Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression. The up-regulated LSD1’s expression ...has been reported in several malignant tumors. In the current study, we designed and synthesized five series of 1,2,3-triazole–dithiocarbamate hybrids and screened their inhibitory activity toward LSD1. We found that some of these compounds, especially compound 26, exhibited the most specific and robust inhibition of LSD1. Interestingly, compound 26 also showed potent and selective cytotoxicity against LSD1 overexpressing gastric cancer cell lines MGC-803 and HGC-27, as well as marked inhibition of cell migration and invasion, compared to 2-PCPA. Furthermore, compound 26 effectively reduced the tumor growth bared by human gastric cancer cells in vivo with no signs of adverse side effects. These findings suggested that compound 26 deserves further investigation as a lead compound in the treatment of LSD1 overexpressing gastric cancer.
This work revealed that BiCuSeO oxyselenide is a potential oxide-based thermoelectric material, whose dimensionless figure of merit (
ZT
) reaches ∼0.70 at 773 K. High phase-purity BiCuSeO ...polycrystalline materials with fine grains were synthesized by a facile method combining a solid-state reaction and spark plasma sintering. Purifying the constitutive phase and reducing the grain sizes by introducing a high-energy ball milling process before spark plasma sintering were found to be effective in property enhancement. The resultant single-phased BiCuSeO sample derived from ball-milled powders shows good electrical conductivity above 4.0 × 10
3
S m
−1
and a large Seebeck coefficient above 200 μV K
−1
. This compound has a low thermal conductivity (∼0.5 W m
−1
K
−1
), which is associated with its low phonon transport speed and Young's modulus. Results indicated that BiCuSeO-based materials are promising for energy conversion applications in the moderate temperature range.
Good electrical conductivity, large Seebeck coefficients and low thermal conductivity were obtained for pristine BiCuSeO oxides with a layered structure of alternately stacked conductive (Cu
2
Se
2
)
2−
and insulating (Bi
2
O
2
)
2+
layers, resulting in a high
ZT
value of 0.70 at 773 K.
We had previously demonstrated that the calcitonin gene‐related peptide (CGRP) suppresses the oxidative stress and vascular smooth muscle cell (VSMC) proliferation induced by vascular injury. A ...recent study also indicated that CGRP protects against the onset and development of angiotensin II (Ang II)‐induced hypertension, vascular hypertrophy and oxidative stress. However, the mechanism behind the effects of CGRP on Ang II‐induced oxidative stress is unclear. CGRP significantly suppressed the level of reactive oxygen species (ROS) generated by NADPH oxidase in Ang II‐induced VSMCs. The Ang II‐stimulated activation of both Src and the downstream transcription factor, STAT3, was abrogated by CGRP. However, the antioxidative effect of CGRP was lost following the expression of constitutively activated Src or STAT3. Pre‐treatment with H‐89 or CGRP8–37 also blocked the CGRP inhibitory effects against Ang II‐induced oxidative stress. Additionally, both in vitro and in vivo analyses show that CGRP treatment inhibited Ang II‐induced VSMC proliferation and hypertrophy, accompanied by a reduction in ROS generation. Collectively, these results demonstrate that CGRP exhibits its antioxidative effect by blocking the Src/STAT3 signalling pathway that is associated with Ang II‐induced VSMC hypertrophy and hyperplasia.
Bone metabolism can be influenced by a range of factors. We selected children with self-limited epilepsy with centrotemporal spikes (SeLECTS) and lifestyles similar to those of healthy children to ...control for the confounding factors that may influence bone metabolism. We aimed to identify the specific effects of epilepsy and/or anti-seizure medications (ASMs) on bone metabolism.
Patients with SeLECTS were divided into an untreated group and a monotherapy group, and the third group was a healthy control group. We determined the levels of various biochemical markers of bone metabolism, including procollagen type I nitrogenous propeptide (PINP), alkaline phosphatase (ALP), osteocalcin (OC), collagen type I cross-linked C-telopeptide (CTX), calcium, magnesium, phosphorus, parathyroid hormone (PTH), and vitamin D
(VD
).
