Protective Effects of Sesamol on Renal Ischemia-Reperfusion Injury Via Regulation of Nuclear Factor Erythroid 2-Related Factor 2 Pathway.

BACKGROUND: Sesamol is a natural antioxidant known for its potent antioxidant and free radical scavenging properties. This study aimed to explore the therapeutic effects and underlying mechanisms of sesamol in the development of renal ischemia-reperfusion injury (IRI) in mice. METHODS: C57BL/6J wild-type mice were divided into 3 groups: IR group, treated with normal saline after undergoing the IRI procedure; Sesamol + IR group, treated with 30 mg/kg/d of sesamol after the IRI procedure; and Sham group, treated with normal saline but not subjected to the IRI process. Renal IRI was induced by performing a right kidney nephrectomy and subjecting the left kidney to 30-minute ischemia, followed by 24-hour reperfusion. Kidney tissues and serum were collected 24 hours post-IRI to assess the impact of sesamol on renal function after IRI. Serum creatinine and blood urea nitrogen levels were assessed, and renal cell apoptosis was detected through terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. The levels of interleukin 1ß and interleukin 18 in kidney tissues, as well as indicators of oxidative stress, were also measured. Furthermore, Nrf2-deficient mice were used to examine the protective function of the nuclear factor erythroid 2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO1) signaling pathways induced by sesamol, as determined by western blot assay. RESULTS: Sesamol demonstrated significant improvement in renal function, along with reductions in renal tubular injury, cell necrosis, and apoptosis in mice. It also effectively lowered key inflammatory mediator levels. Sesamol exhibited antioxidant properties by reducing malondialdehyde levels and enhancing superoxide dismutase activities 24 hours after IRI. Western blot assay revealed increased Nrf2, HO-1, and NQO-1 protein levels with sesamol treatment. Notably, Nrf2-deficient mice did not exhibit the beneficial effects of sesamol. CONCLUSIONS: This study demonstrates that sesamol effectively alleviates renal IRI by enhancing antioxidant defenses and reducing inflammation potentially through the Nrf2/HO-1 and NQO1 signaling pathways.

Effect of Early versus Delayed Use of Norepinephrine on Short-Term Outcomes in Patients with Traumatic Hemorrhagic Shock: A Propensity Score Matching Analysis.

Background: Guidelines recommend norepinephrine (NE) for the treatment of fatal hypotension caused by trauma. However, the optimal timing of treatment remains unclear. Objective: We aimed to investigate the effect of early versus delayed use of NE on survival in patients with traumatic haemorrhagic shock (HS). Materials and Methods: From March 2017 to April 2021, 356 patients with HS in the Department of Emergency Intensive Care Medicine of the Affiliated Hospital of Yangzhou University were identified using the emergency information system and inpatient electronic medical records for inclusion in the study. Our study endpoint was 24 h mortality. We used a propensity score matching (PSM) analysis to reduce bias between groups. Survival models were used to evaluate the relationship between early NE and 24 h survival. Results: After PSM, 308 patients were divided equally into an early NE (eNE) group and a delayed NE (dNE) group. Patients in the eNE group had lower 24 h mortality rates than those in the dNE group (29.9% versus 44.8%, respectively). A receiver operating characteristic analysis demonstrated that a cut-off point for NE use of 4.4 h yielded optimal predictive value for 24 h mortality, with a sensitivity of 95.52%, a specificity of 81.33% and an area under the curve value of 0.9272. Univariate and multivariate survival analyses showed that the survival rate of patients in the eNE group was higher (p < 0.01) than those in the dNE group. Conclusion: The use of NE within the first 3 h was associated with a higher 24 h survival rate. The use of eNE appears to be a safe intervention that benefits patients with traumatic HS.

Prediction of factors influencing the timing and prognosis of early tracheostomy in patients with multiple rib fractures: A propensity score matching analysis.

