Tea polyphenol nanoparticles enable targeted siRNA delivery and multi-bioactive therapy for abdominal aortic aneurysms.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease, while there is a lack of pharmaceutical interventions to halt AAA progression presently. To address the multifaceted pathology of AAA, this work develops a novel multifunctional gene delivery system to simultaneously deliver two siRNAs targeting MMP-2 and MMP-9. The system (TPNs-siRNA), formed through the oxidative polymerization and self-assembly of epigallocatechin gallate (EGCG), efficiently encapsulates siRNAs during self-assembly. TPNs-siRNA safeguards siRNAs from biological degradation, facilitates intracellular siRNA transfection, promotes lysosomal escape, and releases siRNAs to silence MMP-2 and MMP-9. Additionally, TPNs, serving as a multi-bioactive material, mitigates oxidative stress and inflammation, fosters M1-to-M2 repolarization of macrophages, and inhibits cell calcification and apoptosis. In experiments with AAA mice, TPNs-siRNA accumulated and persisted in aneurysmal tissue after intravenous delivery, demonstrating that TPNs-siRNA can be significantly distributed in macrophages and VSMCs relevant to AAA pathogenesis. Leveraging the carrier's intrinsic multi-bioactive properties, the targeted siRNA delivery by TPNs exhibits a synergistic effect for enhanced AAA therapy. Furthermore, TPNs-siRNA is gradually metabolized and excreted from the body, resulting in excellent biocompatibility. Consequently, TPNs emerges as a promising multi-bioactive nanotherapy and a targeted delivery nanocarrier for effective AAA therapy.

Preoperative N-terminal Pro-B-type Natriuretic Peptide and High-sensitivity Cardiac Troponin T and Outcomes after Major Noncardiac Surgery: A Prospective Cohort Study.

BACKGROUND: Patients undergoing noncardiac surgery have varying risk of cardiovascular complications. This study evaluated preoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T to enhance cardiovascular events prediction for major noncardiac surgery. METHODS: This prospective cohort study included adult patients with cardiovascular disease or risk factors undergoing elective major noncardiac surgery at four hospitals in China. Blood samples were collected within 30 days before surgery for NT-proBNP and high-sensitivity troponin T (hs-TnT) measurements. The primary outcome was a composite of any cardiovascular events within 30 days after surgery. Logistic regression models were used to assess associations, and the predictive performance was evaluated primarily using area under the receiver operating characteristics curve (AUC) and fraction of new predictive information. RESULTS: Between June 2019 and September 2021, a total of 2,833 patients were included, with 435 (15.4%) experiencing the primary outcome. In the logistic regression model that included clinical variables and both biomarkers, the odds ratio for the primary outcome was 1.68 (95% CI, 1.37 to 2.07) when comparing the 75th percentile to the 25th percentile of NT-proBNP distribution, and 1.91 (95% CI, 1.50 to 2.43) for hs-TnT. Each biomarker enhanced model discrimination beyond clinical predictors, with a change in AUC of 0.028 for NT-proBNP and 0.029 for high-sensitivity cardiac troponin T, and a fraction of new information of 0.164 and 0.149, respectively. The model combining both biomarkers demonstrated the best discrimination, with a change in AUC of 0.042 and a fraction of new information of 0.219. CONCLUSIONS: Preoperative NT-proBNP and hs-TnT both improved the prediction for cardiovascular events after noncardiac surgery in addition to clinical evaluation, with their combination providing maximal predictive information.

Microarray Profiling and Co-Expression Network Analysis of LncRNAs and mRNAs in Acute Respiratory Distress Syndrome Mouse Model.

