Epithelium-derived kallistatin promotes CD4+ T-cell chemotaxis to TH2-type inflammation in chronic rhinosinusitis.

BACKGROUND: The function of kallistatin in airway inflammation, particularly chronic rhinosinusitis with nasal polyps (CRSwNP), has not been elucidated. OBJECTIVE: We sought to investigate the role of kallistatin in airway inflammation. METHODS: Kallistatin and proinflammatory cytokine expression levels were detected in nasal polyps. For the in vivo studies, we constructed the kallistatin-overexpressing transgenic mice to elucidate the role of kallistatin in airway inflammation. Furthermore, the levels of plasma IgE and proinflammatory cytokines in the airways were evaluated in the kallistatin-/- rat in vivo model under a type 2 inflammatory background. Finally, the Notch signaling pathway was explored to understand the role of kallistatin in CRSwNP. RESULTS: We showed that the expression of kallistatin was significantly higher in nasal polyps than in the normal nasal mucosa and correlated with IL-4 expression. We also discovered that the nasal mucosa of kallistatin-overexpressing transgenic mice expressed higher levels of IL-4 expression, associating to TH2-type inflammation. Interestingly, we observed lower IL-4 levels in the nasal mucosa and lower total plasma IgE of the kallistatin-/- group treated with house dust mite allergen compared with the wild-type house dust mite group. Finally, we observed a significant increase in the expression of Jagged2 in the nasal epithelium cells transduced with adenovirus-kallistatin. This heightened expression correlated with increased secretion of IL-4, attributed to the augmented population of CD4+CD45+Notch1+ T cells. These findings collectively may contribute to the induction of TH2-type inflammation. CONCLUSIONS: Kallistatin was demonstrated to be involved in the CRSwNP pathogenesis by enhancing the TH2 inflammation, which was found to be associated with more expression of IL-4, potentially facilitated through Jagged2-Notch1 signaling in CD4+ T cells.

Trends and disparities in China's cardiovascular disease burden from 1990 to 2019.

BACKGROUND AND AIMS: In order to find the exact strategies in the prevention of cardiovascular diseases (CVD), it is necessary to assess their risk factors systematically. Here, we used the Global Burden of Disease (GBD) to review the long-term trends and epidemiological characteristics among Chinese. METHODS AND RESULTS: We comprehensively analyzed the burden of CVD for the Chinese population using GBD 2019, including prevalence, incidence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALYs). Then, we analyzed trends over time, and predicted mortality and morbidity, using joinpoint regression, age-period-cohort (APC) model, and Bayesian APC approach. Finally, we analyzed the attributable burden of CVD. In 2019, the prevalence of CVD in China was 120 million, representing a 140.02% increase since 1990. The number of DALYs attributed to CVD increased by 52.56% compared to 1990. Joinpoint showed a fluctuating incidence downward, while mortality significantly declined. The APC fitting results indicated that recent generations have a higher prevalence than the past, and the prevalence has increased among individuals of the same age group. The BAPC predicted that CVD's prevalence and mortality in the Chinese would stabilize and decline between 2020 and 2030, with a significant decline among males. The main CVD-attributable burdens in 2019 were metabolic risks, especially high blood pressure. CONCLUSION: Given China's large and rapidly aging population, the burden of CVD is a major concern. Practical strategies to prevent and manage CVD are urgently needed to address this public health challenge.

Therapeutic potential of recombinant human basic fibroblast growth factor on postoperative patients with chronic rhinosinusitis with nasal polyps.

