Purpose::Vibrio vulnificus ( V. Vulnificus) infection is characterized by rapid onset, aggressive progression, and challenging treatment. Bacterial resistance poses a significant challenge for clinical anti-infection treatment and is thus the subject of research. Enhancing host infection tolerance represents a novel infection prevention strategy to improve patient survival. Our team initially identified cytochrome P4501A1 (CYP1A1) as an important target owing to its negative modulation of the body's infection tolerance. This study explored the superior effects of the CYP1A1 inhibitor bergamottin compared to antibiotic combination therapy on the survival of mice infected with multidrug-resistant V. Vulnificus and the protection of their vital organs. Methods::An increasing concentration gradient method was used to induce multidrug-resistant V. Vulnificus development. We established a lethal infection model in C57BL/6J male mice and evaluated the effect of bergamottin on mouse survival. A mild infection model was established in C57BL/6J male mice, and the serum levels of creatinine, urea nitrogen, aspartate aminotransferase, and alanine aminotransferase were determined using enzyme-linked immunosorbent assay to evaluate the effect of bergamottin on liver and kidney function. The morphological changes induced in the presence of bergamottin in mouse organs were evaluated by hematoxylin and eosin staining of liver and kidney tissues. The bacterial growth curve and organ load determination were used to evaluate whether bergamottin has a direct antibacterial effect on multidrug-resistant V. Vulnificus. Quantification of inflammatory factors in serum by enzyme-linked immunosorbent assay and the expression levels of inflammatory factors in liver and kidney tissues by real-time quantitative polymerase chain reaction were performed to evaluate the effect of bergamottin on inflammatory factor levels. Western blot analysis of IκBα, phosphorylated IκBα, p65, and phosphorylated p65 protein expression in liver and kidney tissues and in human hepatocellular carcinomas-2 and human kidney-2 cell lines was used to evaluate the effect of bergamottin on the nuclear factor kappa-B signaling pathway. One-way ANOVA and Kaplan-Meier analysis were used for statistical analysis. Results::In mice infected with multidrug-resistant V. Vulnificus, bergamottin prolonged survival ( p = 0.014), reduced the serum creatinine ( p = 0.002), urea nitrogen ( p = 0.030), aspartate aminotransferase ( p = 0.029), and alanine aminotransferase ( p = 0.003) levels, and protected the cellular morphology of liver and kidney tissues. Bergamottin inhibited interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α expression in serum (IL-1β: p = 0.010, IL-6: p = 0.029, TNF-α: p = 0.025) and inhibited the protein expression of the inflammatory factors IL-1β, IL-6, TNF-α in liver (IL-1β: p = 0.010, IL-6: p = 0.011, TNF-α: p = 0.037) and kidney (IL-1β: p = 0.016, IL-6: p = 0.011, TNF-α: p = 0.008) tissues. Bergamottin did not affect the proliferation of multidrug-resistant V. Vulnificus or the bacterial load in the mouse peritoneal lavage fluid ( p = 0.225), liver ( p = 0.186), or kidney ( p = 0.637). Conclusion::Bergamottin enhances the tolerance of mice to multidrug-resistant V. Vulnificus infection. This study can serve as a reference and guide the development of novel clinical treatment strategies for V. Vulnificus.

BACKGROUND: Patients with atrial fibrillation (AF) and prior stroke history have a high risk of cardiovascular events despite anticoagulation therapy. It is unclear whether catheter ablation (CA) has further benefits in these patients. METHODS: AF patients with a previous history of stroke or systemic embolism (SE) from the prospective Chinese Atrial Fibrillation Registry study between August 2011 and December 2020 were included in the analysis. Patients were matched in a 1:1 ratio to CA or medical treatment (MT) based on propensity score. The primary outcome was a composite of all-cause death or ischemic stroke (IS)/SE. RESULTS: During a total of 4.1 ± 2.3 years of follow-up, the primary outcome occurred in 111 patients in the CA group (3.3 per 100 person-years) and in 229 patients in the MT group (5.7 per 100 person-years). The CA group had a lower risk of the primary outcome compared to the MT group [hazard ratio (HR) = 0.59, 95% CI: 0.47-0.74, P < 0.001]. There was a significant decreasing risk of all-cause mortality (HR = 0.43, 95% CI: 0.31-0.61, P < 0.001), IS/SE (HR = 0.73, 95% CI: 0.54-0.97, P = 0.033), cardiovascular mortality (HR = 0.32, 95% CI: 0.19-0.54, P < 0.001) and AF recurrence (HR = 0.33, 95% CI: 0.30-0.37, P < 0.001) in the CA group compared to that in the MT group. Sensitivity analysis generated consistent results when adjusting for time-dependent usage of anticoagulants. CONCLUSIONS In AF patients with a prior stroke history, CA was associated with a lower combined risk of all-cause death or IS/SE. Further clinical trials are warranted to confirm the benefits of CA in these patients.

