Ghrelin alleviates intestinal ischemia-reperfusion injury by activating the GHSR-1α/Sirt1/FOXO1 pathway.

Ischemia-reperfusion (IR) injury is primarily characterized by the restoration of blood flow perfusion and oxygen supply to ischemic tissue and organs, but it paradoxically leads to tissue injury aggravation. IR injury is a challenging pathophysiological process that is difficult to avoid clinically and frequently occurs during organ transplantation, surgery, shock resuscitation, and other processes. The major causes of IR injury include increased levels of free radicals, calcium overload, oxidative stress, and excessive inflammatory response. Ghrelin is a newly discovered brain-intestinal peptide with anti-inflammatory and antiapoptotic effects that improve blood supply. The role and mechanism of ghrelin in intestinal ischemia-reperfusion (IIR) injury remain unclear. We hypothesized that ghrelin could attenuate IIR-induced oxidative stress and apoptosis. To investigate this, we established IIR by using a non-invasive arterial clip to clamp the root of the superior mesenteric artery (SMA) in mice. Ghrelin was injected intraperitoneally at a dose of 50 µg/kg 20 min before IIR surgery, and [D-Lys3]-GHRP-6 was injected intraperitoneally at a dose of 12 nmol/kg 20 min before ghrelin injection. We mimicked the IIR process with hypoxia-reoxygenation (HR) in Caco-2 cells, which are similar to intestinal epithelial cells in structure and biochemistry. Our results showed that ghrelin inhibited IIR/HR-induced oxidative stress and apoptosis by activating GHSR-1α. Moreover, it was found that ghrelin activated the GHSR-1α/Sirt1/FOXO1 signaling pathway. We further inhibited Sirt1 and found that Sirt1 was critical for ghrelin-mediated mitigation of IIR/HR injury. Overall, our data suggest that pretreatment with ghrelin reduces oxidative stress and apoptosis to attenuate IIR/HR injury by binding with GHSR-1α to further activate Sirt1.

Loss of Sam50 in hepatocytes induces cardiolipin-dependent mitochondrial membrane remodeling to trigger mtDNA release and liver injury.

BACKGROUND AND AIMS: Sam50, a key component of the sorting and assembly machinery (SAM) complex, is also involved in bridging mitochondrial outer-membrane and inner-membrane contacts. However, the physiological and pathological functions of Sam50 remain largely unknown. APPROACH AND RESULTS: Here we show that Sam50 interacts with MICOS (mitochondrial contact site and cristae organizing system) and ATAD3 (ATPase family AAA domain-containing protein 3) to form the Sam50-MICOS-ATAD3-mtDNA axis, which maintains mtDNA stability. Loss of Sam50 causes mitochondrial DNA (mtDNA) aggregation. Furthermore, Sam50 cooperates with Mic60 to bind to cardiolipin, maintaining the integrity of mitochondrial membranes. Sam50 depletion leads to cardiolipin externalization, which causes mitochondrial outer-membrane and inner-membrane (including crista membrane) remodeling, triggering Bax mitochondrial recruitment, mtDNA aggregation, and release. Physiologically, acetaminophen (an effective antipyretic and analgesic)-caused Sam50 reduction or Sam50 liver-specific knockout induces mtDNA release, leading to activation of the cGAS-STING pathway and liver inflammation in mice. Moreover, exogenous expression of Sam50 remarkably attenuates APAP-induced liver hepatoxicity. CONCLUSIONS: Our findings uncover the critical role of Sam50 in maintaining mitochondrial membrane integrity and mtDNA stability in hepatocytes and reveal that Sam50 depletion-induced cardiolipin externalization is a signal of mtDNA release and controls mtDNA-dependent innate immunity.

Experiment and Computational Study on Pd-Catalyzed Methoxyiminoacyl-Directed γ-Alkoxylation of Alkylamides.

The direct alkoxylation of amides has been accomplished via methoxyiminoacyl (MIA)-mediated Pd-catalyzed C-H functionalization. A diverse array of alkylamide substrates is amenable to this protocol, providing γ-C(sp3)-alkoxylation of alkylamide derivatives with good to high efficiency. Two aspects of the research were completed to explore the reaction mechanism. On the one hand, the result of the kinetic isotopic effect experiment and control experiment indicated that reductive elimination is a rate-limiting step. On the other hand, density functional theory calculations demonstrated that a concerted Sn2 reductive elimination mechanism pathway is prior. Finally, the MIA group could be efficiently hydrogenated and protected in a one-pot procedure, which provides a short synthetic route to γ-methoxy amino acid derivatives.

