Tolerogenic CD11c+dendritic cells regulate CD4+Tregs in replacing delayed ischemic preconditioning to alleviate ischemia-reperfusion acute kidney injury.

Ischemia-reperfusion injury (IRI) is one of the primary clinical causes of acute kidney injury (AKI). The key to IRI lies in immune-inflammatory damage, where dendritic cells (DCs) play a central role in eliciting immune responses within the context of inflammation induced by ischemia-reperfusion. Our previous study has confirmed that delayed ischemic preconditioning (DIPC) can reduce the kidney injury by mediating DCs to regulate T-cells. However, the clinical feasibility of DIPC is limited, as pre-clamping of the renal artery is not applicable for the prevention and treatment of ischemia-reperfusion acute kidney injury (I/R-AKI) in clinical patients. Therefore, the infusion of DCs as a substitute for DIPC presents a more viable strategy for preventing renal IRI. In this study, we further evaluated the impact and mechanism of infused tolerogenic CD11c+DCs on the kidneys following IRI by isolating bone marrow-derived dendritic cells and establishing an I/R-AKI model after pre-infusion of DCs. Renal function was significantly improved in the I/R-AKI mouse model after pre-infused with CD11c+DCs. The pro-inflammatory response and oxidative damage were reduced, and the levels of T helper 2 (Th2) cells and related anti-inflammatory cytokines were increased, which was associated with the reduction of autologous DCs maturation mediated by CD11c+DCs and the increase of regulatory T-cells (Tregs). Next, knocking out CD11c+DCs, we found that the reduced immune protection of tolerogenic CD11c+DCs reinfusion was related to the absence of own DCs. Together, pre-infusion of tolerogenic CD11c+DCs can replace the regulatory of DIPC on DCs and T-cells to alleviate I/R-AKI. DC vaccine is expected to be a novel avenue to prevent and treat I/R-AKI.

Risk factors for one-year mortality following discharge in patients with acute aortic dissection: development and validation of a predictive model in a cross-sectional study.

PURPOSE: This study was aimed to identify the risk factors that influence the mortality risk in patients with acute aortic dissection (AAD) within one year after discharge, and aimed to construct a predictive model for assessing mortality risk. METHODS: The study involved 320 adult patients obtained from the Medical Information Mart for Intensive Care (MIMIC) database. Logistic regression analysis was conducted to identify potential risk factors associated with mortality in AAD patients within one year after discharge and to develop a predictive model. The performance of the predictive model was assessed using the receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA). To further validate the findings, patient data from the First Affiliated Hospital of Guangxi Medical University (157 patients) were analyzed. RESULTS: Univariate and multivariate logistic regression analyses revealed that gender, length of hospital stay, highest blood urea nitrogen (BUN_max), use of adrenaline, and use of amiodarone were significant risk factors for mortality within one year after discharge (p < 0.05). The constructed model exhibited a consistency index (C-index) and an area under the ROC curve of 0.738. The calibration curve and DCA demonstrated that these indicators had a good degree of agreement and utility. The external validation results of the model also indicated good predictability (AUC = 0.700, p < 0.05). CONCLUSION: The personalized scoring prediction model constructed by gender, length of hospital stays, BUN_max levels, as well as the use of adrenaline and amiodarone, can effectively identify AAD patients with high mortality risk within one year after discharge.

Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy.

SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.

Prognosis and factors related to severe secondary hyperparathyroidism in long-term peritoneal dialysis patients.

Secondary hyperparathyroidism (SHPT) can progress to severe SHPT (sSHPT), which affects the survival rate and quality of life of patients. This retrospective cohort study investigated risk factors for sSHPT and the association between SHPT and mortality (all-cause and infection-related) among 771 clinically stable patients (421 male patients; mean age, 51.2 years; median dialysis vintage, 28.3 months) who underwent >3 months of regular peritoneal dialysis (PD) between January 2013 and March 2021. The sSHPT and non-sSHPT groups comprised 75 (9.7%) (median progression, 35 months) and 696 patients, respectively. sSHPT was defined as a serum intact parathyroid hormone (PTH) level >800 pg/mL observed three times after active vitamin D pulse therapy. The influence of sSHPT on the prognosis of and risk factors for sSHPT progression were evaluated using logistic and Cox regression analyses. After adjusting for confounding factors, higher (each 100-pg/mL increase) baseline PTH levels (95% confidence interval (CI) 1.206-1.649, p < .001), longer (each 1-year increase) dialysis vintages (95% CI 1.013-1.060, p = .002), higher concomitant diabetes rates (95% CI 1.375-10.374, p = .010), and lower (each 1-absolute unit decrease) Kt/V values (95% CI 0.859-0.984, p = .015) were independent risk factors for progression to sSHPT in patients on PD. During follow-up, 211 deaths occurred (sSHPT group, n = 35; non-sSHPT group, n = 176). The sSHPT group had significantly higher infection-related mortality rates than the non-sSHPT group (12.0% vs. 4.3%; p < .05), and sSHPT was associated with increased infection-related mortality. In conclusion, patients with sSHPT are at higher risk for death and infection-related mortality than patients without sSHPT.

