P. Henn. (
) has been widely used as a traditional herb for many years in Kenya due to its diverse biological effects. Although engleromycin was first isolated from
in 1980, its pharmacological ...activity is still unknown. In this study, engleromycin from
was identified by spectroscopic analyses, and subsequently examined for its antiproliferative activity using human cancer cell lines of SGC-7901, HT-29, HeLa and A549. As a result, it was revealed that engleromycin strongly inhibited the growth of SGC-7901, HT-29, HeLa and A549 cells with IC
values at 26.77 ± 1.69 µM, 7.73 ± 0.18 µM, 7.00 ± 0.12 µM and 3.14 ± 0.03 µM, respectively. The results of topoisomerase II (Top II) inhibition assay in vitro implied that engleromycin might be a Top II inhibitor. Further insights into the potential mechanism of antiproliferative activity displayed that engleromycin could dock into the binding pockets of Top II, like the clinical inhibitor doxorubicin, and then inhibit the biological activity of Top II. Taken together, our findings suggest that engleromycin has an anticancer potential, and may serve as a leading compound for the development of antitumor agents.
Abstract
Background
Isopsoralen (IPRN), one of the active ingredients of
Psoralea corylifolia
Linn, has anti-inflammatory properties. We attempted to investigate the inhibitory effects of IPRN on ...rheumatoid arthritis (RA) and characterize its potential mechanism.
Methods
RA fibroblast-like synoviocytes (FLSs) and mice with collagen-induced arthritis (CIA) were used as in vitro and in vivo models to analyze the antiarthritic effect of IPRN. Histological analysis of the inflamed joints from mice with CIA was performed using microcomputed tomography (micro-CT) and hematoxylin-eosin (HE) staining. RNA sequencing (RNA-Seq), network pharmacology analysis, molecular docking, drug affinity responsive target stability (DARTS) assay, and cellular thermal shift assay (CETSA) were performed to evaluate the targets of IPRN.
Results
IPRN ameliorated the inflammatory phenotype of RA FLSs by inhibiting their cytokine production, migration, invasion, and proangiogenic ability. IPRN also significantly reduced the severity of CIA in mice by decreasing paw thickness, arthritis score, bone damage, and serum inflammatory cytokine levels. A mechanistic study demonstrated that macrophage migration inhibitory factor (MIF), a key protein in the inflammatory process, was the specific target by which IPRN exerted its anti-inflammatory effects in RA FLSs.
Conclusion
Our study demonstrates the antiarthritic effect of IPRN, which suggests the therapeutic potential of IPRN in RA.
Cuproptosis is the most recently discovered mode of cell death. It could affect the metabolism of cancer cells and surrounding infiltrating immune cells. In recent years, many studies have also shown ...that the tumor microenvironment (TME) plays a critical role in tumor growth and development. Mounting evidence suggests that Cuproptosis would bring unique insights into the development of pharmacological and nonpharmacological therapeutic techniques for cancer prevention and therapy. However, no study has been done on the combination of cuproptosis and TME in any cancer. Herein, we investigated the relationship between cuproptosis-related genes (CRGs), TME, and the prognosis of patients with Uterine Corpus Endometrial Carcinoma (UCEC). We identified three CRGs clusters based on 10 CRGs and three CRGs gene clusters based on 600 differentially expressed genes (DEGs) with significant prognostic differences. Following that, the CRGs score based on DEGs with significant prognostic differences was established to evaluate the prognosis and immunotherapeutic efficacy of UCEC patients. The CRGs score was shown to be useful in predicting clinical outcomes. Patients with a low CRGs score seemed to have a better prognosis, a better immunotherapeutic response, and a higher tumor mutation burden (TMB). In conclusion, our study explored the influence of cuproptosis patterns and TME on the prognosis of cancer patients, thereby improving their prognosis.
