Nesprin-2 is a novel scaffold protein for telethonin and FHL-2 in the cardiomyocyte sarcomere.

Nesprins comprise a family of multi-isomeric scaffolding proteins, forming the linker of nucleoskeleton-and-cytoskeleton complex with lamin A/C, emerin and SUN1/2 at the nuclear envelope. Mutations in nesprin-1/-2 are associated with Emery-Dreifuss muscular dystrophy (EDMD) with conduction defects and dilated cardiomyopathy (DCM). We have previously observed sarcomeric staining of nesprin-1/-2 in cardiac and skeletal muscle, but nesprin function in this compartment remains unknown. In this study, we show that specific nesprin-2 isoforms are highly expressed in cardiac muscle and localize to the Z-disc and I band of the sarcomere. Expression of GFP-tagged nesprin-2 giant spectrin repeats 52 to 53, localized to the sarcomere of neonatal rat cardiomyocytes. Yeast two-hybrid screening of a cardiac muscle cDNA library identified telethonin and four-and-half LIM domain (FHL)-2 as potential nesprin-2 binding partners. GST pull-down and immunoprecipitation confirmed the individual interactions between nesprin-2/telethonin and nesprin-2/FHL-2, and showed that nesprin-2 and telethonin binding was dependent on telethonin phosphorylation status. Importantly, the interactions between these binding partners were impaired by mutations in nesprin-2, telethonin, and FHL-2 identified in EDMD with DCM and hypertrophic cardiomyopathy patients. These data suggest that nesprin-2 is a novel sarcomeric scaffold protein that may potentially participate in the maintenance and/or regulation of sarcomeric organization and function.

Impacts of irrigation with treated livestock wastewater on the accumulation characteristic of ARGs in the farmland soil: a case study in Hohhot, China.

Irrigation with treated livestock wastewater (TWW) is a promising strategy for reusing resources. However, TWW irrigation might introduce antibiotic resistant genes (ARGs) into the soil, posing environmental risks associated with antibiotic resistance. This study focuses on investigating the influence of irrigation amounts and duration on the fate of ARGs and identifies key factors driving their changes. The results showed that there were 13 ARGs in TWW, while only 5 ARGs were detected in irrigated soil. That is some introduced ARGs from TWW could not persistently exist in the soil. After 1-year irrigation, an increase in irrigation amount from 0.016 t/m2 to 0.048 t/m2 significantly enhanced the abundance of tetC by 29.81%, while ermB and sul2 decreased by 45.37% and 76.47%, respectively (p < 0.01). After 2-year irrigation, the abundance of tetC, ermB, ermF, dfrA1, and total ARGs significantly increased (p < 0.05) when the irrigation amount increased. The abundances of ARGs after 2-year irrigation were found to be 2.5-34.4 times higher than 1 year. Obviously, the irrigation years intensified the positive correlation between ARGs abundance and irrigation amount. TetC and ermF were the dominant genes resulting in the accumulation of ARGs. TWW irrigation increased the content of organic matter and total nitrogen in the soil, which affected microbial community structure. The changes of the potential host were the determining factors driving the ARGs abundance. Our study demonstrated that continuous TWW irrigation for 2 years led to a substantial accumulation of ARGs in soil.

Concentration-Driven Evolution of Adaptive Artificial Ion Channels or Nanopores with Specific Anticancer Activities.

In nature, ceramides are a class of sphingolipids possessing a unique ability to self-assemble into protein-permeable channels with intriguing concentration-dependent adaptive channel cavities. However, within the realm of artificial ion channels, this interesting phenomenon is scarcely represented. Herein, we report on a novel class of adaptive artificial channels, Pn-TPPs, based on PEGylated cholic acids bearing triphenylphosphonium (TPP) groups as anion binding motifs. Interestingly, the molecules self-assemble into chloride ion channels at low concentrations while transforming into small molecule-permeable nanopores at high concentrations. Moreover, the TPP groups endow the molecules with mitochondria-targeting properties, enabling them to selectively drill holes on the mitochondrial membrane of cancer cells and subsequently trigger the caspase 9 apoptotic pathway. The anticancer efficacies of Pn-TPPs correlate with their abilities to form nanopores. Significantly, the most active ensembles formed by P5-TPP exhibits impressive anticancer activity against human liver cancer cells, with an IC50 value of 3.8 µM. While demonstrating similar anticancer performance to doxorubicin, P5-TPP exhibits a selectivity index surpassing that of doxorubicin by a factor of 16.8.

