Fe(III)/peroxymonosulfate oxidation system for the degradation of rhein, a toxic component abundance in rhubarb residue.

Rhubarb is widely used in health care, but causing a great amount of rhein-containing herbal residue. Rhein with several toxicities might pollute environment, damage ecology and even hazard human health if left untreated. In this study, the degradation effects of bisulfite- (BS) and peroxymonosulfate- (PMS) based oxidation systems on rhein in rhubarb residue were compared and investigated. The effects of BS and PMS with two valence states of ferric ion (Fe) on the degradation of rhein in rhubarb residue were optimized for the selection of optimal oxidation system. The influences of reaction temperature, reaction time and initial pH on the removal of rhein under the optimal oxidation system were evaluated. The chemical profiles of rhubarb residue with and without oxidation process were compared by UPLC-QTOF-MS/MS, and the degradation effects were investigated by PLS-DA and S plot/OPLS-DA analysis. The results manifested that PMS showed relative higher efficiency than BS on the degradation of rhein. Moreover, Fe(III) promoted the degradation effect of PMS, demonstrated that Fe(III)/PMS is the optimal oxidation system to degrade rhein in rhubarb residue. Further studies indicated that the degradation of rhein by the Fe(III)/PMS oxidation system was accelerated with the prolong of reaction time and the elevation of reaction temperature, and also affected by the initial pH. More importantly, Fe(III)/PMS oxidation system could degrade rhein in rhubarb residue completely under the optimal conditions. In conclusion, Fe(III)/PMS oxidation system is a feasible method to treat rhein in rhubarb residue.

Effects of dexmedetomidine as an adjuvant to ropivacaine or ropivacaine alone on duration of postoperative analgesia: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Ropivacaine is a long-acting local anesthetic that is used to treat postoperative pain. Adjuvant use of dexmedetomidine in regional anesthesia may prolong the duration of analgesia. The objective of this systematic review and meta-analysis was to investigate the duration and effect of ropivacaine alone vs. ropivacaine in combination with dexmedetomidine for postoperative analgesia. METHODS: The PubMed, EMBASE, Web of Science, and Google Scholar databases were searched for randomized controlled trials (RCTs) of ropivacaine alone or ropivacaine in combination with dexmedetomidine for regional anesthesia. The primary outcome was duration of analgesia, defined as the time from onset of the block to the time of the first analgesic request or initial pain report. Secondary outcomes were duration of sensory block, duration of motor block, consumption of sufentanil for analgesia, length of hospital stay, and incidence of postoperative nausea and vomiting. RESULTS: Eighteen studies with 1148 patients were included. Overall quality of the RCTs, as assessed by the Jadad scale, was high. The meta-analysis demonstrated that ropivacaine combined with dexmedetomidine significantly prolonged the duration of postoperative analgesia from local anesthetics compared to ropivacaine alone (WMD: 4.14h; 95%CI: 3.29~5.0h; P<0.00001; I2 = 99%). There was evidence of high heterogeneity between studies. The duration of sensory and motor block was significantly increased, and consumption of sufentanil for analgesia and the incidence of postoperative nausea and vomiting were significantly reduced in patients who received ropivacaine combined with dexmedetomidine compared to ropivacaine alone. There was no significant difference in length of hospital stay. CONCLUSIONS: Compared to ropivacaine alone, ropivacaine combined with dexmedetomidine significantly prolonged the duration of postoperative analgesia and sensory and motor block, and reduced consumption of sufentanil for analgesia and the incidence of postoperative nausea and vomiting, across an array of surgeries.

Being a morning man has causal effects on the cerebral cortex: a Mendelian randomization study.

