Breast cancer has become the most commonly diagnosed cancer, surpassing lung cancer, with 2.26 million new breast cancers worldwide in 2020. Hence, there is an urgent need to develop effective ...molecularly targeted therapeutic drugs to treat breast cancer. In this paper, we designed, synthesized and screened a novel thiophene-triazine derivative, XS-2, as a potent dual PI3K/mTOR inhibitor for the treatment of breast cancer. Also, XS-2 was found to be potentially effective against triple-negative breast cancer (TNBC) in vitro during the investigation. We evaluated the in vitro inhibitory effect of XS-2 on 10 cancer cell lines by MTT and 6 kinases to investigated its in vivo antitumor activity in MCF-7 xenograft tumor-bearing BALB/c nude mice. In addition, the in vitro/in vivo toxicity to mice was also assessed by hemolytic toxicity, H&E staining and blood biochemical analysis. In order to investigate the antitumor mechanism of XS-2, a series of experiments were carried out in vitro/in vivo animal model and molecular biological levels such as the cell cycle and the apoptosis assay, real-time PCR, western blot, docking and molecular simulations analysis, etc. What’s more, wound healing assay, Transwell and Western Blot were applied to explore the ability of XS-2 to inhibit the cell invasion and migration. The results showed that XS-2 exhibited strong antitumor activity both in vitro and in vivo. The inhibitory activities of XS-2 on ten cancer cell lines were ranging from 1.07 ± 0.11 to 0.002 ± 0.001 μM, which were 1565 times better than that of the lead compound GDC-0941, inhibitory activities against PI3Kα and mTOR kinases were 291.0 and 60.8 nM, respectively. Notably, XS-2 not only showed significant in vivo antitumor activity and low toxicity, with the tumor inhibition rate of 57.0 %, but also exhibited strong inhibitory in the expression of related proteins of PI3K pathway in tumor tissues. In addition, XS-2 significantly inhibited breast cancer MCF-7 and MDA-MB-231 cells in a concentration- and time-dependent manner, and inhibited the migration and invasion ability of MDA-MB-231 and MCF-7 cells. More than that, XS-2 could inhibit the increase of the expression levels of N-cadherin and vimentin upregulated by EGF and reversed the E-cadherin expression down regulated by EGF, resulting in inhibiting EMT in MCF-7 and MDA-MB-231 cells. The results showed that XS-2 was expected to be successfully developed as a high-efficiency and low-toxicity breast cancer therapeutic drug with the potential to inhibit the invasion and migration of TNBC. This provides a new research idea for the treatment of TNBC, which is of great significance.
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•XS-2, a novel potent dual PI3K/mTOR inhibitor.•XS-2 induced apoptosis of 10 cancer cell lines tested, including MCF-7 and MDA-MB-231 cancer cells.•Molecular biology and cellular approaches were used to evaluate the in vitro antitumor mechanism of XS-2.•XS-2 exhibited significant antitumor activity and low toxicity in vivo experiments.•XS-2 is expected to be developed as a highly effective, low-toxicity breast cancer treatment.
Kojic acid is an important secondary metabolite of industrial importance produced by
. The kojic acid gene cluster plays an essential role in kojic acid production, and harbors
,
and
. The deletion ...of
, encoding a major facilitator superfamily (MFS) transporter, did not completely abolish kojic acid production, implying that other transporters are required for the transport of kojic acid. The aim of this study is to look for the transporters involved in kojic acid production. Here,
encoding a novel MFS transporter was identified, which was adjacent to
in the kojic acid gene cluster. The deletion of
contributed to the hyphal growth, conidial production and biomass of
. Moreover,
is required for heat- and cell-wall-stress tolerance but not oxidative and osmotic stress. The disruption of
impaired kojic acid production with the reduced expression of
,
and
. Furthermore, when
was deleted in the
-disrupted strain, the yield of kojic acid declined to the same level as that of the
-deletion mutant, whereas the production of kojic acid was recovered when
was overexpressed in the
knockout strain, suggesting that
acts downstream of
. AoKap4 was the second identified MSF transporter involved in kojic acid production after
was found a decade ago. This study contributes to a better understanding of the biological roles of the MFS transporter and lays a foundation for future studies on kojic acid synthesis in
.