Non-Covalently Stapled H+ /Cl- Ion Channels Activatable by Visible Light for Targeted Anticancer Therapy.

The development of stimuli-responsive artificial H+ /Cl- ion channels, capable of specifically disturbing the intracellular ion homeostasis of cancer cells, presents an intriguing opportunity for achieving high selectivity in cancer therapy. Herein, we describe a novel family of non-covalently stapled self-assembled artificial channels activatable by biocompatible visible light at 442 nm, which enables the co-transport of H+ /Cl- across the membrane with H+ /Cl- transport selectivity of 6.0. Upon photoirradiation of the caged C4F-L for 10 min, 90 % of ion transport efficiency can be restored, giving rise to a 10.5-fold enhancement in cytotoxicity against human colorectal cancer cells (IC50 =8.5 µM). The mechanism underlying cancer cell death mediated by the H+ /Cl- channels involves the activation of the caspase 9 apoptosis pathway as well as the scarcely reported disruption of the autophagic processes. In the absence of photoirradiation, C4F-L exhibits minimal toxicity towards normal intestine cells, even at a concentration of 200 µM.

Role of soluble epoxide hydrolase in the abnormal activation of fibroblast-like synoviocytes from patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by enigmatic pathogenesis. Polyunsaturated fatty acids (PUFAs) are implicated in RA's development and progression, yet their exact mechanisms of influence are not fully understood. Soluble epoxide hydrolase (sEH) is an enzyme that metabolizes anti-inflammatory epoxy fatty acids (EpFAs), derivatives of PUFAs. In this study, we report elevated sEH expression in the joints of CIA (collagen-induced arthritis) rats, concomitant with diminished levels of two significant EpFAs. Additionally, increased sEH expression was detected in both the synovium of CIA rats and in the synovium and fibroblast-like synoviocytes (FLS) of RA patients. The sEH inhibitor TPPU attenuated the migration and invasion capabilities of FLS derived from RA patients and to reduce the secretion of inflammatory factors by these cells. Our findings indicate a pivotal role for sEH in RA pathogenesis and suggest that sEH inhibitors offer a promising new therapeutic strategy for managing RA.

Chlorogenic Acid Inhibits Epithelial-Mesenchymal Transition and Invasion of Breast Cancer by Down-Regulating LRP6.

Epithelial-mesenchymal transition (EMT) is a crucial biologic process for breast cancer metastasis, and inhibition of EMT could be an effective approach to suppress metastatic potential of mammary cancer. High expression of low-density lipoprotein receptor-related protein 6 (LRP6) is usually observed in breast carcinoma and predicts poor prognosis. In the present study, we investigated whether chlorogenic acid (CA) can inhibit the EMT of breast cancer cells and underlying molecular mechanism. We found that CA treatment transformed MCF-7 cell morphology from spindle shape (mesenchymal phenotype) to spherical shape (epithelial phenotype). CA clearly increased epithelial biomarkers' expression (E-cadherin and ZO-1) but decreased mesenchymal proteins' expression (ZEB1, N-cadherin, vimentin, snail, and slug). In addition, CA attenuated MMP-2 and MMP-9 activities and inhibited cell migration and invasion. CA downregulated the expression of LRP6 in MCF-7 cells. Knockdown LRP6 with siRNA repressed cell mobility and invasion, wheras overexpression of LRP6 promoted EMT and antagonized the EMT inhibitory effect of CA on MCF-7 cells. Furthermore, CA directly interacted with Wnt/ß-catenin signaling coreceptor LRP6 and reduced LRP6, p-LRP6, and ß-catenin expression levels in MCF-7 cells. In vivo study revealed that CA notably reduced tumor volume and tumor weight. CA decreased the expression of LRP6, N-cadherin, ZEB1, vimentin, MMP2, MMP9, and increased the expression of E-cadherin and ZO-1. In conclusion, CA inhibited EMT and invasion of breast cancer by targeting LRP6. SIGNIFICANCE STATEMENT: CA, the familiar polyphenol compound in traditional Chinese medicine, repressed EMT and weakened cellular mobility and invasion in MCF-7 cells. The mechanism studies demonstrated that CA could inhibit EMT and invasion of MCF-7 cells via targeting LRP6. Additionally, CA restrained tumor growth and xenograft tumor EMT in vivo. The EMT inhibitory property of CA warrants further studies of CA as a drug candidate for the therapy of metastatic breast carcinoma.