Introduction: Numerous studies have suggested a connection between circadian rhythm and neurological disorders with cognitive and consciousness impairments in humans, yet little evidence stands for a causal relationship between circadian rhythm and the brain cortex. Methods: The top 10,000 morningness-related single-nucleotide polymorphisms of the Genome-wide association study (GWAS) summary statistics were used to filter the instrumental variables. GWAS summary statistics from the ENIGMA Consortium were used to assess the causal relationship between morningness and variates like cortical thickness (TH) or surficial area (SA) on the brain cortex. The inverse-variance weighted (IVW) and weighted median (WM) were used as the major estimates whereas MR-Egger, MR Pleiotropy RESidual Sum and Outlier, leave-one-out analysis, and funnel-plot were used for heterogeneity and pleiotropy detecting. Results: Regionally, morningness decreased SA of the rostral middle frontal gyrus with genomic control (IVW: ß = -24.916 mm, 95% CI: -47.342 mm to -2.490 mm, p = 0.029. WM: ß = -33.208 mm, 95% CI: -61.933 mm to -4.483 mm, p = 0.023. MR Egger: ß < 0) and without genomic control (IVW: ß = -24.581 mm, 95% CI: -47.552 mm to -1.609 mm, p = 0.036. WM: ß = -32.310 mm, 95% CI: -60.717 mm to -3.902 mm, p = 0.026. MR Egger: ß < 0) on a nominal significance, with no heterogeneity or no outliers. Conclusions and implications: Circadian rhythm causally affects the rostral middle frontal gyrus; this sheds new light on the potential use of MRI in disease diagnosis, revealing the significance of circadian rhythm on the progression of disease, and might also suggest a fresh therapeutic approach for disorders related to the rostral middle frontal gyrus-related.

Delirium in older patients given propofol or sevoflurane anaesthesia for major cancer surgery: a multicentre randomised trial.

BACKGROUND: Delirium is a common and disturbing postoperative complication that might be ameliorated by propofol-based anaesthesia. We therefore tested the primary hypothesis that there is less delirium after propofol-based than after sevoflurane-based anaesthesia within 7 days of major cancer surgery. METHODS: This multicentre randomised trial was conducted in 14 tertiary care hospitals in China. Patients aged 65-90 yr undergoing major cancer surgery were randomised to either propofol-based anaesthesia or to sevoflurane-based anaesthesia. The primary endpoint was the incidence of delirium within 7 postoperative days. RESULTS: A total of 1228 subjects were enrolled and randomised, with 1195 subjects included in the modified intention-to-treat analysis (mean age 71 yr; 422 [35%] women); one subject died before delirium assessment. Delirium occurred in 8.4% (50/597) of subjects given propofol-based anaesthesia vs 12.4% (74/597) of subjects given sevoflurane-based anaesthesia (relative risk 0.68 [95% confidence interval {CI}: 0.48-0.95]; P=0.023; adjusted relative risk 0.59 [95% CI: 0.39-0.90]; P=0.014). Delirium reduction mainly occurred on the first day after surgery, with a prevalence of 5.4% (32/597) with propofol anaesthesia vs 10.7% (64/597) with sevoflurane anaesthesia (relative risk 0.50 [95% CI: 0.33-0.75]; P=0.001). Secondary endpoints, including ICU admission, postoperative duration of hospitalisation, major complications within 30 days, cognitive function at 30 days and 3 yr, and safety outcomes, did not differ significantly between groups. CONCLUSIONS: Delirium was a third less common after propofol than sevoflurane anaesthesia in older patients having major cancer surgery. Clinicians might therefore reasonably select propofol-based anaesthesia in patients at high risk of postoperative delirium. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-IPR-15006209) and ClinicalTrials.gov (NCT02662257).

Long-term survival in older patients given propofol or sevoflurane anaesthesia for major cancer surgery: follow-up of a multicentre randomised trial.

BACKGROUND: Experimental evidence indicates that i.v. anaesthesia might reduce cancer recurrence compared with volatile anaesthesia, but clinical information is observational only. We therefore tested the primary hypothesis that propofol-based anaesthesia improves survival over 3 or more years after potentially curative major cancer surgery. METHODS: This was a long-term follow-up of a multicentre randomised trial in 14 tertiary hospitals in China. We enrolled 1228 patients aged 65-90 yr who were scheduled for major cancer surgery. They were randomised to either propofol-based i.v. anaesthesia or to sevoflurane-based inhalational anaesthesia. The primary endpoint was overall survival after surgery. Secondary endpoints included recurrence-free and event-free survival. RESULTS: Amongst subjects randomised, 1195 (mean age 72 yr; 773 [65%] male) were included in the modified intention-to-treat analysis. At the end of follow-up (median 43 months), there were 188 deaths amongst 598 patients (31%) assigned to propofol-based anaesthesia compared with 175 deaths amongst 597 patients (29%) assigned to sevoflurane-based anaesthesia; adjusted hazard ratio 1.02; 95% confidence interval (CI): 0.83-1.26; P=0.834. Recurrence-free survival was 223/598 (37%) in patients given propofol anaesthesia vs 206/597 (35%) given sevoflurane anaesthesia; adjusted hazard ratio 1.07; 95% CI: 0.89-1.30; P=0.465. Event-free survival was 294/598 (49%) in patients given propofol anaesthesia vs 274/597 (46%) given sevoflurane anaesthesia; adjusted hazard ratio 1.09; 95% CI 0.93 to 1.29; P=0.298. CONCLUSIONS: Long-term survival after major cancer surgery was similar with i.v. and volatile anaesthesia. Propofol-based iv. anaesthesia should not be used for cancer surgery with the expectation that it will improve overall or cancer-specific survival. CLINICAL TRIAL REGISTRATIONS: ChiCTR-IPR-15006209; NCT02660411.