A near-infrared emitted fluorescence probe for the detection of biosulfite in live zebrafish, mouse and real food samples.

Bisulfite (HSO3-) has been widely used as an important food additive in daily life. Furthermore, a normal amount of HSO3- plays a significant role in biological systems. However, excessive intake of HSO3- will lead to a variety of diseases. Therefore, it is of great significance to develop an efficient fluorescent probe that can be used for detection of HSO3- in biological systems and food samples. In this work, a near-infrared (NIR) emitted fluorescent probe (SZY) based on hemicyanine dye was successfully synthesized and applied to detect HSO3- in several food samples and live animals. The proposed nucleophilic addition sensing mechanism of SZY towards HSO3- has been confirmed by 1H NMR titration, high resolution mass spectrometry (HR-MS) and density functional theory (DFT) theoretical computation. The HSO3--induced nucleophilic reaction with α,ß-unsaturated CC binding of SZY results in the dramatic decline of the UV-vis absorption and remarkable quenching of the fluorescence emission. SZY features the advantages of near infrared emission (centered at 720 nm), high water solubility (in 98% aqueous solution), fast response time (50 s), large Stokes shift (244 nm) and low cytotoxicity. The probe SZY was successfully applied to image of HSO3- in live nude mouse and adult zebrafish. Semi-quantitatively analyzing the HSO3- level by "naked eye" in several food samples including canned fruit, white wine, white sugar and jasmine tea drinks has been realized by the colorimetric method.

Relationship between novel anthropometric indices and the incidence of hypertension in Chinese individuals: a prospective cohort study based on the CHNS from 1993 to 2015.

BACKGROUND: Recently, novel anthropometric indices (AHIs), including the body roundness index (BRI) and a body shape index (ABSI), were proposed to evaluate a subject's nutritional status and metabolic disorders. In the present study, we mainly analyzed the relationship between AHIs and the incidence of hypertension and preliminarily compared their abilities to discriminate hypertension incidence in the Chinese population from the China Health and Nutrition Survey (CHNS). METHODS: A total of 12,154 participants were included in this longitudinal study. The age range of this cohort was 18-94 years old (mean age: 40.73 ± 13.85 years old). 4511 participants developed hypertension during a median of 7.00 years of follow-up. Cox regression analysis, stratified analysis, and interaction tests were used to analyze the relationship between AHIs and the incidence of hypertension. Time-dependent receiver operating characteristic (ROC) curves, integrated discrimination improvement (IDI) and net reclassification index (NRI) were calculated to appraise the AHIs' discrimination value of new-onset hypertension. RESULTS: Kaplan‒Meier curves demonstrated that the participants in higher quartiles of AHIs (ABSI or BRI) at baseline were at greater risk of hypertension incidence during the follow-up. After adjusting for confounding factors, multivariate Cox regression models showed that the quartiles of BRI were significantly associated with an increased risk of hypertension in the whole cohort but were relatively weak for ABSI quartiles (P for trend = 0.387). In addition, ABSI z score (HR = 1.08, 95% CI: 1.04-1.11) and BRI z score (HR = 1.27, 95% CI: 1.23-1.30) were positively associated with increased incident hypertension in the total population. Stratified analysis and interaction tests showed a greater risk of new-onset hypertension in those < 40 years old (HR = 1.43, 95% CI: 1.35-1.50) for each z score increase in BRI and a higher incidence of hypertension in participants who were drinkers (HR = 1.10, 95% CI: 1.04-1.14) for each z score increase in ABSI. In addition, we observed that the area under the curve for identifying hypertension incidence for BRI was significantly higher than that for ABSI at 4, 7, 11, 12, and 15 years (all P < 0.05). However, the AUC of both indices decreased over time. Furthermore, the addition of BRI improved the differentiation and reclassification of traditional risk factors with a continuous NRI of 0.201 (95% CI: 0.169-0.228) and an IDI of 0.021 (95% CI: 0.015-0.028). CONCLUSION: Increased ABSI and BRI were associated with an increased risk of hypertension in Chinese individuals. BRI performed better than ABSI in identifying the new onset of hypertension, and the discrimination ability of both indices decreased over time.