BACKGROUND: Long noncoding RNAs (LncRNAs) play critical roles in many respiratory diseases. Acute respiratory distress syndrome (ARDS) is a destructive clinical syndrome of respiratory diseases. However, the potential mechanism of LncRNAs on ARDS remains largely unknown. METHODS: To identify the profiles of LncRNAs and mRNAs in the LPS-induced ARDS mouse model, the microarray analyses were hired to detect the expression of LncRNAs and mRNAs in present study. Subsequently, microarray data were verified by quantitative qRT-PCR. Functional annotation on DE mRNAs and LncRNAs were carried out by bioinformatics analysis. Furthermore, the role of selected DE LncRNAs on correlated genes was confirmed by si-RNA and Western blot. RESULTS: The expression of 2110 LncRNAs and 2690 mRNAs were significantly changed, which were further confirmed by qRT-PCR. GO and KEGG analysis indicated that the up-regulated mRNAs were mainly related to a defense response and tumor necrosis factor (TNF) signaling pathway, respectively. LncRNA-mRNA co-expression analyses showed that LncRNAs NR_003508, ENSMUST00000131638, ENSMUST00000119467, and ENSMUST00000124853 may correlate to MLKL, RIPK3, RIPK1, Caspase1, and NLRP3, respectively, or cooperatively, which were highly involved in the cell necroptosis process. Furthermore, siRNA for NR_003508 confirmed the co-expression analyses results. CONCLUSION: To summarize, this study implied that the DE LncRNAs could be potent regulators and target genes of ARDS and will provide a novel insight into the regulation of the pathogenesis of ARDS.

Effect of anaesthetic depth on primary postoperative ileus after laparoscopic colorectal surgery: protocol for and preliminary data from a prospective, randomised, controlled trial.

INTRODUCTION: Primary postoperative ileus is one of the principal factors affecting in-hospital recovery after colorectal surgery. Research on the relationship between anaesthetic depth and perioperative outcomes has been attracting growing attention. However, the impact of anaesthetic depth on the recovery of gastrointestinal function after surgery is unclear. We aimed to conduct a single-centre, prospective, randomised, controlled trial to explore the effect of anaesthetic depth on primary postoperative ileus after laparoscopic colorectal surgery. METHODS AND ANALYSIS: In this single-centre, prospective, patient-blinded and assessor-blinded, parallel, randomised, controlled trial, a total of 854 American Society of Anesthesiologists physical status I-III patients, aged between 18 and 65 years and scheduled for laparoscopic colorectal surgery lasting ≥2 hours, will be randomly assigned to deep anaesthesia group (Bispectral Index (BIS) 30-40) or light anaesthesia group (BIS 45-55). The primary outcome is primary postoperative ileus during the hospital stay. Secondary outcomes were time to gastrointestinal function recovery, another defined postoperative ileus, 15-item quality of recovery score, length of postoperative stay, postoperative 30-day complications and serum concentrations of intestinal fatty acid-binding protein at 6 hours after surgery. ETHICS AND DISSEMINATION: The protocol was approved by Medical Ethics Committee of Nanfang Hospital, Southern Medical University (Approval number: NFEC-2018-107) prior to recruitment. All participants will provide written informed consent before randomisation. Findings of the trial will be disseminated through peer-reviewed journals and scientific conferences. TRIAL REGISTRATION NUMBER: ChiCTR1800018725.

Synthesis of nanocapsules blended polymeric hydrogel loaded with bupivacaine drug delivery system for local anesthetics and pain management.