A total of 1487 patients (from 19 centers) were diagnosed with SeLECTS; 1032 were analyzed, including 117 patients who did not receive any ASMs (untreated group), 643 patients who received only one ASM (monotherapy group), and 272 children in the healthy control group. Except for VD
, other bone metabolism of the three groups were different (p < .001). Bone metabolism was significantly lower in the untreated group than the healthy control group (p < .05). There were significant differences between the monotherapy and healthy control group in the level of many markers. However, when comparing the monotherapy and untreated groups, the results were different; oxcarbazepine, levetiracetam, and topiramate had no significant effect on bone metabolism. Phosphorus and magnesium were significantly lower in the valproic acid group than the untreated group (adjusted p < .05, Cliff's delta .282-.768). CTX was significantly higher in the lamotrigine group than in the untreated group (adjusted p = .012, Cliff's delta = .316).
Epilepsy can affect many aspects of bone metabolism. After controlling epilepsy and other confounders that affect bone metabolism, we found that the effects of ASMs on bone metabolism differed. Oxcarbazepine, levetiracetam, and topiramate did not affect bone metabolism, and lamotrigine corrected some of the abnormal markers of bone metabolism in patients with epilepsy.
A novel colorimetric and fluorescent dual-mode sensing system based on molybdophosphoric heteropoly acid (PMA) and fluorescent microspheres (FMs) was established for monitoring the activity of ...alkaline phosphatase (ALP). In the presence of ALP,
l
-ascorbic acid-2-phosphate (AAP) could be hydrolyzed catalytically to ascorbic acid (AA), which could reduce PMA to phosphorus molybdenum blue (PMB), accompanied by the generation of colorimetric signals depending on the level of ALP. Meanwhile, the fluorescence of FMs was quenched markedly by the PMB produced due to the inner-filter effect, which constituted the response mechanism for the dual-mode sensing systems of ALP. On this basis, a PMA-FMs based dual-mode sensing system was used for the detection of ALP, which not only possessed remarkable sensitivity, with a limit of detection of 0.27 U L
−1
and 0.11 U L
−1
, but also exhibited good analytical performance in biological samples with satisfactory results. Moreover, a simple and portable test kit for the visual detection of ALP in real serum samples was fabricated utilizing a smartphone with image-recognition and data-processing capabilities as a visual-detection platform.
A novel colorimetric and fluorescent dual-mode sensing system based on molybdophosphoric heteropoly acid (PMA) and fluorescent microspheres (FMs) was established for monitoring the activity of alkaline phosphatase (ALP).
Nitrogen (N) is an important macronutrient and is comprehensively involved in the synthesis of secondary metabolites. However, the interaction between N supply and crop yield and the accumulation of ...effective constituents in an N-sensitive medicinal plant
(Burkill) F. H. Chen is not completely known. Morphological traits, N use and allocation, photosynthetic capacity and saponins accumulation were evaluated in two- and three-year-old
grown under different N regimes. The number and length of fibrous root, total root length and root volume were reduced with the increase of N supply. The accumulation of leaf and stem biomass (above-ground) were enhanced with increasing N supply, and LN-grown plants had the lowest root biomass. Above-ground biomass was closely correlated with N content, and the relationship between root biomass and N content was negatives in
(
= -0.92). N use efficiency-related parameters, NUE (N use efficiency,
.), N
(N content in carboxylation system component) and
(the net photosynthetic rate) were reduced in HN-grown
. SLN (specific leaf N), Chl (chlorophyll), N
(N content in light capture component) increased with an increase in N application. Interestingly, root biomass was positively correlated with NUE, yield and
. Above-ground biomass was close negatively correlated with photosynthetic N use efficiency (PNUE). Saponins content was positively correlated with NUE and
. Additionally, HN improved the root yield of per plant compared with LN, but reduced the accumulation of saponins, and the lowest yield of saponins per unit area (35.71 kg·hm
) was recorded in HN-grown plants. HN-grown medicinal plants could inhibit the accumulation of root biomass by reducing N use and photosynthetic capacity, and HN-induced decrease in the accumulation of saponins (C-containing metabolites) might be closely related to the decline in N efficiency and photosynthetic capacity. Overall, N excess reduces the yield of root and C-containing secondary metabolites (active ingredient) in N-sensitive medicinal species such as
.