OBJECTIVE: To demonstrate the mechanism of mechanical ventilation (MV) induced endoplasmic reticulum stress (ERS) promoting mechanical ventilation-induced pulmonary fibrosis (MVPF), and to clarify the role of angiotensin receptor 1 (AT1R) during the process. METHODS: The C57BL/6 mice were randomly divided into four groups: Sham group, MV group, AT1R-shRNA group and MV+AT1R-shRNA group, with 6 mice in each group. The MV group and MV+AT1R-shRNA group mechanically ventilated for 2 hours after endotracheal intubation to establish MVPF animal model (parameter settings: respiratory rate 70 times/minutes, tidal volume 20 mL/kg, inhated oxygen concentration 0.21). The Sham group and AT1R-shRNA group only underwent intubation after anesthesia and maintained spontaneous breathing. AT1R-shRNA group and MV+AT1R-shRNA group were airway injected with the adeno-associated virus one month before modeling to inhibit AT1R gene expression in lung tissue. The expressions of AT1R, ERS signature proteins [immunoglobulin heavy chain-binding protein (BIP), protein disulfide isomerase (PDI)], fibrosis signature proteins [collagen I (COL1A1), α-smooth muscle actin (α-SMA)] in lung tissues were detected by immunofluorescence and Western blotting. Hematoxylin-eosin (HE) staining was used to evaluate lung injury and Masson staining was used to evaluate pulmonary fibrosis. RESULTS: Compared with the Sham group, the degree of pulmonary fibrosis and lung injury were more significant in the MV group. In the MV group, the protein expressions of AT1R, BIP, PDI, COL1A1 and α-SMA were increased (AT1R/β-actin: 1.40±0.02 vs. 1, BIP/β-actin: 2.79±0.07 vs. 1, PDI/β-actin: 2.07±0.02 vs. 1, COL1A1/α-Tubulin: 2.60±0.15 vs. 1, α-SMA/α-Tubulin: 2.80±0.25 vs. 1, all P < 0.01). The number of E-cad⁺/AT1R⁺ and E-cad⁺/BIP⁺ cells in lung tissue increased, and the fluorescence intensity of COL1A1 and α-SMA increased. Compared with the MV group, the degree of pulmonary fibrosis and lung injury were significantly relieved in the MV+AT1R-shRNA group. In the MV+AT1R-shRNA group, the protein expressions of AT1R, BIP, PDI, COL1A1 and α-SMA were decreased (AT1R/β-actin: 0.53±0.03 vs. 1.40±0.02, BIP/β-actin: 1.73±0.15 vs. 2.79±0.07, PDI/β-actin: 1.04±0.07 vs. 2.07±0.02, COL1A1/α-Tubulin: 1.29±0.11 vs. 2.60±0.15, α-SMA/α-Tubulin: 1.27±0.10 vs. 2.80±0.25, all P < 0.01). The number of E-cad⁺/AT1R⁺ and E-cad⁺/BIP⁺ cells in lung tissue decreased, and the fluorescence intensity of COL1A1 and α-SMA decreased. There was no statistically significant difference in the indicators between AT1R-shRNA group and Sham group. CONCLUSIONS MV up-regulate the expression of AT1R in alveolar epithelial cells, activate the AT1R pathway, induce ERS and promote the progression of MVPF.
Mice ; Animals ; Pulmonary Fibrosis/chemically induced* ; Lung Injury ; Respiration, Artificial/adverse effects* ; Actins/metabolism* ; Tubulin ; Mice, Inbred C57BL ; Endoplasmic Reticulum Stress ; RNA, Small Interfering