Objective: To investigate the factors affecting the timing and prognosis of early tracheostomy in multiple rib fracture patients. Methods: A retrospective case-control study was used to analyze the clinical data of 222 patients with multiple rib fractures who underwent tracheotomy in the Affiliated Hospital of Yangzhou University from February 2015 to October 2021. According to the time from tracheal intubation to tracheostomy after admission, the patients were divided into two groups: the early tracheostomy group (within 7 days after tracheal intubation, ET) and late tracheostomy group (after the 7th day, LT). Propensity score matching (PSM) was used to eliminate the differences in baseline characteristics Logistic regression was used to predict the independent risk factors for early tracheostomy. Kaplan-Meier and Cox survival analyses were used to analyze the influencing factors of the 28-day survival. Results: According to the propensity score matching analysis, a total of 174 patients were finally included in the study. Among them, there were 87 patients in the ET group and 87 patients in the LT group. After propensity score matching, Number of total rib fractures (NTRF) (P < 0.001), Acute respiratory distress syndrome (ARDS) (P < 0.001) and Volume of pulmonary contusion(VPC) (P < 0.000) in the ET group were higher than those in the LT group. Univariate analysis showed that the patients who underwent ET had a higher survival rate than those who underwent LT (P = 0.021). Pearson's analysis showed that there was a significant correlation between NTRF and VPC (r = 0.369, P = 0.001). A receiver operating characteristic(ROC)curve analysis showed that the areas under the curves were 0.832 and 0.804. The best cutoff-value values of the VPC and NTRF were 23.9 and 8.5, respectively. The Cox survival analysis showed that the timing of tracheostomy (HR = 2.51 95% CI, 1.12-5.57, P = 0.004) and age (HR = 1.53 95% CI, 1.00-2.05, P = 0.042) of the patients had a significant impact on the 28-day survival of patients with multiple rib fractures. In addition, The Kaplan-Meier survival analysis showed that the 28-day survival of patients in the ET group was significantly better than that of the LT group, P = 0.01. Conclusions: NTRF, ADRS and VPC are independent risk factors for the timing and prognosis of early tracheotomy. A VPC ≥ 23.9% and/or an NTRF ≥ 8.5 could be used as predictors of ET in patients with multiple rib fractures. Predicting the timing of early tracheostomy also need prediction models in the future.

Bioinformatics Analysis Screened and Identified Key Genes as Potential Biomarkers for Progression of Lung Cancer.

OBJECTIVE: To screen and identify key genes as potential biomarkers of lung cancer using bioinformatics analysis. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Department of Critical Care Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China, from August 2018 to April 2021. METHODOLOGY: Independent microarray datasets (GSE85841 and GSE118370) were downloaded from the Gene Expression Omnibus (GEO) database and the differentially expressed genes (DEGs) were screened using GEO2R. Cytohubba was employed to identify the hub genes. Cellular component analysis, hierarchical clustering, and survival analyses of hub genes were performed via BiNGO, UCSC, and cBioPorta. A series of analyses of FGF2 and PIK3R1 were conducted using Oncomine. RESULTS: A total of 463 DEGs were identified and 11 hub genes were determined. BDNF, FGF2, JAK2, NCAM1, CAV1, TJP1, and PIK3R1 may affect the survival probability and life expectancy of lung cancer patients, but the p-values were not statistically significant. FGF2 and PIK3R1 had the highest node degrees, 40 and 32 respectively. The expression of FGF2 and PIK3R1 were significantly lower in the 4 lung cancer data sets compared with non-lung cancer tissues. And the low expression of FGF2 and PIK3R1 is related to tumor grades, family history of cancer, multiple tumors present, and prior therapy of lung cancer. CONCLUSION: Evaluation of FGF2 and PIK3R1 as potential biomarkers can contribute to the subsequent theoretical analysis of potential molecular mechanisms and development of lung cancer, so that the diagnosis of lung cancer may be more accurate, and it is possible to provide therapeutic and prognostic medicine targets. KEY WORDS: Lung neoplasms, Differentially expressed genes, Bioinformatical analysis, Microarray analysis, biomarkers.

Comparison of the gut microbiota of short-term and long-term medical workers and non-medical controls: a cross-sectional analysis.

