Value of [18F]AlF-NOTA-FAPI-04 PET/CT for differential diagnosis of malignant and various inflammatory lung lesions: comparison with [18F]FDG PET/CT.

OBJECTIVE: Uptake of the imaging tracers [18F]AlF-NOTA-FAPI-04 and [18F]FDG varies in some inflammatory lesions, which may result in false-positive findings for malignancy on PET/CT. Our aim was to compare the [18F]AlF-NOTA-FAPI-04 and [18F]FDG PET/CT imaging features of malignant and various inflammatory lung lesions and to analyze their value for differential diagnosis. METHODS: We retrospectively analyzed [18F]AlF-NOTA-FAPI-04 PET/CT scans from 67 cancer patients taken between December 2020 and January 2022, as well as the scans of 32 patients who also underwent [18F]FDG PET/CT imaging. The maximum and mean standardized uptake values (SUVmax and SUVmean, respectively) and lesion-to-background ratio (LBR) were calculated. The predictive capabilities of semiquantitative PET/CT parameters were analyzed by receiver operating characteristic curve analysis. RESULTS: A total of 70 inflammatory and 37 malignant lung lesions were evaluated by [18F]AlF­NOTA­FAPI­04 PET/CT, and 33 inflammatory and 26 malignant lung lesions also were evaluated by [18F]FDG PET/CT. Inflammatory lesions exhibited lower [18F]AlF-NOTA-FAPI-04 and [18F]FDG uptake compared to malignant lesions, with statistically significant differences in SUVmax, SUVmean, and LBR (all p < 0.001). [18F]AlF-NOTA-FAPI-04 uptake also varied among different types of inflammatory lesions (SUVmax, p = 0.005; SUVmean, p = 0.008; LBR, p < 0.001), with the highest uptake observed in bronchiectasis with infection, followed by postobstructive pneumonia, and the lowest in pneumonia. [18F]FDG uptake was higher in postobstructive pneumonia than in pneumonia (SUVmax, p = 0.009; SUVmean, p = 0.016; LBR, p = 0.004). CONCLUSION: [18F]AlF-NOTA-FAPI-04/[18F]FDG PET/CT showed significantly lower uptake in inflammatory lesions than malignancies as well as variation in different types of inflammatory lesions, and thus, may be valuable for distinguishing malignant and various inflammatory findings. CLINICAL RELEVANCE STATEMENT: Our study confirmed that the uptake of [18F]AlF-NOTA-FAPI-04/[18F]FDG PET/CT in inflammatory and malignant lung lesions is different, which is beneficial to distinguish inflammatory and malignant lung lesions in clinic. KEY POINTS: • Malignant and different inflammatory lung lesions showed varying degrees of uptake of [18F]AlF-NOTA-FAPI-04 and [18F]FDG. • Inflammatory lung lesions showed significantly less uptake than malignancies, and uptake varied among different types of inflammatory lesions. • Both types of PET/CT could differentiate malignant and various inflammatory lung findings.

What Are the Reliable Plasma Biomarkers for Mild Cognitive Impairment? A Clinical 4D Proteomics Study and Validation.

Objective: At present, Alzheimer's disease (AD) lacks effective treatment means, and early diagnosis and intervention are the keys to treatment. Therefore, for mild cognitive impairment (MCI) and AD patients, blood sample analysis using the 4D nonstandard (label-free) proteomic in-depth quantitative analysis, looking for specific protein marker expression differences, is important. These marker levels change as AD progresses, and the analysis of these biomarkers changes with this method, which has the potential to show the degree of disease progression and can be used for the diagnosis and preventive treatment of MCI and AD. Materials and Methods: Patients were recruited according to the inclusion and exclusion criteria and divided into three groups according to scale scores. Elderly patients diagnosed with AD were selected as the AD group (n = 9). Patients diagnosed with MCI were classified into the MCI group (n = 10). Cognitively healthy elderly patients were included in the normal cognition control group (n = 10). Patients' blood samples were used for 4D label-free proteomic in-depth quantitative analysis to identify potential blood biomarkers. The sample size of each group was expanded (n = 30), and the selected biomarkers were verified by enzyme-linked immunosorbent assay (ELISA) to verify the accuracy of the proteomic prediction. Results: Six specific blood markers, namely, APOE, MMP9, UBR5, PLA2G7, STAT5B, and S100A8, were detected by 4D label-free proteomic quantitative analysis. These markers showed a statistically significant upregulation trend in the MCI and AD groups compared with the normal cognition control group (P < 0.05). ELISA results showed that the levels of these six proteins in the MCI group were significantly higher than those in the normal cognition control group, and the levels of these six proteins in the AD group were significantly higher than those in the MCI group (P < 0.05). Conclusion: The plasma levels of APOE, MMP9, UBR5, PLA2G7, STAT5B, and S100A8 in cognitively healthy elderly patients and patients with MCI and AD were significantly different and, more importantly, showed a trend of increasing expression. These results indicate that these six human plasma markers have important diagnostic and therapeutic potential in the identification of cognitive impairment and have value for in-depth research and clinical application.

Aptamer-modified atomically precise gold nanoclusters as targeted nanozymes to scavenge reactive oxygen species in white adipocytes.

