB signaling pathway.

[Application of partial least squares algorithm to explore bioactive components of crude and stir-baked hawthorn for invigorating spleen and promoting digestion].

This study was aimed at identifying the bioactive components of the crude and stir-baked hawthorn for invigorating spleen and promoting digestion, respectively, to clarify the processing mechanism of hawthorn by applying the partial least squares(PLS) algorithm to build the spectrum-effect relationship model. Firstly, different polar fractions of crude and stir-baked hawthorn aqueous extracts and combinations of different fractions were prepared, respectively. Then, the contents of 24 chemical components were determined by ultra-high performance liquid chromatography-mass spectrometry. The effects of different polar fractions of crude hawthorn and stir-baked hawthorn aqueous extracts and combinations of different fractions were evaluated by measuring the gastric emptying rate and small intestinal propulsion rate. Finally, the PLS algorithm was used to establish the spectrum-effect relationship model. The results showed that there were significant differences in the contents of 24 chemical components for different polar fractions of crude and stir-baked hawthorn aqueous extracts and combinations of different fractions, and the gastric emptying rate and small intestinal propulsion rate of model rats were improved by administration of different polar fractions of crude and stir-baked hawthorn aqueous extracts and combinations of different fractions. The bioactive components of crude hawthorn identified by PLS models were vitexin-4″-O-glucoside, vitexin-2″-O-rhamnoside, neochlorogenic acid, rutin, gallic acid, vanillic acid, citric acid, malic acid, quinic acid and fumaric acid, while neochlorogenic acid, cryptochlorogenic acid, rutin, gallic acid, vanillic acid, citric acid, quinic acid and fumaric acid were the bioactive components of stir-baked hawthorn. This study provided data support and scientific basis for identifying the bioactive components of crude and stir-baked hawthorn, and clarifying the processing mechanism of hawthorn.

Spin-Distribution-Directed Regioselective Substitution Strategy for Highly Stable Olympicenyl Radicals.

The synthesis of bench-stable conjugated π-radicals is challenging owing to the lack of modular approaches, which greatly hampers their practical material screens and applications. Here, we demonstrate a spin-distribution-directed regioselective substitution strategy to introduce substituents into the specific positions of an olympicenyl radical in a stepwise manner, resulting in a series of highly stable radical species. The substituents can also adjust the crystal packing by means of steric and electronic factors, enabling the changing from a π-dimer to a pseudo-one-dimensional chain. The first single crystal organic field-effect transistor device based on a graphenic radical is fabricated in air, showing a hole mobility of up to 0.021 cm2 V-1 s-1 and excellent device stability. This approach may be generalized to diverse spin-delocalized open-shell organic radicals.

Stable Crystalline Nanohoop Radical and Its Self-Association Promoted by van der Waals Interactions.

A stable nanohoop radical (OR3) combining the structures of cycloparaphenylene and an olympicenyl radical is synthesized and isolated in the crystalline state. X-ray crystallographic analysis reveals that OR3 forms a unique head-to-tail dimer that further aggregates into a one-dimensional chain in the solid state. Variable-temperature NMR and concentration-dependent absorption measurements indicate that the π-dimer is not formed in solution. An energy decomposition analysis indicates that van der Waals interactions are the driving force for the self-association process, in contrast with other olympicenyl derivatives that favor π-dimerization. The physical properties in solution phase have been studied, and the stable cationic species obtained by one-electron chemical oxidation. This study offers a new molecular design to modulate the self-association of organic radicals for overcoming the spin-Peierls transition, and to prepare novel nanohoop compounds with spin-related properties.