OBJECTIVES: The hospital environment has been implicated in the enrichment and exchange of pathogens and antibiotic resistance, but its potential in shaping the symbiotic microbial community of hospital staff is unclear. This study was designed to evaluate the alteration of the gut microbiome in medical workers compared to non-medical controls. METHODS: A prospective cross-sectional cohort study was conducted in the intensive care unit (ICU) and other departments of a centre in north-eastern China. Faecal samples of 175 healthy medical workers-short-term (1-3 months) workers (n = 80) and long-term (>1 year) workers (n = 95)-and 80 healthy non-medical controls were analysed using 16S rRNA amplicon sequencing. The hospital environmental samples (n = 9) were also analysed. RESULTS: The gut microbiomes of medical workers exhibited marked deviations in diversity and alteration in microbial composition and function. Short-term workers showed significantly higher abundances of taxa such as Lactobacillus, Butyrivibrio, Clostridiaceae, Clostridium, Ruminococcus, Dialister, Bifidobacterium, Odoribacter, and Desulfovibrio and lower abundances of Bacteroides and Blautia than the controls. Long-term workers showed higher abundances of taxa such as Dialister, Veillonella, Clostridiaceae, Clostridium, Bilophila, Desulfovibrio, Pseudomonas, and Akkermansia and lower abundances of Bacteroides and Coprococcus than the controls. The medical workers' department (ICU versus non-ICU) and position (resident doctor versus nursing staff) also impacted their gut microbiome. Compared with the non-ICU workers, workers in the ICU showed a significant increase in the abundances of Dialister, Enterobacteriaceae, Phascolarctobacterium, Pseudomonas, Veillonella, and Streptococcus and a marked depletion of Faecalibacterium, Blautia, and Coprococcus. In contrast with the nursing staff, the resident doctors showed a significant increase in Erysipelotrichaceae and Clostridium and a decrease in Bacteroides, Blautia, and Ruminococcus in the gut microbiome. Moreover, we found that the microbiota of hospital environments potentially correlated with the workers' gut microbiota. CONCLUSIONS: Our findings demonstrated structural changes in the gut microbial community of medical workers.

Flubendazole, FDA-approved anthelmintic, targets breast cancer stem-like cells.

Cancer stem-like cell (CS-like cell) is considered to be responsible for recurrence and drug resistance events in breast cancer, which makes it a potential target for novel cancer therapeutic strategy. The FDA approved flubendazole, has been widely used in the treatment of intestinal parasites. Here, we demonstrated a novel effect of flubendazole on breast CS-like cells. Flubendazole inhibited breast cancer cells proliferation in dose- and time-dependent manner and delayed tumor growth in xenograft models by intraperitoneal injection. Importantly, flubendazole reduced CD44high/CD24low subpopulation and suppressed the formation of mammosphere and the expression of self-renewal related genes including c-myc, oct4, sox2, nanog and cyclinD1. Moreover, we found that flubendazole induced cell differentiation and inhibited cell migration. Consistently, flubendazole reduced mesenchymal markers (ß-catenin, N-cadherin and Vimentin) expression and induced epithelial and differentiation marker (Keratin 18) expression in breast cancer cells. Mechanism study revealed that flubendazole arrested cell cycle at G2/M phase and induced monopolar spindle formation through inhibiting tubulin polymerization. Furthermore, flubendazole enhanced cytotoxic activity of conventional therapeutic drugs fluorouracil and doxorubicin against breast cancer cells. In conclusion, our findings uncovered a remarkable effect of flubendazole on suppressing breast CS-like cells, indicating a novel utilization of flubendazole in breast cancer therapy.

Aurora kinase a suppresses metabolic stress-induced autophagic cell death by activating mTOR signaling in breast cancer cells.