Enantioselective formal total synthesis of dihydrospirotryprostatin B.

Spirotryprostatins are representative members of medicinally interesting bioactive molecules of the spirooxindole natural products. In this communication, we present a novel enantioselective total synthesis of the spirooxindole alkaloid dihydrospirotryprostatin B. The synthesis takes advantage of copper-catalyzed tandem reaction of o-iodoanilide chiral sulfinamide derivatives with alkynone to rapidly construct the key quaternary carbon stereocenter of the natural product dihydrospirotryprostatin B.

Inhibition of ERK downregulates autophagy via mitigating mitochondrial fragmentation to protect SH-SY5Y cells from OGD/R injury.

BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) is the main cause leading to high mortality and neurological disability in patients with cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Our previous study found that extracellular signal-regulated kinase (ERK) activation, dynamin-related protein1 (Drp1)/Mitofusin2 (Mfn2)-dependent mitochondrial dynamics imbalance, and excessive autophagy were involved in the mechanism of nerve injury after CA/CPR. However, the specific pathological signaling pathway is still unknown. This study aimed to explore the molecular function changes of ERK-Drp1/Mfn2-autophagy signaling pathway in SH-SY5Y cell oxygen-glucose deprivation/reoxygenation (OGD/R) model, to further clarify the pathophysiological mechanism of CIRI, and to provide a new strategy for cerebral protection after CIRI. METHODS: SH-SY5Y cells were pretreated with drugs 24 h before OGD/R. The Drp1 and Mfn2 knockdown were adopted small interfering RNAs. The overexpression of p-Drp1S616 and Mfn2 were used recombinant plasmids. The expression levels of mitochondrial dynamics proteins (p-Drp1, Drp1, Mfn2, Mfn1 and Opa1) and autophagy markers (LC3, Beclin1 and p62) were measured with the Western blotting. The mRNA levels after transfection were determined by PCR. Cell injury and viability were evaluated with released LDH activity and CCK8 assay kits. Mitochondria morphology and autophagosome were observed under transmission electron microscopy. Mitochondrial function was detected by the mitochondrial permeability transition pore assay kit. The co-expression of p-ERK, p-Drp1 and LC3 was assessed with multiple immunofluorescences. One-way analysis of variance followed by least significance difference post hoc analysis (for equal homogeneity) or Dunnett's T3 test (for unequal homogeneity) were used for statistical tests. RESULTS: ERK inhibitor-PD98059 (PD) protects SH-SY5Y cells from OGD/R-induced injury; while ERK activator-TPA had the opposite effect. Similar to autophagy inhibitor 3-MA, PD downregulated autophagy to improve cell viability; while autophagy activator-rapamycin further aggravated cell death. PD and Drp1-knockdown synergistically attenuated OGD/R-induced Drp1 activation, mPTP opening and cell injury; overexpression of Drp1S616E or ablating Mfn2 partly abolished the protective effects of PD. Multiple immunofluorescences showed that p-ERK, p-Drp1 and LC3 were co-expressed. CONCLUSION: Inhibition of ERK downregulates autophagy via reducing Drp1/Mfn2-dependent mitochondrial fragmentation to antagonize mitochondrial dysfunction and promotes cell survival in the SH-SY5Y cells OGD/R model. Video Abstract.

Melanin nanoparticles enhance the neuroprotection of mesenchymal stem cells against hypoxic-ischemic injury by inhibiting apoptosis and upregulating antioxidant defense.

Polydopamine nanoparticles are artificial melanin nanoparticles (MNPs) that show strong antioxidant activity. The effects of MNPs on the neuroprotection of mesenchymal stem cells (MSCs) against hypoxic-ischemic injury and the underlying mechanism have not yet been revealed. In this study, an oxygen-glucose deprivation (OGD)-injured neuron model was used to mimic neuronal hypoxic-ischemic injury in vitro. MSCs pretreated with MNPs and then cocultured with OGD-injured neurons were used to investigate the potential effects of MNPs on the neuroprotection of MSCs and to elucidate the underlying mechanism. After coculturing with MNPs-pretreated MSCs, MSCs, and MNPs in a transwell coculture system, the OGD-injured neurons were rescued by 91.24%, 79.32%, and 59.97%, respectively. Further data demonstrated that MNPs enhanced the neuroprotection against hypoxic-ischemic injury of MSCs by scavenging reactive oxygen species and superoxide and attenuating neuronal apoptosis by deactivating caspase-3, downregulating the expression of proapoptotic Bax proteins, and upregulating the expression of antiapoptotic Bcl-2 proteins. These findings suggest that MNPs enhance the neuroprotective effect of MSCs against hypoxic-ischemic injury by inhibiting apoptosis and upregulating antioxidant defense, which could provide some evidence for the potential application of combined MNPs and MSCs in the therapy for ischemic stroke.

