PIEZO1 mechanically regulates the antitumour cytotoxicity of T lymphocytes.

The killing function of cytotoxic T cells can be enhanced biochemically. Here we show that blocking the mechanical sensor PIEZO1 in T cells strengthens their traction forces and augments their cytotoxicity against tumour cells. By leveraging cytotoxic T cells collected from tumour models in mice and from patients with cancers, we show that PIEZO1 upregulates the transcriptional factor GRHL3, which in turn induces the expression of the E3 ubiquitin ligase RNF114. RNF114 binds to filamentous actin, causing its downregulation and rearrangement, which depresses traction forces in the T cells. In mice with tumours, the injection of cytotoxic T cells collected from the animals and treated with a PIEZO1 antagonist promoted their infiltration into the tumour and attenuated tumour growth. As an immunomechanical regulator, PIEZO1 could be targeted to enhance the outcomes of cancer immunotherapies.

Diagnose and treatment for Type D congenital esophageal atresia with tracheoesophageal fistula.

Importance: Type D esophageal atresia (EA) with tracheoesophageal fistula (TEF) is characterized by EA with both proximal and distal TEFs. It is a rare congenital anomaly with a very low incidence. Objective: To investigate diagnostic and treatment strategies for this rare condition. Methods: We retrospectively reviewed the clinicopathological features of patients with EA/TEF treated at our institution between January 2007 and September 2021. Results: Among 386 patients with EA/TEF, 14 (3.6%) had type D EA/TEF. Only two patients were diagnosed with proximal TEF preoperatively. Seven patients were diagnosed intraoperatively. Five patients were missed for diagnosis during the initial surgery but was later confirmed by bronchoscopy. During the neonatal period, seven patients underwent a one-stage repair of proximal and distal TEF via thoracoscopy or thoracotomy. Due to missed diagnosis and other reasons, the other 7 patients underwent two-stage surgery for repair of the proximal TEF, including cervical incision and thoracoscopy. Ten of the 14 patients experienced postoperative complications including anastomotic leakage, pneumothorax, esophageal stricture, and recurrence. Patients who underwent one-stage repair of distal and proximal TEF during the neonatal period showed a higher incidence of anastomotic leak (4/7). In contrast, only one of seven patients with two-stage repair of the proximal TEF developed an anastomotic leak. Interpretation: Type D EA/TEF is a rare condition, and proximal TEFs are easily missed. Bronchoscopy may aim to diagnose and determine the correct surgical approach. A cervical approach may be more suitable for repairing the proximal TEF.

Comparison of the analgesic effect of dezocine and esketamine in combination with sufentanil respectively after laparoscopic cholecystectomy: a prospective randomized controlled study.

BACKGROUND: Sufentanil in combination with dezocine or esketamine is often used for postoperative analgesia. However, there is a lack of clinical evidence of efficacy. This study compares the analgesic effects of esketamine and dezocine combined with sufentanil for relieving pain after laparoscopic cholecystectomy(LC). METHODS: A total of 58 patients were randomly assigned to the esketamine group (ES group) and dezocine group (DE group). In the ES group, 1.5 mg/kg esketamine was used. In the DE group, 0.3 mg/kg dezocine was used. Primary outcome measures were Visual Analog Scale (VAS) score at 4 h, 8 h, 24 h and 48 h after surgery. The second outcome measures were Interleukin-6 (IL-6) and C-reactive protein (CRP) levels in the serum 10 minutes before anesthesia induction, and at 24 h and 48 h after surgery. RESULTS: The VAS scores at 4 h, 8 h, 24 h and 48 h after the surgery in the ES group vs DE group were 2.70 vs 3.50(P=0.013),2.35 vs 3.15(P=0.004),1.69 vs 2.58(P=0.002), and 1.50 vs 2.26(P=0.002), respectively. The serum IL-6 concentrations 10 minutes before anesthesia induction, and at 24 h and 48 h after surgery in the ES group and DE group were 34.39 and 34.12(P=0.901),112.33 and 129.60(P=0.014), and 89.69 and 108.46(P<0.001), respectively. The CRP levels in serum 10 minutes before anesthesia induction, and at 24 h and 48 h after the surgery in the ES group and DE group were 5.99 and 5.86(P=0.639), 28.80 and 35.37(P<0.001), and 23.17 and 30.11(P<0.001), respectively. CONCLUSION: For postoperative pain after LC, 1.5mg/kg esketamine provided better analgesia and reduced inflammation levels than 0.3mg/kg dezocine. TRIAL REGISTRATION: This trial was registered in the China Clinical Research Information Center in 31/05/2023 : https://www.chictr.org.cn/bin/home (Registration number: ChiCTR2300072011).

