BACKGROUND: Asthma is a common chronic inflammatory airway disease and intermittent hypoxia is increasingly recognized as a factor that may impact disease progression. The present study investigated whether intermittent hypoxia (IH) could aggravate asthma by promoting hypoxia-inducible factor-1α (HIF-1α)/nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3)/interleukin (IL)-1β-dependent pyroptosis and the inflammatory response and further elucidated the underlying molecular mechanisms involved. METHODS: A total of 49 patients diagnosed with severe bronchial asthma and diagnosed by polysomnography were enrolled at Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, between January 2022 and December 2022, and their general data and induced sputum were collected. BEAS-2B cells were treated with IL-13 and subjected to IH. An ovalbumin (OVA)-treated mouse model was also used to assess the effects of chronic intermittent hypoxia (CIH) on asthma. Pyroptosis, the inflammatory response, and related signalling pathways were assessed in vivo and in vitro . RESULTS: In this study, as the apnoea and hypopnea index (AHI) increased, the proportion of patients with uncontrolled asthma increased. The proportions of neutrophils and the levels of IL-6, IL-8, HIF-1α and NLRP3 in induced sputum were related to the AHI. NLRP3-mediated pyroptosis, which could be mediated by the HIF-1α signalling pathway, was activated in IL-13 plus IH-treated BEAS-2B cells and in the lungs of OVA/CIH mice. HIF-1α downregulation significantly reduced lung pyroptosis and ameliorated neutrophil inflammation by modulating the NLRP3/IL-1β pathway both in vitro and in vivo . Similarly, pretreatment with LW6, an inhibitor of HIF-1α, effectively blocked the generation of inflammatory cytokines in neutrophils. In addition, administration of the NLRP3 activator nigericin obviously increased lung neutrophil inflammation. CONCLUSIONS Obstructive sleep apnoea-hypopnea syndrome (OSAHS) is a risk factor for asthma exacerbation. IH aggravates neutrophil inflammation in asthma via NLRP3/IL-1β-dependent pyroptosis mediated by the HIF-1α signalling pathway, which should be considered a potential therapeutic target for the treatment of asthma with OSAHS.
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Humans ; Asthma/metabolism* ; Animals ; Pyroptosis/physiology* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Mice ; Signal Transduction/physiology* ; Male ; Hypoxia/metabolism* ; Female ; Interleukin-1beta/metabolism* ; Adult ; Inflammation/metabolism* ; Middle Aged ; Mice, Inbred C57BL

The structure of intestinal tissue is complex. In vitro simulation of intestinal structure and function is important for studying intestinal development and diseases. Recently, organoids have been successfully constructed and they have come to play an important role in biomedical research. Organoids are miniaturized three-dimensional (3D) organs, derived from stem cells, which mimic the structure, cell types, and physiological functions of an organ, making them robust models for biomedical research. Intestinal organoids are 3D micro-organs derived from intestinal stem cells or pluripotent stem cells that can successfully simulate the complex structure and function of the intestine, thereby providing a valuable platform for intestinal development and disease research. In this article, we review the latest progress in the construction and application of intestinal organoids.
Organoids/cytology* ; Intestines/physiology* ; Humans ; Animals ; Pluripotent Stem Cells

OBJECTIVE: To evaluate the prospective association between cumulative resting heart rate (cumRHR) and rapid renal function decline (RRFD) in a cohort of individuals aged 60 and older. METHODS: In the Tianjin Chronic Kidney Disease Cohort Study, the individuals who underwent three consecutive physical examinations between 2014 and 2017, with estimated glomerular filtration rate (eGFR) greater than 60 mL/min per 1.73 m² and aged 60 years or older were enrolled. A total of 27,564 patients were prospectively followed up from January 1, 2017 to December 31, 2020. The 3-year cumRHR was calculated. The primary outcome was RRFD, defined as an annualized decline in eGFR of 5 mL/min per 1.73 m² or greater. Logistic and restricted spline regression models and subgroup analysis were used to investigate the association of cumRHR with RRFD after adjusting for all confounders. RESULTS: During a median follow-up of 3.2 years, a total of 4,347 (15.77%) subjects developed RRFD. In fully-adjusted models, compared with the lowest quartile of cumRHR, the odds ratio (OR) for the highest was 1.44 (1.28-1.61), P < 0.001. Furthermore, each 1-standard deviation (27.97 beats/min per year) increment in cumRHR was associated with a 17% (P < 0.001) increased risk of RRFD, with a linear positive correlation (P for non-linear = 0.803). Participants with a 3-year cumRHR ≥ 207 (beats/min) * year (equivalent to ≥ 69 beats/min per year in 3 years) were found to be at a higher risk of RRFD. CONCLUSIONS The cumRHR is significantly associated with a higher risk of RRFD among older adults. These results might provide an effective goal for managing and delaying the decline of renal function in the older adults.