Nesprin-1: novel regulator of striated muscle nuclear positioning and mechanotransduction.

Nesprins (nuclear envelope spectrin repeat proteins) are multi-isomeric scaffolding proteins. Giant nesprin-1 and -2 localise to the outer nuclear membrane, interact with SUN (Sad1p/UNC-84) domain-containing proteins at the inner nuclear membrane to form the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex, which, in association with lamin A/C and emerin, mechanically couples the nucleus to the cytoskeleton. Despite ubiquitous expression of nesprin giant isoforms, pathogenic mutations in nesprin-1 and -2 are associated with tissue-specific disorders, particularly related to striated muscle such as dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy. Recent evidence suggests this muscle-specificity might be attributable in part, to the small muscle specific isoform, nesprin-1α2, which has a novel role in striated muscle function. Our current understanding of muscle-specific functions of nesprin-1 and its isoforms will be summarised in this review to provide insight into potential pathological mechanisms of nesprin-related muscle disease and may inform potential targets of therapeutic modulation.

Evaluation of the effect of green tea and its constituents on embryo development in a zebrafish model.

As one of the most popular beverages, green tea has attracted much interest for its beneficial effects on human health. However, the toxicity of green tea and its underlying mechanism are still poorly understood. Here, we evaluated the effect of green tea and its constituents on development by exposing zebrafish embryos to them. Morphologic results demonstrated that 0.1% and 0.2% green tea increased mortality, delayed epiboly of gastrulation, and shortened body length. Green tea altered the expression pattern of dlx3, cstlb, myod, and papc and decreased the expression levels of wnt5 and wnt11, suggesting that green tea disturbed convergence and extension movement through the downregulation of wnt5 and wnt11. The increased expression of the dorsal gene chordin and reduced expression of wnt8 and its target genes vox and vent in embryos exposed to 0.1% and 0.2% green tea indicated that green tea could affect dorsoventral differentiation by inhibiting the wnt8 signaling pathway. Additionally, green tea could inhibit epiboly progression by disrupting F-actin organization or removing F-actin in vegetal yolks during gastrulation. However, no malformation was caused by exposure to the five catechins and gallic acid individually. The mixture of constituents showed a similar effect to green tea solution on the embryos, such as smaller eyes and head, shorter body length, and slower heart rate, which indicated that the effect of green tea solution on embryo development was mainly due to the comprehensive effect of multiple components in the green tea solution.

Structural insights into multifunctionality of human FACT complex subunit hSSRP1.

Human structure-specific recognition protein 1 (hSSRP1) is an essential component of the facilitates chromatin transcription complex, which participates in nucleosome disassembly and reassembly during gene transcription and DNA replication and repair. Many functions, including nuclear localization, histone chaperone activity, DNA binding, and interaction with cellular proteins, are attributed to hSSRP1, which contains multiple well-defined domains, including four pleckstrin homology (PH) domains and a high-mobility group domain with two flanking disordered regions. However, little is known about the mechanisms by which these domains cooperate to carry out hSSRP1's functions. Here, we report the biochemical characterization and structure of each functional domain of hSSRP1, including the N-terminal PH1, PH2, PH3/4 tandem PH, and DNA-binding high-mobility group domains. Furthermore, two casein kinase II binding sites in hSSRP1 were identified in the PH3/4 domain and in a disordered region (Gly617-Glu709) located in the C-terminus of hSSRP1. In addition, a histone H2A-H2B binding motif and a nuclear localization signal (Lys677‒Asp687) of hSSRP1 are reported for the first time. Taken together, these studies provide novel insights into the structural basis for hSSRP1 functionality.