Ferrostatin-1 alleviates ventilator-induced lung injury by inhibiting ferroptosis.

Ventilator-induced lung injury (VILI) has become an increasingly common complication in the clinic concerning mechanical ventilation. Previous research showed that VILI is the result of a response to cascade inflammation; however, the inflammatory mechanism involved remains unclear. As a newly recognized form of cell death, ferroptosis can release damage-related molecules (DAMPs) to trigger and amplify the inflammatory response and is involved in several inflammatory diseases. The present study aimed to investigate a previously unrecognized role of ferroptosis in VILI. A mouse model of VILI and a model of cyclic stretching (CS)-induced lung epithelial cell injury were established. Mice and cells were pretreated with ferrostain-1, an inhibitor of ferroptosis. Lung tissue and cells were then harvested to determine lung injury, inflammatory responses, indicators and protein expression associated with ferroptosis. Compared to the control group, mice subjected to high tidal volumes (HTV) for 4 h showed more severe pulmonary edema and inflammation and the activation of ferroptosis. Ferrostain-1 significantly ameliorated histological injury and inflammation in the VILI mouse and alleviated CS-induced lung epithelial cell injury. Mechanistically, ferrostain-1 markedly limited the activation of ferroptosis and recovered functionality of the SLC7A11/GPX4 axis both in vitro and in vivo, thus demonstrating its potential as a novel therapeutic target for VILI.

Primer exchange reaction-amplified protein-nucleic acid interactions for ultrasensitive and specific microRNA detection.

Protein-nucleic acid interactions are not only fundamental to genetic regulation and cellular metabolism, but molecular basis to artificial biosensors. However, such interactions are generally weak and dynamic, making their specific and sensitive quantitative detection challenging. By using primer exchange reaction (PER)-amplified protein-nucleic acid interactions, we here design a universal and ultrasensitive electrochemical sensor to quantify microRNAs (miRNAs) in blood. This PER-miR sensor leverages specific recognition between S9.6 antibodies and miRNA/DNA hybrids to couple with PER-derived multi-enzyme catalysis for ultrasensitive miRNA detection. Surface binding kinetic analysis shows a rational Kd (8.9 nM) between the miRNA/DNA heteroduplex and electrode-attached S9.6 antibody. Based on such a favorable affinity, the programmable PER amplification enables the sensor to detect target miRNAs with sensitivity up to 90.5 aM, three orders of magnitude higher than that without PER in routine design, and with specificity of single-base resolution. Furthermore, the PER-miR sensor allows detecting multiple miRNAs in parallel, measuring target miRNA in lysates across four types of cell lines, and differentiating tumor patients from healthy individuals by directly analyzing the human blood samples (n = 40). These advantages make the sensor a promising tool to enable quantitative sensing of biomolecular interactions and precision diagnostics.

Transforming growth factor-ß1 attenuates inflammation and lung injury with regulating immune function in ventilator-induced lung injury mice.

