Thirty‐eight disulfides containing N‐arylacetamide were designed and synthesized in an effort to develop novel urease inhibitors. Biological evaluation revealed that some of the synthetic compounds ...exhibited strong inhibitory potency against both cell‐free urease and urease in intact cell with low cytotoxicity to mammalian cells even at concentration up to 250 μM. Of note, 2,2′‐dithiobis(N‐(2‐fluorophenyl)acetamide) (d7), 2,2′‐dithiobis(N‐(3,5‐difluorophenyl)acetamide) (d24), and 2,2′‐dithiobis(N‐(3‐fluorophenyl)acetamide) (d8) were here identified as the most active inhibitors with IC50 of 0.074, 0.44, and 0.81 μM, showing 32‐ to 355‐fold higher potency than the positive control acetohydroxamic acid. These disulfides were confirmed to bind urease without covalent modification of the cysteine residue and to inhibit urease reversibly with a mixed inhibition mechanism. They also showed very good anti‐Helicobacter pylori activities with d8 showing a comparable potency to the clinical used drug amoxicillin. The impressive in vitro biological profile indicated their immense potential as therapeutic agents to tackle H. pylori caused infections.
Potent and reversible: Dithiobisacetamides were determined to be urease inhibitors that function through a mechanism of mixed inhibition. They showed excellent potency against Helicobacter pylori urease and good antibacterial activity with nearly no cytotoxicity. The impressive biological profile of d8 (shown) underscores its suitability for further development as a therapeutic agent to tackle infections caused by H. pylori.
To explore the effect and mechanism of action of miR-210 on postmenopausal osteoporosis (PMPO) in ovariectomized rats in vivo.
An ovariectomized (OVX) rat model was established by ovariectomy. Tail ...vein injection was performed to overexpress and knock down miR-210 in OVX rats, followed by the collection of blood and femoral tissues from each group of rats. And quantitative real-time polymerase chain reaction (qRT-PCR) was applied to assess the expression level of miR-210 in femoral tissues of each group. Micro computed tomography (Micro CT) was adopted to scan the microstructure of the femoral trabecula in each group to obtain relevant data like bone mineral density (BMD), bone mineral content (BMC), trabecular bone volume fraction (BV/TV), trabecular thickness (Tb.Th), bone surface-to-volume ratio (BS/BV), and trabecular separation (Tb.Sp). ELISA was used for determining the level of bone alkaline phosphatase (BALP), amino-terminal propeptide of type I procollagen (PINP), osteocalcin (OCN), and C-terminal telopeptide of type I collagen (CTX-1) in serum; and Western blot for the protein level of Runt-related transcription factor 2 (Runx2), osteopontin (OPN), and collagen type I alpha 1 (COL1A1) in femoral tissues.
MiR-210 expression was significantly decreased in femoral tissues of OVX rats. Overexpression of miR-210 could obviously increase BMD, BMC, BV/TV and Tb.Th, whereas significantly decrease BS/BV and Tb.Sp in femurs of OVX rats. Moreover, miR-210 also downregulated BALP and CTX-1 level, upregulated PINP and OCN level in the serum of OVX rats promoted the expression of osteogenesis-related markers (Runx2, OPN and COL1A1) in the femur of OVX rats. Additionally, further pathway analysis revealed that high expression of miR-210 activated the vascular endothelial growth factor (VEGF)/Notch1 signaling pathway in the femur of OVX rats.
High expression of miR-210 may improve the micromorphology of bone tissue and modulate bone formation and resorption in OVX rats by activating the VEGF/Notch1 signaling pathway, thereby alleviating osteoporosis. Consequently, miR-210 can serve as a biomarker for the diagnosis and treatment of osteoporosis in postmenopausal rats.
