Breast cancer is the most common malignancy affecting women, yet effective targets and related candidate compounds for breast cancer treatment are still lacking. The lipogenic enzyme, stearoyl-CoA ...desaturase-1 (SCD1), has been considered a potential target for breast cancer treatment. Icaritin (ICT), a prenylflavonoid derivative from the Traditional Chinese Medicine Epimedii Herba, has been reported to exert anticancer effects in various types of cancer. The purpose of the present study was to explore the effect of the new ICT derivative, IC2, targeting SCD1 on breast cancer cells and to explore the specific mechanism.
Immunohistochemistry and semiquantitative evaluation were performed to detect the expression level of SCD1 in normal and tumor samples. Computer-aided drug design (CADD) technology was used to target SCD1 by molecular docking simulation, and several new ICT derivatives were prepared by conventional chemical synthesis. Cell viability was evaluated by an MTT assay and dead cell staining. SCD1 expression in cancer cells was determined by Western blot and qRT-PCR analyses. The enzymatic activity of SCD1 was evaluated by detecting the conversion rate of d31 palmitic acid (PA) using Gas chromatography-mass spectrometry (GC-MS). DAPI staining, flow cytometry and Western blot were used to detect cell apoptosis. Mitochondrial membrane potential and reactive oxygen species (ROS) assays were used to determine cell mitochondrial function. Lentiviral transduction was utilized to generate SCD1-overexpressing cell lines.
We found that SCD1 was overexpressed and correlated with poor prognosis in breast cancer patients. Among a series of ICT derivatives, in vitro data showed that IC2 potentially inhibited the viability of breast cancer cells, and the mechanistic study revealed that IC2 treatment resulted in ROS activation and cellular apoptosis. We demonstrated that IC2 inhibited SCD1 activity and expression in breast cancer cells in a dose-dependent manner. Moreover, SCD1 overexpression alleviated IC2-induced cytotoxicity and apoptosis in breast cancer cells.
The new ICT derivative, IC2, was developed to induce breast cancer cell apoptosis by inhibiting SCD1, which provides a basis for the development of IC2 as a potential clinical compound for breast cancer treatment.
Concurrently achieving suitable second harmonic generation (SHG) effect and high laser-induced damage threshold (LIDT) is challenging for infrared nonlinear optical (NLO) materials. Here, a series of ...pentanary infrared NLO materials CsMIIIMIVSnSe6 (MIII = Ga, In; MIV = Si, Ge) have been obtained by a three-in-one strategy, viz. three kinds of elements (MIII, MIV, and Sn) in one position, which is first adopted to design NLO materials. Their three-dimensional structures are constructed by the MQ4 (M denotes MIII, MIV, and Sn) tetrahedral units. They exhibit promising hybrid NLO properties, witnessed by their moderate/large SHG effects of 0.52, 0.98, 1.05, and 1.12 × AgGaS2, and high powder LIDT values of 6.9, 4.1, 8.1, and 5.4 × AgGaS2, respectively. These NLO properties are well verified by the DFT calculation results. The three-in-one strategy of designing high-performance infrared NLO materials will stimulate more investigations in this field.
A novel general randomized method is proposed to investigate multifractal properties of long time series. Based on multifractal temporally weighted detrended fluctuation analysis (MFTWDFA), we obtain ...randomized multifractal temporally weighted detrended fluctuation analysis (RMFTWDFA). The innovation of this algorithm is applying a random idea in the process of dividing multiple intervals to find the local trend. To test the performance of the RMFTWDFA algorithm, we apply it, together with the MFTWDFA, to the artificially generated time series and real genomic sequences. For three types of artificially generated time series, consistency tests are performed on the estimated h(q), and all results indicate that there is no significant difference in the estimated h(q) of the two methods. Meanwhile, for different sequence lengths, the running time of RMFTWDFA is reduced by over ten times. We use prokaryote genomic sequences with large scales as real examples, the results obtained by RMFTWDFA demonstrate that these genomic sequences show fractal characteristics, and we leverage estimated exponents to study phylogenetic relationships between species. The final clustering results are consistent with real relationships. All the results reflect that RMFTWDFA is significantly effective and timesaving for long time series, while obtaining an accuracy statistically comparable to other methods.
Clinical studies have demonstrated that decreased adiponectin is associated with the development of Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD). We focused on determining the ...neuroprotective effect offered by adiponectin against streptozotocin-induced brain damage in ICV-STZ rat model. We found that adiponectin supplements significantly restored the cognitive deficits in ICV-STZ rat model including shorter escape latency, more crossing times and increased time spent in the target quadrant. Adiponectin supplements also increased number of dendritic branches and mushroom percentage. In addition, adiponectin supplements attenuated tau hyperphosphorylation at multiple AD-related sites through activation of protein Ser9-phosphorylated glycogen synthase kinase-3β (Ser9-GSK-3β) with increased the Akt and PI3K activity. Our data suggest that adiponectin supplements have neuroprotective effects on the ICV-STZ rat model, which may be mediated by the activation of the PI3K/Akt/GSK-3β signaling pathway.