Multiple sources of unconscious-information processing affect a single response: independent unconscious priming effects.

At present there is little knowledge on whether and how multiple pieces of unconscious information can simultaneously affect a single conscious response. In the present study, we manipulated the congruency relation between a masked prime arrow and the target arrow, as well as that between masked flankers and the target arrow. The results demonstrated that the masked prime and flankers produced independent unconscious priming effects on the response to the target. In the process of studying the above phenomenon, two secondary findings were made. First, although the prime congruency effect was obtained, the flanker congruency effect was smaller when the flankers were displayed simultaneously with the target than when they were displayed sequentially before the target. This suggested that priming stimulation required enough time to be processed to a sufficient extent to produce an unconscious priming effect. Second, when the prime stimulus was removed, leaving only the flankers, the flanker priming effect increased, suggesting that the attention attracted to the prime and its conscious mask could also reduce the flanker congruency effect. These results observed across several experiments were replicated in one within-subjects experiment. We proposed an "independent unconscious influence hypothesis" for the phenomenon. This hypothesis was further integrated into a more comprehensive unconscious information processing model. The possible causes of the observed phenomena were discussed.

Two-Dimensional Biodegradable Black Phosphorus Nanosheets Promote Large Full-Thickness Wound Healing through In Situ Regeneration Therapy.

Large full-thickness skin lesions have been one of the most challenging clinical problems in plastic surgery repair and reconstruction. To achieve in situ skin regeneration and perfect clinical outcomes, we must address two significant obstacles: angiogenesis deficiency and inflammatory dysfunction. Recently, black phosphorus has shown great promise in wound healing. However, few studies have explored the bio-effects of BP to promote in situ skin regeneration based on its nanoproperties. Here, to investigate whether black phosphorus nanosheets have positive bio-effects on in situ skin repair, we verified black phosphorus nanosheets' positive effects on angiogenic and anti-inflammatory abilities in vitro. Next, the in vivo evaluation performed on the rat large full-thickness excisional wound splinting model more comprehensively showed that the positive bio-effects of black phosphorus nanosheets are multilevel in wound healing, which can effectively enhance anti-inflammatory ability, angiogenesis, collagen deposition, and skin re-epithelialization. Then, multiomics analysis was performed to explore further the mechanism of black phosphorus nanosheets' regulation of endothelial cells in depth. Molecular mechanistically, black phosphorus nanosheets activated the JAK-STAT-OAS signaling pathway to promote cellular function and mitochondrial energy metabolism in endothelial cells. This study can provide a theoretical basis for applying two-dimensional black phosphorus nanosheets as nanomedicine to achieve in situ tissue regeneration in complex human pathological microenvironments, guiding the subsequent optimization of black phosphorus.

The role of circRNAs in regulation of drug resistance in ovarian cancer.

Ovarian cancer is one of the female reproductive system tumors. Chemotherapy is used for advanced ovarian cancer patients; however, drug resistance is a pivotal cause of chemotherapeutic failure. Hence, it is critical to explore the molecular mechanisms of drug resistance of ovarian cancer cells and to ameliorate chemoresistance. Noncoding RNAs (ncRNAs) have been identified to critically participate in drug sensitivity in a variety of human cancers, including ovarian cancer. Among ncRNAs, circRNAs sponge miRNAs and prevent miRNAs from regulation of their target mRNAs. CircRNAs can interact with DNA or proteins to modulate gene expression. In this review, we briefly describe the biological functions of circRNAs in the development and progression of ovarian cancer. Moreover, we discuss the underneath regulatory molecular mechanisms of circRNAs on governing drug resistance in ovarian cancer. Furthermore, we mention the novel strategies to overcome drug resistance via targeting circRNAs in ovarian cancer. Due to that circRNAs play a key role in modulation of drug resistance in ovarian cancer, targeting circRNAs could be a novel approach for attenuation of chemoresistance in ovarian cancer.