The literature indicates that LINC00174 promotes the growth of colorectal cancer (CRC) cells, but its research needs to be enriched. We tried to explore the function and mechanism of LINC00174 in CRC ...cell proliferation and migration. Bioinformatics analysis predicted the binding relationship and expressions of lncRNA, miRNA and mRNA. Clinical study analyzes the relationship between LINC00174 and clinical data characteristics of CRC patients. The expressions of LINC00174, miR-3127-5p and E2F7 were verified by RT-qPCR, and the combination of the two was verified by dual luciferase analysis and RNA immunoprecipitation as needed. Western blot was used to detect the expression of EMT-related protein and E2F7 protein. Functional experiments were used to evaluate the function of the target gene on CRC cells. LINC00174 was up-regulated in CRC clinical samples and cells and was related to the clinical characteristics of CRC patients. High-expression of LINC00174, contrary to the effect of siLINC00174, promoted cell viability, proliferation, migration and invasion, up-regulated the expressions of N-Cadherin, Vimentin, E2F7, and inhibited the expression of E-Cadherin. MiR-3127-5p was one of the targeted miRNAs of LINC00174 and was down-regulated in CRC samples. In addition, miR-3127-5p mimic partially reversed the malignant phenotype of CRC cells induced by LINC00174. Besides, E2F7 was a target gene of miR-3127-5p, and LINC00174 repressed miR-3127-5p to regulate E2F7. Our research reveals that LINC00174 affected the biological characteristics of CRC cells through regulated miR-3127-5p/ E2F7 axis.
Gold cation–water complexes with attached argon atoms are produced via a laser vaporization supersonic cluster source. The Au(H2O) n Ar x + (n = 1–8; x = 1 or 2) complexes are each mass selected and ...studied by infrared photodissociation spectroscopy in the OH stretching frequency region to explore the coordination and solvation structures of the Au+ cation. Density functional calculations have been performed, and the calculated vibrational spectra are compared to the experimental spectra to identify the gas-phase structures of the Au(H2O) n + complexes. Confirming previous theoretical predications, the first coordination shell of the Au+ cation contains two water molecules forming a linear O–Au+–O arrangement; subsequent water molecules bind to the two H2O ligands of the Au(H2O)2 + core ion via hydrogen bond forming of the second hydration shell, which is complete at n = 6. For the complexes with n ≤ 7, the experimental spectrum can in general be assigned to the predicted global minimum structure. However, the spectrum suggests that two or more conformers coexist for the n = 8 complex, indicating that the identification of a single global minimum becomes less important upon increasing the number of solvating water molecules.
Seed weight (SW) is one of three determinants of seed yield, which positively correlates with silique length (SL) in
(rapeseed). However, the genetic mechanism underlying the relationship between ...seed weight (SW) and silique length (SL) is largely unknown at present. A natural population comprising 157 inbred lines in rapeseed was genotyped by whole-genome re-sequencing and investigated for SW and SL over four years. The genome-wide association study identified 20 SNPs in significant association with SW on A01, A04, A09, C02, and C06 chromosomes and the phenotypic variation explained by a single locus ranged from 11.85% to 34.58% with an average of 25.43%. Meanwhile, 742 SNPs significantly associated with SL on A02, A03, A04, A07, A08, A09, C01, C03, C04, C06, C07, and C08 chromosomes were also detected and the phenotypic variation explained by a single locus ranged from 4.01 to 48.02% with an average of 33.33%, out of which, more than half of the loci had not been reported in the previous studies. There were 320 overlapping or linked SNPs for both SW and SL on A04, A09, and C06 chromosomes. It indicated that both overlapping and independent genetic loci controlled both SW and SL in
. On the haplotype block on A09 chromosome, the allele variants of a known gene
controlling both SW and SL were identified in the natural population by developing derived cleaved amplified polymorphic sequence (dCAPS) markers. These findings are valuable for understanding the genetic mechanism of SW and SL and also for rapeseed molecular breeding programs.
The dynamics of Gross Primary Productivity (GPP) is key to understand the global carbon cycle. Multiple GPP products are currently available based on remote sensing, Light Use Efficiency model (LUE) ...or diagnostic biophysical model. However, little knowledge is available on the spatial patterns of the uncertainty of different GPP products and their potential drivers over the Central Asia (CA), a fragile environment for accurate GPP estimation. This study investigates the sensitivity of the 8-day, monthly and yearly GPP uncertainties based on the three-cornered hat (TCH) method and Shapley additive explanation (SHAP) model in terms of vegetation, energy, water, climate and terrain factors in the dryland ecosystem during the 2003-2015 period. Ten GPP products were examined, including one product (FLUXCOM) from machine learning (ML), six products (EC-LUE, FluxSat, LUEopt, MODIS, MuSyQ and VPM) based on the (LUE), two products (GOSIF and NIRv) from satellite-based direct proxies (Proxies) and one product (PML) from the diagnostic biophysical model. The results indicate that the spatial distribution of the ten GPP products in CA showed similar patterns at different time scales, but with values varied at different products and time scales. According to the eddy covariance (EC) observations and the TCH-based uncertainties, the FLUXCOM product showed smaller relative uncertainties than other products. The attribution analysis denotes that the sources of uncertainty of the GPP varied for each product, and thus the improvement strategies for different products should be implemented separately The FLUXCOM should adapt the vegetation- related module to the dryland environment of CA. The LUE model should optimize the LUE parameters for the dryland ecosystem and incorporate the water related variables in the model. The Proxies model should incorporate the water and energy variables (such as soil moisture and radiation) as input data to improve their performance in CA. The diagnostic model should consider the elevation variable as input data, which may improve the performance of the PML in CA. Our results do not only provide an important basis for the selection of GPP products in the study of the carbon cycle in CA, but also offer a new insight into the GPP model development and improvement for the dryland ecosystem.