Oxidative stress caused by excessive reactive oxygen species (ROS) leads to the dysfunction of white adipocytes and white fat, and also promotes triglyceride storage by inhibiting the respiration of adipocytes directly. Nanozymes, as a new generation of artificial enzymes, have exhibited attractive potential in scavenging ROS and treatment of ROS-related diseases. Herein, aptamer-modified atomically precise gold Au25nanoclusters (Apt-Au25NCs), are employed as targeted nanozymes to scavenge ROS in white adipocytes. Our results show that Apt-Au25NCs have high targeting capability toward white adipocytes with low cytotoxicity. Furthermore, Apt-Au25NCs show high superoxide dismutase (SOD)-like and catalase (CAT)-like activity in a concentration-dependent manner, and also good thermal and pH stability compared with natural SOD and CAT. Finally, the efficiency of ROS scavenging by Apt-Au25NCs in white adipocytes is evaluated. This work demonstrates that Apt-Au25NCs, as targeted nanozymes, are efficient in scavenging ROS in white adipocytes, exhibiting promising potential for the treatment of obesity and related diseases.

Comparative Efficacy of Subthreshold Micropulse Laser Photocoagulation versus Conventional Laser Photocoagulation for Diabetic Macular Edema: A Meta-Analysis.

BACKGROUND: Laser photocoagulation is an effective procedure for the treatment of diabetic macular edema (DME). However, the beneficial effects of conventional laser photocoagulation (CLP) are accompanied by the destruction of retinal photoreceptors. Therefore, subthreshold micropulse laser photocoagulation (SMLP) was proposed for DME. OBJECTIVES: This meta-analysis study was performed to evaluate the efficacy and safety of SMLP compared with CLP for the management of DME. METHODS: The PubMed, Embase, Web of Science, Cochrane, SinoMed, ClinicalTrials.gov, Wanfang, and China National Knowledge Infrastructure (CNKI) databases, published until Dec 2021, were searched to identify studies evaluating the clinical outcomes of SMLP for DME. RESULTS: Eight randomized controlled trials were selected for this meta-analysis involving a total of 546 eyes (275 eyes in SMLP group and 271 eyes in CLP group). SMLP of different wavelengths (577 nm and 810 nm) and duty cycles (5% and 15%) was applied. The pooled outcomes showed that SMLP group, especially 577 nm and 810 nm 15% duty cycle parameter settings, had a statistically significant higher efficacy than CLP group in terms of BCVA (MD = -0.02, 95% CI: -0.03 to -0.01, p < 0.01; MD = -0.09, 95% CI: -0.09 to -0.09, p < 0.01) and showed more significant advantages than CLP group in resolving macular edema assessed by reduction of CMT (MD = -32.87, 95% CI: -37.61 to -28.13, p < 0.01; MD = -8.01, 95% CI: -9.06 to -6.96, p < 0.01), whereas the efficacy of 577 nm and 810 nm 5% duty cycle SMLP subgroups remained numerically superior to CLP group, but nonsignificantly (p > 0.05). In the field of CS, SMLP group (no matter parameter settings) resulted in better preservation of CS compared to CLP group (MD = 1.96, 95% CI: 1.47-2.46, p < 0.01). CONCLUSIONS: Compared with CLP, SMLP may get superior efficacy and safety on improvement of BCVA, reduction of CMT, and preservation of CS. In clinical, SMLP can be considered as a safe and effective therapy in the management of DME.

Sirt3 regulates mitophagy level to promote diabetic corneal epithelial wound healing.

We aim to investigate how Sirt3 (silent mating type information regulation 2 homolog 3) promoting diabetic corneal epithelial wound healing by regulating mitophagy. The effect of HG(High Glucose, 25 mM D-glucose) on Sirt3 and LC3B(light chain 3 beta)which representing of mitophagy were investigated in TKE2 cells (a murine limbal/corneal epithelium-derived progenitor cell line) and corneal epithelium from C57BL/6J-Ins2Akita (Ins2Akita/+) mice using RT-PCR and Western blotting. How overexpression of Sirt3 promoting diabetic corneal epithelial wound healing was investigated with cell migration assay、immunofluorescence、 immunofluorescence colocalization and corneal injury model. We found that HG reduced the expression of Sirt3 as well the mitophagy both in TKE2 cells and corneas from Ins2Akita/+ mice. And overexpression of Sirt3 prominently promoted wound healing speed under HG condition via upregulating the level of mitophagy. Mitophagy level was increased dramatically when the Foxo3a (Forkhead box O3)/PINK1(PTEN Induced putative kinase protein 1)-Parkin pathway was activated by Sirt3 overexpression which suggested that the mitophagy was involved in cell injury under HG condition. This study demonstrated the mechanism of Sirt3 regulating mitophagy to promote diabetic corneal epithelial wound healing in vivo and in vitro, which suggested that Sirt3 may positively impact diabetic keratopathy(DK).

Association between sleep traits and sarcopenia-related traits: A two-sample bidirectional Mendelian randomization study.

