Experience from transport teams on interhospital transfer of patients with extracorporeal membrane oxygenation support: A qualitative study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) can be a life-saving treatment for patients requiring advanced cardiopulmonary support. Several ECMO centres offer interhospital transport (ECMO IHT) services that involve establishing ECMO teams to initiate ECMO at referring hospitals and then transfer patients to ECMO centres. ECMO IHT is often high risk and complex. Understanding the experience of transport team members is crucial to ensure patient safety and promote quality improvement. AIM: To explore the experiences of transport teams performing ECMO IHT. STUDY DESIGN: A descriptive qualitative methodology was adopted. RESULTS: Thirteen health care professionals who have performed ECMO IHT at a general hospital in China agreed to be interviewed and enrolled in this study. Two investigators conducted face-to-face individual interviews in September-November 2022. All interviews were audio-recorded, transcribed verbatim and analysed using inductive thematic analysis. Three main themes and nine sub-themes were developed: (1) practicing with good organizational management (conducting training programs, cultivating the spirit of good teamwork and developing a standardized transport procedure), (2) dedicated to ensuring patient safety (adequate preparation and regular checking to reduce risk, accurate evaluation to avoid futility and maintaining communication to increase safety) and (3) having confidence despite being uneasy (feeling stressed is common, facing insecurity in transport settings and gaining confidence through practice). CONCLUSIONS: Health care professionals must adequately prepare and assess ECMO IHT to ensure patient safety. Supportive measures should be taken to ensure team members' health and improve patient safety. Good communication and teamwork could improve this challenging task. Further research is required for training programs and establishing standardized transport procedures. RELEVANCE TO CLINICAL PRACTICE: This study presents multi-professional perspectives on the experience of performing ECMO IHT to help management identify what needs to be further developed. With the increasing number of ECMO IHT, promoting its standardization is warranted.

Effects of Combined Maternal Voice Stimulation and Gravity Feeding Intervention for Low-Birth-Weight Preterm Infants in Neonatal Care.

Background: This study aims to investigate the impact and safety of combining maternal voice stimulation with gravity feeding on low-birth-weight preterm infants. The research focuses on key outcomes such as gastric tube indwelling time, feeding transition time, adequate gastrointestinal nutrition time, recovery of birth weight time, length of hospital stay, and oral motor function in preterm infants. Methods: A total of 150 low birth weight preterm infants meeting inclusion criteria were recruited from the neonatal care unit and randomly assigned to three groups: traditional nasal feeding, gravity feeding with a homemade bracket, and a combined group receiving both gravity feeding and maternal voice stimulation. The groups were compared using parameters such as feeding intolerance incidence, gastric tube indwelling time, feeding transition time, adequate gastrointestinal nutrition time, recovery of birth weight time, hospital stay, and oral motor function. Results: The combined group exhibited a significantly lower incidence of feeding intolerance (26% lower than traditional nasal feeding, 18% lower than gravity feeding, P < .001). The traditional nasal feeding group had the highest incidence at 62%. The combined group showed a shorter indwelling time (19.01 ± 11.67 days), compared to the gravity feeding group (23.50 ± 13.04 days) and the traditional nasogastric feeding group (27.43 ± 11.91 days, P = .001). The combined group had a shorter hospital stay (27.09 ± 14.16 days) compared to the gravity feeding group (32.74 ± 13.32 days) and the traditional nasogastric feeding group (33.84 ± 12.42 days, P = .013). The combined group demonstrated a slightly longer recovery time (11.56 ± 4.08 days) than the gravity feeding group (11.14 ± 4.76 days) but significantly shorter than the traditional nasogastric feeding group (14.44 ± 5.42 days, P = .003). The combined group exhibited the highest improvement in oral motor function at 4 weeks after feeding (17.81 ± 0.39 points), surpassing both the gravity feeding group (16.10 ± 0.23 points) and the traditional nasogastric feeding group (15.15 ± 0.07 points, P < .001). The combined group demonstrated a significantly lower feeding transition time than the traditional nasal feeding group (P < .05) and comparable time to the gravity feeding group (P > .05). All the comparison results were statistically significant. Conclusion: Maternal voice stimulation combined with gravity feeding shows promising positive effects and high safety for low-birth-weight preterm infants. The combined approach outperformed both gravity feeding alone and traditional nasogastric feeding across various critical parameters. These findings support the potential clinical applicability and merit further consideration for wider implementation as a feeding method in neonatal care settings. Clinical Significance: The observed reductions in feeding intolerance, shortened gastric tube indwelling time, and enhanced oral motor function in low-birth-weight preterm infants receiving combined maternal voice stimulation and gravity feeding highlight a promising clinical approach. These improvements signify the potential for earlier oral feeding initiation, shorter hospital stays, and better overall outcomes in the care of these vulnerable infants. Limitations: This study is limited by its single-center design, potential selection bias, and the absence of blinding. Uncontrolled confounding factors may influence results, and long-term outcomes were not assessed. Implications for Practice: Healthcare professionals should cautiously consider the observed benefits of combining maternal voice stimulation with gravity feeding, recognizing the study's limitations. Further research is warranted to validate these findings and explore long-term implications for the care of low-birth-weight preterm infants.