A deep learning model based on contrast-enhanced computed tomography for differential diagnosis of gallbladder carcinoma.

BACKGROUND: Gallbladder carcinoma (GBC) is highly malignant, and its early diagnosis remains difficult. This study aimed to develop a deep learning model based on contrast-enhanced computed tomography (CT) images to assist radiologists in identifying GBC. METHODS: We retrospectively enrolled 278 patients with gallbladder lesions (> 10 mm) who underwent contrast-enhanced CT and cholecystectomy and divided them into the training (n = 194) and validation (n = 84) datasets. The deep learning model was developed based on ResNet50 network. Radiomics and clinical models were built based on support vector machine (SVM) method. We comprehensively compared the performance of deep learning, radiomics, clinical models, and three radiologists. RESULTS: Three radiomics features including LoG_3.0 gray-level size zone matrix zone variance, HHL first-order kurtosis, and LHL gray-level co-occurrence matrix dependence variance were significantly different between benign gallbladder lesions and GBC, and were selected for developing radiomics model. Multivariate regression analysis revealed that age ≥ 65 years [odds ratios (OR) = 4.4, 95% confidence interval (CI): 2.1-9.1, P < 0.001], lesion size (OR = 2.6, 95% CI: 1.6-4.1, P < 0.001), and CA-19-9 > 37 U/mL (OR = 4.0, 95% CI: 1.6-10.0, P = 0.003) were significant clinical risk factors of GBC. The deep learning model achieved the area under the receiver operating characteristic curve (AUC) values of 0.864 (95% CI: 0.814-0.915) and 0.857 (95% CI: 0.773-0.942) in the training and validation datasets, which were comparable with radiomics, clinical models and three radiologists. The sensitivity of deep learning model was the highest both in the training [90% (95% CI: 82%-96%)] and validation [85% (95% CI: 68%-95%)] datasets. CONCLUSIONS: The deep learning model may be a useful tool for radiologists to distinguish between GBC and benign gallbladder lesions.

Salivary microbiome diversity in Chinese children with various caries states.

OBJECTIVE: This study aimed to explore oral microbiome diversity among children with various caries status based on dmft scores. METHODS: A total of 320 children aged 3-5 years were recruited, with 66 healthy children and 254 children affected by dental caries. According to dmft scores, these children with dental caries were classified as "mild group" (dmft score 1-3), "moderate group" (dmft score 4-6), and "severe group" (dmft score 7-14). Healthy children with dmft score of 0 served as control group. Illumina MiSeq sequencing was employed to analyze all salivary samples collected from these children. RESULTS: The salivary microbial diversity among four groups was similar (p > 0.05). A total of five bacterial genera were highly abundant in the control group including Bergeyella, Acidimicrobiales, Acidimicrobiia, Halomonas, and Blautia (p < 0.05). For mild group, there were nine bacterial genera identified to be predominant: Porphyromonadaceae, Porphyromonas, Enterobacteriales, Enterobacteriaceae, Weissella, Leuconostocaceae, Alphaproteobacteria, Stenotrophomonas, and Rhizobiales (p < 0.05). Only one genus, Aggregatibacter was predominant in moderate group (p < 0.05). There were six bacterial genera (Alistipes, Lachnoclostridium, Escherichia-Shigella, Romboutsia, Sphingomonadales, and Denitratisoma) enriched in severe group (p < 0.05). CONCLUSION: Oral microbial profile was different in children with various caries status based on dmft scores. CLINICAL RELEVANCE: The results might be beneficial to deeply understand microbiological diversity of early childhood caries (ECC) at various stages and inform effective strategies for ECC prevention.

Hypoxia-Inducible Exosomes Facilitate Liver-Tropic Premetastatic Niche in Colorectal Cancer.

