MnO2 and roflumilast-loaded probiotic membrane vesicles mitigate experimental colitis by synergistically augmenting cAMP in macrophage.

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 MnO2 were encapsulated in MVs (Rof&MnO2@MVs). Roflumilast inhibited cAMP degradation via PDE4 deactivation and MnO2 boosted cAMP generation by activating adenylate cyclase (AC). Compared with roflumilast, co-delivery of roflumilast and MnO2 apparently produced more cAMP and less TNF-α in macrophage. Besides, Rof&MnO2@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 MnO2 into macrophage. This biomimetic nanoparticle could synergistically modulate cAMP in macrophage and ameliorate experimental colitis.

Hydrogel-Based Controlled Drug Delivery for Cancer Treatment: A Review.

As an emerging drug carrier, hydrogels have been widely used for tumor drug delivery. A hydrogel drug carrier can cause less severe side effects than systemic chemotherapy and can achieve sustained delivery of a drug at tumor sites. In addition, hydrogels have excellent biocompatibility and biodegradability and lower toxicity than nanoparticle carriers. Smart hydrogels can respond to stimuli in the environment (e.g., heat, pH, light, and ultrasound), enabling in situ gelation and controlled drug release, which greatly enhance the convenience and efficiency of drug delivery. Here, we summarize the different sizes of hydrogels used for cancer treatment and their related delivery routes, discuss the design strategies for stimuli-responsive hydrogels, and review the research concerning smart hydrogels reported in the past few years.

Frequency, prognosis and treatment modalities of newly diagnosed small bowel cancer with liver metastases.

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.

Comparison of Bispectral Index-Guided Individualized Anesthesia with Standard General Anesthesia on Inadequate Emergence and Postoperative Delirium in Elderly Patients Undergoing Esophagectomy: A Retrospective Study at a Single Center.

BACKGROUND Elderly patients are susceptible to general anesthetics, with a higher bispectral index (BIS) at loss of consciousness (LOC) achieved by propofol infusion compared with young patients. Overexposure to general anesthetics can have adverse effects such as inadequate emergence and postoperative delirium (PD). This study aimed to compare the effects of BIS-guided individualized anesthesia with standard general anesthesia on emergence and delirium after esophagectomy. MATERIAL AND METHODS Data on 161 elderly patients undergoing esophagectomy for cancer were retrospectively obtained from electronic medical records. We performed propensity score matching analysis between patients receiving individualized anesthesia (BIS value maintained at about 10 less than the value at LOC) and those receiving standard anesthesia (BIS value maintained at 40-60). In addition, we conducted univariate and multivariate logistic -analyses in the entire cohort. RESULTS Patients receiving individualized anesthesia had higher BIS values and a lower propofol requirement during surgery than those receiving standard general anesthesia (P<0.05). The overall incidences of inadequate emergence and PD were 37.9% and 18.0% (n=161), respectively. Logistic regression analysis revealed that the independent risk factors for PD were organic brain disease (odds ratio [OR] 6.308; 95% confidence interval [CI] 2.458-16.187) and inadequate emergence (OR 4.063; 95% CI 1.645-10.033). CONCLUSIONS BIS-guided individualized anesthesia (lighter) does not reduce inadequate emergence or PD compared with standard general anesthesia in elderly patients undergoing esophagectomy. Independent risk factors for PD include organic brain disease and inadequate emergence.

Design, Synthesis, and Biological Application of Novel Photoaffinity Probes of Dihydropyridine Derivatives, BAY R3401.

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.

Design, Synthesis, and Use of Novel Photoaffinity Probes in Measuring the Serum Concentration of Glycogen Phosphorylase.

A procedure to measure the serum concentration of glycogen phosphorylase during acute myocardial infarction is presented. This method was based on the synthesis of photoaffinity probes, and used the semiquantitative protein electrophoretic mobility shift technique. Three novel photoaffinity probes bearing different secondary tags were synthesized. Their potency was evaluated in an enzyme inhibition assay against rabbit muscle glycogen phosphorylase a (RMGPa). The inhibitory activity of probe 1 was only 100-fold less potent than the mother compound CP-320626. The photoaffinity labeling experiments were also performed, and a protein with molecular weight (MW) of about 90⁻100 kDa, which was consistent with the MW of GP, was clearly labeled by probe 1. A semiquantitative evaluation of the GP level in serum with probe 1 was also performed. The results showed that the protein band with a MW of about 90⁻100 kDa was tagged, and the concentration of the protein in serum was found to be between 25 and 50 ng/mL. Mass spectrometric analysis revealed that alpha-1,4 glucan phosphorylase (GPMM) was well-preserved in the bands.

