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Background Ulcerative colitis (UC) is one chronic and relapsing inflammatory bowel disease. Macrophage has been reputed as one trigger for UC. Recently, phosphodiesterase 4 (PDE4) inhibitors, for instance roflumilast, have been regarded as one latent approach to modulating macrophage in UC treatment. Roflumilast can decelerate cyclic adenosine monophosphate (cAMP) degradation, which impedes TNF-α synthesis in macrophage. However, roflumilast is devoid of macrophage-target and consequently causes some unavoidable adverse reactions, which restrict the utilization in UC. Results Membrane vesicles (MVs) from probiotic Escherichia coli Nissle 1917 (EcN 1917) served as a drug delivery platform for targeting macrophage. As model drugs, roflumilast and MnO 2 were encapsulated in MVs (Rof&MnO 2 @MVs). Roflumilast inhibited cAMP degradation via PDE4 deactivation and MnO 2 boosted cAMP generation by activating adenylate cyclase (AC). Compared with roflumilast, co-delivery of roflumilast and MnO 2 apparently produced more cAMP and less TNF-α in macrophage. Besides, Rof&MnO 2 @MVs could ameliorate colitis in mouse model and regulate gut microbe such as mitigating pathogenic Escherichia–Shigella and elevating probiotic Akkermansia . Conclusions A probiotic-based nanoparticle was prepared for precise codelivery of roflumilast and MnO 2 into macrophage. This biomimetic nanoparticle could synergistically modulate cAMP in macrophage and ameliorate experimental colitis. Graphical Abstract

This paper investigates post-disaster restoration and stable operation of three-phase unbalanced distribution networks with high penetration of distributed generation and electric-vehicle integration. A two-stage hierarchical restoration and coordinated dispatch strategy is developed to improve restoration feasibility and reliability while reducing post-fault restoration cost. In Stage I, island partitioning and load prioritization are carried out using DFS and BFS to maximize the restoration of critical loads. In Stage II, without reducing the Stage I restoration level, branch switch statuses and coordinated outputs of DG-EV-BESS are jointly optimized under three-phase unbalanced power flow, radiality, and other operational constraints. The objective minimizes the total restoration cost, including network losses, switching operations, three-phase voltage-unbalance penalties, and customer compensation. Simulation results on a modified IEEE 33-bus system demonstrate that the proposed method reduces restoration cost and improves the system restoration ratio. In addition, phase-wise EV dispatch provides targeted compensation for weak-phase power deficits and improves post-fault inter-phase operating quality. The results validate the effectiveness of the proposed strategy.

Introduction The efficacy of dexmedetomidine supplementation for thoracoscopic surgery remains controversial. We conduct a systematic review and meta-analysis to explore the impact of dexmedetomidine for thoracoscopic surgery. Methods We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through September 2020 for randomized controlled trials (RCTs) assessing the effect of dexmedetomidine supplementation on thoracoscopic surgery. This meta-analysis is performed using the random-effect model. Results Six RCTs involving 510 patients are included in the meta-analysis. Overall, compared with control group for thoracoscopic surgery, dexmedetomidine supplementation results in significantly reduced pain scores (SMD = − 1.50; 95% CI = − 2.63–− 0.37; P = 0.009), anesthetic consumption (SMD = − 3.91; 95% CI = − 6.76–− 1.05; P = 0.007), mean heart rate (SMD = − 0.41; 95% CI = − 0.65–− 0.18; P = 0.0007), and the risk ratio (RR) of ICU stay (RR = 0.39; 95% CI = 0.19–0.80; P = 0.01), but showed no obvious effect on mean blood pressure (SMD = − 0.07; 95% CI = − 0.45–0.31; P = 0.72) or hospital stay (SMD = − 0.61; 95% CI = − 1.30–0.08; P = 0.08). Conclusions Dexmedetomidine supplementation can substantially improve the analgesic efficacy for thoracoscopic surgery.