Effect of Infusion Set Replacement Intervals on Central Line-Associated Bloodstream Infection in the Intensive Care Unit: Study Protocol of the INSPIRATION Study.

INTRODUCTION: The replacement intervals for infusion sets may differ among healthcare institutions, which may have an impact on the occurrence of central line-associated bloodstream infections (CLABSI). Nevertheless, there exists a limited amount of high-quality evidence available to assist clinicians in determining the most suitable replacement intervals for infusion sets. Therefore, the objective of this trial is to compare the efficacy of 24-h and 96-h replacement intervals for infusion sets on CLABSI among critically ill adults who have central venous access devices. METHODS: This is a multicenter, parallel-group randomized controlled trial that will investigate the effect of infusion set replacement intervals on CLABSI in adult patients admitted to intensive care units (ICUs). The study will enroll 1240 participants who meet the inclusion criteria, which includes being 18 years or older, expected to stay in the ICU for longer than 96 h, and in need of central venous access. Participants will be randomly assigned to either a control group receiving a 96-h replacement interval or a treatment group receiving a 24-h replacement interval. PLANNED OUTCOME: The primary outcome of this trial is the rate of CLABSI within 28 days after randomization. CONCLUSION: This is the first randomized controlled trial to investigate the effects of infusion set replacement at 24-h and 96-h intervals on CLABSI in ICU patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05359601.

Dapagliflozin Suppresses Isoprenaline-Induced Cardiac Hypertrophy Through Inhibition of Mitochondrial Fission.

ABSTRACT: Dapagliflozin (DAPA) is a novel oral hypoglycemic agent, and there is increasing evidence that DAPA has a protective effect against cardiovascular disease. The study aimed to investigate how DAPA inhibits cardiac hypertrophy and explore its potential mechanisms. By continuously infusing isoprenaline (ISO) for 2 weeks using a subcutaneous osmotic pump, a cardiac hypertrophic model was established in male C57BL/6 mice. On day 14 after surgery, echocardiography showed that left ventricle mass (LV mass), interventricular septum, left ventricle posterior wall diastole, and left ventricular posterior wall systole were significantly increased, and ejection fraction was decreased compared with control mice. Masson and Wheat Germ Agglutinin staining indicated enhanced myocardial fibrosis and cell morphology compared with control mice. Importantly, these effects were inhibited by DAPA treatment in ISO-induced mice. In H9c2 cells and neonatal rat cardiomyocytes, we found that mitochondrial fragmentation and mitochondrial oxidative stress were significantly augmented in the ISO-induced group. However, DAPA rescued the cardiac hypertrophy in ISO-induced H9c2 cells and neonatal rat cardiomyocytes. Mechanistically, we found that DAPA restored the PIM1 activity in ISO-induced H9c2 cells and subsequent increase in dynamin-associated protein 1 (Drp1) phosphorylation at S616 and decrease in Drp1 phosphorylation at S637 in ISO-induced cells. We found that DAPA mitigated ISO-induced cardiac hypertrophy by suppressing Drp1-mediated mitochondrial fission in a PIM1-dependent fashion.

Health-related quality of life assessment instruments for extracorporeal membrane oxygenation survivors: A scoping review.