Background
During ablation for atrial fibrillation (AF), energy delivery toward the left atrial posterior wall may cause esophageal injury (EI). Ablation index (AI) was introduced to estimate ...ablation lesion size, however, the impact of AI technology on the risk of EI has not been explored.
Method
From March 2019 to December 2019, 60 patients with paroxysmal AF undergoing first‐time ablation were prospectively enrolled. The first 30 consecutive patients were ablated with the AI target value of 400 (AI‐400 group), and the later 30 consecutive patients were ablated with the AI target value of 350 at the posterior wall (AI‐350 group). Endoscopic ultrasonography was used to evaluate EI postablation. EI was classified as a category 1 (erythema or erosion) or a category 2 (hematoma or ulceration).
Results
Compared with the AI‐400 group (59.9 ± 8.4 years; male, 60%), the AI‐350 group (59.1 ± 9.9 years; male, 50%) had a lower incidence of EI (3.3% vs 26.7%, P = .03). There was no significant difference in the percentage of first‐pass PVI between the AI‐400 group and the AI‐350 group (left PVI: 80% vs 73.4%, P = .54; right PVI: 80% vs 60%, P = .1). Neither ablation time nor fluoroscopy time was significantly different between the AI‐400 group and the AI‐350 group.
Conclusions
AF ablation guide by AI target value of 350 may reduce esophageal thermal injury and has a similar efficiency on the acute success rate of first‐pass PVI compared with an AI target value of 400 at the posterior wall.
Glycolysis caused by hypoxia-induced abnormal activation of hypoxia inducible factor-1α (HIF-1α) in the immune microenvironment promotes the progression of hepatocellular carcinoma (HCC), leading to ...enhanced drug resistance in cancer cells. Therefore, altering the immunosuppressive microenvironment by imp-roving the hypoxic state is a new goal in improving cancer treatment.
To analyse the role of HIF-1α, which is closely related to tumour proliferation, invasion, metastasis, and angiogenesis, in the proliferation and invasion of liver cancer, and to explore the HIF-1α pathway-mediated anti-cancer mechanism of sirolimus (SRL) combined with Huai Er.
Previous studies on HCC tissues identified the importance of HIF-1α, glucose transporter 1 (GLUT1), and lactate dehydrogenase A (LDHA) expression. In this study, HepG2 and Huh7 cell lines were treated, under hypoxic and normoxic conditions, with a combination of SRL and Huai Er. The effects on proliferation, invasion, cell cycle, and apoptosis were analysed. Proteomics and genomics techniques were used to analyze the HIF-1α-related signalling pathway during SRL combined with Huai Er treatment and its inhibition of the proliferation of HCC cells.
High levels of HIF-1α, LDHA, and GLUT-1 were found in poorly differentiated HCC, with lower patient survival rates. Hypoxia promoted the proliferation of HepG2 and Huh7 cells and weakened the apoptosis and cell cycle blocking effects of the SRL/Huai Er treatment. This was achieved by activation of HIF-1α and glycolysis in HCC, leading to the upregulation of LDHA, GLUT-1, Akt/mammalian target of rapamycin (mTOR), vascular endothelial growth factor (VEGF), and Forkhead box P3 and downregulation of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and p27. The hypoxia-induced activation of HIF-1α showed the greatest attenuation in the SRL/Huai Er (S50 + H8) group compared to the drug treatments alone (
0.001). The S50 + H8 treatment significantly downregulated the expression of mTOR and HIF-1α, and significantly reduced the expression of VEGF mRNA. Meanwhile, the combined blocking of mTOR and HIF-1α enhanced the downregulation of
,
,
, and
mRNA and resulted in the downregulation of
, and
mRNA (
< 0.001).
SRL increases the anti-cancer effect of Huai Er, which reduces the promotion of hypoxia-induced HIF-1α on the Warburg effect by inhibition of the PI3K/Akt/mTOR-HIF-1α and HIF-1α-PTEN signalling pathways in HCC.
Polysaccharides are important active ingredients in Ophiocordyceps gracilis with many physiological functions. It can be obtained from the submerged fermentation by the anamorph (Paraisaria dubia) of ...Ophiocordyceps gracilis. However, it was found that the mycelial pellets of Paraisaria dubia were dense and increased in volume in the process of fermentation, and the center of the pellets was autolysis due to the lack of nutrient delivery, which extremely reduced the yield of polysaccharides. Therefore, it is necessary to excavate a fermentation strategy based on morphological regulation for Paraisaria dubia to promote polysaccharides accumulation.
In this study, we developed a method for enhancing polysaccharides production by Paraisaria dubia using microparticle enhanced technology, talc microparticle as morphological inducer, and investigated the enhancement mechanisms by transcriptomics. The optimal size and dose of talc were found to be 2000 mesh and 15 g/L, which resulted in a high polysaccharides yield. It was found that the efficient synthesis of polysaccharides requires an appropriate mycelial morphology through morphological analysis of mycelial pellets. And, the polysaccharides synthesis was found to mainly rely on the ABC transporter-dependent pathway revealed by transcriptomics. This method was also showed excellent robustness in 5-L bioreactor, the maximum yields of intracellular polysaccharide and exopolysaccharides were 83.23 ± 1.4 and 518.50 ± 4.1 mg/L, respectively. And, the fermented polysaccharides were stable and showed excellent biological activity.