Thoracic Paravertebral Block versus Epidural Anesthesia Combined with Moderate Sedation for Percutaneous Nephrolithotomy.

OBJECTIVE: To investigate the feasibility of thoracic paravertebral block (TPVB) for percutaneous nephrolithotomy (PCNL) in comparison with epidural anesthesia (EA) combined with moderate sedation. SUBJECTS AND METHODS: One hundred American Society of Anesthesiologists (ASA) I-II adult patients scheduled for first-stage unilateral PCNL were randomly assigned to receive either TPVB or EA. All patients were given standard sedation and analgesia with propofol and sufentanil. Patient characteristics, surgical outcomes, anesthetic outcomes, and time to first use of a patient-controlled intravenous analgesic (PCIA) device and postoperative consumption of sufentanil in the first 24 h were recorded. Intergroup differences of the parameters were analyzed using an independent t test, Mann-Whitney test, and χ2 test as appropriate. RESULTS: Patients who received TPVB consumed more propofol during ureteroscopy (56.2 ± 28.4 vs. 42.9 ± 27.5 mg, p < 0.05) and more sufentanil during ureteroscopy (9.7 ± 4.8 vs. 3.9 ± 2.7 µg, p < 0.05) and during PCNL (7.0 ± 4.3 vs. 1.9 ± 1.8 µg, p < 0.05) than those who received EA. The volume fluids infused in patients who received TPVB was less than in those who received EA (854 ± 362 vs. 1,320 ± 468 ml, p < 0.05). Time to first PCIA use, postoperative 24-hour consumption of sufentanil, and other parameters were comparable between groups. CONCLUSIONS: In this study, TPVB was as effective and safe as EA in providing intraoperative anesthesia and postoperative analgesia for PCNL, although more sedatives and analgesics were used during PCNL in patients who received TPVB.

Comparison of erector spinae plane block with paravertebral block for thoracoscopic surgery: a meta-analysis of randomized controlled trials.

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.

Effect of dexmedetomidine supplementation for thoracoscopic surgery: a meta-analysis of randomized controlled trials.

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.

Curing and Molecular Dynamics Simulation of MXene/Phenolic Epoxy Composites with Different Amine Curing Agent Systems.

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.

Outcome of manipulation under anesthesia with or without intra-articular steroid injection for treating frozen shoulder: A retrospective cohort study.

ABSTRACT: Manipulation under anesthesia (MUA) combined with intra-articular steroid injection (ISI) is preferred in management of the refractory frozen shoulder (FS). This study aimed to evaluate the effect of MUA with ISI or not on pain severity and function of the shoulder.Data on 141 patients receiving MUA with primary FS refractory to conservative treatments for at least 1 month were retrospectively obtained from medical records. We performed propensity score matching analysis between patients receiving MUA only and those receiving MUA plus ISI, and then conducted logistic regression analysis to identify the risk factors for the need to other treatments during 6-month follow-up.More improvement in terms of the SPADI pain scores and passive ROM at 2 weeks after first intervention remained in patients receiving MUA plus ISI after matching. The need to other treatments during 6-month follow-up occurred in 10.6% patients (n = 141). Logistic regression analysis revealed that a repeat MUA 1 week after first intervention was a protective factor (OR 0.042; 95% CI 0.011-0.162; P = .000) and duration of disease was the only one risk factor (OR 1.080; 95% CI 1.020-1.144; P = .008) for the need to other treatments during follow-up.ISI immediately following MUA provided additional benefits in rapid relief of pain and disability for patients with refractory FS. Pain and disability of the shoulder may be rapidly alleviated by an earlier MUA from the onset of the symptoms and a repeat MUA 1 week after first intervention.

Addition of dexmedetomidine to epidural morphine to improve anesthesia and analgesia for cesarean section.

