Activation of osteoblast ferroptosis via the METTL3/ASK1-p38 signaling pathway in high glucose and high fat (HGHF)-induced diabetic bone loss.

Diabetes mellitus (DM) and osteoporosis are two common diseases that may develop as a cause-and-effect relationship since the incidence of osteoporotic fractures is significantly increased in DM patients. However, the pathophysiology of diabetic osteoporosis is yet to be clearly understood. Iron overload has been reported to lead to bone loss and closely related to osteoporosis. In this study, we hypothesized that high glucose and high fat (HGHF) may induce osteoblastic ferroptosis for the pathogenesis of diabetic osteoporosis and explored the possible molecular mechanisms behind. Using the diabetic rat model established by HGHF feeding with a subsequent intraperitoneal injection of a single low dose of streptozocin, we found that the serum ferritin level (a biomarker for body iron store) was significantly elevated in HGHF-fed rats and the expression of SLC7A11 and GPX4 (inhibitory marker proteins for ferroptosis) was markedly attenuated in the bone tissue of the rats with diabetic bone loss as compared to the normal rats. In an osteoblast cell model, treatment of pre-osteoblastic MC3T3-E1 cells with high glucose and palmitic acid (HGPA) not only suppressed osteoblast differentiation and mineralization but also triggered ferroptosis-related osteoblastic cell death. m6 A-seq revealed that m6 A methylation on ASK1 was 80.9-fold higher in HGPA-treated cells. The expression of p-ASK1 and p-p38 was also significantly elevated in the HGPA-treated cells. Knockout of METTL3 (methyltransferase-like 3), one of the major m6 A methyltransferases, in MC3T3-E1 cells not only abrogated HGPA-induced activation of ASK1-p38 signaling pathway but also attenuated the level of ferroptosis. Therefore, HGHF-induced ferroptosis in osteoblasts may be the main cause of osteoporosis in DM via activation of METTL3/ASK1-p38 signaling pathway, and inhibition of ferroptosis in osteoblasts may provide a potential therapeutic strategy for diabetic osteoporosis.

Effects of different exercise programs on cardiorespiratory fitness and body composition in college students.

OBJECTIVE: The cardiorespiratory fitness (CRF) of college students is showing a downward trend, this study aimed to explore the effects of three exercise programs on CRF and body composition indicators in college students. METHODS: A total of 50 non-smoking, healthy and physically inactive students were recruited from campus in Beijing, China, and randomly assigned to 4 groups: low-intensity continuous training with blood flow restriction (LICT-BFR, n = 13), moderate-intensity continuous training (MICT, n = 13), high-intensity interval training (HIIT, n = 12), and no exercise control (n = 12), the intervention continued for 8 weeks. Body composition and aerobic capacity were measured before and after the intervention. RESULTS: Exercise groups reached significant improvements in maximal oxygen uptake (VO2max, p < 0.01) and a decrease in body fat percentage (p < 0.05) comparing to the control group. The fat mass and visceral fat area reduced significantly (p < 0.05) with a muscle mass growth (p < 0.05) in the LICT-BFR and MICT groups comparing to the control group. Changes of fat and muscle mass were trivial in the HIIT group (p = 0.842, p = 0.247). CONCLUSION: All three exercise programs can improve the CRF of college students, with LICT-BFR has the most profound effects, and MICT is more beneficial for body composition improvement than other programs. From an overall perspective, LICT-BFR should be the ideal choice, however, due to limited equipment, college students can choose MICT or HIIT according to their situations.

Prophylactic Noninvasive Ventilation Versus Conventional Care in Patients After Cardiac Surgery.

BACKGROUND: Cardiac surgery can be accompanied by postoperative complications, which are associated with increased postoperative morbidity and mortality. Therefore, it is necessary to investigate the effect of prophylactic noninvasive ventilation (NIV) after extubation versus conventional pulmonary care on complications after cardiac surgery. MATERIALS AND METHODS: An electronic search of PubMed, Cochrane Library, Ovid, and EMBASE was conducted to find randomized controlled trials which compared the effect of prophylactic NIV with controlled strategies on complications and which were published before April 2018. RESULTS: Ten studies (1011 patients) were included in the final analysis. The atelectasis rate was 32.6% in the prophylactic-NIV group, which was lower than that in the control group (48.71%). Prophylactic NIV could lower the rate of atelectasis, reintubation, and other respiratory complications (pleural effusion, pneumonia, and hypoxia) (odds ratio = 0.43, 0.33, and 0.45; 95% confidence interval: 0.21-0.88, 0. 13-0.84, 0.27-0.75; P = 0.02, 0.02, and 0.002, respectively). The effect on cardiac and distal organ complications (P = 0.07) and hospital mortality (P = 0.62) might be limited. CONCLUSIONS: Prophylactic NIV is associated with a lower rate of postoperative pulmonary complications. The effect on the other complications and hospital mortality might be limited. Further evidence with randomized controlled trials can discern the benefits.

Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-ß1 Production.

Sepsis is one of the leading causes of death worldwide. Although the prevailing theory for the sepsis syndrome is a condition of uncontrolled inflammation in response to infection, sepsis is increasingly being recognized as an immunosuppressive state known as endotoxin tolerance. We found sialylation of cell surface was significantly increased on LPS-induced tolerant cells; knockdown of Neu1 in macrophage cell line RAW 264.7 cells resulted in enhanced LPS-induced tolerance, whereas overexpression of Neu1 or treatment with sialidase abrogated LPS-induced tolerance, as defined by measuring TNF-α levels in the culture supernatants. We also found that the expression of Siglec-1 (a member of sialic acid-binding Ig (I)-like lectin family members, the predominant sialic acid-binding proteins on cell surface) was specifically up-regulated in endotoxin tolerant cells and the induction of Siglec-1 suppresses the innate immune response by promoting TGF-ß1 production. The enhanced TGF-ß1 production by Siglec-1 was significantly attenuated by spleen tyrosine kinase (Syk) inhibitor. Knockdown of siglec-1 in RAW 264.7 cells resulted in inhibiting the production of TGF-ß1 by ubiquitin-dependent degradation of Syk. Mechanistically, Siglec-1 associates with adaptor protein DNAX-activation protein of 12 kDa (DAP12) and transduces a signal to Syk to control the production of TGF-ß1 in endotoxin tolerance. Thus, Siglec-1 plays an important role in the development of endotoxin tolerance and targeted manipulation of this process could lead to a new therapeutic opportunity for patients with sepsis.

Expression of circulating miR-486 and miR-150 in patients with acute myocardial infarction.

BACKGROUND: With its high morbidity and mortality, acute myocardial infarction (AMI) places a major burden on society and on individual patients. Correct, early correct diagnosis is crucial to the management of AMI. METHODS: In this study, the expression of circulating miR-486 and miR-150 was investigated in AMI patients and the two miRNAs were evaluated as potential biomarkers for AMI. Plasma samples from 110 patients with AMI (65 patients with ST-segment elevation myocardial infarction (STEMI) and 45 patients with non-ST-segment elevation myocardial infarction (NSTEMI)) and 110 healthy adults were collected. Circulating levels of miR-486 and miR-150 were detected using quantitative real-time PCR in plasma samples. RESULTS: Results showed that the levels of miR-486 and miR-150 were significantly higher in AMI patients than in healthy controls. Receiver operating characteristic (ROC) curve analyses indicated that the two plasma miRNAs were of significant diagnostic value for AMI, especially NSTEMI. The combined ROC analysis revealed an AUC value of 0.771 in discriminating AMI patients from healthy controls and an AUC value of 0.845 in discriminating NSTEMI patients from healthy controls. CONCLUSION: Results indicated that the levels of circulating miR-486 and miR-150 are associated with AMI. They may be novel and powerful biomarkers for AMI, especially for NSTEMI.

Effects of different tidal volume ventilation on paraquat-induced acute lung injury in piglets.

BACKGROUND: The aim of this study was to explore the effects of different tidal volume (VT) ventilation on paraquat-induced acute lung injury or acute respiratory distress syndrome (ALI/ARDS) in piglets. MATERIAL AND METHODS: We developed ALI/ARDS models in piglets by intraperitoneal injection of paraquat (PQ). The piglets were randomly divided into three groups: small VT group (VT=6 ml/kg, n=6), middle VT group (VT=10 ml/kg, n=6), and large VT group (VT=15 ml/kg, n=6), with the positive end-expiratory pressure (PEEP) set as 10 cmH2O. The hemodynamics were monitored by pulse-indicated continuous cardiac output (PiCCO) and the airway pressure changes and blood gas analysis indexes were recorded at different time points. The pathological changes were observed by lung puncture. RESULTS: The piglets showed ALI/ARDS in 4.5±0.8 hours after PQ intraperitoneal injection. PH, PaO2 and oxygenation indexes in the three groups all decreased after modeling success compared with baseline, and PaCO2 increased significantly. PH in the small VT group decreased most obviously after ventilation for 6 hours. PaO2 and oxygenation indexes in the small VT group showed the most obvious increase after ventilation for 2 hours and were much higher than the other two groups after ventilation for 6 hours. PaCO2 increased gradually after mechanical ventilation and the small VT group showed most obvious increase. The ELWI increased obviously after ventilation for 2 hours and then the small VT group clearly decreased. PIP and plateau pressure (Pplat) in the small VT group decreased gradually and in the middle and large VT group they increased after ventilation. The lung histopathology showed that the large VT group had the most severe damage and the small VT group had only minimal damage. CONCLUSIONS: Small tidal volume ventilation combined with PEEP could alleviate the acute lung injury induced by paraquat and improve oxygenation.