Objective:To observe the changing characteristics of pharmacokinetic and pharmacodynamic (PK-PD) parameters of vancomycin in critical patients under different drug regimens and to further explore the influencing factors.Methods:The clinical data of patients who treated with vancomycin and recorded by steady-state through concentration (C min) admitted to intensive care unit (ICU) of Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2011 to December 2018 were analyzed retrospectively. The patients were divided into three groups according to the dosing interval (groups of q12 h, q8 h and q6 h respectively) and C min was collected. The serum concentration of vancomycin before (0 hour) and 1, 2, 4, 6, 8, 12 and 24 hours after administration were estimated by JPKD Ver 3.1. Area under the curve (AUC 0-24 h) was estimated by trapezoidal area method. Minimum inhibitory concentration (MIC) of pathogenic microorganisms in the same period was retrieved, thus AUC 0-24 h/MIC was calculated. Results:285 patients with 529 records of C min were enrolled in the study, including 375 data in q12 h group, 121 data in q8 h group and 33 data in q6 h group. After unifying daily dose by JPKD Ver 3.1, the C min (10-20 mg/L) reaching rate of q12 h group, q8 h group, q6 h group were 35.7%, 43.8% and 60.6%, respectively, while only q12 h group was statistically significant compared with q6 h group ( P < 0.01). q6 h group and q8 h group showed higher C min than q12 h group (mg/L: 13.8±5.2, 13.5±7.3 vs. 11.4±7.9, both P < 0.05) and lower peak concentration (C max) than q12 h group (mg/L: 19.4±5.3, 21.5±7.3 vs. 23.9±8.1, both P < 0.05). However, there was no significant difference in terms of percentage of PD target (AUC 0-24 h/MIC≥400) among the three groups (q12 h group, q8 h group, q6 h group were 38.1%, 41.3%, 45.5%, P > 0.05). Multiple linear regression analysis showed that creatinine clearance (CCr) and vancomycin clearance (CLvancomycin) were the main influencing factors of vancomycin PD parameters such as C min and AUC 0-24 h/MIC ( r values of CCr were -0.391, -0.424, and rvalues of CLvancomycin were -0.673, -0.663, all P < 0.01), and were negatively correlated with age ( r values were -0.432 and -0.488, respectively, both P < 0.01). Conclusions:At the same daily dose, C min can be increased and C max can be decreased by increasing the frequency of vancomycin administration, thus minimize the fluctuation of vancomycin serum concentration, but AUC 0-24 h/MIC is not affected. Vancomycin administration regimen in severe patients should be optimized according to CCr, CLvancomycin and age.

Objective This study was aimed to investigate the effects of Ginger combined with Rhubarb on hyperuricemia in mice. Methods The mice hyperuricemic model was made by orally administering yeast extract, The mice were randomly divided into 7 groups,includinglow,middle and high dose of Ginger combined with Rhubarb group, Rhubarb group, and allopurinol group was given corresponding drugs respectively by gavage, and the uric acid (uA), creatinine (Cr), urea nitrogen (BUN) level in blood and XOD activity in liver were observed for all mice in each group. Results Compared to hyperuricaemia model control group,UA level and XOD activity in liver of mice of the three doses of Ginger combined with Rhubarb groups received dose-dependent decrease. Conclusion Ginger combined with Rhubarb can reduce UA level and XOD activity in liver in hyperuricaemia mice model.

Cardiomyocyte hypertrophy is a major cause of morbidity and mortality worldwide. The aim of this study is to determine the effects of sodium tanshinone IIA sulfonate (STS) on cardiomyocyte hypertrophy induced by angiotensin II (Ang II) in vivo and in vitro. In long-term treatment, adult Wistar rats were infused with Ang II for three weeks via osmotic mini-pumps and some of them were given intragastrically of STS. Left ventricle was isolated; the ratio of left ventricular weight to body weight and systolic blood pressure (SBP) were determined and heart morphometry was assessed after hematoxylin and eosin staining. Results indicated STS inhibited Ang II-induced increases in myocyte diameter and decreased the LVW/BW ratio independent of decreasing systolic blood pressure. In vitro, treatment of cultured cardiomyocytes with STS inhibited Ang II-induced increase in cell size, protein synthesis, ANP expression, activation of extracellular signal-regulated kinase (ERK) and ERK kinase (MEK). Then we reexamined the mechanism of STS-induced anti-hypertrophic effects. Results revealed MEK inhibitor U0126 (20 microM) markedly enhanced STS-induced depressions in [3H]leucine incorporation and ANP expression. In conclusion, MEK/ERK pathway plays a significant role in the anti-hypertrophic effects of STS.
Rats, Wistar ; Rats ; Phenanthrenes/chemistry/*pharmacology ; Myocytes, Cardiac/*drug effects/enzymology/pathology ; Molecular Structure ; Mitogen-Activated Protein Kinase Kinases/*metabolism ; MAP Kinase Signaling System/*drug effects ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Enzyme Activation/drug effects ; Cardiomegaly/chemically induced/enzymology/*metabolism/pathology ; Animals ; Angiotensin II/*antagonists & inhibitors/pharmacology

