We report an efficient copper-catalyzed dehydrogenation method for the synthesis of aroyl triazines from arylmethyl triazines with water in the absence of additional oxidants or hydrogen acceptors. ...The use of substrates with both electron-donating and electron-withdrawing groups resulted in moderate to good yields. Using liquid chromatography–mass spectrometry, 18O-labeled-water reactions and hydrogen capture experiments confirmed that water was the only oxygen donor and hydrogen was the by-product. This oxidation strategy provides a new approach for the synthesis of aroyl triazines with a broad substrate scope.
Circular RNA (circRNA) possesses great pre-clinical diagnostic and therapeutic potentials in multiple cancers. It has been reported playing roles in multiple malignant behaviors including ...proliferation, migration, metastasis and chemoresistance. However, the underlying correlation between circRNAs and cancer stem cells (CSCs) has not been reported yet.
circZKSCAN1 level was detected in HCC tissue microarrays to clarify its prognostic values. Gain and loss function experiments were applied to investigate the role of circZKSCAN1 in HCC stemness. Bioinformatic analysis was used to predict the possible downstream RNA binding protein and further RNA immunoprecipitation sequencing was carried out to identify the RBP-regulated genes.
The absence of circZKSCAN1 endowed several malignant properties including cancer stemness and tightly correlated with worse overall and recurrence-free survival rate in HCC. Bioinformatics analysis and RNA immunoprecipitation-sequencing (RIP-seq) results revealed that circZKSCAN1 exerted its inhibitive role by competitively binding FMRP, therefore, block the binding between FMRP and β-catenin-binding protein-cell cycle and apoptosis regulator 1 (CCAR1) mRNA, and subsequently restrain the transcriptional activity of Wnt signaling. In addition, RNA-splicing protein Quaking 5 was found downregulated in HCC tissues and responsible for the reduction of circZKSCAN1.
Collectively, this study revealed the mechanisms underlying the regulatory role of circZKSCAN1 in HCC CSCs and identified the newly discovered Qki5-circZKSCAN1-FMRP-CCAR1-Wnt signaling axis as a potentially important therapeutic target for HCC treatment.
Summary
Sterols have long been associated with diverse fields, such as cancer treatment, drug development, and plant growth; however, their underlying mechanisms and functions remain enigmatic. Here, ...we unveil a critical role played by a GmNF‐YC9‐mediated CCAAT‐box transcription complex in modulating the steroid metabolism pathway within soybeans. Specifically, this complex directly activates squalene monooxygenase (GmSQE1), which is a rate‐limiting enzyme in steroid synthesis. Our findings demonstrate that overexpression of either GmNF‐YC9 or GmSQE1 significantly enhances soybean stress tolerance, while the inhibition of SQE weakens this tolerance. Field experiments conducted over two seasons further reveal increased yields per plant in both GmNF‐YC9 and GmSQE1 overexpressing plants under drought stress conditions. This enhanced stress tolerance is attributed to the reduction of abiotic stress‐induced cell oxidative damage. Transcriptome and metabolome analyses shed light on the upregulation of multiple sterol compounds, including fucosterol and soyasaponin II, in GmNF‐YC9 and GmSQE1 overexpressing soybean plants under stress conditions. Intriguingly, the application of soybean steroids, including fucosterol and soyasaponin II, significantly improves drought tolerance in soybean, wheat, foxtail millet, and maize. These findings underscore the pivotal role of soybean steroids in countering oxidative stress in plants and offer a new research strategy for enhancing crop stress tolerance and quality from gene regulation to chemical intervention.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Neuropathic pain seriously affects people's life, but its mechanism is not clear. Interleukin-17 (IL-17) is a proinflammation cytokine and involved in pain regulation. Our previous study found that ...IL-17 markedly enhanced the excitatory activity of spinal dorsal neurons in mice spinal slices. The present study attempts to explore if IL-17 contributes to neuropathic pain and spinal synapse plasticity. A model of spared nerve injury (SNI) was established in C57BL/6 J mice and IL-17a mutant mice. The pain-like behaviors was tested by von Frey test and dynamic mechanical stimuli, and the expression of IL-17 and its receptor, IL-17RA, was detected by immunohistochemical staining. C-fiber evoked field potentials were recorded in vivo. In the spinal dorsal horn, IL-17 predominantly expressed in the superficial spinal astrocytes and IL-17RA expressed mostly in neurons and slightly in astrocytes. The SNI-induced static and dynamic allodynia was significantly prevented by pretreatment of neutralizing IL-17 antibody (intrathecal injection, 2 μg/10 μL) and attenuated in IL-17a mutant mice. Post-treatment of IL-17 neutralizing antibody also partially relieved the established mechanical allodynia. Moreover, spinal long-term potentiation (LTP) of C-fiber evoked field potentials, a substrate for central sensitization, was suppressed by IL-17 neutralizing antibody. Intrathecal injection of IL-17 recombinant protein (0.2 μg/10 μL) mimicked the mechanical allodynia and facilitated the spinal LTP. These data implied that IL-17 in the spinal cord played a crucial role in neuropathic pain and central sensitization.