BACKGROUND AND AIMS: Liver metastasis is a frequent occurrence in patients with colorectal cancer (CRC), with 15%-25% of CRC patients having liver metastases at the time of initial diagnosis. Specifically, some regional-stage patients with mild symptoms (stage 1 or 2) will also advance to liver metastases rapidly, even if the CRC lesion in situ is resected in time. Nevertheless, the precise mechanism of liver metastasis is still unclear. APPROACH AND RESULTS: Fresh tumor tissues from patients with CRC, adjacent noncancerous tissues, and colorectal adenoma tissues were subjected to microarray analysis to identify differentially expressed microRNA. Exosomes from human serum and cell culture medium were separated, quantitated, and verified by transmission electronic microscopy and Zetasizer Nano. Luciferase reporter assay, real-time quantitative PCR, western blot, immunoprecipitation, chromatin and re-chromatin immunoprecipitation, migration and invasion assay, PDX mouse model, flow cytometry, immunohistochemistry, and immunofluorescence staining were employed to explore the regulation among CRC liver metastases, immunosuppression, and cell adhesion. In this study, we demonstrated that the hypoxic microenvironment in primary CRC lesions boosted exosome release, selectively initiated favorable premetastatic niche formation in the liver but not in other organs. Mechanistically, Kupffer cells (KCs) can phagocytose exosomes containing highly expressed miR-135a-5p from the blood circulation into the liver. Exosomal miR-135a-5p initiated the large tumor suppressor kinase 2-yes-associated protein-matrix metalloproteinase 7 axis to promote the occurrence of CRC liver metastasis, and cluster of differentiation 30-TNF receptor-associated factor 2-p65-mediated immunosuppression signaling also contributed to this process. CONCLUSIONS: Hypoxia-induced exosomal miR-135a-5p correlates with the development, clinical severity, and prognosis of CRC liver metastases through the premetastatic niche; and our findings revealed that miR-135a-5p might be a promising target in halting CRC liver metastases.

Supramolecular Combination Chemotherapy: Cucurbit[8]uril Complex Enhanced Platinum Drug Infiltration and Modified Nanomechanical Property of Colorectal Cancer Cells.

Combination chemotherapy is recognized as a vital medical treatment for cancer, but it has not achieved clinical ideal effects of combination therapy. Herein, we designed a supramolecular combination chemotherapy strategy based on cucurbit[8]uril (CB[8]), which can be facilely assembled into dual platinum drugs. Interestingly, employing the CB[8] carrier led to a greater than 10-fold intracellular Pt content compared to that of dual drugs at 4 h, and the CB[8] complex (CLE) can enhance the infiltration of platinum drugs in colorectal tumor cells tremendously. The platinum drugs can be released from CLE through consuming more tumor biomarker spermidine. Through analyzing the nanomechanical property of the colorectal tumor cellular surface by bioscope AFM, it was revealed that CLE modified the property by decreasing the adhesion and increasing the stiffness. This study provided a facile and sensitive strategy for improving combination chemotherapy by supramolecular materials.

Pd-Catalyzed γ-Acetoxylation of Alkylamides: Structural Influence of Directing Groups.

Although direct acetoxylation and cyclization of alkylamide have been extensively reported, investigation of the structural influence of directing groups on selectivity is limited. Pd-catalyzed 2-methoxyiminoacyl (MIA) assisted γ-acetoxylation of alkylamides has been developed. Further DFT studies have demonstrated that the directing groups have a significant influence on the reductive elimination step. The strong electron-donating effect of the OMe group in MIA leads to the preferential formation of a five-membered cyclopalladium (OAc-Pd-C) complex, which favors the acetoxylation pathway.

Ischemic postconditioning attenuates acute kidney injury following intestinal ischemia-reperfusion through Nrf2-regulated autophagy, anti-oxidation, and anti-inflammation in mice.

Intestinal ischemia-reperfusion (IIR) often occurs during and following major cardiovascular or gut surgery and causes significant organ including kidney injuries. This study was to investigate the protective effect of intestinal ischemic postconditioning (IPo) on IIR-induced acute kidney injury (AKI) and the underling cellular signaling mechanisms with focus on the Nrf2/HO-1. Adult C57BL/6J mice were subjected to IIR with or without IPo. IIR was established by clamping the superior mesenteric artery (SMA) for 45 minutes followed by 120 minutes reperfusion. Outcome measures were: (i) Intestinal and renal histopathology; (ii) Renal function; (iii) Cellular signaling changes; (iv) Oxidative stress and inflammatory responses. IPo significantly attenuated IIR-induced kidney injury. Furthermore, IPo significantly increased both nuclear Nrf2 and HO-1 expression in the kidney, upregulated autophagic flux, inhibited IIR-induced inflammation and reduced oxidative stress. The protective effect of IPo was abolished by the administration of Nrf2 inhibitor (Brusatol) or Nrf2 siRNA. Conversely, a Nrf2 activator t-BHQ has a similar protective effect to that of IPo. Our data indicate that IPo protects the kidney injury induced by IIR, which was likely mediated through the Nrf2/HO-1 cellular signaling activation.