OBJECTIVES: To explore the effect of intranasal administration of recombinant human basic fibroblast growth factor (rh-bFGF) on postoperative chronic rhinosinusitis with nasal polyps (CRSwNP) patients. DESIGN: A prospective, randomised, controlled, single-blinded trial. SETTING AND PARTICIPANTS: Seventy-five hospitalised patients who met the criteria of primary bilateral CRSwNP were enrolled from March 2020 to January 2021. MAIN OUTCOME MEASURES: Visual analogue scale, 22-item Sino-Nasal Outcome Test, Lund-Kennedy (L-K) system and scanning electron microscopy and quantitative real-time polymerase chain reaction. RESULTS: Seventy-five patients with CRSwNP were randomly assigned to three groups, and 72 patients completed the 1-month medication regimen and 1-year follow-up. Rh-bFGF nasal-spray and drop application reduced general nasal VAS scores within 2 weeks after endoscopic sinus surgery (ESS) compared to the control group. In contrast, only rh-bFGF nasal-drops reduced SNOT-22 scores at 2 weeks and 1 year compared with the control group. A significant reduction in the endoscopic L-K score was observed in the rh-bFGF nasal-spray and drop group compared with the control group. This is primarily because rh-bFGF promotes cilia growth in the nasal mucosal epithelium after the operation, as illustrated by scanning electron microscopy and expression of CP110, Tap73 and Foxj1 mRNA. For eosinophilic CRSwNP, the general VAS score of rh-bFGF nasal-drops was more obviously reduced compared to the control group after ESS. A similar trend was observed for L-K score. CONCLUSIONS: Rh-bFGF nasal-drops and sprays can quickly and effectively relieve postoperative symptoms and improve long-term prognosis of patients with CRSwNP. Moreover, rh-bFGF nasal-drops is also an effective method for postoperative patients with eosinophilic CRSwNP.

Telomerase expression marks transitional growth-associated skeletal progenitor/stem cells.

Skeletal progenitor/stem cells (SSCs) play a critical role in postnatal bone growth and maintenance. Telomerase (Tert) activity prevents cellular senescence and is required for maintenance of stem cells in self-renewing tissues. Here we investigated the role of mTert-expressing cells in postnatal mouse long bone and found that mTert expression is enriched at the time of adolescent bone growth. mTert-GFP+ cells were identified in regions known to house SSCs, including the metaphyseal stroma, growth plate, and the bone marrow. We also show that mTert-expressing cells are a distinct SSC population with enriched colony-forming capacity and contribute to multiple mesenchymal lineages, in vitro. In contrast, in vivo lineage-tracing studies identified mTert+ cells as osteochondral progenitors and contribute to the bone-forming cell pool during endochondral bone growth with a subset persisting into adulthood. Taken together, our results show that mTert expression is temporally regulated and marks SSCs during a discrete phase of transitional growth between rapid bone growth and maintenance.

A spiral cystic fibroma originating from left ventricular fascicular muscle: a case report.

BACKGROUND: In adults, cardiac fibromas are fairly rare, mostly round in shape, and few cases of ventricular fibromas of other morphology have been reported. CASE PRESENTATION: We report a case of a 47-year-old male patient admitted with recurrent nocturnal paroxysmal dyspnea, diagnosed by transthoracic cardiac ultrasound, transesophageal ultrasound, and computed tomography (CT) as a left ventricular occupancy with a spiral shape resembling a conch with a fixed base and a free distal end. CONCLUSION: This case reports a rare but noteworthy morphological features of the adult uncommon ventricular tumor pathological type. Furthermore, the patient had no notable postoperative issues and was followed up on for a year following surgery, with no residual tumors or arrhythmias discovered during the examination.

PK/PD integration and pharmacodynamic cutoff of cefquinome against cow mastitis due to Escherichia coli.

Cefquinome is the fourth generation of cephalosporin approved solely in animal usage. In order to slow down the resistance development of E. coli to cefquinome, and to protect and maintain the effectiveness of cefquinome, an ex vivo PK/PD modeling of cefquinome against E. coli in cows after intramammary infusion administration was conducted. The epidemiologic cutoff (ECOFF) and pharmacodynamic cutoff (COPD) of cefquinome against E. coli in lactation cows after intramammary infusion administration were recommended. The MICs of cefquinome against 1073 clinical E. coli isolates ranged from 0.015 to >64 µg/ml, and the ECOFF was defined as 0.125 µg/ml. The pharmacokinetic results showed that cefquinome maintained high concentration in milk for a long period with the T1/2ß of 10.60 h after intramammary infusion in dairy cows. The drug concentration in skimmed milk was still as high as 0.15 mg/ml after 48 h. Cefquinome displayed bacterial killing effect at 2× MIC with the initial inoculum of 106  cfu/ml in vitro; however, the same effect was attained with a concentration as high as 32× MIC with the initial inoculum of 108  cfu/ml both in artificial medium and in skimmed milk. The initial inoculum is an important factor on time-killing curve accounting for weakened killing pattern of cefquinome. The AUC0-24 h /MIC index correlated well with ex vivo efficacy. The AUC0-24 h /MIC values for bactericidal effect were 50, 016, and 67,644, respectively, for initial inoculum of 106 and 108  cfu/ml, indicating the bacterial loading or the severity of infection would infect the PK/PD modeling results. The ex vivo PK/PD-based population dose prediction indicated a target attainment rate (TAR) at the existing daily dose (75 mg/udder) of 84.77% against E. coli. Thus, it was recommended as rational dosage. The COPD of cefquinome against E. coli was determined as 8 µg/ml at the dose of 75 mg/udder. The derived ECOFF, COPD, together with ex vivo PK/PD-based population dose prediction served as important steps in the establishment of optimum dose regimen and provided a useful interpretative criterion to categorize the antimicrobial susceptibility testing results of cefquinome.