Ventilator-induced lung injury (VILI) is a lung injury induced or aggravated by mechanical ventilation. Transforming growth factor (TGF)-ß1 is a cytokine that mediates immune function, enabling inflammatory attenuation and tissue repair. Here, we hypothesized that it plays an important role in the attenuation of VILI and inflammation. Ventilation with high tidal volume was performed on C57BL/6 mice to establish a VILI model. After 4 h of ventilation, mice were sacrificed (end of ventilation [EOV]) or extubated for resuscitation at 4 h (post-ventilation 4 h [PV4h]), 8 h (PV8h) and 24 h post-ventilation (PV1d). Recombinant mouse TGF-ß1 (rTGF-ß1) and the neutralization antibody of TGF-ß1 (nTAb) were used in vivo to examine the effect of TGF-ß1 on immune function and inflammatory attenuation in VILI mice. Lung injury was exacerbated at the same trend as the interleukin (IL)-1ß level, peaking at PV1d, whereas IL-6 and tumor necrosis factor (TNF)-α levels gradually reduced. Most active phagosomes, swollen round mitochondria, and cavitating lamellar bodies were observed at PV4h. The CD4+ T cells were significantly increased from PV4h to PV1d, and the CD8a + T cells were higher in the PV4h and PV1d groups; furthermore, the mice in the PV8h group showed highest proportion of CD4+CD8a+ T cells and CD4+/CD8a+ ratio. CD19 + and CD5 + CD19 + B cells in VILI mice began to increase at PV1d. The pulmonary expression of latent and monomer TGF-ß1 increased at PV4h and PV8h. Treatment of rTGF-ß1 only induced high expression of latent and monomer TGF-ß1 at EOV to decrease pulmonary levels of IL-1ß, IL-6, and TNF-α; however, lung injury attenuated from EOV to PV1d. TGF-ß1 induced the delayed elevation of CD4+/CD8a+ T cells ratio and activation of pulmonary CD4+CD8a+ double-positive T cells under certain conditions. Elastic fibers and celluloses, although relatively less proteoglycan, were observed with the overexpression of TGF-ß1 at PV4h and PV8h. In conclusion, TGF-ß1 attenuates the inflammatory response and lung injury of VILI via immune function regulation.

A resorufin-based fluorescence probe for visualizing biogenic amines in cells and zebrafish.

Biogenic amines (BAs) are a family of nitrogen-bearing natural organic molecules with at least one primary amine, which play an important role in living organisms. Elevated concentration of BAs may cause neuron disorder, Parkinson's disease and many other diseases. Therefore, it is essential to monitor BAs in living organisms. Herein, we reported a resorufin-based fluorescence probe for sensing of various BAs. Upon nucleophilic substitution reaction with BAs, the probe released resorufin, affording to strong fluorescence emission at 592 nm with rapid response (<8 min), good selectivity and a low detection limit (LOD = 0.47 µM). The probe has low cytotoxicity and good membrane permeability, and has been successfully used to visualize BAs in living cells and zebrafish with good performance.

LncRNA NALT1 promotes colorectal cancer progression via targeting PEG10 by sponging microRNA-574-5p.

Colorectal cancer (CRC) is currently one of the commonest tumors and the main reason for cancer-related deaths worldwide. It has been reported that long non-coding RNAs (lncRNAs) act as important indicators and regulators in various cancers. There is an urgent need to explore new lncRNA biomarkers in CRC, as well as their functions and molecular mechanisms. NALT1 has been implicated in the occurrence of gastric cancer (GC). However, the detailed function and mechanism of NALT1 in CRC progress have not been reported. In this study, RT-qPCR was conducted to detect the expression of NALT1 in 76 CRC patients ranging from stages I through IV. To assess the biological function of NALT1, loss- and gain-of-function experiments were conducted both in vivo and in vitro. Moreover, RNA-seq, bioinformatics analysis, RNA pulldown assay, dual-luciferase reporter, Ago2-RIP, quantitative PCR, Western blot assays, and rescue experiments were performed to reveal the molecular mechanisms of competitive endogenous RNAs (ceRNAs). It was observed that high expression of NALT1 was markedly correlated with advanced cancer stage in the clinic. Functionally, NALT1 downregulation inhibited cell proliferation, migration and invasion, whereas NALT1 overexpression exhibited an opposite trend both in vivo and in vitro. Bioinformatics analysis, RNA pulldown, Ago2-RIP, and luciferase reporter assays showed that miRNA-574-5p was a target of NALT1. Additionally, dual-luciferase reporter assays, Ago2-RIP, and rescue experiments indicated that miRNA-574-5p could target the PEG10 gene directly. Our results suggested that NALT1 promoted CRC proliferation and migration by sponging miRNA-574-5p to upregulate PEG10 expression, and implied that NALT1 might act as a promising biomarker and therapeutic target for CRC.

Identification of hub genes associated with acute kidney injury induced by renal ischemia-reperfusion injury in mice.

