Inhibition of Phosphoinositide 3-Kinase Gamma Protects Endothelial Cells via the Akt Signaling Pathway in Sepsis-Induced Acute Kidney Injury.

INTRODUCTION: Sepsis is a primary cause of death in critically ill patients and is characterized by multiple organ dysfunction, including sepsis-induced acute kidney injury (AKI), which contributes to high mortality in sepsis. However, its pathophysiological mechanisms remain unclear. The kidney has one of the richest and most diversified endothelial cell populations in the body. This study was designed to investigate the effects of endothelial dysfunction in sepsis-induced AKI and explore possible intervention measures to offer new insight into the pathogenesis and treatment of sepsis-induced AKI. METHODS: The circulating levels of endothelial adhesion molecules were detected in patients with sepsis and healthy controls to observe the role of endothelial damage in sepsis and sepsis-induced AKI. A murine sepsis model induced by cecal ligation and perforation was pretreated with a phosphoinositide 3-kinase gamma (PI3Kγ) inhibitor (CZC24832), and survival, kidney damage, and renal endothelial injury were assessed by pathological examination, immunohistochemistry, quantitative polymerase chain reaction, and Western blotting. Lipopolysaccharides and CZC24832 were administered to human umbilical vein endothelial cells in vitro, and endothelial cell function and the expression of adhesion molecules were evaluated. RESULTS: Endothelial damage was more serious in sepsis-induced AKI than that in non-AKI, and the inhibition of PI3Kγ alleviates renal endothelial injury in a murine sepsis model, protecting endothelial cell function and repairing endothelial cell injury through the Akt signaling pathway. CONCLUSIONS: In this study, endothelial cell dysfunction plays an important role in sepsis-induced AKI, and the inhibition of PI3Kγ alleviates endothelial cell injury in sepsis-induced AKI through the PI3Kγ/Akt pathway, providing novel targets for treating sepsis and related kidney injury.

Recycling drinking water treatment sludge in construction and building materials: A review.

Drinking water treatment sludge (DWTS) is a by-product of water treatment, and it is difficult to recycle to high value and poses potential environmental risks. Recycling DWTS into cement-based materials is an effective measure to achieve its high-volume utilization and reduce its environmental load. DWTS is rich in silica-alumina phases and has potential pozzolanic activity after drying, grinding and calcination, giving it similar properties to traditional supplementary cementitious materials. Adjusting the sludge production process and coagulant type will change its physical and chemical properties. Adding a small amount of DWTS can generate additional hydration products and refine the pore structure of the cement sample, thus improving the mechanical properties and durability of the sample. However, adding high-volume DWTS to concrete causes microstructural deterioration, but it is feasible to use high-volume DWTS to produce artificial aggregates, lightweight concrete, and sintered bricks. Meanwhile, calcined DWTS has similar compositions to clay, which makes it a potential raw material for cement clinker production. Cement-based materials can effectively solidify heavy metal ions in DWTS, and alkali-activated binders, magnesium-based cement, and carbon curing technology can further reduce the risk of heavy metal leaching. This review provides support for the high-value utilization of DWTS in cement-based materials and the reduction of its potential environmental risks.

Celastrol inhibits mouse B16-F10 melanoma cell survival by regulating the PI3K/AKT/mTOR signaling pathway and repressing HIF-1α expression.