Supramolecular Chemotherapy: Noncovalent Bond Synergy of Cucurbit[7]uril against Human Colorectal Tumor Cells.

Supramolecular chemotherapy has drawn increasing interest due to its ability to improve the efficiency of antitumor drugs and fewer associated toxic side effects. In this study, the smart supramolecular cargo, the doxorubicin-ZnO-cucurbit[7]uril (CDZ) nanocomplex, was constructed through ion-dipole interactions between cucurbit[7]uril {CB[7]} and doxorubicin-ZnO (dox-ZnO). The binding affinity of CB[7] and dox-ZnO was determined to be 104 M-1 by isothermal titration calorimetry. Importantly, spermine had a stronger binding affinity (106 M-1) with CB[7] than dox-ZnO through host-guest interactions. In the tumor microenvironment, spermine disassembled the CDZ nanocomplex, and dox was released from the nanocomplex by XRD, UV-visible spectra, and contact angle analysis. Compared to the single drug dox, the CDZ nanocomplex was demonstrated to possess higher activity of killing colorectal tumor cells by confocal laser scanning microscopy and cytotoxicity, which could be attributed to spermine concentration, spermine synthase, free radical damage, and G1 cell cycle arrest. Overall, the supramolecular delivery of dox can enhance the inhibition of human colorectal tumor cell proliferation and reduce cytotoxicity in human myocardial cells through the noncovalent bond synergy of {CB[7]}.

A phenothiazine-based turn-on fluorescent probe for the selective detection of hydrogen sulfide in food, live cells and animals.

In this work, a phenothiazine-based fluorescent probe (PR) has been developed for the selective detection of hydrogen sulfide (H2S) in biosystems and monitoring H2S produced in the food spoilage process. The nucleophilic attack of H2S on the CC double bond of PRvia a Michael addition interdicted the ICT process to trigger 34-fold enhancement of the fluorescence emission. PR featured high selectivity and sensitivity (1.8 µM), low cytotoxicity and reliability at physiological pH. "Naked-eye" monitoring of H2S produced in the food spoilage process using PR was successfully accomplished. The preliminary fluorescence imaging studies showed that PR is suitable for the visualization of exogenous and endogenous H2S in living cells and live animals. Moreover, PR has been successfully applied to the visualization of H2S generation in an inflammation model. The results indicated that PR is an effective tool to monitor H2S production in the fields of biomedicine and food safety.

Combined management can decrease blood pressure: an investigation of health-seeking behaviors among hypertensive patients in urban communities in China.

BACKGROUND: Hypertensive patients can freely choose informal medical facilities, such as pharmacies, community health service centres, and cardiology clinics in secondary or tertiary hospitals, as routine places for medical treatment in China currently. The proportions, influencing factors and effects of different health-seeking behaviours on blood pressure (BP) among hypertensive patients in urban communities are not clear. The aim of the study was to investigate health-seeking behaviours and the effects of different health-seeking behaviours on BP among hypertensive patients in urban communities in China. METHODS: A cross-sectional survey of hypertension was conducted in urban communities in Chengdu. A total of 437 hypertensive patients seeking medical help regularly were sequentially enrolled to complete a the questionnaire on health-seeking behaviours. RESULTS: The average age was 67.1 ± 7.5 years old. The control rate of BP was 41.0%, and the systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 144.2 ± 17.9 mm Hg and 75.4 ± 10.4 mm Hg, respectively. Among the hypertensive patients investigated, 62.8% chose community health service centre, 5.2% chose informal medical facilities, 21.5% chose cardiology clinics in secondary or tertiary hospitals, and 10.5% chose both community health service centre and cardiology clinics as the usual places for medical treatment. There were significant differences in education levels, proportions of home BP monitoring, establishment of chronic disease archives in the community, medication adherence and side effects of drugs among the four groups. The control rates of BP were 39.4%, 23.8%, 43.0% and 54.8% (P = 0.100), respectively. The SBPs were 145.1 ± 18.0, 150.9 ± 19.8, 143.8 ± 17.5 and 136.3 ± 15.1 mm Hg (P = 0.007), respectively, and it was significantly lower in the combined management group than in the other three groups. Compared with patients choosing community health service centre, patients in the combined management group had a significantly lower BP level (ß = -0.119, P = 0.038) adjusting for age, sex, education level, establishment of chronic disease archives, medication adherence and number of antihypertensive drugs. CONCLUSIONS: Combined management with both community health service centre and higher-level hospitals can decrease BP.