Background: Acute kidney injury (AKI) is a severe clinical syndrome, and ischemia-reperfusion injury is an important cause of acute kidney injury. The aim of the present study was to investigate the related genes and pathways in the mouse model of acute kidney injury induced by ischemia-reperfusion injury (IRI-AKI). Method: Two public datasets (GSE39548 and GSE131288) originating from the NCBI Gene Expression Omnibus (GEO) database were analyzed using the R software limma package, and differentially expressed genes (DEGs) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genomes (KEGG) and gene set enrichment analysis (GSEA) were performed using the differentially expressed genes. Furthermore, a protein-protein interaction (PPI) network was constructed to investigate hub genes, and transcription factor (TF)-hub gene and miRNA-hub gene networks were constructed. Drugs and molecular compounds that could interact with hub genes were predicted using the DGIdb. Result: A total of 323 common differentially expressed genes were identified in the renal ischemia-reperfusion injury group compared with the control group. Among these, 260 differentially expressed genes were upregulated and 66 differentially expressed genes were downregulated. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes analysis results showed that these common differentially expressed genes were enriched in positive regulation of cytokine production, muscle tissue development, and other biological processes, indicating that they were involved in mitogen-activated protein kinase (MAPK), PI3K-Akt, TNF, apoptosis, and Epstein-Barr virus infection signaling pathways. Protein-protein interaction analysis showed 10 hub genes, namely, Jun, Stat3, MYC, Cdkn1a, Hif1a, FOS, Atf3, Mdm2, Egr1, and Ddit3. Using the STRUST database, starBase database, and DGIdb database, it was predicted that 34 transcription factors, 161 mi-RNAs, and 299 drugs or molecular compounds might interact with hub genes. Conclusion: Our findings may provide novel potential biomarkers and insights into the pathogenesis of ischemia-reperfusion injury-acute kidney injury through a comprehensive analysis of Gene Expression Omnibus data, which may provide a reliable basis for early diagnosis and treatment of ischemia-reperfusion injury-acute kidney injury.

Propofol produces neurotoxicity by inducing mitochondrial apoptosis.

Propofol is a fast and short-acting intravenous anesthetic widely used in clinical anesthesia and intensive care unit sedation. However, its use can cause abnormal effects on the central nervous system. Thus, the purpose of this study was to investigate the mechanism of propofol on primary hippocampal neuron injury. In addition, we aimed to determine whether a correlation exists between propofol and mitochondrial apoptosis-induced neurotoxicity. Hippocampal neurons cultured for 4 days were exposed to different drugs. The treatment groups were divided according to drug exposure into propofol, a rotenone inhibitor, and a coenzyme Q10 agonist groups. The final concentrations of propofol were 1, 10 and 100 µM. The content of ATP and reactive oxygen species (ROS) in the neurons of each group were detected using commercial kits in the culture supernatant after 3 h of drug exposure. Western blotting was used to analyze the expression of apoptosis-related proteins. The JC-1 kit was used to detect the mitochondrial membrane potential. The results revealed that, compared with the non-propofol treatment groups, the expression of apoptosis-related proteins, ATP content, and mitochondrial membrane potential were significantly decreased while the ROS content was markedly increased in the propofol treatment group. In conclusion, propofol treatment promoted damage to hippocampal neuronal mitochondria in a dose-dependent manner. This damage may lead to neuronal apoptosis and neurotoxicity by inducing the inhibition of mitochondrial respiratory chain complex I.

microRNA-130b-3p delivery by mesenchymal stem cells-derived exosomes confers protection on acute lung injury.

OBJECTIVE: Researchers have investigated miR-130b-3p in lung disease pathology, such as lung fibrosis. The present study was performed to elucidate the miR-130b-3p-involved mechanism in acute lung injury (ALI) through delivery by mesenchymal stem cells-derived exosomes (MSCs-Exo). METHODS: ALI mouse models were induced via intratracheal administration of lipopolysaccharide (LPS) and treated with MSCs-Exo. Lung dry-wet (W/D) ratio, inflammatory factors in the bronchoalveolar lavage fluid, pathological damage and apoptosis in the lung tissues were analyzed. Expression levels of miR-130b-3p and TGFBR1 were measured in the mouse lung tissues, and the interaction between miR-130b-3p and TGFBR1 was studied. RESULTS: MSCs-Exo relieved LPS-induced ALI in mice by reducing lung W/D ratio and inflammatory response, and attenuating lung tissue pathological damage and reducing the alveolar cell apoptosis. miR-130b-3p delivery by MSCs-Exo reduced LPS-induced ALI in mice. TGFBR1 was determined to be a downstream target gene of miR-130b-3p. Inhibition of TGFBR1 could remit LPS-induced ALI in mice. The protection mediated by MSCs-Exo carrying miR-130b-3p could be rescued by elevating TGFBR1 expression. CONCLUSION: miR-130b-3p delivery by MSCs-Exo confers protection on ALI in mice via the downregulation of TGFBR1.