In-organoid single-cell CRISPR screening reveals determinants of hepatocyte differentiation and maturation.

BACKGROUND: Harnessing hepatocytes for basic research and regenerative medicine demands a complete understanding of the genetic determinants underlying hepatocyte differentiation and maturation. Single-cell CRISPR screens in organoids could link genetic perturbations with parallel transcriptomic readout in single cells, providing a powerful method to delineate roles of cell fate regulators. However, a big challenge for identifying key regulators during data analysis is the low expression levels of transcription factors (TFs), which are difficult to accurately estimate due to noise and dropouts in single-cell sequencing. Also, it is often the changes in TF activities in the transcriptional cascade rather than the expression levels of TFs that are relevant to the cell fate transition. RESULTS: Here, we develop Organoid-based Single-cell CRISPR screening Analyzed with Regulons (OSCAR), a framework using regulon activities as readouts to dissect gene knockout effects in organoids. In adult-stem-cell-derived liver organoids, we map transcriptomes in 80,576 cells upon 246 perturbations associated with transcriptional regulation of hepatocyte formation. Using OSCAR, we identify known and novel positive and negative regulators, among which Fos and Ubr5 are the top-ranked ones. Further single-gene loss-of-function assays demonstrate that Fos depletion in mouse and human liver organoids promote hepatocyte differentiation by specific upregulation of liver metabolic genes and pathways, and conditional knockout of Ubr5 in mouse liver delays hepatocyte maturation. CONCLUSIONS: Altogether, we provide a framework to explore lineage specifiers in a rapid and systematic manner, and identify hepatocyte determinators with potential clinical applications.

Efficacy and safety of Chinese patent medicine compound preparation combined with routine treatment in vitiligo: A Bayesian network meta-analysis.

BACKGROUND AND PURPOSE: Treating vitiligo in clinical practice is challenging. Furthermore, oral drugs used in Western medicine have considerable side effects and are unsuitable for long-term treatment. In contrast, Chinese patent medicines (CPMs) are more suitable for long-term oral vitiligo treatment, but medical evidence of their efficacy and safety is lacking. Therefore, in this study, the efficacy and safety of CPMs were evaluated and ranked using a Bayesian network meta-analysis. METHODS: Seven Chinese and English databases were searched for all relevant articles published up to February 2023. The Bayesian network meta-analysis method was used to analyze the extracted data to evaluate efficacy and safety. RESULTS: Six common CPMs for treating vitiligo were selected in our study, and 48 targeted articles and 4446 patients were included. This study showed that Qubai Babuqi tablets (QT) were the most effective for short-term treatment of vitiligo, and that vitiligo capsules or pills (VCP) were the most effective for long-term treatment, together with compound Quchong Banjiuju pills (QP). In terms of surface area under the cumulative ranking curve (SUCRA) values, the order of efficacy of each treatment was as follows: QT (92.18%) > Taohong Qingxue pills (TP) (63.81%) > VCP (55.53%) > QP (50.72%) > Bailing tablets or capsules (BTC) (49.01%) > Baishi pills (BP) (35.69%)>routine therapy (RT) (3.1%) in terms of total effective rate and QT (92.05%) > VCP (71.50%) > QP (66.60%) > TP (42.95%) > BTC (39.66%) > BP (36.60%)>RT (0.6%) in terms of improvement rate. In addition, the safety of the 6 CPMs did not significantly differ in terms of adverse effects. The SUCRA values indicated that QT performed slightly worse than other drugs. DISCUSSION: In treating vitiligo, QT is most effective but only suitable for short-term administration owing to its poor safety. VCP and QP could be used as first-choice long-term medications. TP may positively affect repigmentation in patients with limited lesion areas.