Local anesthetics are used clinically for the control of postoperative pain management. This study aimed to develop chitosan (CS) with genipin (GP) hydrogels as the hydrophilic lipid shell loaded poly(ε-caprolactone) (PC) nanocapsules as the hydrophobic polymeric core composites (CS-GP/PC) to deliver bupivacaine (BPV) for the prolongation of anesthesia and pain relief. The swelling ratio, in vitro degradation, and rheological properties enhancement of CS-GP/PC polymeric hydrogel. The incorporation of PC nanocapsules into CS-GP hydrogels was confirmed by SEM, FTIR, and XRD analysis. Scanning electron microscopy results demonstrated that the CS-GP hydrogels and CS-GP/PC polymeric hydrogels have a porous structure, the pore dimensions being non-uniform with diameters between 25 and 300 µm. The in vitro drug release profile of CS-GP/PC polymeric hydrogel has been achieved 99.2 ± 1.12% of BPV drug release in 36 h. Cellular viability was evaluated using the CCK-8 test on 3T3 fibroblast cells revealed that the obtained CS-GP/PC polymeric hydrogel with BPV exhibited no obvious cytotoxicity. The CS-GP/PC polymeric hydrogel loaded with BPV showed significant improvement in pain response compared to the control group animals for at least 7 days. When compared with BPV solution, CS-GP hydrogel and CS-GP/PC polymeric hydrogel improved the skin permeation of BPV 3-fold and 5-fold in 24 h, respectively. In vitro and in vivo results pointed out PC nanocapsules loaded CS-GP hydrogel can act as effective drug carriers, thus prolonging and enhancing the anesthetic effect of BPV. Histopathological results demonstrated the excellent biodegradability and biocompatibility of the BPV-loaded CS-GP/PC polymeric hydrogel system on 7, 14, and 21 days without neurotoxicity.HIGHLIGHTSPreparation and characterization of CS-GP/PC polymeric hydrogel system.BPV-loaded CS-GP/PC exhibited prolonged in vitro release in PBS solution.Cytotoxicity of BPV-loaded CS-GP/PC polymeric hydrogel against fibroblast (3T3) cells.Development of CS-GP/PC a promising skin drug-delivery system for local anesthetic BPV.

Pre-operative N-terminal pro-B-type natriuretic peptide for prediction of acute kidney injury after noncardiac surgery: A retrospective cohort study.

BACKGROUND: Acute kidney injury (AKI) is associated with poor outcomes after noncardiac surgery. Whether pre-operative N-terminal pro-B-type natriuretic peptide (NT-proBNP) predicts AKI after noncardiac surgery is unclear. OBJECTIVE: To investigate the predictive role of pre-operative NT-proBNP on postoperative AKI. DESIGN: Retrospective cohort study. SETTING: Nanfang Hospital, Southern Medical University, China. PATIENTS: Adult patients who had a serum creatinine and NT-proBNP measurement within 30 pre-operative days and at least one serum creatinine measurement within 7 days after noncardiac surgery between February 2008 and May 2018 were identified. MAIN OUTCOME MEASURES: The primary outcome was postoperative AKI, defined by the kidney disease: improving global outcomes creatinine criteria. RESULTS: In all, 6.1% (444 of 7248) of patients developed AKI within 1 week after surgery. Pre-operative NT-proBNP was an independent predictor of AKI after adjustment for clinical variables (OR comparing top to bottom quintiles 2.29, 95% CI, 1.47 to 3.65, P < 0.001 for trend; OR per 1-unit increment in natural log transformed NT-proBNP 1.27, 95% CI, 1.16 to 1.39). Compared with clinical variables alone, the addition of NT-proBNP improved model fit, modestly improved the discrimination (change in area under the curve from 0.764 to 0.773, P = 0.005) and reclassification (continuous net reclassification improvement 0.210, 95% CI, 0.111 to 0.308, improved integrated discrimination 0.0044, 95% CI, 0.0016 to 0.0072) of AKI and non-AKI cases, and achieved higher net benefit in decision curve analysis. CONCLUSIONS: Pre-operative NT-proBNP concentrations provided predictive information for AKI in a cohort of patients undergoing noncardiac surgery, independent of and incremental to conventional risk factors. Prospective studies are required to confirm this finding and examine its clinical impact. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900024056. www.chictr.org.cn/showproj.aspx?proj=40385.

Incidence and risk factors of postoperative ileus after hysterectomy for benign indications.