AIM: Despite limited evidence regarding the impact of sleep quality on sarcopenia, it is widely recognized as being associated with various diseases. This study aimed to explore the causal relationship between sleep traits and sarcopenia-related traits. METHODS: This study utilized a two-sample bidirectional Mendelian randomization analysis. Genetic genome-wide summary data of sleep quality indicators, including chronotype, morning wake-up time, sleep duration, daytime napping, insomnia and daytime dozing, were used. Data on sarcopenia-related traits, such as appendicular lean mass, grip strength of both hands, walking pace and waist circumference, were collected from a large cohort study. The primary method used was the inverse-variance weighted analysis. RESULTS: A causal association was found between chronotype and appendicular lean mass (odds ratio [OR] 1.019, 95% confidence interval [CI] 1.016-1.211, P = 0.021). Napping during the day was connected with walking pace (OR 0.879, 95% CI 0.834-0.928, P = 2.289 × 10-6) and waist circumference (OR 1.234, 95% CI 1.081-1.408, P = 0.002). Insomnia was related to lower grip strength of the right hand (OR 0.844, 95% CI 0.747-0.954, P = 0.007), left hand (OR 0.836, 95% CI 0.742-0.943, P = 0.003), as well as walking pace (OR 0.871, 95% CI 0.798-0.951, P = 0.002). Furthermore, the reverse Mendelian randomization analysis showed associations between certain sarcopenia-related traits and poor sleep quality. CONCLUSIONS: Some sleep traits were associated with the occurrence of sarcopenia. These findings emphasized the significance of prioritizing sleep quality as a preventive measure against sarcopenia. Geriatr Gerontol Int 2024; 24: 537-545.

Response Prediction Using 18F-FAPI-04 PET/CT in Patients with Esophageal Squamous Cell Carcinoma Treated with Concurrent Chemoradiotherapy.

This prospective study examined whether imaging results obtained using the tracer 18F-AlF-NOTA-fibroblast activation protein inhibitor (FAPI)-04 (denoted as 18F-FAPI-04) in PET/CT can predict the short-term outcome in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC) treated with concurrent chemoradiotherapy (CCRT). Methods: The 18 enrolled LA-ESCC patients underwent 18F-FAPI-04 PET/CT scanning before CCRT. The SUVmax, SUVmean, SUVpeak, metabolic tumor volume, and total lesion fibroblast activation protein expression of the primary tumor were recorded. Additionally, the SUVmax of the primary tumor and SUVmean of normal tissue (muscle and blood) were measured, and their ratios were denoted as target-to-background ratios (TBRmuscle and TBRblood). Patients were classified as responders or nonresponders according to RECIST (version 1.1), and variables were compared between the 2 groups. Results: The TBRblood, TBRmuscle, and SUVmean were significantly higher in nonresponders than in responders (all P < 0.05). Receiver-operating-characteristic curve analysis identified TBRblood (area under the curve [AUC], 0.883; P = 0.008), TBRmuscle (AUC, 0.896; P = 0.006) and SUVmean (AUC, 0.870; P = 0.010) as significant predictors of the response to CCRT, with cutoffs of 10.68, 10.95, and 6.88, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were also determined for TBRblood (100.0%, 72.7%, 66.7%, 88.9%, and 77.8%, respectively), TBRmuscle (100.0%, 72.7%, 66.7%, 88.9%, and 77.8%, respectively), and SUVmean (85.7%, 81.8%, 75.0%, 90.0%, and 83.3%, respectively). On univariate logistic regression analysis, TBRblood (P = 0.026), TBRmuscle (P = 0.036), SUVmean (P = 0.045), and tumor site (P = 0.032) were significantly correlated with the short-term outcome. On multivariable logistic regression analysis, TBRblood (P = 0.046) was an independent prognostic factor for short-term outcome. Conclusion: A higher baseline TBRblood on 18F-FAPI-04 PET/CT scans was associated with a poor response to CCRT in LA-ESCC patients, and thus, TBRblood may be useful for screening LA-ESCC patients before CCRT treatment.

[Diagnostic yield of bronchoscopic rapid on-site evaluation in severe invasive bronchopulmonary aspergillosis].