Kinome-wide CRISPR-Cas9 knockout screens revealed PLK1 as a therapeutic target for osteosarcoma.

Osteosarcoma is the most common malignant bone tumor, tending to be aggressive and recurrent. The therapeutic development for treating osteosarcoma has been largely hampered by the lack of effective and specific targets. Using kinome-wide CRISPR-Cas9 knockout screens, we systematically revealed a cohort of kinases essential for the survival and growth of human osteosarcoma cells, in which Polo-like kinase 1 (PLK1) appeared as a specific prominent hit. PLK1 knockout substantially inhibited proliferation of osteosarcoma cells in vitro and the tumor growth of osteosarcoma xenograft in vivo. Volasertib, a potent experimental PLK1 inhibitor, can effectively inhibit the growth of the osteosarcoma cell lines in vitro. It can also disrupt the development of tumors in the patient-derived xenograft (PDX) models in vivo. Furthermore, we confirmed that the mode of action (MoA) of volasertib is primarily mediated by the cell-cycle arrest and apoptosis triggered by DNA damage. As PLK1 inhibitors are entering phase III clinical trials, our findings provide important insights into the efficacy and MoA of the relevant therapeutic approach for combating osteosarcoma.

Research progress of colon-targeted oral hydrogel system based on natural polysaccharides.

The quality of life is significantly impacted by colon-related diseases. There have been a lot of interest in the oral colon-specific drug delivery system (OCDDS) as a potential carrier to decrease systemic side effects and protect drugs from degradation in the upper gastrointestinal tract (GIT). Hydrogels are effective oral colon-targeted drug delivery carriers due to their high biodegradability, substantial drug loading, and great biocompatibility. Natural polysaccharides give the hydrogel system unique structure and function to effectively respond to the complex environment of the GIT and deliver drugs to the colon. In this paper, the physiological factors of colonic drug delivery and the pathological characteristics of common colonic diseases are summarized, and the latest advances in the design, preparation and characterization of natural polysaccharide hydrogels are reviewed, which are expected to provide new references for colon-targeted oral hydrogel systems using natural polysaccharides as raw materials.

The Novel Circular RNA circTRIO Silence Inhibits the Progression of Laryngeal Squamous Cell Carcinoma.

Laryngeal squamous cell carcinoma (LSCC) is the most common and prevalent malignant tumor in head and neck squamous cell carcinoma. Recent studies have shown that circular RNAs (circRNAs) play a vital role in cancer development, but their specific role in the tumorigenesis and development of LSCC remains unclear. We selected five pairs of LSCC tumor tissues and paracancerous tissues for RNA sequencing. Reverse transcription-quantitative PCR (RT-qPCR), Sanger sequencing, and fluorescence in situ hybridization were utilized to study the expression, localization, and clinical significance of circTRIO in LSCC tissues, and TU212 and TU686 cell lines. Furthermore, cell counting Kit-8, colony-forming assay, Transwell, and flow cytometry assays were assessed to illustrate the crucial role played by the circTRIO in proliferation, colony-forming ability, migration, and apoptosis in LSCC cells. Finally, the molecule's role as a microRNA (miRNA) sponge was analyzed. In the results, we screened out a promising upregulated novel circRNA-circTRIO in LSCC tumor tissues compared with paracancerous tissues using RNA sequencing. Then, we used qPCR to evaluate the expression of circTRIO in 20 additional paired LSCC tissues and two cells, and the results showed that circTRIO was highly expressed in LSCC and that this high expression was closely related to the malignant progression of LSCC. Furthermore, we examined circTRIO expression in the Gene Expression Omnibus data sets GSE142083 and GSE27020, and circTRIO expression was considerably higher in tumor tissues compared with the adjacent tissues. Kaplan-Meier survival analysis showed that the expression of circTRIO was associated with worse disease-free survival. The Gene Set Enrichment Analysis biological pathway evaluation results demonstrated that circTRIO was mainly enriched in cancer pathways. Moreover, we confirmed that silencing circTRIOs can help to significantly inhibit LSCC cell proliferation and migration while triggering apoptosis. Upregulated circTRIO expression levels may play an important role in the tumorigenesis and development of LSCC.