PURPOSE: Postoperative ileus (POI) after abdominal surgery is associated with prolonged hospital stay and increased costs. The aim of this study is to investigate the incidence of, risk factors for, and outcomes associated with POI in patients undergoing hysterectomy for benign indications. METHODS: A retrospective review of 1017 consecutive patients undergoing benign hysterectomy over the period 2012-2017 in a single center was performed. POI was predefined as absence of flatus and defecation for more than 2 days with the presence of one or more of the following symptoms: nausea, vomiting, and abdominal distention. The association between perioperative variables and the risk of POI was evaluated by univariate analysis. Independent risk factors were identified by multivariate logistic regression analysis. RESULTS: Overall incidence of POI was 9.2%. Incidence of POI did not differ significantly among three different surgical approaches (abdominal hysterectomy, 10.6%; laparoscopic hysterectomy, 7.8%; vaginal hysterectomy, 11.3%; P = 0.279). Independent risk factors of POI identified by multivariate analysis included anesthesia technique (odds ratio [OR] 2.662, 95% interval [CI] 1.533-4.622, P = 0.001), adhesiolysis (odds ratio [OR] 1.818, 95% interval [CI] 1.533-4.622, P = 0.011), duration of operation (odds ratio [OR] 1.005, 95% interval [CI] 0.942-6.190, P = 0.029), previous cancer (odds ratio [OR] 4.789, 95% interval [CI] 1.232-18.626, P = 0.024), and dysmenorrhea (odds ratio [OR] 1.859, 95% interval [CI] 1.182-2.925, P = 0.007). CONCLUSION: POI is a common complication after hysterectomy. This study identified risk factors of POI specifically for gynecologic patients. Patients exposed to these factors should be monitored closely for the development POI.

Magnesium sulfate attenuates lipopolysaccharides-induced acute lung injury in mice.

Acute lung injury (ALI) is a common and severe respiratory disease with high morbidity and mortality. Although some progress has been made in the past years, the pathogenesis of ALI is still poorly understood and the therapeutic outcome has still not been significantly improved. It is well-recognized that magnesium sulfate (MgSO4) possesses potent anti-inflammation capacity. The present study was designed to investigate the protective effects of MgSO4 in lipopolysaccharides (LPSs)-induced ALI taken into account that excessive inflammatory response plays critical role in the development of ALI. In this study, Kunming mice were intravenously injected with LPS through tail vein to establish the ALI model and in parallel, A549 cells were used to establish cell model. The lung wet-to-dry weight ratio, malondialdehyde (MDA) levels in lung tissue, lung permeability index, hematoxylin and eosin staining, cytokines in the serum and bronchoalveolar lavage fluid (BALF), neutrophil counts in BALF, LPS-induced A549 cell apoptosis as well as apoptosis-inducing factor (AIF), and Poly(ADP-ribose) polymerase-1 (PARP-1) expression in both mice and A549 cells were detected. Our results demonstrated that MgSO4 significantly attenuated the LPS-induced ALI, oxidative stress (decreased MDA levels), and lung inflammatory response. Moreover, MgSO4 exerted protective effects by mitigating LPS-induced A549 cell apoptosis. Furthermore, MgSO4 decreased the AIF and PARP-1 expression both in vivo and in vitro. Our results, taken together, demonstrated that MgSO4 is a potential therapeutic agent for ALI taken into consideration that MgSO4 is commonly used in clinical settings.

[Corrigendum] Knockdown of lncRNA HNF1A-AS1 inhibits oncogenic phenotypes in colorectal carcinoma.

Following the publication of the article, the authors noted an error associated with the presentation of Fig. 3B. This Figure part showed the cell cycle analysis as determined by flow cytometry of HT29 cells transfected with either a HNF1A-AS1-specific siRNA or a negative control siRNA at 48 h post-transfection. An error was made in the compilation of this Figure, and the same data were inadvertently selected to represent the cell cycle analysis of both the HT29-SI and the HT29-NC cells (i.e., the data relating to the HT29-NC cells were included in the Figure twice). A corrected version of Fig. 3 is shown on the next page. Note that this correction affects neither the interpretation of the data nor the reported conclusions of this work. The authors all agree to this Corrigendum, and regret that this error went unnoticed during the proofs correction stage. They also wish to thank the Editor for allowing them the opportunity to publish this Corrigendum, and regret any inconvenience this error has caused. [the original article was published in Molecular Medicine Reports 16: 4694-4700, 2017; DOI: 10.3892/mmr.2017.7175].