The clinical applications of human leukocyte antigen (HLA) haploidentical hematopoietic stem cells transplantation (haplo‐HSCT) have offered most of the young severe aplastic anemia (SAA) patients an ...opportunity to accept curative therapy at the early stage of bone marrow lesions. However, the outcome of juvenile SAA patients received haplo‐HSCT remain to be improved due to high incidence of graft failure and graft vs host disease (GVHD). Mesenchymal stem cells (MSCs) have been characterized by their hematopoiesis‐supporting and immunomodulatory properties. In the current study, we designed a combination of haplo‐HSCT with allogenic MSC for treatment of SAA in pediatric and adolescent patients and evaluated its effects. Juvenile patients (<18 years) with SAA (n = 103) were given HLA‐haploidentical HSC combined with allogenic MSC after a conditioning regimen consisting of busulfan, cyclophosphamide, fludarabine, and antithymocyte globulin and an intensive GVHD prophylaxis, including cyclosporine, short‐term methotrexate, mycophenolate mofetil, and basiliximab. Neutrophil engraftment was achieved in 102 of 103 patients in a median time of 14.3 days (range 9‐25 days). The median time of platelet engraftment was 25.42 days (range 8‐93 days). The cumulative incidence of II‐IV acute GVHD at day +100 was 26.32% ± 0.19% and III‐IV acute GVHD was 6.79% ± 0.06% at day +100, respectively. The cumulative incidence of chronic GVHD was 25.56% ± 0.26%. The overall survival was 87.15% ± 3.3% at a median follow‐up of 40 (1.3‐98) months. Our data suggest that cotransplantation of HLA‐haploidentical HSC and allogenic mesenchymal stem cell may provide an effective and safe treatment for children and adolescents with SAA who lack matched donors.
The cotransplantation of allogenic mesenchymal stem cells (MSCs) and haploidentical hematopoietic stem cells transplantation (haplo‐HSCs) for juvenile severe aplastic anemia (SAA). In the current study, the transplantation‐related mortality rate was 14.72% ± 3.51%. A total of 103 patients have survived with an overall survival (OS) was 87.15% ± 3.3% at the follow‐up of 40 (1.3‐98) months. The OS for the volume of MSC ≥ 1.09 × 106/kg and MSC < 1.09 × 106/kg were 93.12% ± 3.83% and 81.03% ± 5.16% (P = .08), respectively.
The medicinal plant Panax notoginseng is considered a promising source of secondary metabolites due to its saponins. However, there are relatively few studies on the response of saponins to nitrogen ...(N) availability and the mechanisms underlying the N-driven regulation of saponins. Saponins content and saponins -related genes were analyzed in roots of P. notoginseng grown under low N (LN), moderate N (MN) and high N (HN). Saponins was obviously increased in LN individuals with a reduction in β-glucosidase activity. LN facilitated root architecture and N uptake rate. Compared with the LN individuals, 2872 and 1122 genes were incorporated into as differently expressed genes (DEGs) in the MN and HN individuals. Clustering and enrichment showed that DEGs related to “carbohydrate biosynthesis”, “plant hormone signal transduction”, “terpenoid backbone biosynthesis”, “sesquiterpenoid and triterpenoid biosynthesis” were enriched. The up-regulation of some saponins-related genes and microelement transporters was found in LN plants. Whereas the expression of IPT3, AHK4 and GS2 in LN plants fell far short of that in HN ones. Anyways, LN-induced accumulation of C-based metabolites as saponins might derive from the interaction between N and phytohormones in processing of N acquisition, and HN-induced reduction of saponins might be result from an increase in the form of β-glucosidase activity and N-dependent cytokinins (CKs) biosynthesis.