Alteration of neurofilament heavy chain and its phosphoforms reveals early subcellular damage beyond the optic nerve head in glaucoma.

Background: Retinal ganglion cells (RGCs) axon loss at the site of optic nerve head (ONH) is long believed as the common pathology in glaucoma since different types of glaucoma possessing different characteristic of intraocular pressure, and this damage was only detected at the later stage. Methods: To address these disputes and detect early initiating events underlying RGCs, we firstly detected somatic or axonal change and compared their difference in acute and chronic phase of primary angle-closed glaucoma (PACG) patient using optical coherence tomography (OCT), then an axonal-enriched cytoskeletal protein neurofilament heavy chain and its phosphoforms (NF-H, pNF-H) were utilized to reveal spatio-temporal undetectable damage insulted by acute and chronic ocular hypertension (AOH, COH) in two well characterized glaucoma mice models. Results: In clinic, we detected nonhomogeneous changes such as ONH and soma of RGCs presenting edema in acute phase but atrophy in chronic one by OCT. In AOH animal models, an increase expression of NF-H especially its phosphorylation modification was observed as early as 4 h before RGCs loss, which presented as somatic accumulation in the peripheral retina and at the sites of ONH. In contrast, in microbeads induced COH model, NF-H and pNF-H reduced significantly, these changes firstly occurred as NF-H or pNF-H disconnection at ONH and optic nerve after 2 weeks when the intraocular pressure reaching the peak; Meanwhile, we detected aqueous humor pNF-H elevation after AOH and slight reduction in the COH. Conclusion: Together, our data supports that early alteration of NF-H and its phosphoforms would reveal undetectable subcellular damage consisting of peripheral somatic neurofilament compaction, impaired axonal transport and distal axonal disorganization of cytoskeleton beyond the ONH, and identifies two distinct axonal degeneration which were Wallerian combination with retrograde degeneration in acute PACG and retrograde degeneration in the chronic one.

Risk factors for difficult mask ventilation and difficult intubation among patients undergoing pharyngeal and laryngeal surgery.

Background: The prediction of difficult mask ventilation (DMV) and difficult intubation (DI) are key questions in anesthesia fields. DMV or DI related to pharyngeal and laryngeal diseases are a special kind of difficult airways. However, there is a lack of risk factors for prediction. Methods: This study retrospectively collected data from patients who were admitted to the Eye & ENT Hospital of Fudan University from May 2014 to May 2018 and underwent laryngopharyngeal surgery under general anesthesia. Results: A total of 126 patients were included. Twenty patients suffered from DMV. Preoperative laryngeal obstruction classification (OR = 7.46, 95% CI: 2.56-21.76, P < 0.001) and airway patency after sevoflurane inhalation (OR = 10.96, 95% CI: 2.70-44.43, p = 0.001) were independently associated with DMV. Seventy-six patients could be intubated at the first attempt. Preoperative laryngeal obstruction grade (OR = 0.28, 95% CI: 0.13-0.62, P = 0.002), neoplasm size (OR = 0.43, 95% CI: 0.22-0.82, P = 0.011), and airway patency after sevoflurane inhalation (OR = 0.14, 95% CI: 0.05-0.36, P < 0.001) were independently associated with first-attempt successful intubation. Conclusion: Among patients with pharyngeal and laryngeal diseases, the degree of laryngeal obstruction before the operation and the degree of airway obstruction after inhaling sevoflurane are the risk factors of DMV. The degree of laryngeal obstruction before the operation, airway obstruction after inhaling sevoflurane, and the neoplasm size are the risk factors of DI.

The association between retinal microvasculature derived from optical coherence tomography angiography and systemic factors in type 2 diabetics.

