Since cellular metabolism reprogramming is one of the crucial hallmarks of tumor, glucose metabolic pathways are emerging as an important target for modulating immunosuppressive tumor ...microenvironment (TME) in favor of anti-PD-L1 therapy. Aiming at boosting immune response by modulation immunosuppressive TME via balancing the glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) of tumor cells, we developed a dual-responsive mPEG-PLA-PHis-ss-PEI polyplexes (DRP/Res/siP) for robust co-delivery of PD-L1 siRNA and resveratrol (Res). Isothermal titration calorimetry confirmed the non-electrostatic interactions between PD-L1 siRNA and PHis block of the copolymer, which contributed to the efficient and synchronized release of siRNA with Res in response to the acidic and reductive environment by destabilizing the siRNA polyplexes. The extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) as well as some key enzymes involved in glycolysis and mitochondrial OXPHOS pathways were determined to quantify the glucose metabolism balance. Effective downregulation of glycolysis and upregulation of mitochondrial OXPHOS were observed in the tumor cells treated with DRP/Res/siP, leading to remarkably reduced lactate production and glucose consumption. In vivo anti-tumor results showed that upregulation of mitochondrial OXPHOS pathways not only significantly promoted CD8+ and CD4+ T cells infiltration, IFN-γ secretion but also significantly suppressed the Treg cells and MDSCs at the same glycolysis level, resulting in superior anti-tumor effect in combination with PD-L1 silencing. Our findings indicate that balancing glucose metabolic pathways of glycolysis and mitochondrial OXPHOS provides a more reliable immune boosting strategy to PD-L1 silencing than exclusive glycolysis inhibition.
Background and Aims
Add‐on devices have been widely used in clinical practice. The aim of this meta‐analysis was to compare the adenoma detection rate between Endocuff‐assisted colonoscopy (EAC) and ...cap‐assisted colonoscopy (CAC).
Methods
PubMed, EMBASE, SCOPUS, and Cochrane databases were searched. Outcomes included adenoma detection rate, cecal intubation rate, cecal intubation time, and withdrawal time. Dichotomous data were pooled to obtain the odds ratio or risk ratio. Continuous data were pooled using the mean difference.
Results
Of the 240 articles reviewed, six randomized controlled trials were included, with a total of 1994 patients. In the meta‐analysis, no statistical difference in adenoma detection rate was detected between EAC and CAC (47.0% vs 45.1%; P = 0.33). EAC significantly improved detection rate of diminutive adenomas/polyps compared with CAC (P = 0.01). Cecal intubation was achieved in 96.5% in EAC group and 97.9% in CAC group (P = 0.04). Besides, no statistical difference was found in cecal intubation time (P = 0.86), withdrawal time (P = 0.88), small adenomas/polyps (P = 0.60), or large adenomas/polyps (P = 0.95).
Conclusion
EAC and CAC have their respective merits. EAC significantly improve the detection of diminutive adenomas/polyps. CAC was better in cecal intubation rate.
Idiopathic pulmonary fibrosis (IPF) is a chronic fatal disease with limited therapeutic options. The infiltration of monocytes and fibroblasts into the injured lungs is implicated in IPF. Enolase-1 ...(ENO1) is a cytosolic glycolytic enzyme which could translocate onto the cell surface and act as a plasminogen receptor to facilitate cell migration via plasmin activation. Our proprietary ENO1 antibody, HL217, was screened for its specific binding to ENO1 and significant inhibition of cell migration and plasmin activation (patent: US9382331B2).
In this study, effects of HL217 were evaluated in vivo and in vitro for treating lung fibrosis.
Elevated ENO1 expression was found in fibrotic lungs in human and in bleomycin-treated mice. In the mouse model, HL217 reduced bleomycin-induced lung fibrosis, inflammation, body weight loss, lung weight gain, TGF-β upregulation in bronchial alveolar lavage fluid (BALF), and collagen deposition in lung. Moreover, HL217 reduced the migration of peripheral blood mononuclear cells (PBMC) and the recruitment of myeloid cells into the lungs. In vitro, HL217 significantly reduced cell-associated plasmin activation and cytokines secretion from primary human PBMC and endothelial cells. In primary human lung fibroblasts, HL217 also reduced cell migration and collagen secretion.
These findings suggest multi-faceted roles of cell surface ENO1 and a potential therapeutic approach for pulmonary fibrosis.