•Low nitrogen-induced accumulation of saponin might derive from the interaction between nitrogen and phytohormones.•High nitrogen-induced depression of saponin might be caused by an increase in β-glucosidase activity and nitrogen-dependent cytokinin.•First study on nitrogen-driven biosynthesis of triterpene saponins in Panax.notoginseng.•Nitrogen-driven changes in expression of genes showed positive correlation with secondary metabolites content.
Nitrogen (N) is a primary factor limiting leaf photosynthesis. However, the mechanism of high-N-driven inhibition on photosynthetic efficiency and photoprotection is still unclear in the ...shade-tolerant and N-sensitive species such as
Panax notoginseng
. Leaf chlorophyll (Chl) content, Ribulose-1,5-bisphosphate carboxylase oxygenase (Rubisco) activity and content, N allocation in the photosynthetic apparatus, photosynthetic performance and Chl fluorescence were comparatively analyzed in a shade-tolerant and N-sensitive species
P. notoginseng
grown under the levels of moderate nitrogen (MN) and high nitrogen (HN). The results showed that Rubisco content, Chl content and specific leaf nitrogen (SLN) were greater in the HN individuals. Rubisco activity, net photosynthetic rate (
A
net
), photosynthetic N use efficiency (PNUE), maximum carboxylation rate (
V
cmax
) and maximum electron transport rate (
J
max
) were lower when plants were exposed to HN as compared with ones to MN. A large proportion of leaf N was allocated to the carboxylation component under the levels of MN. More N was only served as a form of N storage and not contributed to photosynthesis in HN individuals. Compared with the MN plants, the maximum quantum yield of photosystem II (
F
v
/
F
m
), non-photochemical quenching of PSII (NPQ), effective quantum yield and electron transport rate were obviously reduced in the HN plants. Cycle electron flow (CEF) was considerably enhanced in the MN individuals. There was not a significant difference in maximum photo-oxidation P
700+
(
P
m
) between the HN and MN individuals. Most importantly, the HN individuals showed higher K phase in the fast chlorophyll fluorescence induction kinetic curve (OJIP kinetic curve) than the MN ones. The results obtained suggest that photosynthetic capacity might be primarily inhibited by the inactivated Rubisco in the HN individuals, and HN-induced depression of photoprotection might be caused by the photodamage to the donor side of PSII oxygen-evolving complex.
MicroRNAs (miRNAs) have been shown to play critical roles in regulating the progress of leukemia. We performed miRNA expression profile in six Chinese patients with chronic lymphocytic leukemia ...(CLL), and in peripheral B cells from pooled 30 healthy donors, using a platform containing 866 human miRNAs. The most frequent changes in miRNAs in CLL cells included downregulation of miR-126, miR-572, miR-494, miR-923, miR-638, miR-130a, miR-181a and miR-181b and up-regulation of miR-29a, miR-660, miR-20a, miR-106b, miR-142-5p, miR-101, miR-30b, miR-34a, miR-let-7f, miR-21 and miR-155. Among the miRNAs down-regulated in CLL cells, we showed that miR-181a/b expression levels were significantly lower in poor prognostic subgroups defined by unmutated immunoglobulin heavy chain variable status and p53 aberrations. Furthermore, under-expression of miR-181a and miR-181b was associated with shorter overall survival and treatment-free survival in CLL patients. We further evaluated fludarabine-induced apoptosis after transfection of primary CLL cells from 40 patients with miR-15a, miR-16-1, miR-34a, miR-181a and miR-181b mimics. Transfection of miR-34a, miR-181a and miR-181b mimics into CLL cells from p53 wild-type patients led to significant increase in apoptosis compared with miRNA control. However, enforced expression of these miRNAs had no effect on B-CLL cells from p53-attenuated patients. We further demonstrated that miR-181a and miR-181b inhibiting BCL-2, MCL-1 and X-linked inhibitor of apoptosis protein by direct binding to 3'UTR. Thus, these results suggest that miR-181a/b may play important roles in the pathogenesis of CLL and may provide a possible therapeutic avenue and a sensitive indicator of the activity of the p53 axis in CLL.
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