Pathological components and CT imaging analysis of the area adjacent pleura within the pure ground-glass nodules with pleural deformation in invasive lung adenocarcinoma.

BACKGROUND: Pleural deformation is associated with the invasiveness of lung adenocarcinoma(LAC). Our study focused on the pathological components of the area adjacent pleura in pulmonary pure ground-glass nodules(pGGNs) with pleural deformations(P-pGGNs) confirmed to be invasive LAC without visceral pleural invasion (VPI) pathologically. METHODS: Computed tomography(CT) imaging features of nodules and pathological components of the area adjacent pleura were analyzed and recorded. Statistical analysis was performed for subgroups of P-pGGNs. RESULTS: The 81 enrolled patients with 81 P-pGGNs were finally involved in the analysis. None of solid/micropapillary group and none of VPI was observed, 54 alveoli/lepidics and 27 acinar/papillarys were observed. In P-pGGN with acinar/papillary components of the area adjacent pleura, invasive adenocarcinoma (IAC) was more common compared to minimally invasive adenocarcinoma (MIA, 74.07% vs. 25.93%; p < 0.001). The distance in alveoli/lepidic group was significantly larger (1.50 mm vs. 0.00 mm; p < 0.001) and the depth was significantly smaller (2.00 mm vs. 6.00 mm; p < 0.001) than that in acinar/papillary group. The CT attenuation value, maximum diameter and maximum vertical diameter was valuable to distinguish acinar/papillary group form alveoli/lepidic group(p < 0.05). The type d pleural deformation was the common pleural deformation in IAC(p = 0.028). CONCLUSIONS: The pathological components of the area adjacent pleura in P-pGGN without VPI confirmed to be invasive LAC could included alveoli/lepidics and acinar/papillarys. Some CT indicators that can identify the pathological invasive components of the area adjacent pleura in P-pGGNs.

Synthesis and anti-inflammatory activities of glycyrrhetinic acid derivatives containing disulfide bond.

A series of glycyrrhetinic acid (GA, aglycone of glycyrrhizic acid) derivatives containing disulfide bond were synthesized and their anti-inflammatory and anti-fibrosis activities were evaluated in vivo and in vitro. Among them, compound 7 displayed the highest toxicity to all the tested cell lines including macrophages. Compounds 3 and 4 showed higher activities than GA in the cell and animal model. In the anti-inflammatory tests, compounds 3 and 4 down-regulated the expressions of several inflammatory factors, such as HMGB1, TLR4, IL-1ß, TNF-α and TGF-ß1 in LPS-treated RAW264.7 cells in a dose-dependent manner. Compounds 3 and 4 at 30 µM respectively reduced the levels of HMGB1 in the LPS group to 42.7% and 38.2%. In addition, the level of TLR4 decreased to close to that of control group when treated by compound 4 at the concentration of 30 µM. In the process of anti-fibrosis tests using TGF-ß1-induced A549 cell line as the model, compounds 3 and 4 also decreased the expression levels of Col1 and α-SMA in a dose-dependent manner. Compound 3 and 4 at 30 µM respectively reduced the expression of α-SMA level by 2.2-fold and 2.6-fold compared to the TGF-ß1-treated control group. Moreover, they influenced the ROS level and mitochondrial membrane potential (MMP) in A549 cells. In the paraquat-induced pulmonary fibrosis mice model, the symptoms of inflammation and fibrosis of mice were alleviated after administration of compound 3 or 4. The above results suggest that compounds 3 and 4 may be promising candidates for inflammation and lung fibrosis treatment.

Toxicity of polymer-modified CuS nanoclusters on zebrafish embryo development.