Olaquindox (OLA) has been widely used as an animal feed additive in China for decades; however, its toxicity and toxic mechanisms have not been well investigated. In this study, the developmental ...neurotoxicity and toxic mechanisms of OLA were evaluated in zebrafish. Zebrafish embryos were exposed to different concentrations of OLA (25–1,000 mg/L) from 6 to 120 hours post fertilization (hpf). OLA exposure resulted in many abnormal phenotypes in zebrafish, including shortened body length, notochord degeneration, spinal curvature, brain apoptosis, damage of axon and peripheral motor neuron, and hepatotoxicity. Interestingly, OLA increased zebrafish spontaneous tail coiling, while reduced locomotor capacity. Quantitative polymerase chain reaction (Q‐PCR) showed that the expression levels of nine marker genes for nervous system functions or development, namely, α1‐tubulin, glial fibrillary acidic protein (gfap), myelin basic protein (mbp), synapsinII a (syn2a), sonic hedgehog a (shha), encoding HuC (elavl3), mesencephalic astrocyte‐derived neurotrophic factor (manf) growth associated protein 43 (gap43), and acetylcholinesterase (ache) were all down‐regulated significantly in zebrafish after treated with OLA. Besides, the anti‐apoptotic and pro‐apoptotic genes bcl‐2/bax ratio was reduced. These results show that OLA exposure could cause severe developmental neurotoxicity in the early stages of zebrafish life and OLA might induce neurotoxicity by inhibiting the expression of neuro‐developmental genes and promoting apoptosis.
OLA exposure resulted in many abnormal phenotypes in zebrafish, including shortened body length, notochord degeneration, spinal curvature, brain apoptosis, damage of axon and peripheral motor neuron and hepatotoxicity. OLA increased zebrafish spontaneous tail coiling, while reduced locomotor capacity. Q‐PCR showed that the expression of nine marker genes for nervous system functions or development were all down‐regulated significantly, and the apoptotic bcl‐2/bax gene expression ratio was reduced. These results show that OLA exposure could cause developmental neurotoxicity in the early stages of zebrafish life for the first time.
microRNAs (miRNAs) have been reported to regulate angiogenesis by down-regulating the expression of pro-angiogenic or anti-angiogenic factors. The aims of this study were to investigate whether ...miR-26a inhibited angiogenesis by down-regulating vascular endothelial growth factor A (VEGFA) and its clinical relevance in hepatocellular carcinoma (HCC).
The expression of miR-26a was modified in HepG2 and HCCLM3 cell lines respectively, and a panel of angiogenic factors was measured by real-time PCR in the cells. A luciferase reporter assay was used to validate the target gene of miR-26a. Specific inhibitors of signal transduction pathway and siRNA approaches were used to explore the regulatory mechanism of miR-26a. Migration and tube forming assays were conducted to show the changes of angiogenesis induced by miR-26a and its target genes. Finally animal studies were used to further validate those findings.
Ectopic expression of miR-26a exhibited decreased levels of VEGFA in HepG2 cells. Migration and tube forming of human umbilical vein endothelial cells (HUVECs) were decreased in the conditioned medium from ectopic expression of miR-26a in HepG2 cells compared to control HepG2 cells. The pro-angiogenic effects of the conditioned medium of HepG2 cells on HUVECs were specifically decreased by LY294002, YC-1, and bevacizumab. Integrated analysis disclosed PIK3C2α as a downstream target gene of miR-26a. Ectopic expression of miR-26a suppressed ectopic and orthotopic tumor growth and vascularity in nude mice. The results in HCCLM3 were consistent with those in HepG2. miR-26a expression was inversely correlated with VEGFA expression in HCC patients.
miR-26a modulated angiogenesis of HCC through the PIK3C2α/Akt/HIF-1α/VEGFA pathway. The expression of VEGFA was inversely correlated with miR-26a expression in HCC tumors.
Land-use classification based on spaceborne or aerial remote sensing images has been extensively studied over the past decades. Such classification is usually a patch-wise or pixel-wise labeling over ...the whole image. But for many applications, such as urban population density mapping or urban utility planning, a classification map based on individual buildings is much more informative. However, such semantic classification still poses some fundamental challenges, for example, how to retrieve fine boundaries of individual buildings. In this paper, we proposed a general framework for classifying the functionality of individual buildings. The proposed method is based on Convolutional Neural Networks (CNNs) which classify façade structures from street view images, such as Google StreetView, in addition to remote sensing images which usually only show roof structures. Geographic information was utilized to mask out individual buildings, and to associate the corresponding street view images. We created a benchmark dataset which was used for training and evaluating CNNs. In addition, the method was applied to generate building classification maps on both region and city scales of several cities in Canada and the US.