OBJECTIVE: To explore the diagnostic yield of bronchoscopic rapid on-site evaluation (B-ROSE) in patients with severe invasive bronchopulmonary aspergillosis (IBPA) and provide evidence for starting antifungal treatment before microbiological results were available. METHODS: A prospective cohort study was conducted to select patients with severe pneumonia suspected of IBPA admitted to the respiratory intensive care unit (RICU) in the First Affiliated Hospital of Xinjiang Medical University from June 2014 to June 2022, and those who were primarily infected with other pathogens (such as bacteria, Mycobacterium tuberculosis) at admission were excluded. Whether the antifungal treatment was initiated or not on the basis of the bedside B-ROSE, the B-ROSE was administered as soon as possible within 24 hours after admission to RICU. The current international definition of invasive aspergillosis was used as the gold diagnostic standard, the diagnostic accordance rate, the sensitivity and specificity of B-ROSE were calculated respectively, and the receiver operator characteristic curve (ROC curve) was also plotted, to evaluate the predictive value in diagnosing IBPA. RESULTS: A total of 176 patients with severe pneumonia suspected of IBPA were included in the study. According to international diagnostic standards, there were 81 cases of IBPA and 95 cases of non-IBPA. According to the early diagnosis of B-ROSE, there were 89 cases of IBPA and 87 cases of non-IBPA. The diagnostic accordance rate of B-ROSE was 84.09% (148/176), the area under the ROC curve for B-ROSE in diagnosing severe IBPA was 0.844, the 95% confidence interval (95%CI) was 0.782-0.905, the sensitivity was 87.65%, the specificity was 81.05%, the positive predictive value was 79.78%, the negative predictive value was 88.51%, the rate of underdiagnosis was 12.35% (10/81), and the rate of misdiagnosis was 18.95% (18/95). Compared with the true negative group, the proportion of long-term (≥ 14 days) use of glucocorticoid [70.0% (7/10) vs. 9.1% (7/77), P < 0.01] and the proportion of cases with diabetes [40.0% (4/10) vs. 10.4% (8/77), P < 0.05] were significantly higher in the false negative group (underdiagnosis group). However, B-ROSE of both groups showed mucosal bleeding, congestion and edema [100.0% (10/10) vs. 94.8% (73/77), P > 0.05], indicating that acute mucosal inflammation was non-characteristic. Compared with the true positive group, the proportion of long-term (≥ 14 days) use of glucocorticoid in the false positive group (misdiagnosis group) was significantly reduced [33.3% (6/18) vs. 60.6% (43/71), P < 0.05]. The B-ROSE results showed the proportion of cases with mucosal white spots, black plaques and pseudomembrane was significantly reduced [16.7% (3/18) vs. 52.1% (37/71), P < 0.01] in the misdiagnosed group, which suggest that cases of long-term use of glucocorticoid and cases with B-ROSE showing mucosal white spots, black plaques and pseudomembrane were less likely to be misdiagnosed. The main diseases that were easily misdiagnosed as IBPA included pulmonary tuberculosis (38.9%, 7/18), inflammatory lung adenocarcinoma (27.8%, 5/18) and pulmonary vasculitis (16.7%, 3/18). CONCLUSIONS: Before obtaining microbiological evidence, B-ROSE can assist in decision-making of early anti-aspergillus treatment for severe IBPA. This method is prompt, simple, and has high accuracy and reliability. If B-ROSE lacks characteristic manifestations, especially for severe pneumonia in patients with long-term use of glucocorticoid or diabetes, attention should be paid to the underdiagnosis of IBPA. Diseases such as lung tuberculosis, inflammatory lung adenocarcinoma and lung vasculitis should be vigilant against misdiagnosis as IBPA.

Transplantation of mesenchymal stem cells preconditioned with hydrogen sulfide enhances repair of myocardial infarction in rats.

Stem cell transplantation has become a promising therapeutic approach for the treatment of myocardial infarction (MI). However, the poor survival of the donor cells after transplantation has restricted its therapeutic efficacy. Hydrogen sulfide (H(2)S), one gaseous signaling molecule, has been applied to inhibit cell apoptosis and promote cell survival. In the present study, we therefore examined the effects of H(2)S on the survival of mesenchymal stem cells (MSCs). MSCs were isolated from the femur of male Sprague-Dawley rats (about 4 weeks old, 100 g). Preconditioning MSCs with 200 µmol/L NaHS (as the donor of H(2)S) for 30 min decreased the hypoxia-induced cell apoptosis in vitro. The mechanisms contributing to the beneficial effects of H(2)S on MSCs were associated with increased levels of phosphorylated Akt (pAkt), phosphorylated Erk1/2 (pErk1/2) and phosphorylated glycogen synthase kinase-3ß (pGSK-3ß) in MSCs. Subsequently, MSCs (1 × 10(6)), MSCs preconditioned with H(2)S (1 × 10(6)), or phosphate buffered saline (PBS) were injected into rat hearts immediately after MI (the ligation of the left anterior descending of coronary artery). Real-time PCR for the Sry gene, located on the Y chromosome, indicated that preconditioning with H(2)S improved the survival rate of the transplanted MSCs in infarcted myocardium 4 days after MI, compared with the untreated MSCs. Furthermore, transplantation of the H(2)S-pretreated MSCs reduced the infarct size and increased left ventricular (LV) function, as judged by transthoracic echocardiography. In conclusion, H(2)S preconditioning effectively promotes MSCs survival under ischemic injury and helps cardiac repair after MI, which has great clinical significance.

[Factors influencing the choice of endotracheal intubation and mechanical ventilation in patients with acute respiratory distress syndrome caused by viral pneumonia].