Restless leg syndrome and multiple sclerosis: a case-control study in China.

BACKGROUND: As a common neurological movement disorder, restless leg syndrome (RLS) is often seen in patients with multiple sclerosis (MS). However, the relationship between RLS and MS is still unclear. This case-control study aimed to measure RLS prevalence and uncover its association with MS, as well as to identify possible associated risk factors. METHODS: Six hundred and ninety-five patients were randomly selected from a cohort of patients with MS at the Neurology Department of our hospital, and a group of age- and sex-matched healthy controls (n = 603) was enrolled from the general population. Using a face-to-face interview questionnaire, we collected data on RLS incidence in participants with or without MS. We further assessed sleep quality in all the participants. RESULTS: We found there to be a significantly higher prevalence of RLS among patients with MS compared to healthy controls (odds ratio [OR], 3.8; P < 0.001). Risk factors such as an older MS age at onset and a longer MS duration were significantly associated with the presence of RLS. Furthermore, patients with both MS and RLS were more likely to suffer from sleep complaints compared to patients with MS without RLS. CONCLUSIONS: RLS was significantly associated with MS and was found to have a significant impact on sleep quality, particularly in patients with MS.

[Observation on the best dose of methylprednisolone improving lung injury in swine with paraquat intoxication].

OBJECTIVE: To observe the best dose of methylprednisolone improving lung injury in swine with paraquat intoxication. METHODS: Acute lung injury (ALI/ARDS) model was made by an intraperitoneal injection of a large dose of 20%PQ solution20 millilitres in swine. Then 24 swine were randomly divided into 4 groups: exposed PQ control group, 5 mg/kg of methylprednisolone group, 15 mg/kg of methylprednisolone group, 30 mg/kg of methylprednisolone group. All groups were based on the conventional rehydration for intervention, Arterial blood samples were collected before modeling and 0, 12, 24, 36 hours after different processing for blood gas analysis. At the same time heart rate (HR), mean arterial pressure (MAP), extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) were measured by using PICCO (pulse indicator continuous cardiac output), lung tissue was obtained by punctureneedle to produce lung biopsy, then observe the pathological changes of lung tissue in the microscope. RESULTS: 1. Comparison between groups: there is no significant difference about extravascular lung water index (EVLWI) and semi-quantitative score of lung tissue pathology in four groups (P > 0.05) before modeling, so is t0, there is significant difference at about extravascular lung water index and semi-quantitative score of lung tissue pathology 12 h, 24 h and 36 h after different processing (P < 0.05). Within the group: EVLWI and semi-quantitative score of Lung tissue pathology in four groups significantly increased when the model was made (P < 0.05), after different processing, EVLWI and semi-quantitative score of Lung tissue pathology in exposed PQ control group kept going up, in other three groups, EVLWI and semi-quantitative score of lung tissue pathology went down first and then went up, there is significant difference compared with t0 (P < 0.05). 2. Comparison between groups: there is no significant difference about oxygenation index in four groups (P > 0.05) before modeling, so is t0, there is significant difference about oxygenation at 12 h, 24 h and 36 h after different processing (P < 0.05). Within the group: oxygenation index in four groups significantly decreased when the model was made (P < 0.05), after different processing, oxygenation index in exposed PQ control group kept going down, in other three groups, it showed a downward trend after the first rise, there is significant difference compared with t0 (P < 0.05). 3. After medication for 36h, correlation analysis showed that EVLWI were negatively associated with oxygenation index (r = -0.427, P = 0.022) and positively associated with semi-quantitative score of Lung tissue pathology (r = 0.903, P = 0.034). CONCLUSION: Methylprednisolone can obviously relieve lung injury caused by paraquat poisoning and improve oxygenation. After the model was made, within 24 hours, 30 mg/kg of methylprednisolone have advantage for the PQ poisoning swine, but 15mg/kg of methylprednisolone is best for improving lung injury induced by paraquat intoxication within 24 hours to 36 hours.

[Abnormal calcium re-uptake in myocardium sarcoplasmic reticulum in rabbits with heart failure and the influencing factors].