BACKGROUND AND OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) has been successfully and widely used in adult patients for the past 5 years. About 50% of these patients can survive and are discharged from hospitals. Health-related quality of life (HRQOL) is crucial for evaluating survived ECMO patients. This scoping review aims to identify instruments commonly used to measure HRQOL of ECMO survivors and give pertinent instrument characteristics. METHODS: A systematic search was conducted in PubMed, Web of Science, EMBASE (OVID), MEDLINE (OVID), CINAHL (EBSCO), Cochrane Library, and three Chinese databases from January 2012 to December 2021. Two reviewers independently reviewed publication selection and data extraction. RESULTS: Twenty-nine studies met the inclusion criteria. Most studies (93%) were cross-sectional, and the median (or average) follow-up time ranged from 3 months to 9 years. Two prospective studies (7%) followed patients longitudinally until 1 year after discharge. ECMO survivors had poorer long-term HRQOL than the general population. However, it is comparable to or better than patients with other critical or chronic illnesses. Identified HRQOL assessment instruments show four generic HRQOL instruments, one disease-specific HRQOL instrument, and nineteen single-dimensional instruments. Seven instruments were used in more than three articles. SF-36 (86.2%), IES/IES-R (41.4%), and HADS (37.9%) were the most frequently used instruments. CONCLUSION: The timing, frequency, and tools for HRQOL assessment of ECMO survivors are variable. No ECMO-specific HRQOL instrument was developed and validated. Further studies on assessment instruments are warranted. Research is also needed to identify interventions that may enhance HRQOL in ECMO survivors.

The pre-Jurassic Meng-Shaan paleochannel and its control on the accumulation model of Yan 10 reservoir in Central Ordos Basin.

In the setting of the increasing density of exploration wells, and the decreasing scale and increasing difficulty of discovering Jurassic paleogeomorphology reservoirs, it is urgent to deepen the fine depiction of pre-Jurassic paleogeomorphology features and to analyze their controlling effect on reservoirs. Based on abundant logging data combined with indoor microscopic observation and experimental testing, the paper applies the theory of reservoir configuration analysis for the first time to the single-channel period division of the pre-Jurassic Meng-Shaan paleochannel which deposited with the braided channel sand bodies. Meanwhile, it reveals the controlling effect of hydrocarbon accumulation and the distribution characteristics of the Yan 101 reservoir as ' paleogeomorphology and sedimentary facies combination' to determine the type, 'migration channel' to determine the distributing range, and 'low-amplitude structure' to determine the trap in the study area, and also the reservoir accumulation modes in different channel ranges have established. In conclusion, the single-channel boundary of the Meng-Shaan paleochannel in different periods controls the path of oil and gas migration, thus controlling the distribution range and reservoir type of the Yan 10 reservoir. Moreover, depending on the production data we derived that it should prefer the composite trap reservoir of the Fuxian period and the Yan 102 period, as well as the structural reservoir on the periphery of the Yan 102 period single-channel for the further exploration of the Yan 10 paleogeomorphology reservoirs within the development range of the Meng-Shaan ancient river. In particular, the lithologic trap reservoirs within the Fuxian period channel and the Meng-Shaan main channel, such as the reservoirs of the 'Source' of the secondary channel type and the paleochannel type, which could as a replacement accumulation model for increasing reserves and production.

Characterising baseflow signature variability in the Yellow River Basin.

Baseflow is pivotal in maintaining catchment ecological health and improving sustainable economic development. The Yellow River Basin (YRB) is northern China's most important water supplier. However, it faces water shortage due to synergistic effects between natural conditions and anthropogenic activities. Investigating baseflow characteristics quantitively is, therefore, beneficial to promoting the sustainable development of the YRB. In this study, daily ensemble means baseflow data derived from four revised baseflow separation algorithms (i.e., the United Kingdom Institute of Hydrology (UKIH), Lyne-Hollick, Chapman-Maxwell, and Eckhardt methods) - was obtained from 2001 to 2020. Thirteen baseflow dynamics signatures were extracted to investigate baseflow spatiotemporal variations and their determinants across the YRB. The main findings were: (1) There were significant spatial distribution patterns of baseflow signatures, and most signatures had higher values in upstream and downstream reaches than in the middle reaches. There were also mixing patterns with higher values in middle and downstream reaches simultaneously. (2) The magnitude of temporal variation in baseflow signatures was most strongly correlated with catchment terrain (r = -0.4), vegetation growth (r > 0.3), and cropland coverage (r > 0.4). (3) There was a strong synergistic effect of multiple factors (e.g., soil textures, precipitation and vegetation conditions) on baseflow signature values. This study provided a heuristic evaluation of baseflow characteristics in the YRB, contributing to water resources management in the YRB and similar catchments.

Angiotensin-(1-9) prevents angiotensin II-induced endothelial apoptosis through CNPY2/PERK pathway.