A novel risk score for disease control prediction of chronic rhinosinusitis.

OBJECTIVES: To assess the impact of risk factors on the disease control among chronic rhinosinusitis (CRS) patients, following 1 year of functional endoscopic sinus surgery (FESS), and combining the risk factors to formulate a convenient, visualised prediction model. DESIGN: A retrospective and nonconcurrent cohort study. SETTING AND PARTICIPANTS: A total of 325 patients with CRS from June 2018 to July 2020 at the First Affiliated Hospital of Sun Yat-sen University, the Third Affliated Hospital of Sun Yat-sen University, the Seventh Affiliated Hospital of Sun Yat-sen University. MAIN OUTCOMES MEASURES: Outcomes were time to event measures: the disease control of CRS after surgery 1 year. The presence of nasal polyps, smoking habits, allergic rhinitis (AR), the ratio of tissue eosinophil (TER) and peripheral blood eosinophil count (PBEC) and asthma was assessed. The logistic regression models were used to conduct multivariate and univariate analyses. Asthma, TER, AR, PBEC were also included in the nomogram. The calibration curve and area under curve (AUC) were used to evaluate the forecast performance of the model. RESULTS: In univariate analyses, most of the covariates had significant associations with the endpoints, except for age, gender and smoking. The nomogram showed the highest accuracy with an AUC of 0.760 (95% CI, 0.688-0.830) in the training cohort. CONCLUSIONS: In this cohort study that included the asthma, AR, TER, PBEC, which had significantly affected the disease control of CRS after surgery. The model provided relatively accurate prediction in the disease control of CRS after FESS and served as a visualised reference for daily diagnosis and treatment.

Directed Brain Network Analysis for Fatigue Driving Based on EEG Source Signals.

Fatigue driving is one of the major factors that leads to traffic accidents. Long-term monotonous driving can easily cause a decrease in the driver's attention and vigilance, manifesting a fatigue effect. This paper proposes a means of revealing the effects of driving fatigue on the brain's information processing abilities, from the aspect of a directed brain network based on electroencephalogram (EEG) source signals. Based on current source density (CSD) data derived from EEG signals using source analysis, a directed brain network for fatigue driving was constructed by using a directed transfer function. As driving time increased, the average clustering coefficient as well as the average path length gradually increased; meanwhile, global efficiency gradually decreased for most rhythms, suggesting that deep driving fatigue enhances the brain's local information integration abilities while weakening its global abilities. Furthermore, causal flow analysis showed electrodes with significant differences between the awake state and the driving fatigue state, which were mainly distributed in several areas of the anterior and posterior regions, especially under the theta rhythm. It was also found that the ability of the anterior regions to receive information from the posterior regions became significantly worse in the driving fatigue state. These findings may provide a theoretical basis for revealing the underlying neural mechanisms of driving fatigue.

Associations of environment and lifestyle factors with suboptimal health status: a population-based cross-sectional study in urban China.

INTRODUCTION: Suboptimal health status (SHS), an intermediate state between chronic disease and health, is characterized by chronic fatigue, non-specific pain, headaches, dizziness, anxiety, depression, and functional system disorders with a high prevalence worldwide. Although some lifestyle factors (e.g. smoking, alcohol consumption, physical exercise) and environmental factors (e.g. air quality, noise, living conditions) have already been studied, few studies can comprehensively illustrate the associations of lifestyle and environment factors with general, physical, mental, and social SHS. METHODS: A cross-sectional study was conducted among 6750 urban residents aged 14 years or over in five random cities from September 2017 to September 2018 through face-to-face questionnaires. There were 5881 valid questionnaires with a response rate of 87%. A general linear model and structural equation model were developed to quantify the effects of lifestyle behaviors and environment factors on SHS. RESULTS: The detection rates of general, physical, mental, and social SHS were 66.7, 67.0, 65.5, and 70.0%, respectively. Good lifestyle behaviors and favorable environment factors positively affected SHS (P < 0.001). Lifestyle behaviors had the largest effect on physical SHS (ß = - 0.418), but the least on social SHS (ß = - 0.274). Environment factors had the largest effect on mental SHS (ß = 0.286), but the least on physical SHS (ß = 0.225). CONCLUSIONS: Lifestyle behaviors and environment factors were important influencing factors of SHS. Physical SHS was more associated with lifestyle. Lifestyle and environment were similarly associated with mental and social SHS.