The aim of the present study was to investigate the abnormal calcium re-uptake function of myocardium sarcoplasmic reticulum (SR) in rabbits with heart failure, as well as potential mechanisms. Heart failure model was established in rabbits through aortic insufficiency and constriction of abdominal aorta. The SR Ca(2+) re-uptake function was measured with a calcium imaging device. The activity of myocardium SR calcium adenodine triphosphatase 2a (SERCA2a) was measured by inorganic phosphate. The protein expressions of SERCA2a, CaMKII, PKA, PP1α, phospholamban (PLB), PLB-Ser(16) and PLB-Thr(17) were evaluated by Western blot. The activities of PKA and CaMKII were detected by γ-(32)P substrate incorporation. The results showed that, compared with the sham operation group, the heart failure group exhibited reduced Ca(2+) re-uptake amount (P < 0.01) and the expression and activity of SERCA2a (P < 0.05 or P < 0.01), decreased expression of PLB and its phosphorylation status in sites of Ser(16) and Thr(17) (P < 0.05), increased expressions and activities of PKA and CaMKII (P < 0.05 or P < 0.01), and increased expression of PP1α (P < 0.05). These results suggest that the abnormal Ca(2+) re-uptake function in heart failure is related with reduced expression and activities of SERCA2a, as well as reduced expression of PLB and its phosphorylation status. Both PLB-Ser(16) and -Thr(17) may be involved in the regulation of myocardium SR calcium pump activity in heart failure.

[Construction of a predictive model of death for sepsis-associated acute kidney injury].

OBJECTIVE: To establish a predictive model nomogram for 30-day death in patients with sepsis-associated acute kidney injury (SA-AKI) by using the data from the large international database, the Electronic Intensive Care Unit-Collaborative Research Database (eICU-CRD), and to validate its predictive performance. METHODS: A retrospective cohort study was conducted using data from the eICU-CRD. Data of SA-AKI patients were screened from the eICU-CRD database, including demographic characteristics, medical history, SA-AKI type, Kidney Disease: Improving Global Outcomes (KDIGO)-AKI staging, severity of illness scores, vital signs, laboratory indicators, and treatment measures; with admission time as the observation start point, death as the outcome event, and a follow-up time of 30 days. Relevant variables of patients with different 30-day prognoses were compared. Univariate Logistic regression analysis and multivariate Logistic regression forward likelihood ratio analysis were used to screen for risk factors associated with 30-day death in SA-AKI patients, and a predictive model nomogram was constructed. Receiver operator characteristic curve (ROC curve), calibration curve, and Hosmer-Lemeshow test were used to validate the predictive performance of the model. RESULTS: A total of 201 SA-AKI patients' data were finally enrolled, among which 51 survived for 30 days and 150 died, with a mortality of 74.63%. Compared with the survival group, patients in the death group were older [years old: 68 (60, 78) vs. 59 (52, 69), P < 0.01], had lower body weight, proportion of transient SA-AKI, platelet count (PLT) and blood glucose [body weight (kg): 79 (65, 95) vs. 91 (71, 127), proportion of transient SA-AKI: 61.33% (92/150) vs. 82.35% (42/51), PLT (×109/L): 207 (116, 313) vs. 260 (176, 338), blood glucose (mmol/L): 5.5 (4.4, 7.1) vs. 6.4 (5.1, 7.6), all P < 0.05] and higher proportion of persistent SA-AKI, sequential organ failure assessment (SOFA) score, lactic acid (Lac), and total bilirubin [TBil; proportion of persistent SA-AKI: 38.67% (58/150) vs. 17.65% (9/51), SOFA score: 7 (5, 22) vs. 5 (2, 7), Lac (mmol/L): 0.4 (0.2, 0.7) vs. 0.3 (0.2, 0.4), TBil (µmol/L): 41.0 (17.1, 51.3) vs. 18.8 (17.1, 34.2), all P < 0.05]. Univariate Logistic regression analysis showed that age [odds ratio (OR) = 1.035, 95% confidence interval (95%CI) was 1.013-1.058, P = 0.002], body weight (OR = 0.987, 95%CI was 0.977-0.996, P = 0.007), persistent SA-AKI (OR = 2.942, 95%CI was 1.333-6.491, P = 0.008), SOFA score (OR = 1.073, 95%CI was 1.020-1.129, P = 0.006), PLT (OR = 0.998, 95%CI was 0.996-1.000, P = 0.034), Lac (OR = 1.142, 95%CI was 1.009-1.292, P = 0.035), TBil (OR = 1.422, 95%CI was 1.070-1.890, P = 0.015) were associated with 30-day death risk in SA-AKI patients. Multivariate Logistic regression forward likelihood ratio analysis showed that age (OR = 1.051, 95%CI was 1.023-1.079, P = 0.000), body weight (OR = 0.985, 95%CI was 0.974-0.995, P = 0.005), cardiovascular disease (OR = 9.055, 95%CI was 1.037-79.084, P = 0.046), persistent SA-AKI (OR = 3.020, 95%CI was 1.258-7.249, P = 0.013), SOFA score (OR = 1.076, 95%CI was 1.013-1.143, P = 0.017), and PLT (OR = 0.997, 95%CI was 0.995-1.000, P = 0.030) were independent risk factors for 30-day death in SA-AKI patients. Based on the above risk factors, a predictive model nomogram for 30-day death in SA-AKI patients was constructed. ROC curve analysis showed that the area under the ROC curve (AUC) of the model was 0.798 (95%CI was 0.722-0.873), with a sensitivity of 86.7% and a specificity of 62.7%. Calibration curve showed that the fitted curve was close to the standard line, indicating that the predicted probability was close to the actual probability, suggesting good predictive performance of the model. Hosmer-Lemeshow test showed χ 2 = 6.393, df = 8, P = 0.603 > 0.05, suggesting that the model could fit the observed data well. The quality of model fitting was judged by the accuracy of model prediction. The results showed that the prediction accuracy rate of the model was 95.3%, and the overall prediction accuracy rate of the model was 81.6%, indicating good model fitting. CONCLUSIONS: A predictive model for 30-day death in SA-AKI patients based on risk factors can be successfully constructed, and the model has high accuracy, sensitivity, reliability, and certain specificity, which can help to early identify high-risk patients for death and adopt more proactive treatment strategies.