Endothelial apoptosis caused by activation of renin-angiotensin system (RAS) plays a vital part in the occurrence and progress of hypertension. Angiotensin-(1-9) (Ang-(1-9)) is a peptide of the counter-regulatory non-classical RAS with anti-hypertensive effects in vascular endothelial cells (ECs). However, the mechanism of action remains unclear. Considering that the endothelial apoptosis was closely related to endoplasmic reticulum stress (ERS) and mitochondrial function. Herein, we aimed to elucidate the effects of Ang-(1-9) on endothelial apoptosis and the underlying molecular mechanism in angiotensin II (Ang II) induced hypertension. In human umbilical vascular endothelial cells (HUVECs), we observed Ang-(1-9) inhibited Ang II-induced ERS associated endothelial apoptosis. Mechanically, Ang-(1-9) inhibited endothelial apoptosis by blocking CNPY2/PERK mediated CaMKII/Drp1-dependent mitochondrial fission and eIF2α/CHOP signal. Consistent with above effects in HUVECs, in Ang II-induced hypertensive mice, we found administration of exogenous Ang-(1-9) attenuated endothelial apoptosis and arterial blood pressure, which were mediated by CNPY2/PERK signaling pathway. Our study indicated Ang-(1-9) inhibited Ang II-induced hypertension through CNPY2/PERK pathway. These findings may provide new insights for prevention and treatment of hypertension in future.

Construction of a synthetic methodology-based library and its application in identifying a GIT/PIX protein-protein interaction inhibitor.

In recent years, the flourishing of synthetic methodology studies has provided concise access to numerous molecules with new chemical space. These compounds form a large library with unique scaffolds, but their application in hit discovery is not systematically evaluated. In this work, we establish a synthetic methodology-based compound library (SMBL), integrated with compounds obtained from our synthetic researches, as well as their virtual derivatives in significantly larger scale. We screen the library and identify small-molecule inhibitors to interrupt the protein-protein interaction (PPI) of GIT1/ß-Pix complex, an unrevealed target involved in gastric cancer metastasis. The inhibitor 14-5-18 with a spiro[bicyclo[2.2.1]heptane-2,3'-indolin]-2'-one scaffold, considerably retards gastric cancer metastasis in vitro and in vivo. Since the PPI targets are considered undruggable as they are hard to target, the successful application illustrates the structural specificity of SMBL, demonstrating its potential to be utilized as compound source for more challenging targets.

Hydrogen Sulfide Diminishes Activation of Adventitial Fibroblasts Through the Inhibition of Mitochondrial Fission.

ABSTRACT: Activation of adventitial fibroblasts (AFs) on vascular injury contributes to vascular remodeling. Hydrogen sulfide (H2S), a gaseous signal molecule, modulates various cardiovascular functions. The aim of this study was to explore whether exogenous H2S ameliorates transforming growth factor-ß1 (TGF-ß1)-induced activation of AFs and, if so, to determine the underlying molecular mechanisms. Immunofluorescent staining and western blot were used to determine the expression of collagen I and α-smooth muscle actin. The proliferation and migration of AFs were performed by using cell counting Kit-8 and transwell assay, respectively. The mitochondrial morphology was assessed by using MitoTracker Red staining. The activation of signaling pathway was evaluated by western blot. The mitochondrial reactive oxygen species and mitochondrial membrane potential were determined by MitoSOX and JC-1 (5,5',6,6'-tetrachloro-1,1,3,3'-tetraethylbenzimidazolyl carbocyanine iodide) staining. Our study demonstrated exogenous H2S treatment dramatically suppressed TGF-ß1-induced AF proliferation, migration, and phenotypic transition by blockage of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and regulated mitochondrial reactive oxygen species generation. Moreover, exogenous H2S reversed TGF-ß1-induced mitochondrial fission and AF activation by modulating Rho-associated protein kinase 1-dependent phosphorylation of Drp1. In conclusion, our results suggested that exogenous H2S attenuates TGF-ß1-induced AF activation through suppression of Drp1-mediated mitochondrial fission in a Rho-associated protein kinase 1-dependent fashion.

Combining palladium and ammonium halide catalysts for Morita-Baylis-Hillman carbonates of methyl vinyl ketone: from 1,4-carbodipoles to ion pairs.