The graph-based hyperspectral image classification (HSIC) method has attracted wide attention because it can extract information with a non-Euclidean structure. Many graph-based HSIC works have ...achieved good results, but unresolved technical issues remain. For example, many graph nodes lead to high computational costs, and the mining of non-Euclidean structures is not sufficient. To solve these problems, we propose a graph attention network with an adaptive graph structure mining (GAT-AGSM) approach. Specifically, we first propose an HSIC framework with a superpixel feature subdivision (SFS) mechanism. In this framework, the number of nodes in the graph structure is reduced by using superpixel segmentation algorithms, and the SFS mechanism is designed to generate finer classification results. Second, we design the spatial-spectral attention layer with an adaptive graph structure mining (AGSM) mechanism for the graph attention network. The spatial-spectral attention layer can filter information in both spatial and spectral dimensions. The AGSM mechanism requires less manual intervention to dynamically generate non-Euclidean graph structures that better aggregate information. We conduct excessive experiments to compare the proposed GAT-AGSM with seven nongraph methods and three graph-based methods on widely used datasets. On the Indian Pines, Pavia University, and Salinas datasets, compared to the comparison method, the overall accuracy of GAT-AGSM is improved by at least 4.26%, 2.59%, and 1.41%, respectively. Experimental results show that GAT-AGSM has the best performance compared to the baselines in terms of various metrics.
Incomplete recovery from episodes of acute kidney injury (AKI) can predispose patients to develop chronic kidney disease (CKD). Although hypoxia-inducible factor-1α (HIF-1α) is a master regulator of ...the response to hypoxia/ischemia, the role of HIF-1α in CKD progression following incomplete recovery from AKI is poorly understood. Here, we investigated this issue using moderate and severe ischemia/reperfusion injury (I/RI) mouse models. We found that the outcomes of AKI were highly associated with the time course of tubular HIF-1α expression. Sustained activation of HIF-1α, accompanied by the development of renal fibrotic lesions, was found in kidneys with severe AKI. The AKI to CKD progression was markedly ameliorated when PX-478 (a specific HIF-1α inhibitor, 5 mg· kg
·d
, i.p.) was administered starting on day 5 after severe I/RI for 10 consecutive days. Furthermore, we demonstrated that HIF-1α C-terminal transcriptional activation domain (C-TAD) transcriptionally stimulated KLF5, which promoted progression of CKD following severe AKI. The effect of HIF-1α C-TAD activation on promoting AKI to CKD progression was also confirmed in in vivo and in vitro studies. Moreover, we revealed that activation of HIF-1α C-TAD resulted in the loss of FIH-1, which was the key factor governing HIF-1α-driven AKI to CKD progression. Overexpression of FIH-1 inhibited HIF-1α C-TAD and prevented AKI to CKD progression. Thus, FIH-1-modulated HIF-1α C-TAD activation was the key mechanism of AKI to CKD progression by transcriptionally regulating KLF5 pathway. Our results provide new insights into the role of HIF-1α in AKI to CKD progression and also the potential therapeutic strategy for the prevention of renal diseases progression.
The objective of this study was to verify the protective effect of Bifidobacterium longum (BL) and the synergistical effect of Selenium and BL on alcohol plus high fat diet (HFD) induced hepatic ...injury in mice. We also want to explore the mechanism of Selenium-enriched Bifidobacterium longum (SeBL). C57BL/6 mice were treated with alcohol plus HFD with or without different dosage of BL or SeBL for 4 weeks. Serum levels of ALT, AST, TC, TG, LDL-C, HDL-C, FFAs, TNF-α, IL-6 and IL-1β, hepatic MDA level, SOD activity, the mRNA levels of AMPK, PPAR-α and SREBP1 were invested. SeBL inhibited lipid accumulation in hepatocytes; reduced serum AST and ALT levels; improved dyslipidemia; decreased serum FFAs, TC, TG and LDL-C levels. SeBL also inhibited alcohol plus HFD-induced hepatocyte oxidative stress through decrease in hepatic MDA levels and increase in SOD activity. SeBL also regulated lipid metabolism related genes such as AMPK, PPAR-α and SREBP1. Although BL had similar effect as SeBL, SeBL is more effective than BL. SeBL protected mice from alcohol plus HFD-induced hepatic injury in mice because of its inhibitory effect on hepatocellular oxidative stress, lipogenesis and inflammation. Selenium enhanced the protective effect of BL.