Reliability and validity of Healthy Fitness Measurement Scale Version1.0 (HFMS V1.0) in Chinese elderly people.

PURPOSE: We examined the reliability and validity of the Healthy Fitness Measurement Scale Version 1.0 (HFMS V1.0) specifically on elderly people in China. METHODS: We carried out a cross-sectional study in December 2020 and enrolled 800 elderly people through stratified sampling technique, including 777 valid samples (with a mean age of 71.81 ± 8.36 years), of which 382 cases (49.2%) were women. The level of healthy fitness was measured using the HFMS V1.0. The Cronbach's alpha coefficient, split-half reliability, test-retest reliability, convergent and discriminant validity, exploratory factor and confirmatory factor were calculated for assessing the reliability and validity of HFMS V1.0. RESULTS: HFMS V1.0 consists of 8 dimensions and 38 items. The scale had acceptable reliability (Cronbach's alpha = 0.920, split-half = 0.946, test-retest = 0.878). Exploratory factor analysis showed KMO value =0.927, and uncovered 10 factors with the cumulative contribution rate of 65.71% and all factor loads over 0.40. The item distribution was consistent with the initial expectation of the scale. The confirmatory factor analysis indicated good fit: CMIN/DF = 2.796, RMSEA = 0.048, IFI =0.914, TLI = 0.902, CFI = 0.913. CONCLUSION: HFMS V1.0 was shown to have acceptable reliability and validity indices for this sample. Collectively, HFMS V1.0 is reliable and efficient to measure the healthy fitness of elderly people. It is recommended to use it among the elderly in other Chinese cities in the future to ensure uniformity and objectivity. This scale can be carried out to evaluate of the effectiveness of public health measures in improving the healthy fitness level of the elderly and optimizing public health policies.

A Giant Ruptured Noncoronary Sinus of Valsalva Aneurysm: A Case Report.

The occurrence of a giant ruptured aneurysm originating from the noncoronary sinus of Valsalva in the right atrium is extremely rare. Herein, a case is presented of a giant ruptured noncoronary sinus of Valsalva aneurysm (SVA) that was protruding into the right atrium, which was almost completely occupied by an aneurysm. A 61-year-old female was referred to the hospital for exertional palpitation and dyspnea. While a surgical repair was performed by resection of the aneurysm and a sinus remodeling with a patch of fresh bovine pericardium, a very rare case was observed. It was a giant ruptured noncoronary sinus of aneurysm that completely occupied the right atrium, which was difficult to distinguish from the coronary aneurysm. It is also believed that various imaging examinations, such as cardiac computed tomography angiogram (CCTA) and transthoracic echocardiogram (TTE), were useful for the diagnosis.

Bidirectional role of reactive oxygen species during inflammasome activation in acrolein-induced human EAhy926 cells pyroptosis.

Acrolein, a known toxin in tobacco smoke, has been demonstrated to be associated with inflammatory cardiovascular diseases, such as atherosclerosis. However, the definite mechanism of acrolein-induced inflammation remains unclear. Here, we report that acrolein induces reactive oxygen species (ROS) production in EAhy926 cells. Additionally, acrolein induces EAhy926 cells' inflammatory response and pyroptosis by activating NOD-like receptor protein 3 (NLRP3) inflammasome. Also, acrolein-induced cytotoxicity could be attenuated by N-acetyl-L-cysteine (NAC). Furthermore, acrolein upregulates the level of autophagy which can be reversed by NAC. Notably, the present study also indicates that autophagy inhibited by inhibitor 3-methyladenine (3MA) and siAtg7 exacerbate acrolein-induced NLRP3 inflammasome activation and pyroptosis. In summary, acrolein induced cytotoxicity by ROS-mediated NLRP3 inflammasome activation, and ROS upregulates the level of autophagy to inhibit the NLRP3 inflammasome excessive activation, indicating the bidirectional role of ROS in acrolein-induced cellular inflammation. Our results may provide novel mechanistic insights into acrolein-induced cardiovascular toxicity.