OBJECTIVE: Melanoma, with its high degree of malignancy, stands as one of the most dangerous skin cancers and remains the primary cause of death from skin cancer. With studies demonstrating the potential of traditional Chinese medicine to intervene and treat melanoma, we turned our attention to celastrol. Celastrol is a triterpene compound extracted from the traditional Chinese medicine derived from Tripterygium wilfordii. Previous studies have shown that celastrol exerts inhibitory effects on various malignant tumors, including melanoma. Hence, our goal was to clarify the impact of celastrol on cell viability, apoptosis, and cell cycle progression by elucidating its effects on the PI3K/AKT/mTOR pathway. METHODS: CCK-8 and wound healing assays were used to determine the effect of celastrol on the viability and migration of B16-F10 cells. Changes in cell apoptosis, cell cycle, reactive oxygen species (ROS), and mitochondrial membrane potential were detected by flow cytometry. PI3K/AKT/mTOR pathway proteins and HIF-α mRNA expression in B16-F10 cells were detected by western blotting and qPCR. Moreover, the addition of a PI3K activator demonstrated that celastrol could inhibit the function of B16-F10 cells via the PI3K/AKT/mTOR pathway. RESULTS: Celastrol inhibited the viability and migration of B16-F10 cells. Through the inhibition of the PI3K/AKT/mTOR pathway down-regulates the expression of HIF-α mRNA, thereby causing an increase of ROS in cells and a decrease in the mitochondrial membrane potential to promote cell apoptosis and cell cycle arrest. The inhibitory effect of celastrol on B16-F10 cells was further demonstrated by co-culturing with a PI3K activator. CONCLUSION: Celastrol inhibits the function of B16-F10 cells by inhibiting the PI3K/AKT/mTOR cellular pathway and regulating the expression of downstream HIF-α mRNA.

Symptom-to-balloon time and risk of ventricular arrhythmias in patients with STEMI undergoing percutaneous coronary intervention: The VERY-STEMI study.

Background: Ventricular arrhythmias (VAs) mainly occur in the early post-myocardial infarction (MI) period. However, studies examining the association between total myocardial ischemia time interval and the risk of new-onset VAs during a long-term follow-up are scarce. Methods: This study (symptom-to-balloon time and VEntricular aRrhYthmias in patients with STEMI, VERY-STEMI study) was a multicenter, observational cohort and real-world study, which included patients with ST-segment elevation MI (STEMI) undergoing percutaneous coronary intervention (PCI). The primary endpoint was cumulative new-onset VAs during follow-up. The secondary endpoints were the major adverse cardiovascular events (MACE) and changes in left ventricular ejection fraction (ΔLVEF, %). Results: A total of 517 patients with STEMI were included and 236 primary endpoint events occurred. After multivariable adjustments, compared to patients with S2BT of 24 h-7d, those with S2BT ≤ 24 h and S2BT > 7d had a lower risk of primary endpoint. RCS showed an inverted U-shaped relationship between S2BT and the primary endpoint, with an S2BT of 68.4 h at the inflection point. Patients with S2BT ≤ 24 h were associated with a lower risk of MACE and a 4.44 increase in LVEF, while there was no significant difference in MACE and LVEF change between the S2BT > 7d group and S2BT of 24 h-7d group. Conclusions: S2BT of 24 h-7d in STEMI patients was associated with a higher risk of VAs during follow-up. There was an inverted U-shaped relationship between S2BT and VAs, with the highest risk at an S2BT of 68.4 h.

Successful treatment of veno-arterial extracorporeal membrane oxygenation complicated with left ventricular thrombus by intravenous thrombolysis: A case report.

BACKGROUND: Left ventricular thrombus is a rare condition, for which appropriate treatments are not extensively studied. Although it can be treated by thrombectomy, such surgery can be difficult and risky, and not every patient can tolerate the surgery. CASE SUMMARY: We report a case of a middle-aged man receiving veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for acute myocardial infarction who developed left ventricular thrombus despite systemic anticoagulation. After systemic thrombolysis with urokinase, the left ventricular thrombus disappeared, ECMO was successfully withdrawn 9 days later, and the patient recovered and was discharged from hospital. CONCLUSION: Systemic thrombolysis is a treatment option for left ventricular thrombus in addition to anticoagulation and thrombectomy.

Recycling of water treatment sludge in concrete: The role of water-binder ratio from a nanoscale perspective.