Despite the vast amount of research on the toxicity of copper-based nanoparticles, the toxicity of CuS nanoparticles is still largely unknown. Due to the application of CuS-based nanomaterials in biomedical engineering, it is necessary to study their potential toxicity and biological effects. In this study, we evaluated the toxicity of polymer-modified CuS nanoclusters (PATA3-C4@CuS) on embryo development through exposing zebrafish embryos to 1, 2.5, 5, 7.5, and 10 mg/L PATA3-C4@CuS at 0.75-h post-fertilization. The morphological results demonstrated that PATA3-C4@CuS at concentrations greater than 1 mg/L PATA3-C4@CuS induced abnormal phenotypes including smaller heads and eyes, pericardial edema, and epiboly retardation and it increased mortality, lowered the hatching rate, and inhibited swim bladder inflation. In situ hybridization and quantitative reverse transcription polymerase chain reaction showed that PATA3-C4@CuS could alter the expression patterns of tbxta, dlx3, and cstlb and increase the expression levels of wnt5 and wnt11, which suggested that PATA3-C4@CuS disrupts cell migration by increasing the levels of wnt5 and wnt11 during gastrulation. It was also discovered that PATA3-C4@CuS exposure caused a slow heart rate and smaller ventricles in zebrafish larvae. Immunofluorescence and behavioral analyses showed that PATA3-C4@CuS could damage the ventral projection of the primary motor neurons CaP, which was in accordance with the reduction in locomotion ability. Together, our data demonstrated that functional PATA3-C4@CuS could disrupt cell migration during gastrulation, affect cardiac development and function, and decrease locomotive activity.

Resistant starch intake alleviates collagen-induced arthritis in mice by modulating gut microbiota and promoting concomitant propionate production.

Gut dysbiosis precedes clinic symptoms in rheumatoid arthritis (RA) and has been implicated in the initiation and persistence of RA. The early treatment of RA is critical to better clinical outcome especially for joint destruction. Although dietary interventions have been reported to be beneficial for RA patients, it is unclear to whether diet-induced gut microbiome changes can be a preventive strategy to RA development. Here, we investigated the effect of a high fiber diet (HFD) rich with resistant starch (RS) on collagen-induced arthritis (CIA) and gut microbial composition in mice. RS-HFD significantly reduced arthritis severity and bone erosion in CIA mice. The therapeutic effects of RS-HFD were correlated with splenic regulatory T cell (Treg) expansion and serum interleukin-10 (IL-10) increase. The increased abundance of Lactobacillus and Lachnoclostridium genera concomitant with CIA were eliminated in CIA mice fed the RS-HFD diet. Notably, RS-HFD also led to a predominance of Bacteroidetes, and increased abundances of Lachnospiraceae_NK4A136_group and Bacteroidales_S24-7_group genera in CIA mice. Accompanied with the gut microbiome changes, serum levels of the short-chain fatty acid (SCFA) acetate, propionate and isobutyrate detected by GC-TOFMS were also increased in CIA mice fed RS-HFD. While, addition of ß-acids from hops extract to the drinking water of mice fed RS-HFD significantly decreased serum propionate and completely eliminated RS-HFD-induced disease improvement, Treg cell increase and IL-10 production in CIA mice. Moreover, exogenous propionate added to drinking water replicated the protective role of RS-HFD in CIA including reduced bone damage. The direct effect of propionate on T cells in vitro was further explored as at least one mechanistic explanation for the dietary effects of microbial metabolites on immune regulation in experimental RA. Taken together, RS-HFD significantly reduced CIA and bone damage and altered gut microbial composition with concomitant increase in circulating propionate, indicating that RS-rich diet might be a promising therapy especially in the early stage of RA.

Off-label use of letrozole in Chinese short pubertal boys: Effectiveness, safety, and exposure-response analysis.

AIMS: Recently, letrozole has been used off-label to treat short pubertal boys. The experience on letrozole effectiveness and safety has been obtained primarily from Caucasian children. A simple extrapolation of the data to Chinese paediatric populations is questionable because of the substantial ethnic differences between the two populations. Therefore, the present study aimed to determine the effectiveness and safety of letrozole use in Chinese short pubertal boys as well as to establish an exposure-response relationship. METHODS: Forty-one Chinese boys were included in the study. Patients were given letrozole tablets (2.5 mg) once daily in combination with growth hormone, and follow-up visits were made after 1, 3, 6 and 12 months of treatment. Plasma samples were taken from clinical examinations and analysed using high performance liquid chromatography with fluorescence detection. RESULTS: After 1 year of treatment, 35 (88%) boys showed increased predicted adult heights. However, possible adverse drug reactions were seen in nine boys (22%). Predicted adult heights increased significantly from 168.4 ± 3.7 to 173.0 ± 4.2 cm, while oestrogen levels dropped from 33.2 ± 7.4 to 21.6 ± 7.3 pg/mL. Increments in predicted adult height were significantly correlated with trough letrozole concentrations (r = 0.39, P = .01). CONCLUSION: Letrozole treatment in Chinese pubertal populations should be further optimized, and more personalized therapies should be developed.

