Due to the branched structure feature and unique properties, a variety of star‐shaped polymers have been designed and synthesized. Despite those advances, solid‐phase synthesis of star‐shaped ...sequence‐defined synthetic polymers that exhibit hierarchical self‐assembly remains a significant challenge. Hence, we present an effective strategy for the solid‐phase synthesis of three‐armed star‐shaped peptoids, in which ethylenediamine was used as the centric star pivot. Based on the sequence of monomer addition, a series of AA′A′′‐type and ABB′‐type peptoids were synthesized and characterized by UPLC‐MS (ultrahigh performance liquid chromatography‐mass spectrometry). By taking advantage of the easy‐synthesis and large side‐chain diversity, we synthesized star‐shaped peptoids with tunable functions. We further demonstrated the aqueous self‐assembly of some representative peptoids into biomimetic nanomaterials with well‐defined hierarchical structures, such as nanofibers and nanotubes. These results indicate that star‐shaped peptoids offer the potential in self‐assembly of biomimetic nanomaterials with tunable chemistries and functions.
We prove that the weak Morrey space
WM
q
p
is contained in the Morrey space
M
q
1
p
for 1 ≤
q
1
<
q
≤
p
< ∞. As applications, we show that if the commutator
b, T
is bounded from
L
p
to
L
p
,∞
for ...some
p
∈ (1, ∞), then
b
∈ BMO, where
T
is a Calderón-Zygmund operator. Also, for 1 <
p
≤
q
< ∞,
b
∈ BMO if and only if 6,
T
is bounded from
M
q
p
to
WM
q
p
. For
b
belonging to Lipschitz class, we obtain similar results.
Despite recent advances in the assembly of organic nanotubes, conferral of sequence-defined engineering and dynamic response characteristics to the tubules remains a challenge. Here we report a new ...family of highly designable and dynamic nanotubes assembled from sequence-defined peptoids through a unique "rolling-up and closure of nanosheet" mechanism. During the assembly process, amorphous spherical particles of amphiphilic peptoid oligomers crystallize to form well-defined nanosheets before folding to form single-walled nanotubes. These nanotubes undergo a pH-triggered, reversible contraction-expansion motion. By varying the number of hydrophobic residues of peptoids, we demonstrate tuning of nanotube wall thickness, diameter, and mechanical properties. Atomic force microscopy-based mechanical measurements show peptoid nanotubes are highly stiff (Young's Modulus ~13-17 GPa). We further demonstrate the precise incorporation of functional groups within nanotubes and their applications in water decontamination and cellular adhesion and uptake. These nanotubes provide a robust platform for developing biomimetic materials tailored to specific applications.
Objectives
Colorectal cancer is one of the most common malignancies both in men and women. Owing to metastasis and resistance, the prognosis of colorectal cancerCRC patients remains extremely poor ...with chemotherapy. A disintegrin and metalloproteinase 17 (ADAM17) induces the activation of Notch pathway and contributes to the chemoresistance. This study aimed to discover a novel ADAM17 inhibitor and investigate the chemosensitization effect.
Materials and methods
Pharmacophore model, western blot and enzymatic assay were used to discover ZLDI‐8. Cell proliferation was determined by MTT and colony formation assay. Cell migratory and invasive ability were determined by wound healing scratch and transwell assay. Immunofluorescence images and western blot analysed the expression of Notch or epithelial‐mesenchymal transition (EMT) pathway markers. Xenografts were employed to evaluate the chemosensitization effect of ZLDI‐8 in vivo.
Results
We found that ZLDI‐8 cell‐specifically inhibited the proliferation of CRC, and this effect was due to abrogation of ADAM17 and Notch pathway. Meanwhile, we reported for the first time that ZLDI‐8 synergistically improved the anti‐tumour and anti‐metastasis activity of 5‐fluorouracil or irinotecan by reversing Notch and EMT pathways. Interestingly, in vivo studies further demonstrated that ZLDI‐8 promoted the anti‐tumour effect of 5‐fluorouracil through Notch and EMT reversal.
Conclusions
A novel ADAM17 inhibitor ZLDI‐8 may be a potential chemosensitizer which sensitized CRC cells to 5‐fluorouracil or irinotecan by reversing Notch and EMT pathways.