Knockdown of lncRNA HNF1A-AS1 inhibits oncogenic phenotypes in colorectal carcinoma.

Long non-coding RNAs (lncRNAs) have been demonstrated to serve important roles in the development and progression of cancer. Recently HNF1A antisense RNA 1 (HNF1A­AS1), a lncRNA, has been reported as exhibiting a potential oncogenic role in the development of many types of cancer. However, the expression and the role of HNF1A­AS1 in colorectal carcinoma (CRC) remains unclear. In the present study, the role of HNF1A­AS1 in CRC was examined for the first time and its correlation with CRC cell biological behaviors was analyzed. The results demonstrated that HNF1A­AS1 was distinctly upregulated in CRC tissues and associated with CRC metastasis to the lymph nodes. Reverse transcription­quantitative polymerase chain reaction revealed that HNF1A­AS1 was also upregulated in CRC cell lines and localized in the nucleus. In addition, knockdown of HNF1A­AS1 expression notably inhibited CRC cell proliferation, migration, invasion and colony formation, and suppressed S­phase entry in vitro. Taken together, these results suggested that HNF1A­AS1 might serve as a promising prognostic marker for CRC tumorigenesis and progression.

TFP5 peptide, derived from CDK5-activating cofactor p35, provides neuroprotection in early-stage of adult ischemic stroke.

Cyclin-dependent kinase 5 (CDK5) is a multifaceted protein shown to play important roles in the central nervous system. Abundant evidence indicates that CDK5 hyperactivities associated with neuronal apoptosis and death following ischemic stroke. CDK5 activity increases when its cofactor p35 cleaves into p25 during ischemia. Theoretically, inhibition of CDK5/p25 activity or reduction of p25 would be neuroprotective. TFP5, a modified 24-aa peptide (Lys254-Ala277) derived from p35, was found to effectively inhibit CDK5 hyperactivity and improve the outcomes of Alzheimer's disease and Parkinson's disease in vivo. Here, we showed that intraperitoneal injection of TFP5 significantly decreased the size of ischemia in early-stage of adult ischemic stroke rats. Relative to controls, rats treated with TFP5 displayed reduced excitotoxicity, neuroinflammation, apoptosis, astrocytes damage, and blood-brain barrier disruption. Our findings suggested that TFP5 might serve as a potential therapeutic candidate for acute adult ischemic stroke.

TFP5 is comparable to mild hypothermia in improving neurological outcomes in early-stage ischemic stroke of adult rats.

AIM: We compared the efficacy of a modified truncated 24-aa peptide (TFP5), derived from the cyclin-dependent kinase 5 (CDK5)-activating cofactor p35, with mild hypothermia (MH), and determined whether the efficacy of TFP5 is affected by MH. METHODS: Ischemic stroke was induced in adult male Sprague-Dawley rats for 2h. Immediately after initiating reperfusion, TFP5, MH, or the combination of the two were administrated. 48h after reperfusion, neurological outcomes were evaluated. RESULTS: Rats that received either MH, TFP5, or the combined treatment showed smaller brain infarct size than normothermia control (NT), and there was no apparent difference among these three treatment groups. The neurological deficit was significantly improved only by the combined treatment. MH or TFP5 ameliorated the blood-brain barrier (BBB) disruption in ischemic regions with similar efficacy, whereas the combination of them had a trend toward better effect. Besides, the cleavage of p35 into p25 and apoptosis in ischemic regions was inhibited by TFP5 or the combination, but not by MH alone. CONCLUSIONS: TFP5 is comparable to MH in improving neurological outcomes in early-stage adult ischemic stroke. When TFP5 is given along with MH, less neurological deficit tends to be achieved.