Suppression of IRF9 Promotes Osteoclast Differentiation by Decreased Ferroptosis via STAT3 Activation.

Osteoporosis is a chronic disease that endangers the health of the elderly. Inhibiting osteoclast hyperactivity is a key aspect of osteoporosis prevention and treatment. Several studies have shown that interferon regulatory factor 9 (IRF9) not only regulates innate and adaptive immune responses but also plays an important role in inflammation, antiviral response, and cell development. However, the exact role of IRF9 in osteoclasts has not been reported. To elucidate the role of IRF9 in osteoclast differentiation, we established the ovariectomized mouse model of postmenopausal osteoporosis and found that IRF9 expression was reduced in ovariectomized mice with overactive osteoclasts. Furthermore, knockdown of IRF9 expression enhanced osteoclast differentiation in vitro. Using RNA sequencing, we identified that the differentially expressed genes enriched by IRF9 knockdown were related to ferroptosis. We observed that IRF9 knockdown promoted osteoclast differentiation via decreased ferroptosis in vitro and further verified that IRF9 knockdown reduced ferroptosis by activating signal transducer and activator of transcription 3 (STAT3) to promote osteoclastogenesis. In conclusion, we identified an essential role of IRF9 in the regulation of osteoclastogenesis in osteoporosis and its underlying mechanism.

Turning cationic antimicrobial peptide KR-12 into self-assembled nanobiotics with potent bacterial killing and LPS neutralizing activities.

Gram-negative sepsis has become a substantial and escalating global healthcare challenge due to the growing antibiotic resistance crisis and the sluggish development of new antibiotics. LL-37, a unique Cathelicidin species found in humans, exhibits a wide range of bioactive properties, including direct bactericidal effects, inflammation regulation, and LPS neutralization. KR-12, the smallest yet potent peptide fragment of LL-37, has been modified to create more effective antimicrobials. In this study, we designed two myristoylated derivatives of KR-12, referred to as Myr-KR-12N and Myr-KR-12C. These derivatives displayed remarkable ability to spontaneously assemble into nanoparticles when mixed with deionized water. Myristoylated KR-12 derivatives exhibited broad-spectrum and intensified bactericidal activity by disrupting bacterial cell membranes. In particular, Myr-KR-12N showed superior capability to rescue mice from lethal E. coli-induced sepsis in comparison with the conventional antibiotic meropenem. We also confirmed that the myristoylated KR-12 nanobiotic possesses significant LPS binding capacity and effectively reduces inflammation in vitro. In an in vivo context, Myr-KR-12N outperformed polymyxin B in rescuing mice from LPS-induced sepsis. Crucially, toxicological assessments revealed that neither Myr-KR-12N nor Myr-KR-12C nanobiotics induced meaningful hemolysis or caused damage to the liver and kidneys. Collectively, our study has yielded an innovative nanobiotic with dual capabilities of bactericidal action and LPS-neutralization, offering substantial promise for advancing the clinical translation of antimicrobial peptides and the development of novel antibiotics. This addresses the critical need for effective solutions to combat Gram-negative sepsis, a pressing global medical challenge.

Effects of traditional Chinese medicine Xin-Ji-Er-Kang formula on 2K1C hypertensive rats: role of oxidative stress and endothelial dysfunction.