A novel nomogram to predict the overall survival in esthesinoeroblastoma.

BACKGROUND: Increasing evidence indicates that the pathology and the modified Kadish system have some influence on the prognosis of esthesioneuroblastoma (ENB). However, an accurate system to combine pathology with a modified Kadish system has not been established. METHODS: This study aimed to set up and evaluate a model to predict overall survival (OS) accurately in ENB, including clinical characteristics, treatment and pathological variables. We screened the information of patients with ENB between January 1, 1976, and December 30, 2016 from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program as a training cohort. The validation cohort consisted of patients with ENB at Sun Yat-sen University Cancer Center and The First Affiliated Hospital of Sun Yat-sen University in the same period, and 87 patients were included. The Pearson's chi-squared test was used to assess significance of clinicopathological and demographic characteristics. We used the Cox proportional hazards model to examine univariate and multivariate analyses. The model coefficients were used to calculate the Hazard ratios (HR) with 95% confidence intervals (CI). Prognostic factors with a p-value < 0.05 in multivariate analysis were included in the nomogram. The concordance index (c-index) and calibration curve were used to evaluate the predictive power of the nomogram. RESULTS: The c-index of training cohort and validation cohort are 0.737 (95% CI, 0.709 to 0.765) and 0.791 (95% CI, 0.767 to 0.815) respectively. The calibration curves revealed a good agreement between the nomogram prediction and actual observation regarding the probability of 3-year and 5-year survival. We used a nomogram to calculate the 3-year and 5-year growth probability and stratified patients into three risk groups. CONCLUSIONS: The nomogram provided the risk group information and identified mortality risk and can serve as a reference for designing a reasonable follow-up plan.

Multi-Targeting by ß-Elemene and Its Anticancer Properties: A Good Choice for Oncotherapy and Radiochemotherapy Sensitization.

Several studies have focused on chemical agents, tailored from natural edible products, used to prevent and treat various diseases. ß-elemene is a well-known compound derived from Curcuma wenyujin that possesses a wide spectrum of anticancer properties under preclinical and clinical conditions. Several studies have demonstrated its inhibitory effect both in humans and animals with cancers. Numerous in vivo and in vitro experimental models have revealed that ß-elemene can modulate multiple molecular pathways involved in carcinogenesis. In general, (1) ß-elemene itself can inhibit and kill tumor cells through a variety of mechanisms, and (2) can synergistically enhance the effect of radiotherapy and/or chemotherapy, (3) also can regulate autoimmune in the treatment of tumors. In this article, we critically focused on the available scientific evidence discussing the use of ß-elemene in cancer prevention, and its molecular targets and mechanisms of action in different types of cancer. In addition, we have discussed its sources, chemistry, bioavailability, and future research directions.

Effect of Cellulose Powder on Human Nasal Epithelial Cell Activity and Ciliary Beat Frequency.

BACKGROUND: Cellulose powder (CP) has been reported as a safe and effective complementary treatment for allergic rhinitis (AR). Currently, CP has gained increasing application for clinical management worldwide, particularly in China. However, studies focusing on the effect of CP on normal human nasal epithelial cells (hNECs) and ciliary function are lacking. Here, we aimed to explore the adverse effects of CP on the activity and ciliary function of hNECs. METHODS: We biopsied ethmoid sinus or middle turbinate tissues during surgical resection from control subjects who underwent endoscopic sinus surgery for diseases other than AR. Cells were isolated and passaged, followed by differentiation in an air-liquid interface (ALI). Flow cytometry and cell viability test (cell counting kit-8) were performed to detect the cytotoxicity of CP (effects on cell proliferation) on normal hNECs. By using the ALI culture model, we investigated the effects of CP on ciliary beat frequency (CBF). RESULTS: There was a significant reduction in hNEC count at high concentrations of CP (2.5 mg/mL) at days 3 and 7 (both p < 0.05). As the concentration increased, cell death increased progressively from day 3 to day 7. However, these effects were not evident at low concentrations (0.25 mg/mL, p > 0.05). High-dose CP (2.5 mg) significantly reduced the CBF (p < 0.05). At lower concentrations (0.25-2.5 mg/mL), CP initially increased but subsequently reduced the CBF of hNECs compared with control group. CONCLUSIONS: Cytotoxicity and the suppression of ciliary beat at high concentrations justify more prudent use of CP for the management of AR.