Aims: To investigate the correlation between the retinal microvasculature using optical coherence tomography angiography (OCTA) and systemic factors in type 2 diabetes mellitus (T2DM) patients. Methods: This cross-sectional study obtained OCTA data from patients with T2DM administered at hospital and referred to ophthalmic services. Patient data about demographics, comorbid conditions, and blood biomarkers were extracted from electronic medical records. Data from OCTA scans obtained by CIRRUS HD-OCT Model 5,000 were obtained. Vessel density (VD) and perfusion density (PD) within the superficial capillary plexus, and foveal avascular zone (FAZ) area were automatically segmented. These parameters were tested for their correlations with systemic factors by univariate and multivariable linear regression analyses. Results: A total of 144 T2DM patients (236 eyes) were available for analysis, with mean age of 53.6 (SD = 10.34) and 56.9% were male. Chronic kidney disease, cardiovascular disease, increased serum creatinine (Scr), red blood cell count (RBC), platelets (PLT), apolipoprotein B (APOB), and decreased urine albumin to creatinine ratio (UACR) were significantly associated with lower VD and PD (all p < 0.013). UACR and triglyceride (TRIG) were significantly correlated with FAZ area (all p < 0.017). In multivariate analyses, PLT, eGFR, and APOB were independent risk factors for retinal rarefaction, and UACR was a significant predictor of FAZ area. Conclusion: We found several systemic risk factors, such as PLT, renal function and lipid profiles were associated with PD, VD, and FAZ area among Chinese T2DM patients.

Functional characterization and development of novel human kinase insert domain receptor chimeric antigen receptor T-cells for immunotherapy of non-small cell lung cancer.

CAR-T cell therapy, in which T cells are transfected or transduced with a chimeric antigen receptor (CAR), is a transformative type of cancer immunotherapy. Despite outstanding success in hematological malignancies, their efficacy against solid tumors has been limited. Here, we aimed to explore whether T cells modified by a CAR targeting the vascular endothelial growth factor 2 receptor/ kinase insert domain receptor (KDR) could destroy tumors and their vasculature. A second-generation KDR-CAR was constructed and transfected into T cells using lentivirus. The 3D structure of the CAR construct and target antigen was predicted. Moreover, in silico analysis, including molecular docking and molecular dynamics (MD) simulation, were used to evaluate the minimum energy of interaction and stability of the complex. The anti-cancer effect of KDR-specific CAR-T cells was tested with KDR-expressing and KDR overexpressing A549 cell line. The in-silico study suggested that this CAR construct could be effective for lung cancer therapy. We evaluated this using both in vitro and in vivo experiments. The KDR-CAR-T cells targeted and killed KDR-A549 with high efficiency by expressing IFN-γ and releasing granzyme B. The in vivo study showed that KDR-CAR-T cells dramatically inhibited the growth of lung cancer KDR-A549 xenografts in BALB/c-nu mice at day 10. The characterization of T cells modified by KDR-CAR by computational biology and wet-lab experiments suggested its applicability as a new treatment strategy for lung cancer and, potentially, for other vascularized solid tumors.

Preliminary exploration of the efficacy of laparoscopic fluorescence cholangiography (LFC) in the diagnosis of biliary atresia compared with intraoperative cholangiography (IOC).

BACKGROUND: Intraoperative cholangiography (IOC) has been the gold standard for diagnosing biliary atresia (BA). Our study attempted to diagnose BA using laparoscopic fluorescein cholangiography (LFC). METHODS: We retrospectively included 18 patients with preoperative suspected BA as the case group and 4 without extrahepatic biliary obstruction requiring laparoscopic surgery as the control group. All patients received indocyanine green (ICG) intravenously at 0.05 mg/Kg. The first 6 patients in the case group underwent IOC and LFC simultaneously, and the control group completed LFC. The imaging characteristics of LFC were recorded and summarized by the conventional and fluorescence mode of the endoscopic fluorescence imaging system (DPM-ENDOCAM-03). On this basis, 12 patients in the case group were diagnosed as BA according to LFC without IOC, and all 18 patients completed open Kasai surgery to confirm the diagnosis. RESULTS: Laparoscopic fluorescence mode in BA detected liver fluorescence but no visualization of the extrahepatic bile ducts. However, the extrahepatic bile ducts in the control group were visible. Based on the imaging characteristics summarized from the LFC of the first 6 cases with BA in the case group, the remaining 12 cases who only underwent LFC were also successfully diagnosed with BA. Furthermore, the formation of hepatic hilar fibrous mass was found in all the patients during the open Kasai procedure, which confirmed the BA diagnosis. CONCLUSIONS: LFC appears as a specific pattern in BA and may be used for intraoperative diagnosis of BA. It has the advantages of simplicity, short time-consuming, and no radiation damage.

linc00174 deteriorates the pathogenesis of diabetic retinopathy via miR-26a-5p/PTEN/Akt signalling cascade-mediated pyroptosis.