Bromodomain-containing protein 4 (BRD4) is one of the most important members in the bromodomain and extra terminal domain(BET) family, it plays an important role in cellular physiology in human body, such as cell cycles, cell proliferation, and immune response. Recent studies have shown that BRD4 is associated with occurrence and development of acute myeloblastic leukemia, multiple myeloma and lymphoma. The mechanisms of BRD4 in hematologic malignancies including the regulation of c-Myc expression, and participation of the composition of super-enhancer, etc. At present, many kinds of inhibitors have been developed to target inhibit BRD4 for therapy in hematologic malignancies, and some of BRD4 inhibitors have entered phase Ⅱ clinical trials, which suggested that BRD4 inhibitors are expected to become new therapeutic agents for hematologic malignancies. In this review, the research advance of BRD4 and BRD4 inhibitors in hematologic malignancies was summarized briefly.
Cell Cycle Proteins ; Cell Proliferation ; Hematologic Neoplasms/drug therapy* ; Humans ; Nuclear Proteins ; Protein Domains ; Transcription Factors

To explore therapeutic effect of irbesartan combined metoprolol on patients with chronic heart failure (CHF) complicated atrial or ventricular arrhythmia .Methods : A total of 168 CHF patients with atrial or ventricular arrhythmia treated in our hospital from 2017 were randomly and equally divided into metoprolol group (re‐ceived metoprolol based on routine treatment ) and combined treatment group (received irbesartan based on metoprolol group) , both groups were treated for three months .LVEF , left ventricular posterior wall thickness (LVPWT) , interven‐tricular septal thickness (IVST) before and after treatment , therapeutic effect were observed and compared between two groups.Results : Total effective rate of combined treatment group was significantly higher than that of metoprolol group (90.5% vs.73.8%) , P＝ 0.005. Compared with before treatment , there was significant rise in LVEF [ (55.16 ± 6.52)% vs.(64.24 ± 8.72)%] , and significant reductions in LVPWT [ (14.72 ± 1.78) mm vs.(13.27 ± 1.14) mm] , IVST [ (10.18 ± 1.15) mm vs.(9.12 ± 0.64) mm] in combined treatment group after treatment , P＝0.001 all ;and compared with metoprolol group after three‐month treatment , there was significant rise in LVEF [ (56.13 ± 6.15)%vs.(64. 24 ± 8.72)%] , and significant reductions in LVPWT [ (14. 35 ± 1. 23) mm vs.(13.27 ± 1.14) mm] and IVST [(9. 88 ± 0.85) mm vs.(9. 12 ± 0. 64) mm] in combined treatment group , P＝0. 001 all.There was no signif‐icant difference in incidence rate of adverse between two groups , P＝ 0.799. Conclusion : Irbesartan combined metoprolol possess significant therapeutic effect on patients with CHF complicated atrial or ventricular arrhythmia with good safety .Inhibition on ventricular remodeling may be its main mechanism .

To observe therapeutic effect of early use of nicorandil on patients with myocardial infarction (MI) undergoing percutaneous coronary intervention (PCI) and its influence on cardiac function .Methods : A total of 124 MI patients undergoing PCI in our hospital from 2016 to 2018 were randomly and equally divided into PCI group and nicorandil + PCI group (received nicorandil based on PCI group ) , both groups were treated for 28d. Therapeutic effect , incidence of adverse , LVEF , LVEDd and cardiac index (CI) before and three months after PCI were recorded and compared between two groups .Results : Compared with PCI group , there was significant rise in total effective rate (72.6% vs .90.3%) , and significant reductions in incidence rates of recurrent angina pectoris (25.8% vs.11.3%) and malignant arrhythmia (22.6% vs.8.1%) in nicorandil + PCI group , P＜0. 05 all.Compared with before PCI , there were significant rise in LVEF and CI , and significant reduction in LVEDd in two groups on three months after PCI ;compared with PCI group , there were significant rise in LVEF [ (40.52 ± 4.38)% vs.(46.81 ± 4.53)%] and CI [ (2.43 ± 0.35) L·min－1 ·m－2 vs.(2.66 ± 0.38) L·min－1 ·m－2 ] , and significant reduction in LVEDd [ (54. 32 ± 6.23) mm vs.(48. 24 ± 5.34) mm] in nicorandil + PCI group on three months after PCI , P＝0.001 all.There was no significant difference in incidence rate of adverse drug reactions dur‐ing treatment between two groups , P＝0.753. Conclusion : Early use of nicorandil can significantly improve thera‐peutic effect , contribute to recovery of cardiac function with good safety in MI patients undergoing PCI , which is worth extending .