Nesfatin-1 inhibits free fatty acid (FFA)-induced endothelial inflammation via Gfi1/NF-κB signaling.

Nesfatin-1 is a neuropeptide produced in the hypothalamus. It is known that Nesfatin-1 is involved in food uptake, fat storage, and other metabolic regulation. We hypothesized that Nesfatin-1 may play a role in cardiovascular tissue. Free fatty acids (FFAs) are known to be the risk factor for cardiovascular diseases. FFA-mediated endothelial dysfunction is the critical mechanism of many cardiovascular disorders. The present study explores the protective effects of Nesfatin-1 on FFA-induced endothelial inflammation and the underlying mechanism. We found that significantly increased lactate dehydrogenase release and production of inflammatory factors were observed in FFA-treated human aortic endothelial cells (HAECs), accompanied by the enhanced attachment of U937 monocytes to HAECs and upregulated cell adhesion molecule vascular cell adhesion molecule-1, which were dramatically reversed by the treatment with Nesfatin-1. In addition, the promoted level of nuclear regulator NF-κB p65 and transcriptional function of NF-κB in FFA-treated HAECs were greatly suppressed by HAECs. Growth Factor Independent 1 Transcriptional Repressor 1 (Gfi1), an important negative regulator of NF-κB activity, was significantly downregulated in HAECs by FFAs and was upregulated by Nesfatin-1. Lastly, the inhibitory effects of Nesfatin-1 against FFA-induced NF-κB activation and adhesion of U937 monocytes to HAECs were abolished by the knockdown of Gfi1. In conclusion, our data reveal that Nesfatin-1 inhibited FFA-induced endothelial inflammation mediated by the Gfi1/NF-κB signaling pathway.

lncRNA SOX2-OT ceRNA network enhances the malignancy of long-term PM2.5-exposed human bronchial epithelia.

Exposure to fine particulate matter (PM2.5) in outdoor air is carcinogenic and associated with the development of lung cancer; however, the underlying mechanism remains unclear. In the present study, the profiles of lncRNA, microRNA and mRNA expression profiles in human bronchial epithelia (HBE) following exposure to PM2.5, diesel exhaust particles (DEPs), or aluminum oxide nanoparticles (Al2O3 NPs) were explored by microarray to reveal the lncRNA-microRNA-mRNA network participating in the malignant transformation of HBE cells following long-term PM2.5 exposure. The results showed that lncRNA SOX2 overlapping transcript (SOX2-OT) was significantly induced in HBE cells exposed to PM2.5, DEPs, or Al2O3 NPs, acting as a sponge to microRNA-345-5p, which subsequently increased the expression levels of epidermal growth factor receptor (EGFR). EGFR is a therapeutic target in non-small cell lung cancer. Here, we found that SOX2-OT is an upstream trigger of EGFR in HBE cells during long-term PM2.5 exposure. Importantly, SOX2-OT knockdown effectively reduced the colony formation and migration capacities of HBE cells, compared to the wild type control. Collectively, SOX2-OT/microRNA-345-5p/EGFR is a ceRNA mechanism underlying the malignant transformation of bronchial epithelia exposed to PM2.5, which improves our understanding of the association between ambient PM2.5 exposure and the development of lung cancer.

CircPTK2 (hsa_circ_0005273) as a novel therapeutic target for metastatic colorectal cancer.