OBJECTIVE: To investigate the influencing factors of endotracheal intubation and mechanical ventilation (ETI-MV) in patients with acute respiratory distress syndrome (ARDS) caused by viral pneumonia, and to provide evidence for individualized use of ETI-MV. METHODS: Patients with ARDS due to viral pneumonia admitted to the respiratory intensive care unit (RICU) of the First Affiliated Hospital of Xinjiang Medical University were retrospectively analyzed from November 2017 to March 2022. The gender, age, concomitant diseases, clinical symptoms and signs, complications, lab results, ARDS severity, infectious virus type, acute physiology and chronic health evaluation II (APACHE II), respiratory support methods and prognosis-related variables were collected. Univariate analysis was performed on each factor, and the variables with statistical significance in the univariate analysis were subjected multivariate logistic regression analysis. The receiver operating characteristic curve (ROC curve) was drawn to evaluate the predictive value of each index for the implementation of ETI-MV. RESULTS: A total of 117 patients were enrolled in the study, including 61 patients in the ETI-MV group, and 3 patients (4.9%), 39 patients (63.9%) and 19 patients (31.1%) with mild, moderate and severe ARDS, respectively. There were 56 patients in non-ETI-MV group, and the mild, moderate and severe ARDS cases were 16 cases (28.6%), 38 cases (67.8%) and 2 cases (3.6%), respectively. There was significant difference between the two groups (P < 0.05). Univariate analysis showed that during 24 hours admitted to RICU, the levels of interleukin-6 [IL-6 (ng/L): 104.0±90.0 vs. 62.4±76.0], oxygenation index [PaO2/FiO2 (mmHg, 1 mmHg ≈ 0.133 kPa): 123.9±30.9 vs. 173.6±28.5], the proportion of cases with pulmonary infiltrating opacity distribution range ≥ 3/4 lung fields [85.3% (52/61) vs. 21.5% (12/56)], APACHE II score ≥ 16.5 [67.2% (41/61) vs. 42.9% (24/56)], the rate of nosocomial invasive aspergillus infection [14.8% (9/61) vs. 3.6% (2/56)], the percentage of nosocomial bacterial infection [16.4% (10/61) vs. 3.6% (2/56)], and the lowest CD4+ T lymphocyte count in the course of the disease [cells/mm3: 192.2±35.8 vs. 215.0±58.3] had significant differences between ETI-MV and non-ETI-MV group (all P < 0.05). Multivariate Logistic regression analysis showed that during 24 hours admitted to RICU the distribution range of pulmonary infiltrating opacity ≥ 3/4 the lung fields [odds ratio (OR) = 12.527, 95% confidence interval (95%CI) = 3.279-47.859, P < 0.001], APACHE II score ≥ 16.5 (OR = 30.604, 95%CI = 4.318-216.932, P = 0.001), PaO2/FiO2 (OR = 0.948, 95%CI = 0.925-0.972, P < 0.001), CD4+ T lymphocytes cell count (OR = 0.975, 95%CI = 0.955-0.995, P = 0.015), and nosocomial bacterial infection (OR = 38.338, 95%CI = 1.638-897.158, P = 0.023) were independent risk factors for ETI-MV. The area under the ROC curve (AUC) of ROC showed that PaO2/FiO2 had the greatest predictive value for ETI-MV, with AUC of 0.903, sensitivity of 91.1% and specificity of 95.1% in case of cutoff value of 151 mmHg. The AUC of pulmonary infiltrating opacity distribution range was 0.809, the sensitivity of 85.2%, specificity of 78.6% when the cutoff value was ≥ 3/4 lung field. APACHE II scores had the lowest predictive value for selecting ETI-MV, with AUC of 0.704, sensitivity of 83.6% and specificity of 57.1% under the cutoff value was 16.5. CONCLUSIONS: For patients with ARDS caused by viral pneumonia, PaO2/FiO2 is still the classic reference for selecting ETI-MV, however, the distribution range of pulmonary infiltrating opacity and the systemic severity of the disease during 24 hours admitted to the RICU may provide supplemental helpful information to determine whether the patients choose ETI-MV, especially for moderate ARDS.

Silencing miR-125b-5p attenuates inflammatory response and apoptosis inhibition in mycobacterium tuberculosis-infected human macrophages by targeting DNA damage-regulated autophagy modulator 2 (DRAM2).

Tuberculosis is one of the most important infectious diseases worldwide and macrophage apoptosis is the major host defense mechanism against TB. We attempted to characterize the role of miRNA (miR)-125b-5p on mycobacterium tuberculosis (Mtb) infection and macrophages behaviors in vitro. According to fluorescence-activated cell separation (FACS), primary monocytes (CD14+) in TB patients were accumulated, and apoptotic monocytes were decreased. Peripheral blood mononuclear cells (PBMCs)-derived macrophages (MDMs) and monocytic cells THP-1-derived macrophage-like cells (TDMs) in vitro were used to be infected with H37Rv. After infection, colony-forming units assay revealed the increase of bacterial activity, FACS demonstrated the decrease of apoptosis rate of MDMs and TDMs, as well as promoted levels of IL-6, TNF-α, Bax, and Bim and suppressed levels of IL-10 and Bcl-2, examined by enzyme-linked immunosorbent assay (ELISA) and western blot assay. Expression of miR-125b-5p and DNA damage-regulated autophagy modulator 2 (DRAM2) was examined, and real-time PCR and western blot assay showed that miR-125b-5p was upregulated, whereas DRAM2 was downregulated in primary monocytes and H37Rv-infected macrophages (MDMs and TDMs). Moreover, blocking miR-125b-5p could attenuated H37Rv-induced bacterial activity and inflammatory response of MDMs and TDMs, accompanied with apoptosis inhibition. Whereas these effects of miR-125b-5p knockdown were abolished by downregulating DRAM2. In mechanism, DRAM2 was a downstream target of miR-125b-5p, as evidenced by dual-luciferase reporter assay. Collectively, silencing miR-125b-5p could protect human macrophages against Mtb infection through promoting apoptosis and inhibiting inflammatory response via targeting DRAM2, suggesting a novel target for Mtb eliminating. Abbreviations: TB: tuberculosis; PBMCs: peripheral blood mononuclear cells; Mtb: mycobacterium tuberculosis; AFB: acid fast bacilli; FITC: fluorescein isothiocyanate; MDMs: monocytes-derived macrophages; TDMs: THP-1-derived macrophage-like cells; ERFP: Mtb-enhanced red fluorescent protein; CFU: colony-forming units; ELISA: enzyme-linked immunosorbent assay; FACS: fluorescence-activated cell separation; PI: propidium iodide; DRAM2: DNA damage-regulated autophagy modulator 2; Real-time PCR: real-time polymerase chain reaction; in-miR-125b-5p: miR-125b-5p inhibitor; si-DRAM2: siRNA against DRAM2.