AIMTo investigate whether chronic bacterial prostatitis might increase oxidative stress and oxidative damage in chronic bacterial prostatitis patients (CBPP), and to explore its possible mechanism.

METHODSEnrolled in a case-control study were 70 randomly sampled CBPP and 70 randomly sampled healthy adult volunteers (HAV), on whom plasma nitric oxide (NO), vitamin C (VC), vitamin E (VE) and beta-carotene (beta-CAR) level, erythrocyte malondialdehyde (MDA) level, as well as erythrocyte superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) activities were determined by spectrophotometry.

RESULTSCompared with the HAV group, values of plasma NO and erythrocyte MDA in the CBPP group were significantly increased (P < 0.001); those of plasma VC, VE and beta-CAR as well as erythrocyte SOD, CAT and GPX activities in the CBPP group were significantly decreased (P < 0.001). Findings from partial correlation for the 70 CBPP showed that with prolonged course of disease, values of NO and MDA were gradually increased (P < 0.001), and those of VC, VE, beta-CAR, SOD, CAT and GPX were gradually decreased (P < 0.05-0.001). The findings from stepwise regression for the 70 CBPP suggested that the model was Y = -13.2077 + 0.1894MDA + 0.0415NO - 0.1999GPX, F = 18.2047, P < 0.001, r = 0.6729, P < 0.001.

CONCLUSIONThe findings suggest that there exist increased oxidative stress and oxidative damage induced by chronic bacterial prostatitis in the patients, and such phenomenon was closely related to the course of disease.

Adult ; Ascorbic Acid ; blood ; Bacterial Infections ; blood ; physiopathology ; Case-Control Studies ; Catalase ; blood ; Erythrocytes ; metabolism ; Glutathione Peroxidase ; blood ; Humans ; Male ; Malondialdehyde ; blood ; Nitric Oxide ; blood ; Oxidative Stress ; physiology ; Prostatitis ; blood ; microbiology ; physiopathology ; Reference Values ; Superoxide Dismutase ; blood ; Vitamin E ; blood ; beta Carotene ; blood

OBJECTIVETo investigate whether pregnancy-induced hypertension (PIH) may increase oxidative stress in women with PIH, and to explore the mechanisms by which PIH may increase oxidative stress and potential free radical damage.

METHODSSeventy women with PIH and seventy women with uncomplicated normotensive pregnancy (UNP) whose age, nutritional conditions, levels of hemoglobin and albumin were all matched, were enrolled in a randomized controlled trial. Their plasma concentrations of nitric oxide (NO), vitamin C (VC), vitamin E (VE), and beta-carotene (beta-CAR) as well as their erythrocyte malondialdehyde (MDA), and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) were determined by spectrophotometry.

RESULTSCompared with average values of the above experimental parameters in the women with UNP, the average value of erythrocyte MDA in the women with PIH significantly increased (P<0.0001), while the average values of plasma NO, VC, VE, and beta-CAR as well as those of erythrocyte SOD, CAT, and GPX in the women with PIH significantly decreased (P<0.0005-0.0001). The findings from partial correlation analysis (controlling for age) for 70 women with PIH showed that with elevated systolic blood pressure (SBP) and diastolic blood pressure (DBP), MDA value gradually increased (P<0.001), and NO, VC, VE, beta-CAR, SOD, CAT, and GPX values gradually decreased (P<0.02-0.001). The findings from reliability analysis for NO, VC, VE, beta-CAR, SOD, CAT, GPX, and MDA values used to reflect increased oxidative stress and potential free radical damage in women with PIH showed that the reliability coefficients (alpha, 8 items) = 0.7062, P<0.0001, and the standardized item alpha = 0.9116, P<0.0001.

CONCLUSIONThe findings in the present research suggest that pregnancy-induced hypertension can increase oxidative stress and potential free radical damage in women with pregnancy-induced hypertension.