BACKGROUND: XinJiErKang (XJEK), a Chinese herbal formula, is identified as an effective preparation to treat coronary heart disease and myocarditis. The aim of the study is to investigate the anti-hypertensive effects of XJEK by oral administration and also to find out whether the drug has any role in oxidative stress and vascular endothelial function. METHODS: Clipping of the renal artery resulted in gradual elevation of the systolic blood pressure (SBP) which reached a plateau after 4 weeks of surgery. Treatment of hypertensive rats (20 mmHg higher than basic systolic blood pressure) with XJEK (6, 12, 24 g/kg/day) and fosinopril (15 mg/kg/day) respectively by intragastric administration started 4 weeks after surgery and continued for 4 weeks. The sham-operated (Sh-Op) controls received drinking water. BP was monitored weekly using tail-cuff apparatus. At the end of 8 wk, left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), rate of rise of left ventricular pressure (±dp/dtmax) were examined (PowerLab 8/30, AD Instruments, Australia). The myocardial hypertrophy index was expressed as heart weight/body weight (HW/BW), the histological changes were investigated by hematoxylin and eosin (HE) and Van Gieson (VG) stain. Endothelium-dependent relaxations due to acetylcholine were observed in isolated rat thoracic aortic ring preparation. Superoxide dismutase (SOD) activity, malondialdehyde (MDA) and nitric oxide (NO) content in serum, contents of hydroxyproline (Hyp) in the ventricular tissue were assayed by xanthin oxidase method, thiobarbituric acid (TBA) method, Griess method and alkaline hydrolysis method, respectively. Angiotensin II (Ang II) content in serum was detected by radioimmunoasssay method. RESULTS: XJEK therapy potently improved cardiac function, inhibited myocardial hypertrophy, improved cardiac pathology change, decreased the myocardial cross-section area (CSA), collagen volume fraction (CVF) and perivascular circumferential collagen area (PVCA), reduced the content of Hyp in the left ventricular tissue, inhibited the decrease of SOD activity and increase of MDA, Ang II content in serum. Moreover, treatment with XJEK improved endothelial dysfunction (ED) manifested by promoting endothelial-dependent vasodilation of thoracic aortic rings and enhancing the NO activity in serum. CONCLUSIONS: These findings suggest that administration of XJEK possess protective effects against 2K1C induced hypertension and cardiac remodeling in rats, preserve NO activity and endothelial function.

[Prognostic value of hemoglobin-to-red cell distribution width ratio in patients with cardiopulmonary resuscitation after out-of-hospital cardiac arrest].

OBJECTIVE: To investigate the prognostic value of hemoglobin-to-red cell distribution width ratio (HRR) in patients with cardiopulmonary resuscitation (CPR) after out-of-hospital cardiac arrest (OHCA). METHODS: A retrospective study was conducted. Patients aged ≥ 18 years with OHCA who were transferred to intensive care unit (ICU) after successful CPR from the emergency room of the First Affiliated Hospital of Zhengzhou University from August 2016 to February 2022 were enrolled. General clinical data, initial vital signs, acute physiology and chronic health evaluation II (APACHE II), Glasgow coma scale (GCS), first laboratory indicators after admission to ICU [including white blood cell count (WBC), red blood cell count (RBC), hemoglobin (Hb), pH value, lactic acid (Lac), 6-hour lactic acid clearance (LCR), red cell distribution width (RDW), HRR], length of ICU stay were collected. According to whether the patients died in hospital, the patients were divided into survival group and death group. Binary Logistic regression was used to analyze the independent factors influencing the prognosis of patients after CPR. Receiver operator characteristic curve (ROC curve) was drawn to analyze the predictive value of independent influencing factors for the prognosis of patients after CPR. RESULTS: A total of 122 patients were enrolled after OHCA CPR, of which 88 died in hospital, the in-hospital mortality was 72.13%. There were no significant differences in age, past medical history, initial vital signs and WBC in ICU between the two groups. Compared with the death group, the survival group had higher GCS score, RBC, Hb, pH value, 6-hour LCR, HRR, lower APACHE II score, Lac, RDW level, and longer length of ICU stay. Multivariate Logistic regression analysis showed that APACHE II score, GCS score, 6-hour LCR, HRR, length of ICU stay were independent factors influencing the prognosis of patients after CPR [APACHE II score: odds ratio (OR) = 0.784, 95% confidence interval (95%CI) was 0.683-0.901, P = 0.001; GCS score: OR = 1.390, 95%CI was 1.059-1.823, P = 0.018; 6-hour LCR: OR = 1.039, 95%CI was 1.015-1.064, P = 0.001; HRR: OR = 2.047, 95%CI was 1.383-3.029, P < 0.001; length of ICU stay: OR = 1.128, 95%CI was 1.046-1.216, P = 0.002]. ROC curve analysis showed that HRR, 6-hour LCR and APACHE II score could predict the prognosis of patients after CPR. The sensitivity was 85.3% and the specificity was 54.5% when the area under the ROC curve (AUC) of HRR was 0.731, and the cut-off value was 8.555. The sensitivity was 88.2% and the specificity was 46.6%, when the AUC of 6-hour LCR was 0.701, and the cut-off value was 28.947%. The sensitivity was 73.9% and the specificity was 79.4% when the AUC of APACHE II score was 0.848, the cut-off value was 22.000. The predictive value of the combination of HRR and 6-hour LCR was higher than that of a single index. The sensitivity was 79.3% and the specificity was 76.1%, when the AUC was 0.796, the cut-off value was 0.296. CONCLUSIONS: HRR, 6-hour LCR and APACHE II score have high prognostic value in patients with OHCA after CPR. HRR < 8.555, 6-hour LCR < 28.947% and APACHE II score > 22.000 indicated poor prognosis.