Against the background of the current high level of development of off-campus tutoring institutions and the implementation of the "Double Reduction" policy of education, the establishment of a ...scientific evaluation index system for of the management behavioral norms is a powerful guarantee for the supervision of off-campus tutoring behavioral norms. The construction of the evaluation index system is mainly based on the content of policy supervision of off-campus tutoring. The existing supervision tools use the system model construction and index weight calculation method of the analytic hierarchy process (AHP) for reference. An evaluation system of operations behavioral norms for off-campus tutoring institutions is constructed, which consists of four dimensions: "operations foundation, organizational construction, operations process, and operations results". The evaluation system of behavioral norms for off-campus tutoring institutions includes "4 first-level indicators, 11 second-level indicators and 34 third-level indicators". It implements a scientific dynamic evaluation and monitoring of the degree of behavioral norms for off-campus tutoring. Therefore, it provides a decision-making basis for promoting off-campus tutoring institutions to improve and standardize operations and promote the effective achievement of the "Double Reduction" goal.
A metal-free and efficient visible-light induced cascade cyclization of alkyne-tethered cyclohexadienones with selenosulfonates for the synthesis of ...3-sulfonyl-5-selanyl-4a,5-dihydro-2H-chromen-6(8aH)-one in good to excellent yields has been developed, in which three new stereocenters are formed and both sulfone and selenyl groups are simultaneously introduced.
A metal-free and efficient visible-light induced cascade cyclization of alkyne-tethered cyclohexadienones with selenosulfonates for the synthesis of 3-sulfonyl-5-selanyl-4a,5-dihydro-2H-chromen-6(8aH)-one in good to excellent yields has been developed, in which three new stereocenters are formed and both sulfone and selenyl groups are simultaneously introduced. Display omitted
The Xihuang pill (XHP) is a traditional Chinese medicine formulation that has been historically used in the prevention and treatment of proliferative breast diseases. However, there is a lack of ...guidelines that offer recommendations for its clinical use.
The task force from the Chinese Guangdong Pharmaceutical Association aims to develop evidence-based guidelines for XHP to prevent and treat proliferative breast diseases.
We searched six Chinese and English electronic databases, including the China National Knowledge Infrastructure, the Chinese Scientific Journal Database, the Wanfang Medical Database, PubMed, and Embase, up to November 1, 2022. Publications (case reports, clinical observation, clinical trials, reviews) on using XHP to treat proliferative breast diseases were manually searched. The search terms were Xihuang pill, hyperplasia of the mammary gland, breast lump, and mastalgia. The writing team developed recommendations based on the best available evidence.
Treatment should be customized based on syndrome identification. We recommend using XHP for the prevention and treatment of breast hyperplasia disease when a patient presents the following syndromes: concurrent blood stasis syndrome, concurrent phlegm-stasis syndrome, and concurrent liver fire syndrome. Safety indicators, including blood analysis and liver and kidney function monitoring, should be performed regularly during treatment.
Current clinical evidence suggests that XHP can be used as a standalone treatment or in conjunction with other medications to prevent and manage breast hyperplasia diseases. More randomized controlled studies are warranted to establish high-quality evidence of its use.
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•We examine the protective effect of biliverdin on skin photo-damage in hairless mice.•We observe the clinical and histopathological changes of mouse skin.•Biliverdin inhibits the ...oxidative stress and the release of inflammatory factor.•Biliverdin may act on different levels of cell signaling.
Oxidative stress is shown to be responsible for ultraviolet B (UVB) irradiation-induced skin cancer and premature aging. Biliverdin (BVD), a product of heme oxygenase-1, has strong anti-oxidant and anti-inflammatory properties. In the present study, we investigated the effects of BVD on UVB-induced skin photo-damage in hairless mice. Mice were divided into three groups: control group, UVB group (only UVB irradiation) and BVD+UVB group (mice were intraperitoneally injected with BVD before each UVB irradiation). Intraperitoneal BVD injection resulted in a significant photoprotective effect by reducing morphological and histopathological changes to the skin. BVD also exhibited a significant antioxidant effect by increasing the superoxide dismutase (SOD) level and decreasing the thiobarbituric acid reactive substances (TBARS) level compared with the control group. In addition, BVD activated biliverdin reductase (BVR) expression and inhibited the UVB-induced increase of p38 mitogen-activated protein kinase phosphorylation (p-p38MAPK), MMP (matrix metalloproteinase)-1 and MMP-3 expression (p<0.05). It also significantly decreased the interleukin (IL)-6 level compared with the UVB group (p<0.05). In conclusion, these data suggest that the intraperitoneally administered BVD can prevent UVB irradiation-induced skin photo-damage in hairless mice and that this is likely mediated by its antioxidant and anti-inflammatory mechanisms and cell signal regulatory action.
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