For eutrophic water bodies, potassium permanganate is an effective pre-oxidant to remove algae and its residue in water treatment sludge. Recycling water treatment sludge in concrete is an environmentally friendly and high-value utilization measure. However, little research has been done on the effect of manganese-rich drinking water sludge ash (DWSA) on concrete. The effect of water-binder ratio (w/b) on strength, shrinkage and microstructural characteristics of concrete containing DWSA was investigated, and the structural behavior was explained from a nanoscale perspective. The results show that recycling 10 % DWSA in concrete improved the strength and shrinkage resistance of the samples. Reducing the w/b effectively increased the strength of DWSA-modified concrete and reduced the shrinkage deformation. The paste with high w/b had higher contents of non-evaporated water and calcium hydroxide, as well as higher reaction degree of DWSA. Nanoscale characterization shows that reducing the w/b reduced the volume fraction of pore and unhydrated phases in the matrix and increased the proportion of high-density C-S-H. Meanwhile, reducing the w/b also reduced the interfacial transition zone width of DWSA-modified concrete. Recycling DWSA in concrete effectively reduced the total carbon footprint and cost of the mixture. The combined application of reducing the w/b and incorporating DWSA effectively improved the economic and environmental benefits of concrete material. For the concrete modified with 10 % DWSA (w/b = 0.3), its cost and carbon emissions are reduced by 14 %-21 % and 19 %-25 % compared with the reference sample, respectively. Overall, this study reveals the action mechanism of DWSA in cement system at different w/b from nanoscale perspective, and gives a new insight on determining the optimal w/b in full-scale application of DWSA concrete.

[A clinical study of pituitrin versus norepinephrine in the treatment of patients with septic shock].

OBJECTIVE: To investigate whether pituitrin can lower 28-day mortality as compared with treatment with norepinephrine (NE) in patients with septic shock. METHODS: Randomized, controlled, open-label trial was conducted. One hundred and thirty-nine septic shock patients with dopamine requirements exceeding 5 µg×kg(-1)×min(-1) were divided at random into two groups as the study group and control group. All patients enrolled were treated by the same treatment principle and measures. In patients of study group injection of pituitrin 0.017-0.042 U/min (1.0- 2.5 U/h) was given, and if hemodynamics was still unstable, catecholamines was added to obtain the target blood pressure; while in the control group catecholamines was given to maintain stability of hemodynamics. RESULTS: Among 139 patients enrolled in the study, 66 composed of the clinical study group and 73 in the control group. The main principle of the treatment in the two groups was similar. There was no significant difference in overall 28-day mortality rate between study group and control group (40.9% vs. 46.6%, P > 0.05). In patients whose acute physiology and chronic health evaluation II ( APACHE II ) score was less than 25, the mortality of study group was significantly lower than that of control group [10.3% (3/29) vs. 35.7% (10/28), P < 0.05]. The length of stay in intensive care unit [ICU, days: 5(3,8) vs. 5(3,8)], and duration of mechanical ventilation [days: 4.0 (2.8, 6.0) vs. 4.0 (2.0, 5.0)] were similar in two groups (both P > 0.05). The dosage of NE (µg/min: 7.99 ± 5.02 vs. 10.12 ± 5.12) and heart rate (beat/min: 93.27 ± 7.84 vs. 108.45 ± 12.31) were significantly lower in study group compared with that of control group (both P < 0.05). Serum creatinine and lactate levels in the two groups were similar at baseline, and creatinine [µmol/L: 87.5 (62.8, 157.0) vs. 76.0 (52.5, 117.0)] and lactate level (mmol/L: 3.72 ± 2.47 vs. 3.53 ± 1.86) were still similar in two groups 24 hours later (all P > 0.05). The rate of use of glucocorticoid (43.9% vs. 31.5%) and heparin in small dosage (42.4% vs. 41.1%) had no significant difference between two groups (both P > 0.05). CONCLUSIONS: Combined use of pituitrin in patients with septic shock can reduce the dosage of catecholamines, and decrease the heart rate. Although it can not lower the overall mortality of septic shock, among patients with less severity whose APACHE II score lower than 25, low-dose pituitrin in conjunction with catecholamine vasopressors can reduce 28-day mortality .