Introduction The efficacy of erector spinae plane block versus paravertebral block for thoracoscopic surgery remains controversial. We conduct a systematic review and meta-analysis to explore the impact of erector spinae plane block versus paravertebral block on thoracoscopic surgery. Methods We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through March 2022 for randomized controlled trials (RCTs) assessing the effect of erector spinae plane block versus paravertebral block on thoracoscopic surgery. This meta-analysis is performed using the random-effect model. Results Seven RCTs are included in the meta-analysis. Overall, compared with erector spinae plane block for thoracoscopic surgery, paravertebral block results in significantly reduced pain scores at 12 h (SMD = 1.12; 95% CI 0.42 to 1.81; P  = 0.002) and postoperative anesthesia consumption (SMD = 1.27; 95% CI 0.30 to 2.23; P  = 0.01), but these two groups have similar pain scores at 1-2 h (SMD = 1.01; 95% CI − 0.13 to 2.15; P  0.08) and 4–6 h (SMD = 0.33; 95% CI − 0.16 to 0.81; P  = 0.19), as well as incidence of nausea and vomiting (OR 0.93; 95% CI 0.38 to 2.29; P  = 0.88). Conclusions Paravertebral block may be better for the pain relief after thoracoscopic surgery than erector spinae plane block.

Fluorescently labelled small molecule probes (fluorescent probes) play an important role in cell imaging and are often used in combination with light-affinity probes to determine the subcellular localisation of target proteins. To investigate the target proteins of 18 -glycyrrhetinic acid (18 -GA), which regulates the macrophage inflammatory response, we designed and synthesised three types of fluorescent probes. We analysed its structure-activity relationship by evaluating the biological activity and screening for fluorescent probes with high activity. Our results showed that modifying C-3 hydroxyl and C-30 carboxyl groups enhanced the anti-inflammatory activity of 18 -GA, and found that two preferred probes had similar effects on LPS-induced, inflammation-related factor release (IL-1β, TNF-α, IL-6, HDAC8, P-STAT3, and SOCS3) to those of 18 -GA. Fluorescence signals of the preferred probes and were observed in the cytoplasm. The above results indicated that the anti-inflammatory site of 18 -GA may be located in proteins in the cytoplasm, which would provide useful information for research on the anti-inflammatory targets of 18 -GA.

Background Population-based analysis for the liver metastases of small bowel cancer is currently lacking. This study aimed to analyze the frequency, prognosis and treatment modalities for newly diagnosed small bowel cancer patients with liver metastases. Methods Patients with small bowel cancer diagnosed from 2010 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Binary logistic regression analysis was performed to determine predictors for the presence of liver metastases at diagnosis. Kaplan–Meier method and Cox regression analyses were performed for survival analyses. Results A total of 1461 small bowel cancer patients with liver metastases at initial diagnosis were identified, representing 16.5% of the entire set and 63.9% of the subset with metastatic disease to any distant site. Primary tumor with poorer histological type, larger tumor size, later N staging, more extrahepatic metastatic sites, and tumor on lower part of small intestine had increased propensity of developing liver metastases. The combined diagnostic model exhibited acceptable diagnostic efficiency with AUC value equal to 0.749. Patients with liver metastases had significant poorer survival ( P  < 0.001) than those without liver metastases. In addition, combination of surgery and chemotherapy (HR = 0.27, P  < 0.001) conferred the optimal survival for patients with adenocarcinoma, while the optimal treatment options for NEC and GIST seemed to be surgery alone (HR = 0.24, P  < 0.001) and chemotherapy alone (HR = 0.08, P  = 0.022), respectively. Conclusions The combined predictor had a good ability to predict the presence of liver metastases. In addition, those patients with different histologic types should be treated with distinct therapeutic strategy for obtaining optimal survival.