Warburgia ugandensis Sprague (W. ugandensis), widely distributed in Africa, is a traditional medicinal plant used for the treatment of various diseases including cancer. We intended to evaluate the ...anticolorectal cancer (CRC) activities of the crude extract from W. ugandensis (WUD) and reveal the underlying molecular mechanisms of its action. We found that WUD inhibited the proliferation of HT-29 and HCT116 cells in a time- and dose-dependent manner and induced intracellular ROS generation. The inhibitory effect of WUD on the proliferation of HT-29 and HCT116 cells could be attenuated by NAC (a ROS scavenger) in a dose-dependent manner. WUD induced G0/G1 phase arrest, down-regulated the protein expression of Cyclin D1 via ROS accumulation in HT-29 cells. In search of the molecular mechanism involved in WUD-induced Cyclin D1 down-regulation, it was found that WUD can suppress PI3K/Akt/GSK3β signaling pathway in HT-29 cells. Next, it was found that WUD also activated apoptosis, poly-ADP ribose polymerase 1 (PARP1) cleavage and down-regulated pro-caspase 3 in HT-29 and HCT116 cells. Besides, WUD decreased the growth of colon tumors in vivo in the xenograft mouse model. We demonstrated for the first time that ROS and their modulation in the corresponding intracellular signaling could play a significant role in the potential activity of WUD against CRC cells.
The key enzyme 6-phosphofructo-2-kinase (PFK2)/fructose-2,6-bisphosphatase (FBPase-2) is responsible for regulating the rates of glycolysis and gluconeogenesis in eukaryotes. However, its functions ...and mechanisms in filamentous fungi remain largely enigmatic. In this study, we systematically investigated the function of this enzyme in
, a thermophilic filamentous fungus with great capacity to produce industrial enzymes and organic acids. Our results showed that the
genome encodes three isomers, all with the PFK2/FBPase-2 structure:
, and
. Overexpression of each gene revealed that endogenous expression of
(PFK2 activity) promoted glucose metabolism, while overexpression of
(FBPase-2 activity) inhibited strain growth. Using knockouts, we found that each gene was individually non-essential, but the triple knockout led to significantly slower growth compared with the wild-type strain. Only the
single knockout exhibited 22.15% faster sugar metabolism, exerted through activation of 6-phosphofructo-1-kinase (PFK1), thereby significantly promoting glycolysis and the tricarboxylic acid cycle. The FBPase-2 deletion mutant strain also exhibited overflow metabolism, and knocking out
was proved to be able to improve the production and synthesis rate of various metabolites, such as glycerol and malate. This is the first study to systematically investigate the function of PFK2/FBPase-2 in a thermophilic fungus, providing an effective target for metabolic engineering in filamentous fungi.
Sec1/Munc18-family (SM) proteins are required for SNARE-mediated membrane fusion, but their mechanism(s) of action remain controversial. Using single-molecule force spectroscopy, we found that the SM ...protein Munc18-1 catalyzes step-wise zippering of three synaptic SNAREs (syntaxin, VAMP2, and SNAP-25) into a four-helix bundle. Catalysis requires formation of an intermediate template complex in which Munc18-1 juxtaposes the N-terminal regions of the SNARE motifs of syntaxin and VAMP2, while keeping their C-terminal regions separated. SNAP-25 binds the templated SNAREs to induce full SNARE zippering. Munc18-1 mutations modulate the stability of the template complex in a manner consistent with their effects on membrane fusion, indicating that chaperoned SNARE assembly is essential for exocytosis. Two other SM proteins, Munc18-3 and Vps33, similarly chaperone SNARE assembly via a template complex, suggesting that SM protein mechanism is conserved.
•Subsoiling enhanced the water use from deep soil profiles by winter wheat.•Subsoiling improved water storage capacity of the following year.•Optimizing tillage promoted the post-anthesis dry matter ...accumulation.•Optimizing tillage improved the grain yield and water-use efficiency in the North China Plain.
We conducted a two-year experiment (2007–2009) in the North China Plain with supplemental irrigation to investigate the effects of tillage practices on the water use, biomass accumulation and remobilisation of winter wheat. Five tillage treatments were tested: strip rotary tillage (SR), rotary tillage (R), mouldboard ploughing (P), strip rotary tillage after subsoiling (SRS) and rotary tillage after subsoiling (RS). SRS significantly promoted the changes in soil water storage (ΔS) at soil depths of 60cm to 160cm, and the lowest ΔS level was observed in the SR treatment. The 60cm to 140cm soil moisture content in the SRS treatment was higher by 10.84% than that of the SR treatment before sowing in 2008–2009 and lower by 14.85% at maturity. The lowest dry matter remobilisation during grain filling (DMR) was detected in the SRS treatment. This value was 22.22% and 30.27% lower than those of the SR treatment in 2007–2008 and 2008–2009, respectively. However, the SRS treatment exhibited the highest contribution of dry matter accumulation during grain filling (CDMRG), in which high flag leaf photosynthetic rate (Pn) was observed from anthesis to maturity. The SRS and RS treatments exhibited the highest grain yields (9237.20 and 9261.31kgha−1 for two-year average) with no significant difference between the two treatments. The highest grain yields for the two treatments were 10.76% and 11.05% higher than those of the P treatment, correspondingly. The average water-use efficiency (WUE) for the two growing seasons was 20.49kgha−1mm−1 in the SRS treatment, which was higher than those in the SR, R, P and RS treatments by 17.02%, 13.42%, 8.73% and 3.83%, respectively. Hence, SRS would be a preferable tillage system for planting wheat in this region.