In situ generated silica reinforced polyvinyl alcohol/liquefied chitin biodegradable films for food packaging.

In previous report, polyvinyl alcohol/liquefied ball-milled chitin (PVA/LBMC) blend films with good antibacterial activity were successfully prepared. To further develop a biodegradable food packaging material, various amounts of nano-silica were introduced in situ by the hydrolysis of Na2SiO3 to give a series of silica-reinforced PVA/LBMC blend films. Their structure, morphology, mechanical and thermal properties, food preservation and degradation behavior in soil were comprehensively characterized. The results showed that when the content of Na2SiO3 was 0.2 wt %, the blend film 4PVA-LBMC-0.2Si displayed the optimized performance. Its tensile strength, and the maximum weight loss rate temperature reached 51 MPa and 307 ℃, respectively, which were significantly improved than those of silica-free film. The preservation tests of cherries showed its good fresh keeping performance. Although the degradation rate of silica-reinforced blend films in the soil was slightly decreased, it remained at a good level of 43 % after 30 days of burial.

Mucosal-associated invariant T cells in hepatitis B virus-related liver failure.

BACKGROUND: Liver failure has high mortality and poor prognosis, and establishing new reliable markers for predicting its prognosis is necessary. Mucosal-associated invariant T (MAIT) cells are a novel population of innate-like lymphocytes involved in inflammatory liver disease, and their potential role in liver failure remains unclear. AIM: To investigate alteration of circulating MAIT cells and assess its prognostic value in patients with hepatitis B virus (HBV)-related liver failure. METHODS: We recruited 55 patients with HBV-related liver failure, 48 patients with chronic hepatitis B and 40 healthy controls (HCs) from Nantong Third People's Hospital Affiliated to Nantong University. Peripheral blood mononuclear cells were isolated, and the percentage and number of circulating MAIT cells were detected by flow cytometry. Plasma levels of interleukin (IL)-7, IL-12p70, IL-18 and interferon-α were measured by Luminex assay. RESULTS: Circulating MAIT cells were significantly decreased in HBV-related liver failure patients (percentage: 2.00 ± 1.22 vs 5.19 ± 1.27%, P < 0.0001; number: 5.47 ± 4.93 vs 84.43 ± 19.59, P < 0.0001) compared with HCs. More importantly, there was a significant reduction of MAIT cells in patients with middle/late-stage compared with early-stage liver failure. Circulating MAIT cells partially recovered after disease improvement, both in percentage (4.01 ± 1.21 vs 2.04 ± 0.95%, P < 0.0001) and in cell count (17.24 ± 8.56 vs 7.41 ± 4.99, P < 0.0001). The proportion (2.29 ± 1.01 vs 1.58 ± 1.38%, P < 0.05) and number (7.30 ± 5.70 vs 2.94 ± 1.47, P < 0.001) of circulating MAIT cells were significantly higher in the survival group than in the dead/liver transplantation group, and the Kaplan-Meier curve showed that lower expression of circulating MAIT cells (both percentage and cell count) predicted poor overall survival (P < 0.01). Also, the levels of IL-12 (20.26 ± 5.42 pg/mL vs 17.76 ± 2.79 pg/mL, P = 0.01) and IL-18 (1470.05 ± 1525.38 pg/mL vs 362.99 ± 109.64 pg/mL, P < 0.0001) were dramatically increased in HBV-related liver failure patients compared with HCs. CONCLUSION: Circulating MAIT cells may play an important role in the process of HBV-related liver failure and can be an important prognostic marker.

[The effect of different fluids on early fluid resuscitation in septic shock].