Necrostatin-1 attenuates Caspase-1-dependent pyroptosis induced by the RIPK1/ZBP1 pathway in ventilator-induced lung injury.

BACKGROUND: Ventilator-induced lung injury (VILI) is a complex pathophysiological process leading to acute respiratory distress syndrome (ARDS) and poor outcomes in affected patients. As a form of programmed cell death, pyroptosis is proposed to play an important role in the development of ARDS. Here we investigated whether treating mice with the specific RIPK1 inhibitor Necrostatin-1 (Nec-1) before mechanical ventilation could inhibit pyroptosis and alleviate lung injury in a mouse model. METHODOLOGYS: Anesthetized C57BL/6J mice received a transtracheal injection of Nec-1 (5 mg/kg) or vehicle (DMSO) 30 min before the experiment which was ventilated for up to 4 h. Lung damage was assessed macroscopically and histologically with oedema measured as the wet/dry ratio of lung tissues. The release of inflammatory mediators into bronchoalveolar lavage fluid (BALF) was assessed by ELISA measurements of TNF-α,interleukin-1ß (IL-1ß), and IL-6. The expression of RIPK1, ZBP1, caspase-1, and activated (cleaved) caspase-1 were analyzed using western blot and immunohistochemistry, and the levels of gasdermin-D (GSDMD) and IL-1ß were analyzed by immunofluorescence staining. RESULTS: High tidal ventilation produced time-dependent inflammation and lung injury in mice which could be significantly reduced by pretreatment with Nec-1. Notably, Nec-1 reduced the expression of key pyroptosis mediator proteins in lung tissues exposed to mechanical ventilation, including caspase-1, cleaved caspase-1, and GSDMD together with inhibiting the release of inflammatory cytokines. CONCLUSION: Nec-1 pretreatment alleviates pulmonary inflammatory responses and protects the lung from mechanical ventilation damage. The beneficial effects were mediated at least in part by inhibiting caspase-1-dependent pyroptosis through the RIPK1/ZBP1 pathway.

Arecoline promotes proliferation and migration of human HepG2 cells through activation of the PI3K/AKT/mTOR pathway.

BACKGROUND: Arecoline is a well-known risk factor for oral submucosal fibrosis and cancer. However, the mechanistic correlation between arecoline and hepatocellular cancer remains elusive. Here, we investigated the effect of arecoline on the proliferation and migration of human HepG2 hepatoma cells and its potential oncogenic mechanisms. METHODS: Bioinformatic technologies were used to identify the deferentially expressed miRNAs (DE-miRNAs) and hub target genes of arecoline-induced cancers. These DE-miRNAs, hub genes and pathway were proved in arecoline-treated HepG2 cells. RESULTS: A total of 86 DE-miRNAs and 460 target genes were identified. These target genes are associated with DNA-templated regulation of transcription and other biological processes. Significant molecular functions were protein binding, calcium ion binding, and enrichment in the nucleus and cytoplasm. These genes are involved in the PI3K-AKT pathway. CDK1, CCND1, RAF1, CDKN1B and BTRC were defined as the top 5 hub target genes, and patients with high expression of CDK1 showed poor prognosis. Compared with control group, 2.5 µM arecoline treatment increased the proliferation and migration ability of the HepG2 cells. Treatment with 2.5 µM arecoline increased the levels of miR-21-3p, miR-21-5p and miR-1267, upregulated the expression of PI3K-AKT pathway factors, CDK1, CCND1 but decreased RAF1 expression. CONCLUSION: A low concentration arecoline can induce the proliferation and migration of HepG2 cells, with the potential mechanism of action linked to high levels of exosomal miR-21 and miR-1267, activation of the PI3K-AKT pathway, upregulation of CDK1 and CCND1, and downregulation of RAF1.

[Vitamin D analogues activate vitamin D receptor/glutathione peroxidase 4 pathway to improve ventilator-induced lung injury in mice].