OBJECTIVETo assess the methodological quality of systematic reviews and meta-analyses regarding acupuncture intervention for stroke and the primary studies within them.

METHODSTwo researchers searched PubMed, Cumulative index to Nursing and Allied Health Literature, Embase, ISI Web of Knowledge, Cochrane, Allied and Complementary Medicine, Ovid Medline, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Wanfang and Traditional Chinese Medical Database to identify systematic reviews and meta-analyses about acupuncture for stroke published from the inception to December 2016. Review characteristics and the criteria for assessing the primary studies within reviews were extracted. The methodological quality of the reviews was assessed using adapted Oxman and Guyatt Scale. The methodological quality of primary studies was also assessed.

RESULTSThirty-two eligible reviews were identified, 15 in English and 17 in Chinese. The English reviews were scored higher than the Chinese reviews (P=0.025), especially in criteria for avoiding bias and the scope of search. All reviews used the quality criteria to evaluate the methodological quality of primary studies, but some criteria were not comprehensive. The primary studies, in particular the Chinese reviews, had problems with randomization, allocation concealment, blinding, dropouts and withdrawals, intent-to-treat analysis and adverse events.

CONCLUSIONSImportant methodological flaws were found in Chinese systematic reviews and primary studies. It was necessary to improve the methodological quality and reporting quality of both the systematic reviews published in China and primary studies on acupuncture for stroke.

OBJECTIVETo study the prevention effect of salidroside on contrast-induced-nephropathy (CIN) and its underlying mechanism.

METHODSA total of 24 Wistar rats were randomly divided into 4 groups with 6 in each group. Rats were firstly administrated with normal saline (control and model groups), N-acetylcysteine (NAC, NAC group) and salidroside (salidroside group) for 7 days before model establishment in each group, respectively. Histopathological analysis was performed by periodic acid-Schiff (PAS) staining. Oxidative stress related parameters including superoxide dismutase (SOD) and methane dicarboxylic aldehyde (MDA), nitric oxide (NO), angiotensin II (Ang II), 8-hydroxy-2'-deoxyguanosine (8-OHdG), mRNA and protein levels of endothelial nitric oxide synthase (eNOS), and nitric oxide synthase (NOS) activity were measured.

RESULTSCompared with the control group, the levels of MDA, Ang II and 8-OHdG were all significantly increased and levels of SOD, NO, and eNOS mRNA and protein were decreased significantly in the model group (P<0.05). Meanwhile, the NOS activity was also significantly decreased in the model group (P<0.05). In addition, the levels of these parameters were all improved in the NAC (P<0.05) and salidroside groups and no significant different was found between these two groups (P>0.05).

CONCLUSIONSalidroside can be the potential substitute of NAC to prevent CIN. The underlying mechanism may be associated with oxidative stress damage caused by contrast agents.

Acetylcysteine ; pharmacology ; Animals ; Contrast Media ; adverse effects ; Cytoprotection ; drug effects ; Glucosides ; pharmacology ; Kidney ; drug effects ; pathology ; Kidney Diseases ; chemically induced ; prevention & control ; Oxidative Stress ; drug effects ; Phenols ; pharmacology ; Rats ; Rats, Wistar ; Signal Transduction ; drug effects

OBJECTIVETo establish a method to determine underivatized endogenous amino acids in brain tissues after cerebral ischemia based on RRLC-QQQ.