Aberrant Aur-A signaling is associated with tumor malignant behaviors. However, its involvement in tumor metabolic stress is not fully elucidated. In the present study, prolonged nutrient deprivation was conducted into breast cancer cells to mimic metabolic stress in tumors. In these cells, autophagy was induced, leading to caspase-independent cell death, which was blocked by either targeted knockdown of autophagic gene ATG5 or autophagy inhibitor 3-Methyladenine (3-MA). Aur-A overexpression mediated resistance to autophagic cell death and promoted breast cancer cells survival when exposed to metabolic stress. Moreover, we provided evidence that Aur-A suppressed autophagy in a kinase-dependent manner. Furthermore, we revealed that Aur-A overexpression enhanced the mammalian target of rapamycin (mTOR) activity under metabolic stress by inhibiting glycogen synthase kinase 3ß (GSK3ß). Inhibition of mTOR activity by rapamycin sensitized Aur-A-overexpressed breast cancer cells to metabolic stress-induced cell death. Consistently, we presented an inverse correlation between Aur-A expression (high) and autophagic levels (low) in clinical breast cancer samples. In conclusion, our data provided a novel insight into the cyto-protective role of Aur-A against metabolic stress by suppressing autophagic cell death, which might help to develop alternative cell death avenues for breast cancer therapy.

Up-regulation of P21 inhibits TRAIL-mediated extrinsic apoptosis, contributing resistance to SAHA in acute myeloid leukemia cells.

BACKGROUND/AIM: P21, a multifunctional cell cycle-regulatory molecule, regulates apoptotic cell death. In this study we examined the effect of altered p21 expression on the sensitivity of acute myeloid leukemia cells in response to HDAC inhibitor SAHA treatment and investigated the underlying mechanism. METHODS: Stably transfected HL60 cell lines were established in RPMI-1640 with supplementation of G-418. Cell viability was measured by MTT assay. Western blot was applied to assess the protein expression levels of target genes. Cell apoptosis was monitored by AnnexinV-PE/7AAD assay. RESULTS: We showed HL60 cells that that didn't up-regulate p21 expression were more sensitive to SAHA-mediated apoptosis than NB4 and U937 cells that had increased p21 level. Enforced expression of p21 in HL60 cells reduced sensitivity to SAHA and blocked TRAIL-mediated apoptosis. Conversely, p21 silencing in NB4 cells enhanced SAHA-mediated apoptosis and lethality. Finally, we found that combined treatment with SAHA and rapamycin down-regulated p21 and enhanced apoptosis in AML cells. CONCLUSION: We conclude that up-regulated p21 expression mediates resistance to SAHA via inhibition of TRAIL apoptotic pathway. P21 may serve as a candidate biomarker to predict responsiveness or resistance to SAHA-based therapy in AML patients. In addition, rapamycin may be an effective agent to override p21-mediated resistance to SAHA in AML patients.

[Bleeding and pneumonia in intensive care unit patients given proton pump inhibitor or histamine-2 receptor antagonist for prevention of stress ulcer: a Meta analysis].

OBJECTIVE: To assess the efficacy and safety of proton pump inhibitor (PPI) and histamine-2 receptor antagonist (H(2)RA) in intensive care unit patients for stress ulcer prophylaxis. METHODS: A systematic search of MEDLINE (1966 to March 2009), Ebsco and CNKI was made. Two reviewers were assigned to assess the quality of studies and extracted data independently. Six items were evaluated for each trial (patient selection, patient characteristics, randomization, blinding, definition of bleeding and of pneumonia). Disagreements were resolved through discussion. RevMan 4.2.2 software developed by the cochrane collaboration was used for Meta-analysis. RESULTS: Four series of clinical use involving 771 patients were included. Meta-analysis showed that the incidence of clinically significant bleeding was significantly lower in the PPI group (2.2% vs. 6.8%) as compared to H(2)RA group [odds ratio (OR) 0.45, 95% confidence interval (CI) 0.21 to 0.96, P=0.04]. There was no significant difference of the incidence of nosocomial pneumonia (10.0% vs. 9.9%, OR 1.03, 95%CI 0.63 to 1.70, P=0.89) and mortality (14.5% vs. 14.3%,OR 1.17, 95%CI 0.76 to 1.80, P=0.47) between two groups. CONCLUSION: In comparison with H(2)RA, PPI is more effective in the prevention of stress ulcer bleeding (SUB) in patients under intensive care. There is no significant difference in the incidence of nosocomial pneumonia and mortality between two groups. There were very few randomized controlled clinical trials on prevention of stress ulcer, and these findings were based on a small number of patients, therefore a steadfast conclusion cannot presently be reached. More randomized, multicenter studies with sufficient sample size are warranted.