The abyssal current is important for water renewal and energy conversion in the deep South China Sea (SCS), and it potentially contributes to the upper and middle circulations. A mooring array ...including 11 current and pressure‐recording inverted echo sounders was deployed in the northern SCS between July 2016 and April 2019 to observe large‐scale and long‐term abyssal currents. The yearly averaged current flows southwestward following the boundary with a maximum velocity of 2.25–2.52 cm/s. The spatial structure exhibits a weaker and wider current in the north, where topography is subdued, whereas the current enhances and narrows on the steep slopes. The southwestward current is strong in the summer and autumn but is insignificant in the winter and spring. In the autumn, the current is narrower and closer to the boundary than that in the summer, and a northeastward countercurrent is found ∼60 km away from the western boundary. The southwestward and northeastward currents constitute the cyclonic circulation. Drastic temporal variability is observed in the deep ocean. The abyssal current is dominated by semidiurnal tides, diurnal tides, and near‐inertial waves (NIWs) in the high‐frequency band. Bursts of NIWs are observed in the deep ocean after two typhoons, and the NIWs propagate southwestward at a velocity of 2.4 m/s. The low‐frequency band is dominated by a westward‐propagating 70‐day fluctuation following the characteristics of topographic Rossby waves.
Plain Language Summary
The abyssal cyclonic current in the South China Sea plays an important role in water transport and energy conversion in the deep ocean, and it potentially contributes to the circulations in the upper and middle ocean. Although model simulations and field observations have previously confirmed the existence of this abyssal current, the knowledge about abyssal current is lacking due to the sparseness of in situ observations in time and space. We conducted large‐scale abyssal current observations in the northern South China Sea from July 2016 to April 2019, and found that the yearly averaged current flows follow the western boundary and exhibit a maximum velocity of 2.25–2.52 cm/s. The southwestward current is strong in the summer and autumn but weak in the winter and spring. The current is narrower in the autumn than in the summer, and a northeastward current occurs far away from the boundary in the autumn. The southwestward and northeastward current constitute the cyclonic circulation. Semidiurnal tides, diurnal tides, and near‐inertial waves are significant in the high‐frequency band, whereas the low‐frequency band is dominated by a westward‐propagating 70‐day signal.
Key Points
The abyssal current in the northern South China Sea flows southwestward along the boundary with an average velocity of about 2.5 cm/s
The abyssal current is strong in the summer/autumn but weak in the spring/winter, and a countercurrent occurs in the autumn in the east
The current is dominated by tides and near‐inertial waves at high frequencies and by a westward‐propagating 70‐day low‐frequency signal
The aim of this study was to determine the levels of fluoride in commercial teas and to estimate the contribution of tea consumption to the fluoride recommended daily allowance. A total of 558 tea ...products in 6 categories, green tea, black tea, oolong tea, pu'er tea, white tea, and reprocessed tea, were collected in the period from 2010 to 2013. The levels of fluoride in infusions of these teas were determined by a fluoride‐ion selective electrode. The mean fluoride level in all of the tea samples was 85.16 mg/kg. For each category of tea, the mean fluoride levels were 63.04, 99.74, 52.19, 101.67, 159.78, and 110.54 mg/kg for green tea, black tea, white tea, pu'er tea, oolong tea, and reprocessed tea, respectively. The fluoride content of tea from 4 tea zones in descending order were Southern tea zone (111.39 mg/kg) > Southwest tea zone (78.78 mg/kg) > Jiangnan tea zone (71.73 mg/kg) > Jiangbei tea zone (64.63 mg/kg). These areas produced teas with lower fluoride levels than available foreign‐produced tea (161.11 mg/kg). The mean chronic daily intake (CDI) was 0.02 mg/(kg•day) or 1.27 mg/kg. Generally, consuming tea from these 6 categories does not result in the intake of excessive amounts of fluoride for the general population.
Practical Application
A total of 558 tea products in 6 categories were sampled. The mean fluoride level was determined. The daily intake of fluoride through tea consumption was estimated. Tea consumption does not result in the intake of an excessive amount of fluoride for the general population.
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