Circ_0038467 regulates lipopolysaccharide-induced inflammatory injury in human bronchial epithelial cells through sponging miR-338-3p.

BACKGROUND: Pneumonia is a common acute lower respiratory infection in children and elders. Circular RNAs (circRNAs) have recently been uncovered to play important roles in pneumonia. However, the function and mechanism of circ_0038467 in pneumonia remain elusive. METHODS: Cell viability and apoptosis were determined using the Cell Counting Kit-8 (CCK-8) assay and flow cytometry, respectively. The levels of interleukin 6 (IL-6), IL-8 and IL-1ß were detected by enzyme-linked immunosorbent assay (ELISA). Western blot analysis was performed to assess the expression of related proteins. Circ_0038467 was characterized by Ribonuclease R (RNase) digestion and subcellular localization assays. The levels of circ_0038467 and miR-338-3p were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). The direct interaction between circ_0038467 and miR-338-3p was validated by the dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. RESULTS: Our data indicated that lipopolysaccharide (LPS) induced an inflammatory injury in 16HBE cells by repressing cell viability and enhancing cell apoptosis and proinflammatory cytokines production. Circ_0038467 was upregulated and miR-338-3p was downregulated in LPS-treated 16HBE cells. Circ_0038467 knockdown or miR-338-3p overexpression attenuated LPS-induced 16HBE cell inflammatory injury. Moreover, circ_0038467 acted as a sponge of miR-338-3p in 16HBE cells. MiR-338-3p mediated the alleviated effect of circ_0038467 knockdown on LPS-induced 16HBE cell inflammatory injury. Additionally, the Janus kinase/ signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway was involved in the circ_0038467/miR-338-3p axis-mediated regulation in LPS-induced 16HBE cell inflammatory injury. CONCLUSIONS: The current work had led to the identification of circ_0038467 knockdown that alleviated LPS-induced inflammatory injury in 16HBE cells at least partly through sponging miR-338-3p and regulating JAK/STAT3 pathway, highlighting novel molecular targets for the treatment of pneumonia.

Antibacterial Activity of Chrysanthemum buds Crude Extract Against Cronobacter sakazakii and Its Application as a Natural Disinfectant.

Cronobacter sakazakii is an opportunistic food-borne pathogen that endangers the health of neonates and infants. This study aims to elucidate the antibacterial activity and mechanism of Chrysanthemum buds crude extract (CBCE) against C. sakazakii and its application as a natural disinfectant. The antibacterial activity was evaluated by the determination of the diameter of inhibition zone (DIZ), minimum inhibitory concentration (MIC), and minimum bactericide concentration (MBC). The antibacterial mechanism was explored based on the changes of growth curve assay, intracellular ATP concentration, membrane potential, intracellular pH (pHin), content of soluble protein and nucleic acid, and cell morphology. Finally, the inactivation effects of CBCE against C. sakazakii in biofilm on stainless steel tube, tinplate, glass, and polystyrene were evaluated. The results showed that the DIZ, MIC, and MBC of CBCE against C. sakazakii were 14.55 ± 0.44-14.84 ± 0.38 mm, 10 mg/mL, and 20 mg/mL, respectively. In the process of CBCE acting on C. sakazakii, the logarithmic growth phase of the tested bacteria disappeared, and the concentrations of intracellular ATP, pHin, bacterial protein, and nucleic acid were reduced. Meanwhile, CBCE caused the cell membrane depolarization and leakage of cytoplasm of C. sakazakii. In addition, about 6.5 log CFU/mL of viable C. sakazakii in biofilm on stainless steel tube, tinplate, glass, and polystyrene could be inactivated after treatment with 1 MIC of CBCE for 30 min at 25°C. These findings reveal the antibacterial activity and mechanism of CBCE against C. sakazakii and provide a possibility of using a natural disinfectant to kill C. sakazakii in the production environment, packaging materials, and utensils.

Expression of Neovascular Associated Factors PEDF and αB-crystallin in Human Lens Epithelial Cells.

Objective: To investigate the expression of pigment epithelium-derived factor (PEDF) and αB-crystallin in human lens epithelial cells (LEC) and explore their relationships with diabetes. Methods: Lens anterior capsules attached with LEC were collected from cataract surgeries in patients with or without diabetes, and grouped as following: non-diabetes mellitus (NDM) group, no diabetic retinopathy (NDR) group, non-proliferative diabetic retinopathy (NPDR) group and proliferative diabetic retinopathy (PDR) group. The expression of PEDF and αB-crystallin in all groups was determined by Western blot and immunofluorescence assay. Results: PEDF and αB-crystallin protein were both detected in LEC. PEDF was mainly distributed in the cytoplasm, whereas αB-crystallin was present in both cytoplasm and nucleus. The levels of PEDF protein and αB-crystallin protein in LEC were significantly increased with the appearance and aggravation of diabetic retinopathy (DR) (p < .01). Conclusion: The expression of PEDF and αB-crystallin protein is both positively correlated with the progression of DR, which may contribute to the regulation of iris neovascularization.