Here we report that Morita-Baylis-Hillman carbonates from diverse aldehydes and methyl vinyl ketones can be directly utilised as palladium-trimethylenemethane 1,4-carbodipole-type precursors, and both reactivity and enantioselectivity are finely regulated by adding a chiral ammonium halide as the ion-pair catalyst. The newly assembled intermediates, proposed to contain an electronically neutral π-allylpalladium halide complex and a reactive compact ion pair, efficiently undergo asymmetric [4 + 2] annulations with diverse activated alkenes or isatins, generally with high regio-, diastereo- and enantio-selectivity, and even switchable regiodivergent or diastereodivergent annulations can be well realised by tuning the substrate or catalyst assemblies. An array of control experiments, including UV/Vis absorption study and density functional theory calculations, are conducted to rationalise this new double activation mode combining a palladium complex and an ammonium halide as an ion-pair catalyst.

Leonurine-Repressed miR-18a-5p/SOCS5/JAK2/STAT3 Axis Activity Disrupts CML malignancy.

Leonurine, an active natural alkaloid compound isolated from Herba leonuri, has been reported to exhibit promising anticancer activity in solid tumors. The aim of this study was to explore whether leonurine is able to inhibit chronic myeloid leukemia (CML) malignancy. Here, we found that leonurine dose dependently inhibited the proliferation, migration, colony formation and promoted apoptosis of CML cells. Furthermore, leonurine markedly reduced CML xenograft growth in vivo. Mechanically, leonurine upregulated SOCS5 expression, thus leading JAK2/STAT3 signaling suppression. Silencing of SOCS5 by its siRNA abrogated the effect of leonurine on CML cells, demonstrating that SOCS5 mediates the anti-leukemia effect of leonurine. Notably, we observed that miR-18a-5p was remarkably increased in CML cells. Treating CML cells with leonurine significantly decreased miR-18a-5p expression. Moreover, we found miR-18a-5p repressed SOCS5 by directly targeting its 3'-UTR. miR-18a-5p downregulation induced by leonurine reduced the biological activity of CML cells by relieving miR-18a-5p repression of SOCS5 expression. Taken together, leonurine exerts significant anti-leukemia efficacy in CML by regulating miR-18a-5p/SOCS5/JAK2/STAT3 axis.

Discovery of sertraline and its derivatives able to combat drug-resistant gastric cancer cell via inducing apoptosis.

Resistance phenomena during chemotherapy of tumor has been severely hampering the applications of chemotherapeutics. Due to advantage of drug repurposing, discovery of new chemosensitizers based on approved drugs is an effect strategy to find new candidates. Herein, we found antidepressant drug - sertraline, could sensitize drug-resistant gastric cancer cell (SGC-7901/DDP) with the IC50 value of 18.73 µM. To understand the structure-activity relationship and improve the activity, 30 derivatives were synthesized and evaluated. The IC50 value of the best compound was improved to 5.2 µM. Moreover, we found apoptosis induction and cell cycle arrest was the reason for the cell death of the drug-resistant cells after treatment of sertraline and derivatives, and PI3K/Akt/mTOR pathway was involved.

How to rapidly convert general wards to ICUs during the COVID-19 epidemic: Experience from Wuhan, China.

BACKGROUND: Critically ill patients with coronavirus disease 2019 (COVID-19) were surging and far outnumbered existing beds. AIMS: To describe how to rapidly convert general wards to intensive care units for critically ill patients with COVID-19. MATERIALS AND METHODS: Comprehensive assessment and analysis of available resources and standard requirements. RESULTS: The ICUs were successfully assembled in 4 days. The conversion included environment reconstruction, configuration and management of equipment, information system construction and human resource allocation. A total of 172 critically ill patients had been admitted to the contemporary ICUs and none medical staff was infected. DISCUSSION: The epidemic situation of COVID-19 poses a great challenge to various management departments of the hospital, especially for critically ill patients with a high mortality rate. To save more critically ill patients, the conversion of a general ward to a quarantine ICU ward must be completed in a short time, and the optimal allocation of resources must be appropriate to ensure that the medical team works effectively and is of high quality. In face of the overloaded medical system, the ideal non-negative pressure ward is hard to achieve. However, we have demonstrated with evidence that our conversions are effective in both providing care to critical patients and protecting the safety of our staff. CONCLUSION: The conversion is successful and the running experience would be a reference for hospitals in other areas nationally or globally.

Diallyl Trisulfide Suppresses Angiotensin II-Induced Vascular Remodeling Via Inhibition of Mitochondrial Fission.