The aim of the present study was to evaluate the effectiveness and safety of the combination of epidural dexmedetomidine and morphine in providing anesthesia during cesarean surgery and analgesia for post-cesarean pain relief when added to epidural ropivacaine. A total of 80 females at term scheduled for elective cesarean delivery were randomly assigned to two groups (n=40/group): In the morphine group (group M), patients received an epidural injection of 0.75% ropivacaine (12 ml) and morphine (2 mg) for surgical anesthesia, and epidural infusion of morphine (2 mg) in 100 ml 0.2% ropivacaine at 2 ml/h for 48-h post-operative analgesia; and in the morphine combined with dexmedetomidine group (group DM), patients received an epidural injection of 0.75% ropivacaine (12 ml) and morphine (2 mg) combined with dexmedetomidine (0.5 µg/kg) for surgical anesthesia, and epidural infusion of morphine (2 mg) and dexmedetomidine (200 µg) in 100 ml 0.2% ropivacaine at 2 ml/h for 48-h post-operative analgesia. The primary outcomes included blockade and analgesic effects, sedation and adverse reactions associated with the drugs. Neonatal outcome was also assessed by determining the Apgar score and umbilical cord blood analysis. There was no significant difference between the groups in the cephalad levels of sensory blockade at 20 min post-injection, or in muscle relaxation scores or pain intensity scores at rest or upon movement at 4, 12, 24 or 48 h post-injection (P>0.05). The maternal patients in the DM group experienced more complete motor blockade at 20 min post-injection, better sedation during surgery and following delivery, and less visceral pain caused by peritoneal traction during surgery and by uterine contraction after delivery, compared with those in group M (P<0.05). The patients in group M had a lower incidence and severity score of post-operative nausea than those in the DM group (P<0.05). There was no significant difference between the groups in terms of Apgar score or umbilical cord blood gas values (P>0.05). In conclusion, epidural dexmedetomidine reduces intra-operative and post-operative visceral pain and produces better sedation during surgery and following delivery, without any significant influence on morphine-associated side effects and post-operative analgesia, in females undergoing elective cesarean section under epidural anesthesia with morphine and ropivacaine (registration number ChiCTR1900027942; retrospectively registered with the Chinese Clinical Registry Center on December 6, 2019).

Effect of sericin on the p38MAPK signaling pathway and NLRP3 inflammasome in the kidney of type 2 diabetic rats.

The present study aimed to investigate the effects of sericin on the p38MAPK signaling pathway and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in the kidney of rats with type 2 diabetes mellitus (T2DM). A total of 36 male Sprague-Dawley rats were randomly divided into the normal group, T2DM model group and sericin group (n=12 rats/group). A T2DM model was developed through intraperitoneal injection of streptozotocin (35 mg·kg-1·d-1 for 2 consecutive days), and a high-fat and high-sugar diet. The T2DM rats in the sericin group were administered 2.4 g·kg-1·d-1 sericin for 35 days, and rats in the other groups were administered an equal volume of normal saline for 35 days. Fasting blood glucose was measured using the glucose oxidase method. Kidney tissue morphology was observed by H&E staining. Immunohistochemistry, western blotting, ELISA and reverse transcription-quantitative PCR were used to detect the levels of MKK6, p38MAPK, phosphorylated (p)-p38MAPK, NF-κB, IL-1ß, IL-6, NLRP3 and caspase-1 in rat kidney tissues. The results revealed that blood glucose concentration, and the expression levels of MKK6, p-p38MAPK, NF-κB, IL-1ß, IL-6, NLRP3 and caspase-1 were significantly increased in the T2DM group compared with those in the normal group (P<0.05). In addition, obvious pathological changes were observed in the T2DM group. Conversely, glucose concentration, and the expression levels of MKK6, p-p38MAPK, NF-κB, IL-1ß, IL-6, NLRP3 and caspase-1 were significantly reduced in the sericin group compared with those in the T2DM group (P<0.05). The pathological changes were also obviously reduced. Notably, there was no significant difference in p38MAPK expression among the three groups (P>0.05). Collectively, the present study revealed that sericin may downregulate the expression levels of MKK6, p-p38MAPK, NF-κB, IL-1ß, IL-6, NLRP3 and caspase-1, and inhibit activation of renal p38MAPK signaling and NLRP3-associated inflammation, which in turn may protect against kidney damage caused by T2DM.

[Communication interface and software design for laboratory analyzer].

In this text the interface of hardware and software for laboratory analyzer is analyzed. Adopting VC++ and multi-thread technique, the real-time communication without errors between LIS and the laboratory analyzer is realized. Practice proves that the system based on the technique is stable in running and all data are received accurately and timely.

[Preparation and evaluation in vivo of Scutellaria thermosensitive gel].

OBJECTIVE: To study scutellaria thermosensitive gel in situ. METHOD: The phase transition temperature of gel with various concentration polymer solutions was studied by using stirring method and the viscosity of gel was monitored under different temperatures. Eye irritation experiments were performed with rabbit. The duration of residence time in rabbit eyes of scutellaria thermosensitive gel was observed with 2% fluorescein. RESULT: 20% poloxmar407 and 10% poloxmar 188 were suitable to scutellaria thermosen-sitive gel in situ. The results suggested that the scutellaria thermosensitive gel in situ based on poloxmar were nonirritant and retention time on the surface of eye was (150 +/- 8) min. CONCLUSION: The scutellaria thermosensitive gel in situ forms gel in eye and has longer release time than that of eye drops.