The ratio of 11ß-hydroxysteroid dehydrogenase 1/11ß-hydroxysteroid dehydrogenase 2 predicts glucocorticoid response in nasal polyps.

BACKGROUND: Glucocorticoids are the first-line medical treatment for chronic rhinosinusitis with nasal polyps (CRSwNP), whose local metabolism is catalyzed by 11ß-HSD1 and 11ß-HSD2. This study investigates the role of 11ß-HSD1 and 11ß-HSD2 on the glucocorticoid response of CRSwNP patients and the pathogenic mechanism of these polyps. METHODS: Forty-three adult CRSwNP patients were enrolled in this study. We evaluated the endoscopic scores by a nasal polyp grading system before and after treatment. We estimated the response to glucocorticoids by the total endoscopic scores. The logistic regression models and inflammatory characteristic curves were conducted to explore the prediction of the response to glucocorticoid in CRSwNP. The expression of 11ß-HSD1 and 11ß-HSD2 on human sinonasal epithelial cells (HSECS) was measured under the stimulation of toll-like receptor agonists and dexamethasone. RESULTS: The endoscopic scores in the CRSwNP group declined, the expression of 11ß-HSD1/11ß-HSD2 increased (r = 0.5276, P = 0.0011), and the cutoff value of the ratio of 11ß-HSD1/11ß-HSD2 was 0.4654 (sensitivity 79.17%, specificity 88.89%). Dexamethasone induced a decrease in the ratio of 11ß-HSD1/11ß-HSD2 (P = 0.049) by the stimulation of PGN-BS. CONCLUSION: We found a strong correlation between the response to glucocorticoids and the ratio of 11ß-HSD1/11ß-HSD2, which could be used as a marker in predicting the level of tissue response to glucocorticoid therapy in CRSwNP. In addition, PGN-BS could also be a therapeutic target, as it is the negative factor that will decrease the sensitivity of glucocorticoids by reducing the ratio of 11ß-HSD1/11ß-HSD2.

Comparative pharmacokinetics of florfenicol in healthy and Pasteurella multocida-infected Gaoyou ducks.

Pasteurella multocida is the causative agent of fowl cholera, and florfenicol (FF) has potent antibacterial activity against P. multocida and is widely used in the poultry industry. In this study, we established a P. multocida infection model in ducks and studied the pharmacokinetics of FF in serum and lung tissues after oral administration of 30 mg/kg bodyweight. The maximum concentrations reached (Cmax) were lower in infected ducks (13.88 ± 2.70 µg/ml) vs. healthy control animals (17.86 ± 1.57 µg/ml). In contrast, the mean residence time (MRT: 2.35 ± 0.13 vs. 2.27 ± 0.18 hr) and elimination half-life (T½ß : 1.63 ± 0.08 vs. 1.57 ± 0.12 hr) were similar for healthy and diseased animals, respectively. As a result, the area under the concentration curve for 0-12 hr (AUC0-12 hr ) for FF in healthy ducks was significantly greater than that in infected ducks (49.47 ± 5.31 vs. 34.52 ± 8.29 µg hr/ml). The pharmacokinetic differences of FF in lung tissues between the two groups correlated with the serum pharmacokinetic differences. The Cmax and AUC0-12 hr values of lung tissue in healthy ducks were higher than those in diseased ducks. The concentration of FF in lung tissues was approximately 1.2-fold higher than that in serum both in infected and healthy ducks indicating that FF is effective in treating respiratory tract infections in ducks.

Taurine protects INS-1 cells from apoptosis induced by Di(2-ethylhexyl) phthalate via reducing oxidative stress and autophagy.