OBJECTIVE: We have shown previously that diallyl trisulfide (DATS) ameliorates mitochondrial fission and oxidative stress in a hyperglycemia-induced endothelial apoptosis and diabetic mouse model. The aim of this study was to investigate whether DATS mitigates Ang II-induced vascular smooth muscle cell (VSMC) phenotypic switching and vascular remodeling, and if so, to determine the underlying molecular events. METHODS: Male C57BL/6 mice were used to establish a vascular remodeling model by continuous 2-week Ang II infusion using a subcutaneous osmotic pump. Animals were intraperitoneally injected with DATS or vehicle. Physiological parameters, vascular morphology, and molecular markers were assessed. For in vitro studies, VSMCs were pretreated with or without DATS for 1 h, then were stimulated with Ang II, and mitochondrial morphology and phenotypic switching of VSMCs were also measured. RESULTS: In primary mouse VSMCs, we found that Drp1-dependent mitochondrial fission regulated mitochondrial reactive oxygen species (mtROS) generation, which eventually promoted Ang II-induced VSMC proliferation, migration, and phenotypic switching. Moreover, Ang II was found to up-regulate the Rho-associated coiled coil-containing protein kinase 1 (ROCK1), which regulated mitochondrial fission and VSMC phenotypic switching by phosphorylating Drp1. However, the biological effect of Ang II was abrogated by DATS. Consistent with the effects in VSMCs, we found that DATS markedly alleviated mitochondrial fission, VSMC differentiation, and vessel wall thickening in an animal model of Ang II-induced vascular remodeling, which was regulated by the ROCK1/Drp1 signal. CONCLUSIONS: Our findings showed that DATS mitigated Ang II-induced vascular remodeling by suppressing Drp1-mediated mitochondrial fission in an ROCK1-dependent manner.

Discovery of Novel Autophagy Inhibitors and Their Sensitization Abilities for Vincristine-Resistant Esophageal Cancer Cell Line Eca109/VCR.

Resistance phenomena, especially acquired drug resistance, have been severely hampering the application of chemotherapeutics during cancer chemotherapy. Autophagy plays a role in maintaining the survival of cancer cells and might mediate resistance to chemotherapy drugs. Herein, a new series of 5-amino-2-ether-benzamide derivatives were synthesized and evaluated as autophagy inhibitors. Selected from 14 synthesized compounds as lead autophagy inhibitor, N-(cyclohexylmethyl)-5-(((cyclohexylmethyl)amino)methyl)-2-((4-(trifluoromethyl)benzyl)oxy)benzamide (4 d) showed the most obvious effect of LC3B protein conversion. Further, its autophagy inhibition, evaluated by using transmission electron microscopy and confocal microscopy, showed that the fusion of autophagosomes and lysosomes in the final stage of autophagic flux was suppressed. We also found that 4 d could enhance the chemosensitivity of vincristine in vincristine-resistant esophageal cancer cell line Eca109/VCR in a synergistic, associative manner. Moreover, a computational study showed that 4 d might bind with p62-zz to inhibit autophagy. We also found 4 d to be relatively less cytotoxic to normal cells versus cancer cells than the reported p62-zz inhibitor.

Characterizing the Binding Sites for GK Domain of DLG1 and DLG4 via Molecular Dynamics Simulation.

Discs-large (DLG) is a member that belongs to the membrane-associated guanylate kinase (MAGUK) family. The GK domain of DLGs has evolved into a protein-protein interaction module that could bind with kinds of proteins to regulate diverse cellular functions. Previous reports have demonstrated the GK domain of DLGs functioned as a phosphor-peptide-binding module by resolving the crystal structures. Here we investigated into the interactions of DLG1 and DLG4 with their reported phosphor-peptides by molecular dynamics simulations. Post-dynamics analysis showed that DLG1/4 formed extensive interactions with phosphorylated ligands, including hydrophobic and hydrogen bonding interactions. Among them, the highly conserved residues among the DLGs in phosphor-site and ß5 sheet were crucial for the binding according to the energy decomposition calculations. Additionally, the binding interactions between DLG4 and reported unphosphorylated peptides including MAP1A and designed GK inhibitory (GKI-QSF) peptides were analyzed. We found the key residues that played important roles in DLG4/unphosphorylated peptide systems were very similar as in DLG4/phosphor-peptide systems. Moreover, the molecular dynamic simulation for the complex of DLG1 and GKI-QSF was carried out and predicted that the GKI-QSF could bind with DLG1 with similar Kd value compared to DLG4/GKI-QSF, which was verified by using ITC assay (Kd = 1.20 ± 0.29 µM). Our study might be helpful for the better understanding of the structural and biological function of DLGs GK domain and encourage the discovery of new binders.