Sericin enhances the insulin-PI3K/AKT signaling pathway in the liver of a type 2 diabetes rat model.

The aim of the current study was to investigate the regulatory effect of sericin on the hepatic insulin-phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in a type 2 diabetes rat model. Male Sprague Dawley rats were randomly divided into four groups: Control group, diabetic model group, high-dose sericin group and low-dose sericin group, with 12 rats in each group. Fasting blood glucose was detected by the glucose oxidase method, and hepatic glycogen was determined by periodic acid-Schiff staining. The morphology of the liver was observed by hematoxylin and eosin staining. Immunohistochemical staining, western blotting and reverse transcription-quantitative polymerase chain reaction were used to determine the protein and mRNA expression levels of insulin receptor (IR), IR substrate-1 (IRS-1), PI3K and AKT. Compared with the control group, the blood glucose of the diabetic model group was significantly increased (P<0.05). The glycogen content and the expression levels of IR, IRS-1, PI3K and AKT in the diabetic model group were significantly lower (P<0.05), and the liver morphological structure of the diabetic model group exhibited obvious pathological changes compared with the control group. Compared with the diabetic model group, the blood glucose of the high- and low-dose sericin groups was significantly reduced, while the glycogen content and the expression levels of IR, IRS-1, PI3K and AKT in the sericin treatment groups were significantly increased (P<0.05). Additionally, the liver pathological changes of high-dose and low-dose sericin groups were markedly reduced. Sericin may enhance the signaling transduction effect of insulin by upregulating the expression levels of key factors (IR, IRS-1, PI3K and AKT) in the liver insulin-PI3K/AKT signaling pathway, thus promoting glucose transport and liver glycogen synthesis, and further reducing blood glucose.

Effects of plant coverage on shrub fertile islands in the Upper Minjiang River Valley.

The patchy distribution of vegetation in dry land results in well-documented "fertile islands". However, the response of shrub fertile islands to plant recovery and the underlying mechanisms, such as the linkage plant and soil properties, remain unknown. We sampled soils from areas with three different plant coverages (25%, 45%, and 75%) and three of their adjacent inter-plants to investigate soil physicochemical and microbial properties in the upper Minjiang River arid valley. The results showed that these factors were influenced by the persistence of plants that contrasted with the inter-plant interspaces. We found fertile islands in under-plant soil that were enhanced with increasing plant coverage, from 25% to 45% and 75%; however, there were no significant differences between 45% and 75% plant coverage apart from the soil clay content and the fungi to bacteria ratio. The soil microbial communities in under-plant soil were strongly influenced by the total soil carbon (TC), soil organic carbon (SOC), and available nitrogen (AN), whereas the microbial communities in inter-plant soil were primarily constrained by the AN and available phosphorous (AP). Moreover, the inter-plant soil properties, including gravimetric soil water content, pH, electrical conductivity (EC), and soil C:N ratio, were also strongly influenced by adjacent vegetation, which suggested that fertile islands may be beneficial for plant recovery in this region.

Triple therapy of hepatocellular carcinoma with microRNA-122 and doxorubicin co-loaded functionalized gold nanocages.

A combination of different therapy strategies has great potential to efficaciously treat malignant tumors, by virtue of their synergetic effects. Herein, a co-delivery system based on gold nanocages (AuNCs) was designed to deliver both doxorubicin (DOX) and microRNA-122 mimic (miR-122) for an enhanced cancer therapy. DOX was loaded into the AuNCs and miR-122 was condensed onto the surface of the functionalized AuNCs by an electrostatic interaction. Polyethyleneglycol (PEG) and hyaluronic acid (HA) were also introduced to the co-delivery system for targeted drug delivery. We evaluated the cellular uptake, biodistribution and anti-tumor effect in vitro and in vivo. Our results demonstrated an effective delivery of DOX and miR-122 into tumor cells and the tumor tissue. Importantly, the triple therapy, namely the combination of chemotherapy, gene therapy and photothermal therapy, mediated by this multifunctional drug delivery system, exhibited better anti-tumor effect than any single therapy, both in vitro and in vivo. Additionally, this drug delivery system caused insignificant toxicity to the major organs and had no obvious effect on the body weight of the mice. It could be concluded that multifunctional AuNCs are promising as a co-delivery vector for an enhanced anti-tumor effect.