MicroRNA (miR)-210 is the most consistently and predominantly up-regulated miR in response to hypoxia in multiple cancer cells. The roles of miR-210 in rat adrenal gland pheochromocytoma (PC-12) ...cells remain unknown. We aimed to explore the possible effect of miR-210 in neonatal brain injury. We explored the potential molecular mechanism by using PC-12 cells under hypoxia. Scramble miRs, miR-210 mimic, miR-210 inhibitor or its negative control were respectively transfected into PC-12 cells. Cell viability, migration, invasion and apoptosis were also assessed to evaluate hypoxia-induced cell injury. The expression level of miR-210 was identified by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Apoptosis-related protein expression as well as key kinases in the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signal pathway was studied by Western blot analysis. Hypoxia suppressed cell viability, migration and invasion, but promoted apoptosis through activation of mitochondrial- and caspase-dependent pathways. Hypoxia markedly induced up-regulation of miR-210 in PC-12 cells. Overexpression of miR-210 protected PC-12 cells against hypoxia-induced injury. Bcl-2 adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) was proven to be a target gene of miR-210 in PC-12 cells. miR-210 overexpression ameliorated the hypoxia-induced injury in PC-12 cells by down-regulating BNIP3. Hypoxia-induced alterations of key kinases in the PI3K/AKT/mTOR signal pathway were affected by aberrant expression of BNIP3. These findings suggested that miR-210 protected PC-12 cells against hypoxia-induced injury by targeting BNIP3, involving the PI3K/AKT/mTOR signal pathway.
WRKY transcription factor participates in plant growth and development and response to biotic and abiotic stresses.
Arachis duranensis
, a turfgrass, has high drought tolerance, yet little is known ...about
AdWRKYs
response to drought stress in
A. duranensis
. In this study, RNA-seq identified five
AdWRKYs
, including
AdWRKY18
,
AdWRKY40
,
AdWRKY42
,
AdWRKY56
, and
AdWRKY64
, which were upregulated under drought stress. Orthologous relationships between
AdWRKYs
and
Arabidopsis WRKY
were determined to predict the regulatory networks of the five AdWRKYs based on AtWRKYs. Additionally, protein–protein interactions were predicted using differentially expressed proteins from RNA-seq. The quantitative real-time PCR (qRT-PCR) results showed that
AdWRKY40
was upregulated, while
AdWRKY42
,
AdWRKY56
, and
AdWRKY64
were downregulated at different time-points under drought stress. The predicted regulatory networks showed that AdWRKY40 activates
COR47
,
RD21
, and
RD29A
expression under drought stress. Besides, AdWRKY56 regulated
CesA8
under drought stress. Aradu.YIQ80 (NAC019) interacted with AdWRKY40, AdWRKY42, AdWRKY56, and AdWRKY64, while Aradu.Z5H58 (NAC055) interacted with AdWRKY42 and AdWRKY64 under drought stress. This study used
Arabidopsis
to assess
AdWRKYs
function and regulatory networks, providing a basis for understanding drought tolerance in
A. duranensis
.
Fast computational ghost imaging with high quality and ultra-high-definition resolution reconstructed images has important application potential in target tracking, biological imaging and other ...fields. However, as far as we know, the resolution (pixels) of the reconstructed image is related to the number of measurements. And the limited resolution of reconstructed images at low measurement times hinders the application of computational ghost imaging. Therefore, in this work, a new computational ghost imaging method based on saliency variable sampling detection is proposed to achieve high-quality imaging at low measurement times. This method physically variable samples the salient features and realizes compressed detection of computational ghost imaging based on the salient periodic features of the bucket detection signal. Numerical simulation and experimental results show that the reconstructed image quality of our method is similar to the compressed sensing method at low measurement times. Even at 500 (sampling rate
) measurement times, the reconstructed image of the method still has the target features. Moreover, the
(4K) pixels ultra-high-definition resolution reconstructed images can be obtained at only a sampling rate of
. This method has great potential value in real-time detection and tracking, biological imaging and other fields.
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