•IL-17 in the spinal astrocytes was involved in spinal nerve injury.•IL-17 contributed to the spinal LTP in vivo.•IL-17 mediated the crosstalk of neuron-glia in neuropathic pain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
For years, microbes have been widely applied as chassis in the construction of synthetic metabolic pathways. However, the lack of in vivo enzyme clustering of heterologous metabolic pathways in these ...organisms often results in low local concentrations of enzymes and substrates, leading to a low productive efficacy. In recent years, multiple methods have been applied to the construction of small metabolic clusters by spatial organization of heterologous metabolic enzymes. These methods mainly focused on using engineered molecules to bring the enzymes into close proximity via different interaction mechanisms among proteins and nucleotides and have been applied in various heterologous pathways with different degrees of success while facing numerous challenges. In this paper, we mainly reviewed some of those notable advances in designing and creating approaches to achieve spatial organization using different intermolecular interactions. Current challenges and future aspects in the further application of such approaches are also discussed in this paper.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors ...could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of
C-uric acid in URAT1-expressing HEK293 cells with an IC
value of 2.08 ± 0.31 μM, which was similar to that of RDEA3170 (its IC
value was 1.47 ± 0.23 μM). Using site-directed mutagenesis, we demonstrated that CDER167 might interact with URAT1 at S35 and F365. In GLUT9-expressing HEK293T cells, CDER167 concentration-dependently inhibited GLUT9 with an IC
value of 91.55 ± 15.28 μM, whereas RDEA3170 at 100 μM had no effect on GLUT9. In potassium oxonate-induced hyperuricemic mice, oral administration of CDER167 (10 mg·kg
· d
) for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170 (20 mg·kg
· d
) administered. The animal experiment proved the safety of CDER167. In addition, CDER167 displayed better bioavailability than RDEA3170, better metabolic stability and no hERG toxicity at 100 μM. These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•A macro segment network model for VRFB with serpentine flow field is proposed.•The computational efficiency is greatly improved compared with FEM model.•The battery performance during single and ...multi-cycle is predicted.•The field distributions of key parameters are in good agreement with FEM model.
This paper presents a 3D macro-segment network model for a vanadium redox flow battery with serpentine flow field. The proposed network model is coupled of electrolyte flow module, species transfer module, charge transfer module. In flow resistance network module, the characteristics of electrolyte flow in the serpentine flow channel and under-rib convection in the porous electrode are all considered. In addition, the electrode intrusion and the electrode non-uniform structure caused by compression are taken into account. In species transfer network module, the convection, diffusion and migration between adjacent segments and reversible electrochemical reactions and self-discharge reactions inside the segment are all analyzed in the ion conservation equation. In charge transfer network module, each battery segment, which is composed of the channel, electrode and membrane segment in series, is connected in parallel and has the same output voltage. In this paper, the battery performance including charge-discharge voltages and cell pressure drop under different electrode compression ratios are validated. In the following, the battery performance under single and multiple charge-discharge cycle are investigated using the proposed network model. Besides, the field distribution of key parameters in terms of velocity, pressure, ions concentration and current density are analyzed and validated with finite element method model data. The proposed 3D macro-segment network model is not only able to effectively consider the distribution difference inside the battery caused by the flow field, but also capable of reducing the computational resources, which renders the network model is suitable for the fast prediction of battery performance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We aimed to explore whether superfluous sympathetic activity affects myoblast differentiation, fusion, and myofiber types using a continuous single-dose isoprenaline exposure model in vitro and to ...further confirm the role of distinct NFATs in ISO-mediated effects. Compared with delivery of single and interval single, continuous single-dose ISO most obviously diminished