BACKGROUND: As a novel class of noncoding RNAs, circRNAs have been recently identified to regulate tumorigenesis and aggressiveness. However, the function of circRNAs in colorectal cancer (CRC) metastasis remains unclear. We aimed to identify circRNAs that are upregulated in CRC tissues from patients and study their function in CRC metastasis. METHODS: We compared six pairs of CRC tissues and their matched adjacent non-tumor tissues by using circRNA microarray. We first evaluated the expression of circPTK2 (hsa_circ_0005273) in fresh tissues from CRC tumors and corresponding adjacent tissues by qPCR analysis. CircPTK2 expression levels in the tissue microarray with 5 years of survival information were determined by RNA-ISH analysis. Meanwhile, the expression levels of circulating circPTK2 were further analyzed according to the patients' clinical features. We analyzed cell apoptosis, colony formation, migration, and invasion in CRC cells. To further elucidate the effect of circPTK2 in CRC metastasis, we also conducted a colon cancer hepatic and pulmonary metastasis experiment. We used RNA biotin-labeled pull down and mass spectrometry to identify the target of circPTK2. We established a PDTX model to evaluate the effect of shRNA specifically targeting circPTK2 on tumor metastasis. RESULTS: We identified a novel circRNA, circPTK2, which is back-spliced of three exons (exons 27, 28 and 29) of PTK2 by using circRNA microarray, bioinformatics and functional studies. CircPTK2 was elevated in CRC tissues and positively associated with tumor growth and metastasis. CRC patients with increased circPTK2 expression were positively correlated with poorer survival rates. Furthermore, our studies showed that circPTK2 could promote EMT of CRC cells in vitro and in vivo by binding to vimentin protein on sites Ser38, Ser55 and Ser82. We further demonstrated the interaction of circPTK2 and vimentin mediated the regulation of CRC by knockdown or overexpression of vimentin. In addition, we revealed that tail vein injection of shRNA specifically targeting circPTK2 blunt tumor metastasis in a patient-derived CRC xenograft model. CONCLUSIONS: Collectively, these results demonstrate that circPTK2 exerts critical roles in CRC growth and metastasis and may serve as a potential therapeutic target for CRC metastasis, and also a promising biomarker for early diagnosis of metastasis.

Safety and efficacy of different anesthetic regimens for parturients with COVID-19 undergoing Cesarean delivery: a case series of 17 patients.

PURPOSE: To assess the management and safety of epidural or general anesthesia for Cesarean delivery in parturients with coronavirus disease (COVID-19) and their newborns, and to evaluate the standardized procedures for protecting medical staff. METHODS: We retrospectively reviewed the cases of parturients diagnosed with severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection disease (COVID-19). Their epidemiologic history, chest computed tomography scans, laboratory measurements, and SARS-CoV-2 nucleic acid positivity were evaluated. We also recorded the patients' demographic and clinical characteristics, anesthesia and surgery-related data, maternal and neonatal complications, as well as the health status of the involved medical staff. RESULTS: The clinical characteristics of 17 pregnant women infected with SARS-CoV-2 were similar to those previously reported in non-pregnant adult patients. All of the 17 patients underwent Cesarean delivery with anesthesia performed according to standardized anesthesia/surgery procedures. Fourteen of the patients underwent continuous epidural anesthesia with 12 experiencing significant intraoperative hypotension. Three patients received general anesthesia with tracheal intubation because emergency surgery was needed. Three of the parturients are still recovering from their Cesarean delivery and are receiving in-hospital treatment for COVID-19. Three neonates were born prematurely. There were no deaths or serious neonatal asphyxia events. All neonatal SARS-CoV-2 nucleic acid tests were negative. No medical staff were infected throughout the patient care period. CONCLUSIONS: Both epidural and general anesthesia were safely used for Cesarean delivery in the parturients with COVID-19. Nevertheless, the incidence of hypotension during epidural anesthesia appeared excessive. Proper patient transfer, medical staff access procedures, and effective biosafety precautions are important to protect medical staff from COVID-19.