This study provides a feasible strategy for the efficient preparation of cordyceps polysaccharides via submerged fermentation with talc microparticles, which may also be applicable to similar macrofungi.
Lysine (K) is an important target residue for protein and peptide delivery across membranes. K is the most frequently exposed residue in proteins, leading to high demand for the development of ...K‐compatible transport activators. However, designing activators for K‐rich peptides and proteins is more challenging than for arginine‐rich species because of the kosmotropic nature of K and its recognition difficulty. In this study, we designed a new amphiphilic sulfonatocalix5arene (sCx5‐6C) as a K‐compatible transport activator. sCx5‐6C was tailored with two key elements, recognition of K and the ability to embed into membranes. We measured the membrane transport efficiencies of α‐poly‐l‐lysine, heptalysine, and histones across artificial membranes and of α‐poly‐l‐lysine into live cells, activated by sCx5‐6C. The results demonstrate that sCx5‐6C acts as an efficient activator for translocating K‐rich peptides and proteins, which cannot be achieved by known arginine‐compatible activators.
An amphiphilic sulfonatocalix5arene (sCx5‐6C) was rationally designed as an activator for membrane transport of lysine‐rich peptides and proteins. sCx5‐6C binds tightly with lysine and is able to embed into membranes. The membrane transport efficiencies of α‐poly‐l‐lysine, heptalysine, and histones across artificial membranes and of α‐poly‐l‐lysine into live cells, activated by sCx5‐6C, were measured.
Exploration of new compounds belonging to unusual families is always attractive for the everlasting development of material science. Here, three isomorphic rare-earth sulfide borates RE3S3BO3 ...(RE = Nd, Tb, Dy) have been obtained via a facile metal oxide-boron-sulfur solid-state routine. Their centrosymmetric triclinic structures feature 3D framework built by three types of REOxSy units, viz. REOS6, REO4S3, and REO3S6. Their structural relationship with similar phases and lanthanide contraction rule are discussed. Their optical band gaps are measured to be 2.59–2.70 eV, and the corresponding theoretical calculations are also performed. This work enriches the rarely studied chalcogenide borate system and is conducive to discovering more inorganic materials.
Three new rare-earth sulfide borates RE3S3BO3 (RE = Nd, Tb, Dy) have been obtained via a facile metal oxide-boron-sulfur solid-state routine. They belong to the only RE3S3BO3 family case that three types of REOxQy units REOS6, REO4S3, and REO3S6 coexist in one structure. The optical properties and theoretical calculations analysis are reported. Display omitted
•New RE3S3BO3 (RE = Nd, Tb, Dy) obtained via a facile metal oxide-boron-sulfur solid-state routine.•RE3S3BO3 belong to the rarely studied chalcogenide borate system.•RE3S3BO3 structural relation with similar phases and the lanthanide contraction rule are given.•The optical properites and theoretical calculations analysis are performed.
The monitoring and management of blood glucose concentration are standard practices in critical settings as hyperglycaemia has been shown close association with poorer outcomes. Several meta-analyses ...have revealed that intensive glucose control has no benefit in decreasing short-term mortality among critically ill patients, while the studies these meta-analyses have incorporated have been largely divergent. We aim to perform a more comprehensive meta-analysis addressing this problem to provide stronger evidence.
: We conducted comprehensive searches for relevant randomized controlled studies in online databases, including the Cochrane Library, EMBASE, and PubMed databases, up to September 1, 2018. The clinical data, which included all-cause mortality, severe hypoglycemia, need for RRT, infection resulting in sepsis, ICU mortality, 90-day mortality, 180-day mortality, and hospital and ICU lengths of stay, were screened and analyzed after data extraction. We applied odds ratios (ORs) to analyze dichotomous outcomes and mean differences for continuous outcomes with a random effects model.
A total of 57 RCTs involving a total of 21840 patients were finally included. Patients admitted to the ICU who underwent intensive glucose control showed significantly reduced all-cause mortality (OR: 0.89; 95% CI: 0.80-1.00;
=0.04; I
=32%), reduced infection rate (OR: 0.65, 95% CI: 0.51-0.82, P=0.0002; I
=47%), a lower occurrence of acquired sepsis (OR: 0.80, 95% CI: 0.65-0.99, P=0.04; I
=0%) and shortened length of ICU stay (MD: -0.70, 95% CI: -1.21--0.19, P=0.007, I
=70%) when compared to the same parameters as those treated with the usual care strategy. However, patients in the intensive glucose control group presented with a significantly higher risk of severe hypoglycemia (OR: 5.63, 95% CI: 4.02-7.87,
<0.00001; I
=67%).
Critically ill patients undergoing intensive glucose control showed significantly reduced all-cause mortality, length of ICU stay and incidence of acquired infection and sepsis compared to the same parameters in patients treated with the usual care strategy, while the intensive glucose control strategy was associated with higher occurrence of severe hypoglycemic events.
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