MESP2 binds competitively to TCF4 to suppress gastric cancer progression by regulating the SKP2/p27 axis.

Gastric cancer (GC) is a major cause of human deaths worldwide, and is notorious for its high incidence and mortality rates. Mesoderm Posterior Basic Helix-loop-helix (bHLH) transcription factor 2 (MESP2) acts as a transcription factor with a conserved bHLH domain. However, whether MESP2 contributes to tumorigenesis and its potential molecular mechanisms, remain unexplored. Noticeably, MESP2 expression levels are decreased in GC tissues and cell lines compared to those in normal tissue. Further, in vitro and in vivo experiments have confirmed that MESP2 overexpression suppresses GC cell growth, migration, and invasion, whereas MESP2 knockdown results in the exact opposite. Here, we present the first report that MESP2 binds to transcription factor 7-like 2 (TCF7L2/TCF4) to inhibit the activation of the TCF4/beta-catenin transcriptional complex, decrease the occupancy of the complex on the S-phase kinase Associated Protein 2 (SKP2) promoter, and promote p27 accumulation. MESP2 knockdown facilitated tumorigenesis, which was partially suppressed by SKP2 knockdown. Taken together, we conclude that MESP2 binds competitively to TCF4 to suppress GC progression by regulating the SKP2/p27 axis, thus offering a potential therapeutic strategy for future treatment.

Suppression of TLR4 prevents diabetic bone loss by regulating FTO-mediated m6A modification.

Toll-like receptor-4 (TLR4) has been implicated in the development and progression of diabetic osteoporosis. However, the mechanisms underlying TLR4-regulated bone metabolism in diabetes are yet to be fully understood. Epigenetic modifications have been indicated as a possible mechanism leading to increased risk of osteoporosis and bone fracture. As N6-methyladenosine (m6A) is the most common epigenetic modification in eukaryotic mRNAs, we hypothesized that TLR4 regulates m6A modification in bone tissues of diabetic rats, thereby potentially explaining the pathogenesis of diabetic bone loss. m6A sequencing (m6A-seq) was performed in samples of the femur of TLR4-wild type (TLR4WT) and TLR4-knockout (TLR4KO) diabetic rats to identify genes with differential m6A modifications that may be associated with the bone loss phenotype. We found that in TLR4KO rats, the rapid weight loss of diabetic rats was prevented, and bone mineral density (BMD) was significantly increased. m6A-seq and Gene Ontology enrichment analysis revealed that m6A-modified genes in the femur of TLR4KO diabetic rats were associated with regulation of biological processes such as osteoclast differentiation. qRT-PCR analysis on the expression levels of the m6A-modified methyltransferases and demethylases demonstrated that only the m6A demethylase fat mass and obesity-associated protein（FTO）was decreased. Using an osteoclast cell model, we confirmed that TLR4-mediated osteoclast differentiation was induced by glycolipid toxicity via inhibition of FTO expression. Taken together, these results suggest that inhibition of TLR4 may prevent diabetic bone loss via regulation of FTO-mediated m6A modification.

Aberrant expression of WWOX protein in epithelial ovarian cancer: a clinicopathologic and immunohistochemical study.

Epithelial ovarian cancer is the most frequent cause of death from gynecologic cancer. The WW domain-containing oxidoreductase (WWOX) gene is located at 16q23.3-24.1, a region that spans the second most common human fragile site, FRA16D. Abnormalities affecting WWOX at the genomic and/or expression level(s) have been reported in numerous neoplasias and cancer-derived cell lines. The goal of the study was to evaluate WWOX protein expression in epithelial ovarian carcinoma tissues to determine whether they correlated with clincopathologic parameters. We performed WWOX expression analyses by means of immunohistochemistry on 112 epithelial ovarian carcinoma tissues, and ovarian carcinoma-derived SKOV3, 3AO cells. The basic significant level was fixed at P<0.05. Loss of WWOX expression was observed in 32 (28.6%) of 112 ovarian carcinoma samples and was positively correlated with negative estrogen receptor (ER) (P<0.001) and negative progesterone receptor (PR) (P=0.001). A statistically significant correlation was observed between the lack of WWOX expression and the advanced International Federation of Gynecology and Obstetrics (FIGO) stages (P=0.02). Furthermore, negative WWOX staining was significantly correlated with lymph node metastasis (P=0.013), whereas no significant differences were found between WWOX and HER-2/neu staining (P=0.79). WWOX protein expression was moderately detectable in SKOV3 cells but not in 3AO cells. Our results indicate that loss of WWOX expression in epithelial ovarian carcinomas correlates with negative ER, negative PR, advanced FIGO stages, and lymph node metastases.