OBJECTIVE: To investigate the role of vitamin D analogue paricalcitol in activating vitamin D receptor/glutathione peroxidase 4 (VDR/GPX4) pathway in ventilator-induced lung injury (VILI). METHODS: Twenty-four male C57BL/6J mice were randomly divided into control group, high tidal volume (HVT) induced VILI model group (HVT group), paricalcitol control group (P group), and paricalcitol pretreatment group (P+HVT group), with 6 mice in each group. The mice were endotracheal intubated and ventilated at 40 mL/kg tidal volume to prepare VILI model, while those in the control group were intubated without ventilation. The mice in the P+HVT group were intraperitoneally injected with paricalcitol 0.2 µg/kg once a day 1 week before modeling, while those in the P group were intraperitoneally injected paricalcitol 0.2 µg/kg once a day for 1 week before the experiment. After ventilation for 4 hours, the mice were sacrificed for lung tissue collection. Lung injury was evaluated by wet/dry (W/D) ratio, hematoxylin-eosin (HE) staining and Masson staining. The expressions of VDR and GPX4 were determined by Western blotting and immunohistochemistry. Malondialdehyde (MDA) and glutathione (GSH) contents were determined by micro method. RESULTS: After HVT for 4 hours, compared with the control group, lung injury score and W/D ratio were significantly higher (lung injury score: 0.430±0.035 vs. 0.097±0.025, lung W/D ratio: 4.860±0.337 vs. 3.653±0.332, both P < 0.05), collagen fiber deposition was significantly increased, the content of MDA in lung tissue was significantly increased (nmol/g: 212.420±8.757 vs. 97.073±5.308, P < 0.05), GSH content and the protein expressions and immunoreactive score (IRS) of VDR and GPX4 were significantly decreased [GSH (µg/g): 44.229±1.690 vs. 70.840±0.781; VDR protein (VDR/GAPDH): 0.518±0.029 vs. 0.762±0.081, GPX4 protein (GPX4/GAPDH): 0.452±0.032 vs. 0.649±0.034; IRS score: VDR was 4.168±0.408 vs. 10.167±0.408, GPX4 was 4.333±1.033 vs. 10.333±0.516; all P < 0.05], which meant that the mice in HVT group showed obvious lung injury. After VDR was activated by paricalcitol, compared with the HVT group, lung injury score and W/D ratio were significantly decreased (lung injury score: 0.220±0.036 vs. 0.430±0.035, lung W/D ratio: 4.015±0.074 vs. 4.860±0.337, both P < 0.05), collagen fiber deposition was reduced, MDA content in lung tissue was decreased (nmol/g: 123.840±8.082 vs. 212.420±8.757, P < 0.05), GSH content and the protein expressions and IRS score of VDR and GPX4 were significantly up-regulated [GSH (µg/g): 63.094±0.992 vs. 44.229±1.690; VDR protein (VDR/GAPDH): 0.713±0.056 vs. 0.518±0.029, GPX4 protein (GPX4/GAPDH): 0.605±0.008 vs. 0.452±0.032; IRS score: VDR was 9.000±0.632 vs. 4.168±0.408, GPX4 was 8.833±0.408 vs. 4.333±1.033; all P < 0.05], which meant that lung injury in P+HVT group was significantly improved. CONCLUSION: Vitamin D analogue paricalcitol ameliorates pulmonary oxidation-reduction imbalance by activating the VDR/GPX4 pathway, thereby alleviating VILI.

Association between perinatal pain and postpartum depression: A systematic review and meta-analysis.

INTRODUCTION: In recent years, clinical studies have shown that perinatal pain could increase the risk of postpartum depression, while such a conclusion appears controversial. Therefore, we conducted this systematic review and meta-analysis to explore the association between perinatal pain and postpartum depression, and to evaluate the effectiveness of epidural labor analgesia in reducing the risk of postpartum depression. METHODS: PubMed, Web of Science, Embase and Cochrane Library were searched from inception to Jan 30th, 2022. The effect size of the meta-analysis was calculated using odds ratio and 95 % confidence interval. Statistical analysis was performed using Stata 15.0 software. RESULTS: There were 19 studies included with a total of 96,378 patients. Among the included studies, 10 investigated the association between perinatal pain and the risk of postpartum depression, and 9 reported that between labor analgesia and the risk of postpartum depression. The results of meta-analysis showed that perinatal pain increased the risk of postpartum depression [OR = 1.43, 95% CI (1.23, 1.67), p<0.05], and epidural analgesia could reduce the risk of postpartum depression [OR = 0.42, 95% CI (0.33, 0.55), p < 0.05]. LIMITATIONS: Source of heterogeneity in the association between perinatal pain and PPD could not be identified due to the limitations of the original studies. There were mainly cohort studies included in the assessment for effectiveness of epidural analgesia in reducing the incidence of postpartum pain. Therefore, we look forward to more RCTs to confirm our results. CONCLUSION: Perinatal pain is one of the risk factors for postpartum depression, and epidural analgesia could reduce the risk of PPD. This result might provide guidance for clinical practice. However, psychological health counseling should be combined with epidural analgesia for perinatal pain to reduce the risk of PPD.