The aim of this study was to investigate the hepatoprotective effects of resveratrol in alcoholic liver disease (ALD). Alcohol was administered to healthy female rats starting from 6% (v/v) and gradually increased to 20% (v/v) by the fifth week. After 16 weeks of intervention, liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) were analyzed using a chemistry analyzer, while hepatic antioxidant enzymes, oxidative stress markers, and caspase 3 activity were assessed using ELISA kits. Furthermore, hepatic CYP2E1 protein levels and mRNA levels of antioxidant and inflammation-related genes were determined using western blotting and RT-PCR, respectively. The results showed that resveratrol significantly attenuated alcohol-induced elevation of liver enzymes and improved hepatic antioxidant enzymes. Resveratrol also attenuated alcohol-induced CYP2E1 increase, oxidative stress, and apoptosis (caspase 3 activity). Moreover, genes associated with oxidative stress and inflammation were regulated by resveratrol supplementation. Taken together, the results suggested that resveratrol alleviated ALD through regulation of oxidative stress, apoptosis, and inflammation, which was mediated at the transcriptional level. The data suggests that resveratrol is a promising natural therapeutic agent against chronic ALD.

To explore the molecular mechanisms of BAY R3401, four types of novel photoaffinity probes bearing different secondary tags were synthesized. Their potency for glycogenolysis was evaluated in primary human liver HL-7702 cells and HepG2 cells. Probe 2d showed the best activity in primary human liver HL-7702 cells and HepG2 cells, with IC50 values of 4.45 μM and 28.49 μM, respectively. Likewise, probe 5d showed IC50 values of 6.46 μM in primary human liver HL-7702 cells and 15.29 μM in HepG2 cells, respectively. Photoaffinity labeling experiments were also performed and protein bands larger than 170 kDa were specifically tagged by probe 2d. The results suggest that the synthesized probe 2d might be a very promising tool for the isolation of the target proteins of BAY R3401.

Menopause causes cognitive and memory dysfunction due to impaired neuronal plasticity in the hippocampus. Sirtuin-1 (SIRT1) downregulation in the hippocampus is implicated in the underlying molecular mechanism. Edible bird’s nest (EBN) is traditionally used to improve general wellbeing, and in this study, we evaluated its effects on SIRT1 expression in the hippocampus and implications on ovariectomy-induced memory and cognitive decline in rats. Ovariectomized female Sprague-Dawley rats were fed with normal pellet alone or normal pellet + EBN (6, 3, or 1.5%), compared with estrogen therapy (0.2 mg/kg/day). After 12 weeks of intervention, Morris water maze (four-day trial and one probe trial) was conducted, and serum estrogen levels, toxicity markers (alanine transaminase, alkaline phosphatase, urea, and creatinine), and hippocampal SIRT1 immunohistochemistry were estimated after sacrifice. The results indicated that EBN and estrogen enhanced spatial learning and memory and increased serum estrogen and hippocampal SIRT1 expression. In addition, the EBN groups did not show as much toxicity to the liver as the estrogen group. The data suggested that EBN treatment for 12 weeks could improve cognition and memory in ovariectomized female rats and may be an effective alternative to estrogen therapy for menopause-induced aging-related memory loss.

Herein, the curing kinetics and the glass transition temperature (Tg) of MXene/phenolic epoxy composites with two curing agents, i.e., 4,4-diaminodiphenyl sulfone (DDS) and dicyandiamine (DICY), are systematically investigated using experimental characterization, mathematical modeling and molecular dynamics simulations. The effect of MXene content on an epoxy resin/amine curing agent system is also studied. These results reveal that the MXene/epoxy composites with both curing agent systems conform to the SB(m,n) two-parameter autocatalytic model. The addition of MXene accelerated the curing of the epoxy composite and increased the Tg by about 20 K. In addition, molecular dynamics were used to simulate the Tg of the cross-linked MXene/epoxy composites and to analyze microstructural features such as the free volume fraction (FFV). The simulation results show that the introduction of MXene improves the Tg and FFV of the simulated system. This is because the introduction of MXene restricts the movement of the epoxy/curing agent system. The conclusions are in good agreement with the experimental results.