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•A series of novel 4-aminoquinazoline derivatives were synthesized and characterized.•Their antiproliferative activities against cancer cell lines were evaluated.•6b exhibited PI3K ...inhibitory activity with an IC50 value of 13.6 nM.•6b exhibited potent antiproliferative effects via PI3K/Akt signaling pathway inhibition.•Compound 6b induced G1 phase arrest and apoptosis via the mitochondrial pathway.
Phosphatidylinositol 3-kinase (PI3K) signaling pathway has diverse functions, including the regulation of cellular survival, proliferation, cell cycle, migration, angiogenesis and apoptosis. Among class I PI3Ks (PI3Kα, β, γ, δ), the PIK3CA gene encoding PI3K p110α is frequently mutated and overexpressed in a large portion of human cancers. Therefore, the inhibition of PI3Kα has been considered as a promising target for the development of a therapeutic treatment of cancer. In this study, we designed and synthesized a series of 4-aminoquinazoline derivatives and evaluated their antiproliferative activities against six cancer cell lines, including HCT-116, SK-HEP-1, MDA-MB-231, SNU638, A549 and MCF-7. Compound 6b with the most potent antiproliferative activity and without obvious cytotoxicity to human normal cells was selected for further biological evaluation. PI3K kinase assay showed that 6b has selectivity for PI3Kα distinguished from other isoforms. The western blot assay and PI3K kinase assay indicated that 6b effectively inhibited cell proliferation via suppression of PI3Kα kinase activity with an IC50 of 13.6 nM and subsequently blocked PI3K/Akt pathway activation in HCT116 cells. In addition, 6b caused G1 cell cycle arrest owing to the inhibition of PI3K signaling and induced apoptosis via mitochondrial dependent apoptotic pathway. Our findings suggested that 6b has a therapeutic value as an anticancer agent via PI3Kα inhibition.
Phosphatidylinositol 3-kinase (PI3K) is a pivotal regulator of intracellular signaling pathways and considered as a promising target in the development of a therapeutic treatment of cancer. Among the ...different PI3K subtypes, the PIK3CA gene encoding PI3K p110α is frequently mutated and overexpressed in majority of human cancers. Therefore, the inhibition of PI3Kα has been considered to be an efficient approach for the treatment of cancer. In this study, two series compounds containing hydrophilic group in imidazo1,2-apyridine and quinazolin-4(3H)-one were synthesized and their antiproliferative activities against five cancer cell lines, including HCT-116, SK-HEP-1, MDA-MB-231, SNU638 and A549, were evaluated. Compound 1i with most potent antiproliferative activity was selected for further biological evaluation. PI3K kinase assay showed that 1i has selectivity for PI3Kα distinguished from other isoforms. The western blot assay indicated that 1i is more effective than HS-173, an imidazopyridine-based PI3Ka inhibitor, in reducing the levels of phospho-Akt. All these results suggested that 1i is a potent PI3Kα inhibitor and could be considered as a potential candidate for the development of anticancer agents.
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•Imidazo1,2-apyridine and quinazolin-4(3H)-one derivatives were synthesized.•Their antiproliferative activities against cancer cell lines were evaluated.•1i exhibited an IC50 value of 10 nM against HCT116 and SNU638 cells.•The compounds 1b, 1i and 10b were evaluated for their PI3K inhibitory activity and selectivity.•Compound 1i is considered as a potent PI3Kα inhibitor with IC50 of 0.5 nM.
The bagrid catfish, Pseudobagrus ussuriensis, exhibits significant sexual dimorphism in growth rate and body size with males growing faster than females. Therefore, an all‐male culture can ...dramatically increase the output and profitability of fishery products. According to the monosex breeding route, super‐male individuals’ acquirement by XY male sex reversal and artificial gynogenesis is the key step. An effective protocol to induce meiotic gynogenesis using homologous sperms has been developed in this study. The most effective UV irradiation for sperm genetic inactivation was found to be at a distance of 20 cm with 66 μW/cm2 light intensity for 25 min. Optimal treatment for cold shock was 5 min post‐fertilization at 0‐4°C for 30 min, which gave the best survival rate of 13.65 ± 2.87%. The sex ratio in the meiotic gynogens showed a significant female‐biased deviation (p < .05); thirty meiogynogens and their parents were further analysed using a male‐specific AFLP marker, of which only the male parent produced a male‐specific DNA band of 412 bp. These results indicated the female homogametic XX/XY sex determination system in P. ussuriensis. The optimization of a protocol for the successful induction of meiogynogenesis in the bagrid catfish lays the basis for all‐male production and is useful in ascertaining the genetic sex determination system in this promising aquaculture species.
Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis that highly expresses phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (ERK). The PI3K/AKT/mTOR ...and MAPK/ERK signaling pathways play a crucial role in HCC tumor formation, cell cycle, apoptosis and survival. However, no effective targeted therapies against these pathways is available, mainly due to the extensive and complex negative feedback loops between them. Here we used CK-3, a dual blocker of the PI3K/AKT/mTOR and MAPK/ERK pathways, against HCC cell lines to verify its anti-tumor activity
in vitro
. CK-3 exhibited cytotoxic activity against HCC, as demonstrated with MTT and colony formation assays. The anti-metastatic potential of CK-3 was demonstrated with wound healing and cell invasion assays. The ability of CK-3 to block both the PI3K/AKT/mTOR and MAPK/ERK pathways was also confirmed. CK-3 induced the apoptosis of Hep3B cells, while Bel7402 cells died
via
mitotic catastrophe (MC). Oral administration of CK-3 also inhibited the subcutaneous growth of BEL7402 cells in nude mice. Simultaneous PI3K/AKT/mTOR and MAPK/ERK pathway inhibition with CK-3 may be superior to single pathway monotherapies by inhibiting their feedback-regulation, and represents a potential treatment for HCC.
In this paper, the authors establish the (
L
p
(
μ
),
L
q
(
μ
))-type estimate for fractional commutator generated by fractional integral operators
T
α
with Lipschitz functions (
b
∈
Lip
β
(
μ
)), ...where 1 <
p
< 1/(
α
+
β
) and 1/
q
= 1/
p–
(
α
+
β
), and obtain their weak (
L
1
(
μ
),
L
1/(1–
α
–
β
)
(
μ
))-type. Moreover, the authors also consider the boundedness in the case that 1 /(
α
+
β
) <
p
< 1/
α
, 1/
α
≤
p
≤
∞
and the endpoint cases, namely,
p
= 1/(
α
+
β
).
To provide molecular evidence on the thermogenic mechanism of primary brown adipocytes, western blot analysis was used to detect brown adipose tissue (BAT)-specific gene expressions. BAT protects the ...mammals from hypothermia injury with a large amount of mitochondria and high expression of uncoupling Protein 1 (UCP1), which is the vital protein to determine the heat production in BAT. In our previous study, the compound ZW290 (the structure shown in Fig. 1) was obtained by molecular docking with a UCP1 inducer. In the present study, ZW290 not only significantly upregulated the expression of UCP1 protein (p < 0.01) and its related signaling pathway in the primary brown adipocytes, but also remarkably decreased the mitochondrial membrane potential and the concentration of adenosine triphosphate (ATP) (p < 0.01). Kunming (KM) mice were kept under acute cold exposure (-20°C) to evaluate the preventive and protective effects of ZW290 on cold injury, and revealed its regulating mechanism in vitro. The rectal and body temperatures of ZW290-treated mice were significantly higher than those of the control (or model) group both at room temperature and at -20°C (p < 0.001). Hematoxylin-eosin (HE) staining and immunohistochemistry indicated that ZW290 notably decreased the size of lipid droplets in BAT and increased the content of mitochondria and the expression of UCP1 in BAT and white adipose tissue (WAT). Furthermore, the survival rate showed that ZW290 could prolong the overall survival of mice. Therefore, we obtained the conclusion that ZW290 might transform energy into heat by inhibiting ATP synthesis and increasing the expression of UCP1. Additionally, ZW290 may enhance cold tolerance by increasing heat production through increasing the content of mitochondria and the expression of UCP1 in BAT and WAT.
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