Simvastatin alleviated diabetes mellitus-induced erectile dysfunction in rats by enhancing AMPK pathway-induced autophagy.

BACKGROUND: Diabetes mellitus-induced erectile dysfunction is a common diabetic complication, and new therapeutics and the pathogenesis of diabetes mellitus-induced erectile dysfunction need to be investigated. OBJECTIVES: The aim was to investigate the pathogenesis of diabetes mellitus-induced erectile dysfunction and the pharmacological mechanism of simvastatin treatment in diabetes mellitus-induced erectile dysfunction model rats. MATERIALS AND METHODS: A total of 86 male Sprague Dawley rats aged 8 weeks old were used in this study. The rats were divided into three groups: control (normal), diabetes mellitus-induced erectile dysfunction (streptozotocin-injected), and diabetes mellitus-induced erectile dysfunction + simvastatin (sim). Each group was subdivided into two subgroups for in vitro and in vivo analyses. A bioinformatics method was used to detect differences in gene expression in the corpus cavernosum between normal and diabetes mellitus-induced erectile dysfunction rats. Erectile function was measured by a cavernous nerve electrostimulation test. Corpus cavernosum fibrosis was assessed by Masson staining and Western blotting. Immunofluorescence and Western blotting were performed to explore the differential expression of autophagy-related genes and the AMPK-SKP2-CARM1 pathway genes in rat cavernous smooth muscle cells and the corpus cavernosum. The autophagosomes of the corpus cavernosum tissue were observed by transmission electron microscopy. RESULTS: Autophagy-related genes and pathways (the AMPK and FoxO pathway) were identified by bioinformatics analysis and confirmed at the protein level. Simvastatin, an AMPK agonist, was used to treat diabetes mellitus-induced erectile dysfunction rats for 8 weeks, demonstrating that erectile function was improved for 80.5% (P < .05) of rats. Corpus cavernosum fibrosis was alleviated (P < .05), and autophagy was further enhanced (P < .05); these results might be partially caused by AMPK-SKP2-CARM1 pathway activation (P < .05). DISCUSSION AND CONCLUSION: Simvastatin could enhance protective autophagy by activating the AMPK-SKP2-CARM1 pathway to improve erectile function in diabetes mellitus-induced erectile dysfunction rats.

Effects of blood glucose, blood lipids and blood pressure control on recovery of patients with gastric cancer complicated with metabolic syndrome after radical gastrectomy.

This study aimed to investigate the effects of blood glucose, blood lipids and blood pressure control on recovery of patients with gastric cancer complicated with metabolic syndrome (MS) after radical gastrectomy. A total of 150 patients with gastric cancer, who were treated in Daqing Longnan Hospital from November, 2015 to May, 2017, were enrolled in this study. The patients were divided into the MS group (80 cases) and non-MS group (70 cases). Patients in the MS group were given corresponding drugs to control blood pressure, blood lipids and blood glucose, while patients in the non-MS group were not treated with those drugs. Patients in the MS group were divided into the normal and abnormal groups according to the levels of blood glucose, blood lipids and blood pressure. Moreover, occurrences of complications were compared between the normal and abnormal groups. Before surgery, blood glucose, blood lipids and blood pressure in the MS group were significantly higher than those in the non-MS group (p<0.05). One month after operation, blood glucose, blood lipids and blood pressure of the MS group decreased significantly compared to those before operation (p<0.05). Incidence of complications at 1 and 3 months after operation was significantly lower in the normal groups than that in the corresponding abnormal groups (p<0.05). Postoperative recovery was significantly better in the normal groups than that in the corresponding abnormal groups (p<0.05). Logistic regression analysis showed that the incidence of postoperative complications was related to fasting blood glucose, 2 h postprandial blood glucose, glycosylated hemoglobin, total triglycerides (TGs), LDL, mean blood pressure and BMI (p<0.05). The results show that, control of blood glucose, blood lipids and blood pressure in patients with gastric cancer complicated with MS after radical gastrectomy can reduce the incidence of postoperative complications and promote postoperative recovery.