MiR-34c Participates in Diabetic Corneal Neuropathy Via Regulation of Autophagy.

Purpose: To investigate the contribution and mechanism of miRNAs and autophagy in diabetic peripheral neuropathy. Methods: In this study, we used streptozotocin (STZ)-induced type I diabetes C57 mice as animal models, and we detected the expression of miR-34c and autophagic intensity in trigeminal ganglion (TG) tissue. The bioinformatics software was used to predict and analyze the potential targets of miR-34c. Primary trigeminal ganglion neurons were cultured in vitro to investigate the effect of miR-34c on axon growth and survival of TG cells. A corneal epithelial damage-healing model was established on the diabetic mice, then miR-34c antagomir was injected subconjunctivally. The condition of corneal epithelial healing was observed through sodium fluorescein staining, and the peripheral nerve degeneration of the cornea was evaluated by ß-tublin corneal nerve staining. Results: The expression of miR-34c was significantly increased in TG tissue of type I diabetic mice by real-time PCR. Western blot showed that autophagy-related proteins Atg4B and LC3-II were significantly down-regulated in diabetes TG compared with normal control. Trigeminal neuron immunofluorescence showed that the length of the trigeminal ganglion cell synapses was significantly increased after miR-34c antagomir treatment compared with normal cultures. Subconjunctival injection of miR-34c antagomir can significantly promote corneal epithelium healing of diabetic mice and appreciably promote the regeneration of corneal nerve. At the same time, it can significantly increase the expression of autophagy in TG tissue of type I diabetic mice. Conclusions: In this study , miR-34c was found to affect the growth of trigeminal sensory neurons and the repair of diabetic corneal nerve endings by acting directly on Atg4B.

Antidepressant-like effects of liquiritin and isoliquiritin from Glycyrrhiza uralensis in the forced swimming test and tail suspension test in mice.

Two classic animal behavior despair tests--the Forced Swimming Test (FST) and the Tail Suspension Test (TST) were used to evaluate the antidepressant activity of liquiritin and isoliquiritin from Glycyrrhiza uralensis in mice. It was observed that both liquiritin and isoliquiritin at doses of 10, 20 and 40 mg/kg significantly reduced the immobility time in the FST and TST in mice 30 min after treatment. Measurement of locomotor activity indicated that liquiritin and isoliquiritin had no central nervous system (CNS)-stimulating effects. The main monoamine neurotransmitters and their metabolites in mouse brain regions were also simultaneously determined by HPLC-ECD. It was found that these two compounds significantly increased the concentrations of the main neurotransmitters 5-HT and NE in the hippocampus, hypothalamus and cortex. Liquiritin and isoliquiritin also significantly reduced the ratio of 5-HIAA/5-HT in the hippocampus, hypothalamus and cortex, slowing down 5-HT metabolism compared with mice treated with vehicle+stress. In conclusion, liquiritin and isoliquiritin produced significant antidepressant-like effects, and their mechanism of action may be due to increased 5-HT and NE in the mouse hippocampus, hypothalamus and cortex.

Efficacy and safety of vitrectomy with internal limiting membrane peeling for diabetic macular edema: a Meta-analysis.

AIM: To evaluate the efficacy and safety of vitrectomy with internal limiting membrane (ILM) peeling for diabetic macular edema (DME). METHODS: The PubMed, Embase, Web of Science, Cochrane, SionMed, ClinicalTrials.gov, CNKI databases and Wanfang databases, published until Oct. 2017, were searched to identify studies comparing the clinical outcomes following vitrectomy with and without ILM peeling, for treating DME. Pooled results were expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CI) for vitrectomy with and without ILM peeling with regard to best corrected visual acuity (BCVA), central macular thickness (CMT), and complication incidents. RESULTS: A total of 14 studies involving 857 eyes were included of which three studies were Chinese and the rests were English literatures. Meta-analysis indicated that compared with vitrectomy alone, vitrectomy with ILM peeling could improve BCVA more obviously (OR=1.66, 95%CI: 1.12-2.46, P=0.01) and had higher rate of CMT reduction (OR=3.89, 95%CI: 1.37-11.11, P=0.01). There were significant statistical differences between the two surgical methods for both BCVA and CMT (P<0.05). For the incidence of intraoperative and postoperative complications, the incidence of epiretinal membrane (ERM) was slightly lower in the ILM peeling group than the group without ILM peeling (OR=0.38, 95%CI: 0.07-2.00, P=0.25), although insignificant statistically. Other incidences of overall complications, iatrogenic peripheral retinal break and increased intraocular pressure indicated no significant difference between two groups (OR=1.19, 95%CI: 0.82-1.73, P=0.36; OR=1.21, 95%CI: 0.66-2.21, P=0.53; OR=1.34, 95%CI: 0.75-2.40, P=0.32). CONCLUSION: Vitrectomy is effective for DME and the effect can be improved by additional ILM peeling, especially for anatomical efficacy, without increasing the incidence of intraoperative and postoperative complications. However, it is imperative to gain more evaluation in the future due to the paucity of prospective randomized study.

[Predictive factors for failure of non-invasive positive pressure ventilation in immunosuppressed patients with acute respiratory failure].