Di-(2-ethylhexyl) phthalate (DEHP) is an environmental endocrine disruptor widely employed in plastic bags, industrial paints, cosmetics and food packaging, which has been reported to be harmful to human physical health. Many studies have shown that DEHP causes reproductive system toxicity, but its cytotoxicity to islet cells is few to unknown. In our research, it was found that DEHP could induce apoptosis in INS-1 cells via autophagy and oxidative stress. Taurine, a sulfur-containing ß-amino acid, could reverse DEHP-induced oxidative stress imbalance. Meanwhile, taurine could reduce DEHP-induced excessive autophagy. The interaction between oxidative stress and autophagy has been investigated in this study. After pretreated with autophagy interventional agents, it was found that autophagy was capable of alleviating oxidative stress and ROS production in DEHP-treated INS-1 cells. And down-regulated ROS production by NAC could also turn over uploaded autophagy. Our research provides a perspective about the mechanism of cytotoxicity of DEHP to INS-1 cells and taurine protective effect.

In vivo pharmacokinetic/Pharmacodynamic modeling of Enrofloxacin against Escherichia coli in broiler chickens.

BACKGROUND: Systemic Escherichia coli infections cause early mortality of commercial broiler chickens. Although enrofloxacin has long been used in poultry, the in vivo pharmacokinetic/pharmacodynamic (PK/PD) relationship of enrofloxacin against E. coli is unclear. The present study aimed to establish an in vivo PK/PD model of enrofloxacin against E. coli in seven-day-old chicks and to ascertain whether the selection of target organ for PD determination is critical for parameter magnitude calculation in enrofloxacin PK/PD modeling. RESULTS: The in vivo effectiveness of enrofloxacin against E. coli in different organs varied, with the Emax ranging from - 4.4 to - 5.8 Log10 colony forming units (cfu)/mL or cfu/g. Both the surrogate AUC0-24/MIC of enrofloxacin or AUC0-24/MIC of the combination of enrofloxacin and ciprofloxacin correlated well with effectiveness in each organ. The AUC0-24/MIC ratio of the combination of enrofloxacin and ciprofloxacin producing bactericidal and elimination effects were 21.29 and 32.13 in blood; 41.68, and 58.52 in the liver; and 27.65 and 46.22 in the lung, respectively. CONCLUSIONS: The in vivo effectiveness of enrofloxacin against E. coli in different organs was not identical after administration of the same dosage. To describe the magnitude of PK/PD parameter exactly, bacterial loading reduction in different organs as PD endpoints should be evaluated and compared in PK/PD modeling. The selection of a target organ to evaluate PDs is critical for rational dosage recommendation.

Comparative pharmacokinetics of danofloxacin in healthy and Pasteurella multocida infected ducks.

Pasteurella multocida (P. multocida) infection causes substantial economic loss in the duck industry. Danofloxacin, a fluoroquinolone solely used in animals, shows good antibacterial activity against P. multocida. In this study, the in vitro pharmacodynamics of danofloxacin against P. multocida was studied. The serum and lung tissue pharmacokinetics of danofloxacin were studied in healthy and P. multocida infected ducks following oral administration of a single dose of 5 mg/kg body weight (b.w.). The MIC, MBC and MPC of danofloxacin against P. multocida (C48-1 ) were 0.25, 1 and 3.2 µg/ml, respectively. The Cmax was 0.34 µg/ml, attained at 2.03 hr in healthy ducks, and was 0.35 µg/ml, attained at 2.87 hr in diseased ducks. Compared to the serum pharmacokinetics of danofloxacin in healthy ducks, the absorption rate and extent were similar in healthy and diseased animals. In contrast, the elimination rate was slower, with an elimination half-life (T1/2ß ) of 13.17 and 16.18 hr for healthy and infected animals, respectively; the AUCs in the two groups were 5.70 and 7.68 µg hr/ml, respectively, which means the total amount of drug in the circulation was increased in the infected ducks. The maximum concentration in lung tissues between healthy and infected animals was not significantly different (8.96 vs. 8.93 µg/g). However, the Tmax in healthy ducks was longer than that in infected ducks (4 hr vs. 1.75 hr), which means that the distribution rate of danofloxacin was slower in healthy ducks. The concentration of danofloxacin in lung tissues was approximately 24-fold higher than that in the serum. In the serum pharmacokinetic profiles, the ƒAUC0-24 hr /MIC was 18.19 in healthy ducks and was 25.04 in P. multocida infected ducks at the clinical recommended dose, which is far from the PK/PD target (125 hr) of fluoroquinolones. Danofloxacin, at a dose of 5 mg/kg b.w., seems to be insufficient for ducks infected with P. multocida, with an MIC equal to 0.25 µg/ml.