A new Anderson‐type polyoxometalate(POM)‐based one‐dimensional metal‐organic complex, namely, H2Cu2AlMo6(OH)6O182(3‐bpah)4(H2O)4 ⋅ 6H2O (1) (3‐bpah=N−N′‐bis(3‐pyridinecarboxamide)‐1,2‐cyclohexane) ...was synthesized by hydrothermal method. Implement basic characterization operations of single crystal X‐ray diffraction, IR spectroscopy, X‐ray powder diffraction and thermogravimetric analysis were performed. Complex 1 possesses not only the typical electrochemical behavior of the Anderson‐type polyoxoanion, but also excellent electrochemical stability. The carbon paste electrode bulk modified by complex 1(1‐CPE) can be used as an ampere sensor to detect potassium nitrite. The carbon cloth‐based electrode fabricated by complex 1(1‐CC)was capable of being used as electrocatalyst for hydrogen evolution reaction, the overpotential is 480 mV at the current density of 10 mA cm−2. 1‐CC can also be used as capacitor electrode, which shows an area capacitance of 293 mF cm−2 in 0.1 M H2SO4 solution and up to 10 hours of life stability. It can maintain 89.7 % of the capacitance after 1000 cycles of constant current charge/discharge.
An Anderson‐type polyoxometalate‐based metal‐organic complex was synthesized and structurally characterized, which can be used as a multifunctional material for electrochemical sensing, hydrogen evolution and capacitor.
Recent advances in epoxy resins have been forward to achieving high mechanical performance, thermal stability, and flame retardancy. However, seeking sustainable bio-based epoxy precursors and ...avoiding introduction of additional flame-retardant agents are still of increasing demand. Here we report the synthesis of p-hydroxycinnamic acid-derived epoxy monomer (HCA-EP) via a simple one-step reaction, and the HCA-EP can be cured with 4,4′-diaminodiphenylmethane (DDM) to prepare epoxy resins. Compared with the typical petroleum-based epoxy resin, bisphenol A epoxy resin, the HCA-EP-DDM shows a relatively high glass transition temperature (192.9 °C) and impressive mechanical properties (tensile strength of 98.3 MPa and flexural strength of 158.9 MPa). Furthermore, the HCA-EP-DDM passes the V-1 flammability rating in UL-94 test and presents the limiting oxygen index of 32.6%. Notably, its char yield is as high as 31.6% under N2, and the peak heat rate release is 60% lower than that of bisphenol A epoxy resin. Such findings provide a simple way of using p-hydroxycinnamic acid instead of bisphenol A to construct high-performance bio-based thermosets.
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A novel bio-based monomer, HCA-EP, with low viscosity is synthesized and used to prepare an epoxy resin having low flammability, high Tg and mechanical properties.
Background
Mild ischemic stroke (MIS) has been proved to be closely related to post‐stroke cognitive impairment (PSCI). However, there are relatively few studies on the risk factors of MIS. We aimed ...to evaluate the relationship between serum cystatin C (CysC) level and cognitive function in patients with acute MIS.
Methods
Four hundred consecutive patients with acute MIS were screened and 281 patients were eligible for this study. The serum CysC levels were detected within 24 h after admission. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) at 3 months after acute MIS. Logistic regression was used to identify the predictors of PSCI, and the receiver operating characteristic (ROC) curve was applied to explore the optimal cut‐off value.
Results
One hundred sixty‐four (58.4%) patients were diagnosed with PSCI at 3 months follow‐up. The serum CysC levels in patients with PSCI were significantly higher than patients without PSCI (p < .001). The binary logistic regression analysis showed that higher serum CysC level was an independent predictor for PSCI at 3 months (odds ratio OR, 5.745; 95% confidence interval, CI, 1.089–30.311; p = 0.039). The ROC curve showed that area under the curve (AUC) was 0.723, and at a 0.945 mg/l CysC cut‐off point, the sensitivity and specificity for PSCI at 3 months were 79.9% and 58.1%, respectively.
Conclusion
Our findings suggested that the serum CysC levels were increased after acute MIS, and higher serum CysC levels at baseline might be an independent risk factor for PSCI in patients with acute MIS, but further research are warranted.
The serum CysC level was increased after acute MIS, and elevated CysC level was closely related to the occurrence of PSCI in MIS patients. It was also found to have high sensitivity and specificity through ROC curve.
Spontaneous low-frequency fluctuations (LFF) in the blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal have been shown to reflect cerebral spontaneous neural ...activity, and the present study attempts to explore the functional changes in the regional brain in patients with schizophrenia using the amplitude of the BOLD signals.
A total of 66 treatment-naïve, first-episode schizophrenia (FES) patients and 66 normal age- and sex-matched controls were recruited. Resting-state fMRIs were obtained using a gradient-echo echo-planar imaging sequence. The amplitude of LFF (ALFF) was calculated using REST software. Voxel-based analysis of the ALFF maps between control and patient groups was performed with twos-sample t-tests using SPM2.