PURPOSE: We aim to investigate the potential role and underlying mechanisms of linc00174 on pyroptosis in the pathogenesis of DR. METHODS: Expression patterns of linc00174, miR-26a-5p and PTEN in human retinal microvascular endothelial cells (hRMECs) were detected by quantitative real-time PCR (qRT-PCR) and Western blot, respectively. Biological functions of linc00174 on cell proliferation and pyroptosis were evaluated by CCK-8, flow cytometry, caspase-1 activity assays, respectively. Luciferase reporter assay was employed to verify the interaction between miR-26a-5p and linc00174/PTEN. Streptozotocin (STZ)-induced DR in mice was further constructed to verify the potential role of linc00174 in vivo. Hematoxylin and eosin (H&E) and immunohistochemical staining were performed to assess the pathological changes and caspase-1 expression in retinal tissues. RESULTS: Up-regulated linc00174 and PTEN and down-regulated miR-26a-5p were uncovered in hRMECs treated with high glucose (HG). Mechanistically, linc00174 served as a sponge of miR-26a-5p to facilitate PTEN expression. Functionally, knockdown of linc00174 inhibited HG-induced pyroptosis of hRMECs via targeting miR-26a-5p. Moreover, linc00174/miR-26a-5p axis participated in HG-induced pyroptosis via PTEN/Akt signaling cascade. Further, silencing of linc00174 attenuated pyroptosis via regulating miR-26a-5p/PETN axis in DR mice. CONCLUSIONS: Collectively, our study reveals that linc10074 deteriorates the pathogenesis of DR via miR-26a-5p/PTEN/Akt signalling cascade, which may shed light on the discovery of potential therapeutic agents for DR treatment.

Pretreatment with Low-Dose Esketamine for Reduction of Propofol Injection Pain: A Randomized Controlled Trial.

Background: Propofol-induced injection pain is a common adverse effect during the induction of general anesthesia. The purpose of this study is to investigate the effect of low-dose esketamine in preventing propofol injection pain. Methods: In this double-blind, randomized, controlled trial, patients scheduled for elective ear surgery under general anesthesia received either normal saline (NS), or 40 mg lidocaine, or 0.15 mg/kg esketamine 30 seconds before manual injection of propofol. The primary outcome of this study was the incidence of propofol injection pain. The secondary outcomes included injection pain score, vital signs, total dosage of vasoactive drugs used within 5 minutes after induction, and adverse events related to drugs. Results: A total of 105 patients were included. Compared with the NS group (67%), pretreatment with esketamine and lidocaine significantly reduced the incidence of injection pain to 29% and 33%, respectively (both P < 0.05); however, no significant difference was found between the esketamine and lidocaine groups. The median of injection pain score was significantly lower in the esketamine and lidocaine groups (both median (interquartile range) = 0 (0-1)) than that in the NS group (1 (0-2); P < 0.05). In addition, compared with the NS and lidocaine groups, preinjection esketamine provided more stable hemodynamic parameters within 5 minutes after induction (P < 0.05). No statistical difference was found in adverse events among the three groups. Conclusions: Pretreatment with a low-dose esketamine can not only reduce the incidence of propofol injection pain but also provide a more stable circulation in patients after anesthesia induction. This convenient, well-tolerated, and economic treatment appears as an option to be routinely applied in clinic practice. Clinical Trial Registration. This trial is registered with https://www.chictr.org.cn/showproj.aspx?proj=136690 (the number for the trial registration isChiCTR2100052742).