myotube size while postponing myoblast differentiation/fusion in a time- and dose-dependent pattern, accompanied by an apparent decrease in nuclear NFATc1/c2 levels and a slight increase in nuclear NFATc3/c4 levels. Overexpression of NFATc1 or NFATc2, particularly NFATc1, markedly abolished the inhibitory effects of ISO on myoblast differentiation/fusion, myotube size and Myh7 expression, which was attributed to a remarkable increase in the nuclear NFATc1/c2 levels and a reduction in the nuclear NFATc4 levels and the associated increase in the numbers of MyoG and MEF2C positive nuclei within more than 3 nuclei myotubes, especially in MEF2C. Moreover, knockdown of NFATc3 by shRNA did not alter the inhibitory effect of ISO on myoblast differentiation/fusion or myotube size but partially recovered the expression of Myh7, which was related to the slightly increased nuclear levels of NFATc1/c2, MyoG and MEF2C. Knockdown of NFATc4 by shRNA prominently increased the number of MyHC +, MyoG or MEF2C + myoblast cells with 1 ~ 2 nuclei, causing fewer numbers and smaller myotube sizes. However, NFATc4 knockdown further deteriorated the effects of ISO on myoblast fusion and myotube size, with more than 5 nuclei and Myh1/2/4 expression, which was associated with a decrease in nuclear NFATc2/c3 levels. Therefore, ISO inhibited myoblast differentiation/fusion and myotube size through the NFAT-MyoG-MEF2C signaling pathway.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Tea plant (Camellia sinensis) is one of the most economically valuable crops in the world. Anthracnose can affect the growth of leaves and cause serious yield losses of tea. Tea plants are rich in ...secondary metabolites; however, their roles in resistance to anthracnose are unclear. Herein we compared the contents of total phenolics, catechins, and caffeine in two cultivars with different resistances to anthracnose during Colletotrichum fructicola infection. (−)-Epigallocatechin-3-gallate (EGCG), (+)-catechin (C), caffeine, and critical regulatory genes were induced in C. fructicola-resistant tissues. In vitro antifungal tests showed that caffeine more strongly inhibited mycelial growth than tea polyphenols and catechins. Both electron microscopy and bioactivity analysis results showed that caffeine can affect mycelial cell walls and plasma membranes. Through promoter sequences analysis, a number of stress response-related cis-acting elements were identified in S-adenosylmethionine synthetase and tea caffeine synthase. These results demonstrated that (−)-EGCG, (+)-C, and caffeine may be involved in the resistance of tea plants to anthracnose.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Background Due to negative results in clinical trials of postoperative chemoradiation for gastric cancer, at present, there is a tendency to move chemoradiation therapy forward in gastric and ...gastroesophageal junction (GEJ) adenocarcinoma. Several randomized controlled trials (RCTs) are currently recruiting subjects to investigate the effect of neo-adjuvant radiotherapy (NRT) in gastric and GEJ cancer. Large retrospective studies may be beneficial in clarifying the potential benefit of NRT, providing implications for RCTs. Methods We retrieved the clinicopathological and treatment data of gastric and GEJ adenocarcinoma patients who underwent surgical resection and chemotherapy between 2004 and 2015 from Surveillance, Epidemiology, and End Results (SEER) database. We compared survival between NRT and non-NRT patients among four clinical subgroups (T.sub.1-2N.sup.-, T.sub.1-2N.sup.+, T.sub.3-4N.sup.-, and T.sub.3-4N.sup.+). Results Overall, 5272 patients were identified, among which 1984 patients received NRT. After adjusting confounding variables, significantly improved survival between patients with and without NRT was only observed in T.sub.3-4N.sup.+ subgroup hazard ratio (HR) 0.79, 95% confidence interval (CI): 0.66-0.95; P = 0.01. Besides, Kaplan-Meier plots showed significant cause-specific survival advantage of NRT in intestinal type (P < 0.001), but not in diffuse type (P = 0.11) for T.sub.3-4N.sup.+ patients. In the multivariate competing risk model, NRT still showed survival advantage only in T.sub.3-4 N.sup.+ patients (subdistribution HR: 0.77; 95% CI: 0.64-0.93; P = 0.006), but not in other subgroups. Conclusions NRT might benefit resectable gastric and GEJ cancer patients of T3-4 stages with positive lymph nodes, particularly for intestinal-type. Nevertheless, these results should be interpreted with caution, and more data from ongoing RCTs are warranted. Keywords: Radiotherapy, Preoperative, Survival, Gastric cancer
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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