OBJECTIVE: To study the effects of different fluids on blood pressure (BP), blood lactate clearance and mortality in patients with septic shock after early fluid resuscitation. METHODS: Sixty patients were enrolled and randomly divided into four groups according to the fluids used in resuscitation: normal saline (NS) group (15 cases), hydroxyethyl starch (HES) group (15 cases), 4% hypertonic saline solution (4%NaCl) group (15 cases), hypertonic sodium chloride hydroxyethyl starch 40 solution (HSH40) group, (15 cases). Patients of different groups received fluid resuscitation via central vein, at the same time, received the anti-shock treatment. Hemodynamic parameters, blood lactate clearance and mortality in patients were monitored after resuscitation. RESULTS: The study fluid volume and the total fluid volume in the 4%NaCl group and HSH40 group was lower than that in NS group and HES group significantly (all P<0.01). The mean arterial pressure (MAP) in HSH40 group was significantly higher than in the other three groups 1 hour after the fluid resuscitation (all P<0.01). The 24-hour blood lactate clearance in HSH40 group was also higher than in the other three groups (all P<0.01). The scores of sepsis-related organ failure assessment (SOFA) scores, acute physiology and chronic health evaluation II (APACHE II) scores, and 28-day mortality showed no significant differences among these groups (all P>0.05), but a lowering trend on 28-day mortality could be observed in HSH40 group. CONCLUSION: The rapid elevation of BP can improve blood lactate clearance in patients with septic shock receiving early fluid resuscitation. Compared with other fluids, HSH40 raises BP more quickly and needs lower total resuscitation volume to achieve the same goal.

Glutathione S-transferase P1, gene-gene interaction, and lung cancer susceptibility in the Chinese population: An updated meta-analysis and review.

AIM OF STUDY: To assess the impact of glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism on the risk of lung cancer in the Chinese population, an updated meta-analysis and review was performed. MATERIALS AND METHODS: Relevant studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure, and Chinese Biology Medicine published through January 22, 2015. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of the associations. RESULTS: A total of 13 case-control studies, including 2026 lung cancer cases and 2451 controls, were included in this meta-analysis. Overall, significantly increased lung cancer risk was associated with the variant genotypes of GSTP1 polymorphism in the Chinese population (GG vs. AA: OR=1.36, 95% CI=1.01-1.84). In subgroup analyses stratified by geographic area and source of controls, the significant results were found in population-based studies (GG vs. AA: OR=1.62, 95% CI: 1.13-2.31; GG vs. AG: OR=1.49, 95% CI: 1.03-2.16; GG vs. AA+AG: OR=1.55, 95% CI: 1.12-2.26). A gene-gene interaction analysis showed that there was an interaction for individuals with combination of GSTM1 (or GSTT1) null genotype and GSTP1 (AG+GG) mutant genotype for lung cancer risk in Chinese. CONCLUSION: This meta-analysis suggests that GSTP1 Ile105Val polymorphism may increase the risk of lung cancer in the Chinese population.

Polycomb group proteins are essential for spinal cord development.

Birth defects are the leading cause of infantile mortality, followed by neural tube defects (NTD) and congenital heart defects. Spina bifida and anencephaly are among the most common forms of NTD. NTD etiologies are complex, and are associated with both genetic and environmental factors. Polycomb group proteins are essential for vertebrate development; therefore, the purpose of this study was to determine the role of PcGs in spinal cord morphogenesis in normal and all-trans-retinoic acid (RA)-treated fetal rat models of spina bifida. Pregnant rats were gavage-fed RA, resulting in fetal NTD, and embryos were obtained on day 15.5, 17.5, and 19.5. Western blot and immunohistochemistry were used to reveal PcGs expression in the normal and RA-treated E15.5-19.5 rat sacral cords. Western blot and immunohistochemistry revealed decreased EED, RNF2, SUZ12, and H3K27me3 expression in the normal, E15.5-19.5, rat sacral cords. In addition, the spinal cord of RA-treated rats during embryonic development exhibited altered PcGs protein expression. Administration of excess RA results in NTD. Our results suggest that the Polycomb proteins may be involved in spinal cord development.