Palmprint and face multi-modal biometric recognition based on SDA-GSVD and its kernelization.

When extracting discriminative features from multimodal data, current methods rarely concern themselves with the data distribution. In this paper, we present an assumption that is consistent with the viewpoint of discrimination, that is, a person's overall biometric data should be regarded as one class in the input space, and his different biometric data can form different Gaussians distributions, i.e., different subclasses. Hence, we propose a novel multimodal feature extraction and recognition approach based on subclass discriminant analysis (SDA). Specifically, one person's different bio-data are treated as different subclasses of one class, and a transformed space is calculated, where the difference among subclasses belonging to different persons is maximized, and the difference within each subclass is minimized. Then, the obtained multimodal features are used for classification. Two solutions are presented to overcome the singularity problem encountered in calculation, which are using PCA preprocessing, and employing the generalized singular value decomposition (GSVD) technique, respectively. Further, we provide nonlinear extensions of SDA based multimodal feature extraction, that is, the feature fusion based on KPCA-SDA and KSDA-GSVD. In KPCA-SDA, we first apply Kernel PCA on each single modal before performing SDA. While in KSDA-GSVD, we directly perform Kernel SDA to fuse multimodal data by applying GSVD to avoid the singular problem. For simplicity two typical types of biometric data are considered in this paper, i.e., palmprint data and face data. Compared with several representative multimodal biometrics recognition methods, experimental results show that our approaches outperform related multimodal recognition methods and KSDA-GSVD achieves the best recognition performance.

[Effects of ulinastatin on myocardial injury induced by acute paraquat poisoning].

OBJECTIVE: To investigate the effects of ulinastatin (UTI) on myocardial injury induced by acute paraquat poisoning. METHODS: Twenty-four Japan white rabbits were divided into control group, model group (37 mg/kg paraquat intraperitoneally once), UTI low dosage group and high dosage group [25 kU×kg(-1)×d(-1) and 50 kU×kg(-1)×d(-1) UTI was intravenously injected respectively for 9 days beginning from 1 week before poisoning] through random number table. Rabbits were sacrificed 24 hours after the last UTI administration. Left ventricle of hearts were harvest, and tissue hydroxyproline (HYP) contents were determined. Matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) transcriptional levels were assayed respectively with reverse transcription-polymerase chain reaction (RT-PCR). Expression levels of MMP-2 in tissue of left ventricle were quantified with immunohistochemistry. RESULTS: Compared with normal myocardium, acute paraquat poisoning induced elevated HYP (mg/g) content significantly (3.85 ± 0.36 vs. 2.52 ± 0.29, P < 0.05); with RT-PCR and immunohistochemistry, it was shown that both mRNA expression levels and immunohistochemistry score of MMP-2 were much higher (mRNA: 2.07 ± 0.57 vs. 1.00 ± 0.35; immunohistochemistry score: 2.24 ± 0.82 vs. 1.40 ± 0.62, both P < 0.05). TIMP-2 appeared to be down-regulated in mRNA expression level (0.78 ± 0.24 vs. 1.00 ± 0.17, P > 0.05). Disorganized cardiocytes were observed. Compared with paraquat poisoning model, low and high UTI administration produced depression of tissue HYP contents (3.40 ± 0.48, 3.12 ± 0.43 vs. 3.85 ± 0.36, P > 0.05 and P < 0.05). With low or high dosage of UTI reduced mRNA expression levels and immunohistochemical scores of MMP-2 in left ventricle were observed (mRNA: 1.86 ± 0.44, 1.58 ± 0.46 vs. 2.07 ± 0.57, P > 0.05 and P < 0.05; immunohistochemical score: 1.93 ± 0.86, 1.75 ± 0.67 vs. 2.24 ± 0.82, both P < 0.05), and TIMP-2 mRNA level was increased slightly, though there was no significant differences (0.82 ± 0.35, 0.94 ± 0.33 vs. 0.78 ± 0.24, both P > 0.05). Improvements in disordered myocardium were demonstrated. CONCLUSIONS: UTI significantly attenuated myocardial injury induced by acute paraquat poisoning. Its mechanism might be related to a reduction of expression level of MMP-2 in tissue, with a dose-dependent manner.