OBJECTIVE: To evaluate the predictive factors for failure of non-invasive positive pressure ventilation (NIPPV) in immunosuppressed patients with acute respiratory failure (ARF). METHODS: The clinical data of 118 immuno-deficient patients treated with NIPPV in the respiratory and intensive care unit (RICU) of the First Affiliated Hospital of Xinjiang Medical University from January 2012 to August 2017 were retrospectively analyzed. The patients were divided into a non-endotracheal intubation (ETI) group (n = 62) and ETI group (n = 56) according to whether ETI was performed during the hospitalization period or not. Each observed indicator was analyzed by univariate analysis, and factors leading to failure of NIPPV were further analyzed by Logistic regression. Receiver operating characteristic (ROC) curve was plotted to evaluate the predictive value of risk factors for failure of NIPPV in immunosuppressed patients with ARF. RESULTS: The non-intubation rate for NIPPV in immunosuppressed patients was 50.8% (60/118). Compared with the non-ETI group, the body temperature, pH value in the ETI group were significantly increased, the partial pressure of arterial carbon dioxide (PaCO2) was significantly decreased, the ratio of oxygenation index (PaO2/FiO2) < 100 mmHg (1 mmHg = 0.133 kPa), acute physiology and chronic health evaluation II (APACHE II) score ≥ 20, and the number of cases requiring catecholamine were significantly increased, the mortality was significantly increased. Multivariate Logistic regression analysis showed that the APACHE II score ≥ 20 [odds ratio (OR) = 15.274, 95% confidence internal (95%CI) = 2.175-107.252, χ2 = 7.516, P = 0.006], PaO2/FiO2 < 100 mmHg (OR = 0.075, 95%CI = 0.014-0.408, χ2 = 8.968, P = 0.003), and need for catecholamine (OR = 35.736, 95%CI = 6.974-183.124, χ2 = 18.400, P < 0.001) were independent risk factors for failure of NIPPV. ROC curve analysis showed that the APACHE II score ≥ 20 and PaO2/FiO2 < 100 mmHg could predict failure of NIPPV, the area under ROC curve (AUC) of the APACHE II score ≥ 20 was 0.787, the sensitivity was 83.93%, the specificity was 69.35%, the positive predict value (PPV) was 71.21%, the negative predict value (NPV) was 82.69%, the positive likelihood ratio (PLR) was 2.74, the negative likelihood ratio (NLR) was 0.23, and Youden index was 0.53; the AUC of PaO2/FiO2 < 100 mmHg was 0.757, the sensitivity was 80.65%, the specificity was 66.07%, the PPV was 68.18%, the NPV was 78.85%, the PLR was 2.38, the NLR was 0.29, and Youden index was 0.47. CONCLUSIONS: 50.8% of immunocompromised and ARF patients treated with NIPPV did not require ETI, which is independent of the etiology of ARF. APACHE II score ≥ 20, PaO2/FiO2 < 100 mmHg, and the need for catecholamine are predictive factors for failure of NIPPV in immunocompromised patients.

Identification of perturbed signaling pathways from gene expression data using information divergence.

Abnormal regulation of signaling pathways is the key causative factor in several diseases. Although many methods have been proposed to identify significantly differential pathways between two conditions via microarray gene expression datasets, most of them concentrate on differences in the pathway components-either the differential expression or the correlation of genes in a given pathway. However, as biological functional units, signaling pathways may have diverse activity patterns across different biological contexts. In order to detect overall changes in pathways, we propose an analysis model called SPAID (Signaling Pathway Analysis based on Information Divergence). SPAID is based on the concept of information divergence, which can be used to compare two conditions by computing the differential probability distribution of the regulation capacity. We compared SPAID with several classical algorithms using different datasets, and the results indicate that SPAID produces higher repeatability, has better performance and universality, and extracts more comprehensive information regarding the underlying biological processes. In conclusion, by introducing the idea of information divergence, our study measures differences in pathways from an overall perspective and will provide a complementary analysis framework for pathway analysis.

A computational method using differential gene expression to predict altered metabolism of multicellular organisms.

Altered metabolism is often identified as a cause or an effect of physiology and pathogenesis. But it is difficult to predict the metabolic flux distributions of multicellular organisms due to the lack of an explicit metabolic objective function. Here we present a computational method which can successfully describe the differences in metabolism between two different conditions on a large scale. By integrating gene expression data with an existing comprehensive reconstruction of the global human metabolic network, we qualitatively predicted significantly differential fluxes without prior knowledge or the rate of metabolite uptake and secretion. Therefore, this method can be applied for both microorganisms and multicellular organisms. Different from traditional enrichment analysis methods and constraint-based models, we consider conditions and interactions within the metabolic network simultaneously. To apply the proposed method, we predicted altered fluxes for E. coli strains and clear cell renal cell carcinoma, while the E. coli strains are growing aerobically in a chemostat with different dilution rates and clear cell renal cell carcinoma is compared with normal kidney cells. Then we map the significantly differential reactions to metabolic subsystems defined in the original metabolic network for ccRCC to observe the altered metabolism. In contrast with existing studies, our results show a high accuracy of the E. coli experiment and a more reasonable prediction of the ccRCC experiment. The method presented here provides a computational approach for the genome-wide study of altered metabolism under pairs of conditions for both microorganisms and multicellular organisms.