Chemically synthesized (Ag, Mn2O3)-codecorated ZnO nanoparticles for achieving superior visible light-induced photodegradation and enhanced gas sensing activity.

Heterostructural engineering and noble metal coupling are effective strategies to optimize semiconductor photocatalytic materials. In this work, (Ag, Mn2O3)-codecorated ZnO nanoparticles with different Mn2O3 contents (0-10 mol%) were synthesized by integrating the two strategies by a facile two-step polymer network-gel process. The photocatalytic activity of Ag/ZnO (AZM0) was significantly enhanced with the optimum Mn2O3 molar ratio of 3 mol%. The degradation efficiency of AZM3 is ∼3 times and ∼4.8 times higher than that of AZM0 for the degradation of methylene blue (MB) upon exposure to simulated sunlight and visible light, respectively. Also, this ternary nanocomposite exhibits enhanced gas sensing performance towards NO2 under ultraviolet/visible light irradiation at room temperature. The analysis of its microstructural, optical and photoelectrical characteristics suggests the synergistic coupling effects of Ag and Mn2O3, in which the significantly enhanced visible light response and hetero-interface charge carrier migration are the critical factors for the improvement of photocatalytic efficiency and gas sensing activity. Furthermore, the effects of recycling ability, the influence of the initial solution pH, the catalyst dosage and the main active species during the catalysis process on photocatalytic activity were explored. This study develops a feasible pathway to consciously construct multiheterostructures for enhancing the photocatalytic activity with great potential applications in toxic pollution abatement and noxious gas detection.

Exploration of irradiation intensity dependent external in-band quantum yield for ZnO and CuO/ZnO photocatalysts.

Decorating metal oxides with wide band-gap semiconductor nano-particles constitute an important approach for synthesizing nano-photocatalysts, where the photocatalytic activity is attributed to the band diagram related effective charge separation and external in-band quantum yield (EIQY). However, up to now, the correlation between the irradiation intensity and the functionalization of the in-band quantum yield has not yet been explained. In this work, by investigating the photocatalytic activity of ZnO and CuO/ZnO (CZO) nano-photocatalysts under various irradiative intensities, we show that the effective charge separation in the CuO/ZnO band alignment is sensitive to weak illumination, while ZnO exhibits a competitive photocatalytic activity with CZO under strong illumination. As a consequence, by modifying the irradiation intensity, the intrinsic ZnO can achieve a similar photocatalytic activity to that of metal oxide decorated ZnO. Besides, the optimal photocatalytic activity of CZO is found to be reachable by manipulating the pollutant concentration.

Comparison of Clinical Outcomes between Anteromedial and Transtibial Techniques of Single-Bundle Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-Analysis.

This study compared clinical outcomes obtained after single-bundle anterior cruciate ligament (ACL) reconstruction using the anteromedial (AM) and transtibial (TT) techniques, which comprise the conventional transtibial (cTT) and modified transtibial (mTT) techniques. This study included clinical randomized controlled trials and prospective and retrospective controlled trials with AM and TT techniques from the PubMed and Embase databases and the Cochrane Library. All databases were searched from January 2010 to July 2020. Two independent evaluators verified the quality of the included studies using the Cochrane Collaboration's risk of bias tool and the Newcastle-Ottawa Scale (NOS). Outcome measures analysed included the Lachman test, pivot-shift test, side-to-side difference (SSD), Lysholm score, Tegner activity scale, International Knee Documentation Committee (IKDC) grade and score. Ten randomized controlled trials (RCTs) and 16 prospective and retrospective controlled trials were included with a total of 2202 patients. There were 1180 patients and 1022 patients in the AM and TT groups, respectively. Compared to the cTT group, superior postoperative results were observed in the AM group based on the negative rate of the Lachman test and the pivot-shift test, IKDC grade and score, Lysholm score, Tegner activity scale and SSD (p < 0.05). However, there was no significant difference between the AM and mTT groups (p > 0.05). Compared to the conventional TT technique, the AM technique exhibited superior clinical outcomes. Nevertheless, the modified TT and AM techniques had comparable results. With neither of the techniques (mTT or AM) producing significantly superior outcomes, surgeons can choose either of them depending on their preferences.