Inhibition of IP3R/Ca2+ Dysregulation Protects Mice From Ventilator-Induced Lung Injury via Endoplasmic Reticulum and Mitochondrial Pathways.

Rationale: Disruption of intracellular calcium (Ca2+) homeostasis is implicated in inflammatory responses. Here we investigated endoplasmic reticulum (ER) Ca2+ efflux through the Inositol 1,4,5-trisphosphate receptor (IP3R) as a potential mechanism of inflammatory pathophysiology in a ventilator-induced lung injury (VILI) mouse model. Methods: C57BL/6 mice were exposed to mechanical ventilation using high tidal volume (HTV). Mice were pretreated with the IP3R agonist carbachol, IP3R inhibitor 2-aminoethoxydiphenyl borate (2-APB) or the Ca2+ chelator BAPTA-AM. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected to measure Ca2+ concentrations, inflammatory responses and mRNA/protein expression associated with ER stress, NLRP3 inflammasome activation and inflammation. Analyses were conducted in concert with cultured murine lung cell lines. Results: Lungs from mice subjected to HTV displayed upregulated IP3R expression in ER and mitochondrial-associated-membranes (MAMs), with enhanced formation of MAMs. Moreover, HTV disrupted Ca2+ homeostasis, with increased flux from the ER to the cytoplasm and mitochondria. Administration of carbachol aggravated HTV-induced lung injury and inflammation while pretreatment with 2-APB or BAPTA-AM largely prevented these effects. HTV activated the IRE1α and PERK arms of the ER stress signaling response and induced mitochondrial dysfunction-NLRP3 inflammasome activation in an IP3R-dependent manner. Similarly, disruption of IP3R/Ca2+ in MLE12 and RAW264.7 cells using carbachol lead to inflammatory responses, and stimulated ER stress and mitochondrial dysfunction. Conclusion: Increase in IP3R-mediated Ca2+ release is involved in the inflammatory pathophysiology of VILI via ER stress and mitochondrial dysfunction. Antagonizing IP3R/Ca2+ and/or maintaining Ca2+ homeostasis in lung tissue represents a prospective treatment approach for VILI.

Silencing ROCK1 ameliorates ventilator-induced lung injury in mice by inhibiting macrophages' NLRP3 signaling.

Rho kinase, including two subtypes, ROCK1 and ROCK2, controls a variety of biological processes helping coordinate the tissues response to stress and injury. Some authors believe that alveolar macrophages (AMs) play a key role in the early phase of ventilator-induced lung injury (VILI), which is closely related to the activation of NLRP3 inflammasome and NF-κB signaling. However, there is currently little known about the relationship between ROCK signaling and NLRP3 inflammasome. Accordingly, we focused on exploring the effect of ROCK for NLRP3 inflammasome, the results showed that VILI in C57BL/6 mice significantly increased NF-κB, NLRP3, ASC, caspase1 expression, and the secretion of cytokines, which was reversed by applying the ROCK Inhibitor-Y27632. Moreover, the use of AMs and mechanical stretching suggested that ROCK regulated transcriptional level of NF-κB and NLRP3 inflammasome in AMs. Specifically, we silenced the ROCK1 and ROCK2 respectively, and found that the inflammation of MH-S cells after LPS and ATP priming could be regulated by ROCK1 and ROCK2, while the NLRP3 was only dependent upon ROCK1. Meantime, the related genes of NLRP3 signal are also regulated by ROCK1. Collectively, our data suggest that silencing ROCK1 ameliorates VILI in mice in part by inhibiting AMs' NLRP3 signaling pathway.