Compared to the controls, the FES group showed significantly decreased ALFF in the medial prefrontal lobe (MPFC) and significant increases in the ALFF in the left and right putamen. Significant positive correlations were observed between ALFF values in the bilateral putamen in both the patient and control groups.
Alterations of the ALFF in the MPFC and putamen in FES observed in the present study suggest that the functional abnormalities of those areas are at an early stage of the disease.
Recent studies show that Polydatin （PD） extracted from the roots of Polygonum cuspidatum Sieb, a widely used traditional Chinese remedies, possesses anti-inflammatory activity in several experimental ...models. In this study, we investigated the anti-inflammatory effects of PD on Staphylococcus aureus-induced mastitis in mice and elucidated the potential mechanisms. In mice with S aureus- induced mastitis, administration of PD （15, 30, 45 mg/kg, ip） or dexamethasone （Dex, 5 mg/kg, ip） significantly suppressed the infiltration of inflammatory cells, ameliorated the mammary structural damage, and inhibited the activity of myeloperoxidase, a biomarker of neutrophils accumulation. Furthermore, PD treatment dose-dependently decreased the levels of TNF-α, IL-1β, IL-6 and IL-8 in the mammary gland tissues. PD treatment also dose-dependently decreased the expression of TLR2, MyD88, IRAK1, IRAK4 and TRAF6 as well as the phosphorylation of TAK1, MKK3/6, p38 MAPK, IκB-α and NF-κB in the mammary gland tissues. In mouse mammary epithelial cells （mMECs） infected by S aureus in vitro, pretreatment with PD dose-dependently suppressed the upregulated pro-inflammatory cytokines and signaling proteins, and the nuclear translocation of NF-κB p65 and AP-1. A TLR2-neutralizing antibody mimicked PD in its suppression on S aureus-induced upregulation of MyD88, p-p38 and p-p65 levels in mMECs. PD （50, 100 μg/mL） affected neither the growth of S aureus in vitro, nor the viability of mMECs. In conclusion, PD does not exhibit antibacterial activity against S aureus, its therapeutic effects in mouse S aureus-induced mastitis depend on its ability to down-regulate pro-inflanqmatory cytokine levels via inhibiting TLR2-mediated activation of the p38 MAPK/NF-κB signaling pathway.
To systematically study how the H‐bonding interaction affect the flame retardancy and anti‐dripping behavior of poly(ethylene terephthalate) (PET), two series of PET‐based copolyesters are prepared ...by introducing two benzimidazole monomers with similar structure. One (2‐(4‐methoxycarbonyl‐phenyl)‐1H‐benzimidazole‐5‐carboxylic acid methyl ester, PBM) contains H‐bonding donor, the other (2‐(4‐methoxycarbonyl‐phenyl)‐1‐methylbenzimidazole‐5‐carboxylic acid methyl ester, PNM) weeds out the H‐bonding donor by replacing NH group with NCH3. The dynamic rheological behavior, fire resistance and fire‐retardant mechanism of the PET‐co‐PBMs and PET‐co‐PNMs are contrastively investigated. PET‐co‐PNMs have flow behaviors similar to neat PET. While, for PET‐co‐PBMs, the movements of the molecular chains are restricted due to the H‐bonding interaction, leading to higher melt viscosity, which is conducive to the anti‐dripping property. It can be proved that benzimidazole groups promote the carbonization of substrates to form more stable charred layers in combustion, showing an obvious barrier action in condensed phase. Unfortunately, the enhancement of carbonization alone is not enough to inhibit the dripping behavior satisfactorily, and PET‐co‐PNMs fail to pass UL‐94 V‐0 rating. While, PET‐co‐PBMs exhibit better self‐extinguishing and anti‐dripping performances benefiting from strong H‐bonding interactions. The revealed effects of H‐bonding interactions on the fire resistance and anti‐dripping behavior of polymers will guide further design of flame retardants.
Two PET‐based copolyesters containing benzimidazole structure, one with hydrogen bond donor (2‐(4‐methoxycarbonyl‐phenyl)‐1H‐benzimidazole‐5‐carboxylic acid methyl ester, PBM), the other without hydrogen bond donor (2‐(4‐methoxycarbonyl‐phenyl)‐1‐methylbenzimidazole‐5‐carboxylic acid methyl ester, PNM), show different rheological behavior and fire resistance. H‐bonding can reduce the fluidity of burning melt and provide more time for charring, endowing PET‐co‐PBMs with better self‐extinguishing and anti‐dripping performances than PET‐co‐PNMs.
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