METHODDiamonsil chromatographic column C18 (4.6 mm x 250 mm, 5 microm) was adopted to determine 12 amino acids in 15 min, with acetonitrile-0.1% formic acid for gradient elution. The flow rate was set at 0.5 mL x min(-1). With ESI as the ion source, positive ion scanning mode was adopted for multi-reaction monitoring.

RESULTEach amino acid standard curve (AAs) showed good linear relationship within the detection range (r > 0.996), with the limit of detection of less than 11%, the limit of quantitation of less than 3.09 microg x L(-1). The RSD of intra- and inter-day precisions at high, middle and low concentrations were less than 11%.

CONCLUSIONThe determination results of actual samples showed that compared with the levels of AAs of the sham operation group, all of the remaining amino acids apart from N-acetyl-aspartate increased in brain tissues. Some amino acids showed significant changes in a time-dependent manner after the operation. The method is so simple, rapid and sensitive that it can be used for finding biological metabolite markers of cerebral ischemia, and exploring cerebral ischemia molecular mechanisms and synergistic mechanism of combined administration of multi-component traditional Chinese medicines.

Amino Acids ; metabolism ; Animals ; Brain ; metabolism ; Brain Ischemia ; metabolism ; Chromatography, High Pressure Liquid ; methods ; Male ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results ; Tandem Mass Spectrometry ; methods

OBJECTIVETo observe the effect of nitric oxide (NO) on adhesion, proliferation, and migration of human epidermal stem cells (ESC) in vitro.

METHODSESC were isolated and cultured by the modified method of rapid attachment to type IV collagen. (1) Morphology of cells was observed under inverted phase-contrast microscope. Expression levels of integrin β(1) and cytokeratin 19 (CK19) of cells were determined by Western blotting and immunofluorescence staining. (2) After being treated with scratching, ESC adhered to the wall was respectively treated with nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) in the concentration of 1, 10, 100, 500 µmol/L. ESC without treatment of SNAP was used as control. The migration rate of ESC was detected at post scratching hour (PSH) 12 and 24. The chemotaxis of ESC (treated with SNAP in above-mentioned concentration) was tested by Transwell assay, and the transferred cell number was counted. (3) ESC was respectively treated with SNAP in the concentration of 10, 100, 500 µmol/L for 1 h. ESC without treatment of SNAP was used as control. The adhesion of ESC was detected with adhesion test, and the inhibition rate of adhesion was calculated. The proliferation of ESC (denoted as absorbance value) was determined by microplate reader at post-treatment hour (PTH) 0, 12, 24, 48. Data were processed with one-way analysis of variance and Dunnett t test.

RESULTS(1) Small clone formed on post culture days (PCD) 5 to 9. On PCD 10 to 14, cell proliferation sped up. CK19 and integrin β(1) were detected to be expressed in the isolated cells. The cells were identified as ESC. (2) Compared with that of ESC without treatment of SNAP [(35.7 ± 0.3)%, (45.7 ± 5.0)%], migration of ESC treated with SNAP in the concentration from 1 to 100 µmol/L was promoted at PSH 12 and 24. Migration rates of ESC treated with 100 µmol/L SNAP were the highest [respectively (48.8 ± 2.7)%, (82.1 ± 15.8)%, with t value respectively 8.34, 5.10, P values both below 0.01]. The number of ESC transferred to membrane after being treated with 100 µmol/L SNAP was significantly larger than that of ESC without treatment of SNAP (t = 9.24, P = 0.00). (3) Absorbance values of ESC treated with 100, 500 µmol/L SNAP were obviously higher than that of ESC without treatment of SNAP (with t value respectively 4.30, 4.67, P values both equal to 0.00). Proliferation of ESC treated with 100, 500 µmol/L SNAP was obviously stronger than that of cells without treatment of SNAP at PTH 24, 48 (with t values from 2.84 to 8.17, P values all below 0.05).

CONCLUSIONSExogenous NO in suitable concentration can promote the migration of human ESC. Exogenous NO can inhibit the adhesion and promote the proliferation of human ESC in vitro.

Cell Movement ; drug effects ; Cell Proliferation ; Cells, Cultured ; Epithelial Cells ; cytology ; drug effects ; Humans ; Nitric Oxide ; pharmacology ; Stem Cells ; cytology ; drug effects