RéSUMé: OBJECTIF: Évaluer la gestion et la sécurité de l'anesthésie péridurale ou de l'anesthésie générale pour un accouchement par césarienne chez des parturientes infectées par la maladie à coronavirus 2019 (COVID-19) et pour leurs nouveau-nés, et évaluer les procédures standardisées visant la protection du personnel médical. MéTHODES: Nous avons revu de manière rétrospective les cas de parturientes ayant un diagnostic de syndrome respiratoire aigu sévère lié à l'infection (SARS-CoV-2) par le coronavirus (COVID-19). L'enquête épidémiologique, leurs examens de tomodensitométrie thoracique, les analyses de laboratoire et leur positivité pour l'acide nucléique du SARS-CoV-2 ont été évalués. Nous avons également consigné les caractéristiques démographiques et cliniques des patientes, les données liées à l'anesthésie et à la chirurgie, les complications maternelles et néonatales, ainsi que l'état de santé du personnel médical concerné. RéSULTATS: Les caractéristiques cliniques des 17 femmes enceintes infectées par le SARS-CoV-2 étaient semblables à celles précédemment rapportées chez des patientes adultes non enceintes. Les 17 patientes ont subi un accouchement par césarienne sous anesthésie effectué selon les procédures standardisées d'anesthésie et de chirurgie. Parmi les quatorze patientes ayant eu une anesthésie péridurale continue, 12 patientes ont présenté une hypotension peropératoire significative. Trois patientes ont accouché sous anesthésie générale avec intubation trachéale, car nécessitant une chirurgie d'urgence. Trois parturientes sont encore en convalescence après leur accouchement par césarienne et reçoivent un traitement à l'hôpital pour la COVID-19. Trois nouveau-nés sont nés prématurément. Il n'y a pas eu de décès ou d'événement asphyxique néonatal grave. Toutes les recherches d'acide nucléique du SARS-CoV-2 chez les nouveau-nés ont été négatives. Aucun membre du personnel médical n'a été infecté pendant la durée des soins aux patientes. CONCLUSIONS: L'anesthésie par péridurale et l'anesthésie générale ont été utilisées sans danger pour l'accouchement par césarienne de parturientes atteintes de COVID-19. Cependant, l'incidence de l'hypotension au cours de l'anesthésie péridurale a paru excessive. Un transfert approprié des patientes, les procédures d'accès du personnel médical et des précautions efficaces de biosécurité sont importants pour protéger le personnel médical contre la COVID-19.

Taurine ameliorates particulate matter-induced emphysema by switching on mitochondrial NADH dehydrogenase genes.

Chronic obstructive pulmonary disease (COPD) has been linked to particulate matter (PM) exposure. Using transcriptomic analysis, we demonstrate that diesel exhaust particles, one of the major sources of particulate emission, down-regulated genes located in mitochondrial complexes I and V and induced experimental COPD in a mouse model. 1-Nitropyrene was identified as a major toxic component of PM-induced COPD. In the panel study, COPD patients were found to be more susceptible to PM than individuals with normal lung function due to an increased inflammatory response. Mechanistically, exposure to PM in human bronchial epithelial cells led to a decline in CCAAT/enhancer-binding protein alpha (C/EBPα), which triggered aberrant expression of NADH dehydrogenase genes and ultimately led to enhanced autophagy. ATG7-deficient mice, which have lower autophagy rates, were protected from PM-induced experimental COPD. Using metabolomics analysis, we further established that treatment with taurine and 3-methyladenine completely restored mitochondrial gene expression levels, thereby ameliorating the PM-induced emphysema. Our studies suggest a potential therapeutic intervention for the C/EBPα/mitochondria/autophagy axis in PM-induced COPD.

A Copper (II) Ensemble-Based Fluorescence Chemosensor and Its Application in the 'Naked-Eye' Detection of Biothiols in Human Urine.

Quick and effective detection of biothiols in biological fluids has gained increasing attention due to its vital biological functions. In this paper, a novel reversible fluorescence chemosensor (L-Cu2+) based on a benzocoumarin-Cu2+ ensemble has been developed for the detection of biothiols (Cys, Hcy and GSH) in human urine. The chemosensing ensemble (L-Cu2+) contains a 2:1 stoichiometry structure between fluorescent ligand L and paramagnetic Cu2+. L was found to exclusively bond with Cu2+ ions accompanied with a dramatic fluorescence quenching maximum at 443 nm and an increase of an absorbance band centered at 378 nm. Then, the in situ generated fluorescence sluggish ensemble, L-Cu2+, was successfully used as a chemosensor for the detection of biothiols with a fluorescence "OFF-ON" response modality. Upon the addition of biothiols, the decomplexation of L-Cu2+ led to the liberation of the fluorescent ligand, L, resulting in the recovery of fluorescence and absorbance spectra. Studies revealed that L-Cu2+ possesses simple synthesis, excellent stability, high sensitivity, reliability at a broad pH range and desired renewability (at least 5 times). The practical application of L-Cu2+ was then demonstrated by the detection of biothiols in human urine sample.