UHRF1 predicts poor prognosis by triggering cell cycle in lung adenocarcinoma.

Accumulating evidence suggests that ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) is overexpressed in non-small cell lung cancer (NSCLC); however, the expression and function of UHRF1 in the subtype of NSCLC are still unclear. Here, we investigate the expression and prognosis traits of UHRF1 in large NSCLC cohorts and explore the molecular characters during UHRF1 up-regulation. We find that UHRF1 is predominantly overexpressed in lung squamous cell carcinoma (SCC). Surprisingly, the up-regulated UHRF1 is only associated with the overall survival of lung adenocarcinoma (ADC) and knockdown of UHRF1 dramatically attenuates ADC tumorigenesis. Mechanically, we identify a hub gene that includes a total of 55 UHRF1-related genes, which are tightly associated with cell cycle pathway and yield to the poor clinical outcome in ADC patients. What's more, we observe knockdown of UHRF1 only affects ADC cells cycle and induces cell apoptosis. These results suggest that up-regulated UHRF1 only contributes to lung ADC survival by triggering cell cycle pathway, and it may be a prognostic biomarker for lung ADC patients.

GWAS and co-expression network combination uncovers multigenes with close linkage effects on the oleic acid content accumulation in Brassica napus.

BACKGROUND: Strong artificial and natural selection causes the formation of highly conserved haplotypes that harbor agronomically important genes. GWAS combination with haplotype analysis has evolved as an effective method to dissect the genetic architecture of complex traits in crop species. RESULTS: We used the 60 K Brassica Infinium SNP array to perform a genome-wide analysis of haplotype blocks associated with oleic acid (C18:1) in rapeseed. Six haplotype regions were identified as significantly associated with oleic acid (C18:1) that mapped to chromosomes A02, A07, A08, C01, C02, and C03. Additionally, whole-genome sequencing of 50 rapeseed accessions revealed three genes (BnmtACP2-A02, BnABCI13-A02 and BnECI1-A02) in the A02 chromosome haplotype region and two genes (BnFAD8-C02 and BnSDP1-C02) in the C02 chromosome haplotype region that were closely linked to oleic acid content phenotypic variation. Moreover, the co-expression network analysis uncovered candidate genes from these two different haplotype regions with potential regulatory interrelationships with oleic acid content accumulation. CONCLUSIONS: Our results suggest that several candidate genes are closely linked, which provides us with an opportunity to develop functional haplotype markers for the improvement of the oleic acid content in rapeseed.

Nicotinamide increases the sensitivity of chronic myeloid leukemia cells to doxorubicin via the inhibition of SIRT1.

The NAD-dependent deacetylase Sirtuin 1 (SIRT1) plays a vital role in leukemogenesis. Nicotinamide (NAM) is the principal NAD+ precursor and a noncompetitive inhibitor of SIRT1. In our study, we showed that NAM enhanced the sensitivity of chronic myeloid leukemia (CML) to doxorubicin (DOX) via SIRT1. We found that SIRT1 high expression in CML patients was associated with disease progression and drug resistance. Exogenous NAM efficiently repressed the deacetylation activity of SIRT1 and induced the apoptosis of DOX-resistant K562 cells (K562R) in a dose-dependent manner. Notably, the combination of NAM and DOX significantly inhibited tumor cell proliferation and induced cell apoptosis. The knockdown of SIRT1 in K562R cells enhanced NAM+DOX-induced apoptosis. SIRT1 rescue in K562R reduced the NAM+DOX-induced apoptosis. Mechanistically, the combinatory treatment significantly increased the cleavage of caspase-3 and PARP in K562R in vitro and in vivo. These results suggest the potential role of NAM in increasing the sensitivity of CML to DOX via the inhibition of SIRT1.