Adult ; Case-Control Studies ; Female ; Free Radicals ; metabolism ; Humans ; Hypertension ; metabolism ; Oxidative Stress ; Pregnancy ; Pregnancy Complications, Cardiovascular ; metabolism

OBJECTIVETo explore the changes of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenesis, and the effects of bFGF, angiotensin converting enzyme inhibiter(ACEI) benazepril on the angiogenesis in acute myocardial infarction (AMI) model of rabbits, and to provide a probable evidence for the treatment of AMI.

METHODSAMI model was established by ligating anterior descending branch of coronary artery of Japan-Sino hybridization white rabbits. The postoperative rabbits were randomly divided into 6 groups and each group was treated with different drugs. Groups 1 and 2 were treated with normal saline (NS) for 28 and 14 days (d), group 3 and 4 with bFGF for 28 and 14 d, groups 5 with benazepril for 14 d, and group 6 with benazepril and bFGF for 14 d respectively. The rabbits were killed on the 14th or 28th d and their hearts were excised, sectioned and stained with HE, Masson trichrome to observe VEGF, bFGF and CD(34) under a microscope, which were quantified with a computer-assisted morphometry.

RESULTSCompared with group 1, the granulation tissue of infarction zone (IZ) in group 2 freshened up, and the capillary density (CD) in IZ was increased (P = 0.002). The CD in the IZ as well as VEGF and bFGF in groups 3 and 4 were increased respectively (P = 0.011-0.037). In group 5 the changes of VEGF and bFGF were not found in the IZ and the border zone (BZ) while CD was significantly increased (35.4% and 25.6%, P = 0.036 and 0.037). Compared with group 2, the CD in the IZ and BZ of group 6 was significantly increased (63.4% and 44.3% P = 0.007 and 0.007), meanwhile VEGF and bFGF were increased. Compared with group 5, only VEGF was increased.

CONCLUSIONIntravenous bFGF may increase VEGF and bFGF significantly, thus promoting the angiogenesis in the IZ and BZ in cardiac infarction as VEGF and bFGF are the potent angiogenic growth factors. Benazepril may promote angiogenesis in the IZ and BZ in cardiac infarction, but its mechanism is irrelative to the expression of VEGF and bFGF. The combination of benazepril and bFGF may promote, to some extent, the expression of VEGF and bFGF, but their effect on angiogenesis has not been found.

Angiotensin-Converting Enzyme Inhibitors ; pharmacology ; Animals ; Benzazepines ; metabolism ; pharmacology ; therapeutic use ; Coronary Circulation ; drug effects ; Coronary Vessels ; drug effects ; metabolism ; Disease Models, Animal ; Fibroblast Growth Factor 2 ; metabolism ; therapeutic use ; Myocardial Infarction ; metabolism ; Neovascularization, Physiologic ; Rabbits ; Time Factors ; Vascular Endothelial Growth Factor A ; metabolism ; therapeutic use

OBJECTIVETo estimate the impact of copying on the indoor air quality, and to investigate whether ozone emitted during such a process induces pathological oxidative stress and potential oxidative damage in the bodies of operators.

METHODS67 copying operators (CO) and 67 healthy volunteers (HV) were enrolled in a random control study, in which levels of lipoperoxide (LPO) in plasma and erythrocytes, and levels of vitamin C (VC), vitamin E (VE) and beta-carotene (beta-CAR) in plasma as well as activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) in erythrocytes were determined by spectrophotometric methods.

RESULTSCompared with the HV group, the average values of LPO in plasma and erythrocytes in the CO group were significantly increased (P<0.0001), while those of VC, VE and beta-CAR in plasma as well as those of SOD, CAT and GPX in erythrocytes in the CO group were significantly decreased (P<0.0001). Pearson product-moment correlation analysis showed that with increase of ozone level in copying sites and duration of exposure to ozone, the values of LPO in plasma and erythrocytes in the bodies of operators were gradually increased,while those of VC, VE, beta-CAR, SOD, CAT and GPX were decreased in the same manner. Odds ratio (OR) of risk of biochemical parameters reflecting potential oxidative damage of the copying operators ranged from 4.440 to 13.516, and 95% CI of OR was from 2.113 to 34.061. Reliability coefficient (alpha) of the biochemical parameters used to reflect the potential oxidative damage of the operators was 0.8156, standardized item alpha=0.9929, P<0.0001.

CONCLUSIONFindings in the present study suggest that there exist a series of free radical chain reactions and pathological oxidative stress induced by high dose ozone in the operators, thereby causing potential oxidative and lipoperoxidative damages in their bodies.

Adult ; Copying Processes ; Erythrocytes ; Female ; Humans ; Male ; Occupational Exposure ; Odds Ratio ; Oxidants, Photochemical ; analysis ; toxicity ; Oxidative Stress ; Ozone ; analysis ; toxicity ; Risk Assessment