[Effects of insulin-like growth factor-1 and insulin on modulating glucose metabolism and functions of lung fibroblasts].

OBJECTIVE: It is recognized that lung fibroblasts (LF) act as a common pathway in the development of fibrosis from alveolitis of whatever etiology. The study was undertaken to identify the modulating effects of insulin-like growth factor-1 (IGF-1) on LF glucose metabolism and functions, to explore possible therapeutic targets through modulating LF for the treatment of pulmonary fibrosis. METHODS: Human embryonic lung (HEL) diploid fibroblast cells were cultured for 24 h with blank control, 100 ng/ml IGF-1, 200 ng/ml IGF-1, 100 ng/ml IGF-1 + 100 ng/ml insulin, 100 ng/ml IGF-1 + 200 ng/ml insulin, 100ng/ml insulin, 200 ng/ml insulin, respectively. The culture supernatants and cell pellets were collected to extract proteins and mRNAs. After quantitated with ultraviolet spectrometer, RT-PCR and Northern blotting were performed to determine the content of glucose transporter-4 (Glut-4), hexokinase II, elastin and collagen-IV. RESULTS: RT-PCR showed that the general mean absorbance ratios of Glut-4 and HK-IImRNA in IGF-1 group were (0.67 +/- 0.25) and (0.60 +/- 0.19), significantly increased as compared with that of control group [(0.61 +/- 0.12), (0.55 +/- 0.19)]; but decreased as compared with that of insulin group [(0.74 +/- 0.26), (0.71 +/- 0.23)]. The expression of elastin, collagen protein in IGF-1 group [(174.3 +/- 4.2), (142.1 +/- 1.0)] were significantly stronger than that of insulin group. CONCLUSIONS: IGF-1 can stimulate LF glucose metabolism, companied with increased expression of elastin and collagen IV in a concentration-dependent manner. IGF-1 can decrease the effect of insulin on LF glucose metabolism, whereas insulin can attenuate the effect of IGF-1 on LF in elastin and collagen expression.

[Protective effect of glutamine on rats with pseudomonas pneumonia].

OBJECTIVE: To investigate the protective effect of glutamine in rats with pseudomonas pneumonia receiving total parenteral nutritional (TPN) therapy. METHODS: Forty Sprague-Dawley rats were randomly divided into 4 groups (Group A, B, C and D). Rats in Group A received, by intra-tracheal route, infusion of 0.3 ml normal saline. Rats in Group B received, also by intra-tracheal route, infusion of 0.3 ml pseudomonas aeruginosa soliquoid so that the bacteria entered the lungs directly. A standard TPN solution not containing glutamine was administered intravenously to rats in Group C (160 ml/kg) for 5 days, and a TPN solution containing glutamine was administered intravenously to rats in Group D (160 ml/kg) for 5 days. On day 6, 0.3 ml pseudomonas aeruginosa soliquoid was administered by intra-tracheal route to rats in Group C and D. The weight of rats, their activity and mortality were recorded. 48 h after intratracheal administration, blood and bronchoalveolar lavage fluid (BALF) samples were collected for measurement of white blood cell count, TNFalpha, IL-1, IL-10 and total protein of BALF. Segments of the lung, the liver and the ileum tissues were collected for HE pathological slice. RESULTS: (1) Initially there was no difference in weight between the four groups, but on day 8 the weights of rats in Group B, C, and D were significantly decreased compared with that in Group A (P < 0.05). The mortality of rats in Group C was significantly higher than that in Group B and D (P < 0.05). (2) There were significant differences between Group C and D in white blood cell count, blood TNFalpha and IL-10 level, BALF, and total protein of BALF (P < 0.05). (3) Pathological changes of the lung, the liver and ileum in Group C were more severe than that in Group B and D. Group A was basically normal. CONCLUSION: Glutamine is able to protect gastrointestinal tract function in rats receiving TPN, to improve pulmonary anti-infection ability, and to alleviate injuries of important organs caused by severe infection.