The Association between Baseline Serum Lipids and Mortality in Peritoneal Dialysis Patients.

INTRODUCTION: Lipid disturbances are common in ESRD patients. In peritoneal dialysis (PD) patients, dyslipidemia is even more common. This study aimed to examine whether serum lipids were associated with prognosis of PD patients. METHODS: Patients from a multicenter retrospective cohort were used for the present study. The primary endpoint was all-cause mortality. Cox regression was used to analyze the association between serum lipids including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein, and triglycerides and the prognosis. RESULTS: The results showed that lower total cholesterol and LDL levels at the initiation of PD predicted higher all-cause mortality in PD patients. Multivariate analysis reveal that the association disappeared after adjusting for age, gender, albumin, prealbumin, protein catabolic rate normalized to body weight, C-reactive protein, and residual renal function. Further analysis showed that patients with lower total cholesterol/LDL had a higher mortality only during the first 24 months of follow-up. In the patients who survived >2 years after PD, lower total cholesterol/LDL was not associated with higher long-term all-cause mortality any more. CONCLUSION: Lower total cholesterol/LDL levels at the initiation of PD were associated with overall mortality in PD patients. The association could be potentially modified by malnutrition, inflammation, and residual renal function or disappeared after 24 months.

Relationships among the Dosage of Erythropoiesis-Stimulating Agents, Erythropoietin Resistance Index, and Mortality in Maintenance Hemodialysis Patients.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) constitute an important treatment option for anemia in hemodialysis (HD) patients. We investigated the relationships among the dosage of ESA, erythropoietin resistance index (ERI) scores, and mortality in Chinese MHD patients. METHODS: This multicenter observational retrospective study included MHD patients from 16 blood purification centers (n = 824) who underwent HD in 2011-2015 and were followed up until December 31, 2016. We collected demographic variables, HD parameters, laboratory values, and ESA dosages. Patients were grouped into quartiles according to ESA dosage to study the effect of ESA dosage on all-cause mortality. The ERI was calculated as follows: ESA (IU/week)/weight (kg)/hemoglobin levels (g/dL). We also compared outcomes among the patients stratified into quartiles according to ERI scores. We used the Cox proportional hazards model to measure the relationships between the ESA dosage, ERI scores, and all-cause mortality. Using propensity score matching, we compared mortality between groups according to ERI scores, classified as either > or ≤12.80. RESULTS: In total, 824 patients were enrolled in the study; 200 (24.3%) all-cause deaths occurred within the observation period. Kaplan-Meier analyses showed that patients administered high dosages of ESAs had significantly worse survival than those administered low dosages of ESAs. A multivariate Cox regression identified that high dosages of ESAs could significantly predict mortality (ESA dosage >10,000.0 IU/week, HR = 1.59, 95% confidence intervals (CIs) (1.04, 2.42), and p = 0.031). Our analysis also indicated a significant increase in the risk of mortality in patients with high ERI scores. Propensity score matching-analyses confirmed that ERI > 12.80 could significantly predict mortality (HR = 1.56, 95% CI [1.11, 2.18], and p = 0.010). CONCLUSIONS: Our data suggested that ESA dosages >10,000.0 IU/week in the first 3 months constitute an independent predictor of all-cause mortality among Chinese MHD patients. A higher degree of resistance to ESA was related to a higher risk of all-cause mortality.

Tracing the pollution and human risks of potentially toxic elements in agricultural area nearby the cyanide baths from an active private gold mine in Hainan Province, China.

Mining activities are well-known sources of potentially toxic elements (PTEs) pollution, which often jeopardize the biosphere, pedosphere, and hydrosphere. However, the soil and groundwater pollution caused by active private mining activities has long been neglected. This study investigated the occurrence of PTEs and cyanide (CN) in agricultural soils, mine tailings, and groundwater nearby the cyanide baths from a private gold mine in Hainan Province, southern China. Results indicated that concentrations of Pb, As, Cd, Hg, and CN in different soil depths and mine tailings were up to ten thousand mg/kg, and relatively higher content of As and Pb was detected in groundwater. The chemical forms of Cd, Pb, As, and Hg varied greatly in different soil depths; over 80% of Cd distributed in the water-soluble fraction, suggesting its higher mobility in soils, while approximately 60-90% of Pb, As, and Hg distributed in other chemical fractions, indicating relatively lower mobility in soils. The pollution indices also revealed the serious pollution and deterioration of site quality in this area. Human risk assessments also reflected a high non-carcinogenic/carcinogenic health risk in this area. The framework of integrated management strategies for private metal mines was proposed to mitigate PTEs pollution and reduce health risks.

Biological effects and mechanisms of matrine and other constituents of Sophora flavescens in colorectal cancer.

The plant Sophora flavescens Ait. has been used in the clinical management of colorectal cancer (CRC). Its constituent compounds, notably the alkaloids matrine, oxymatrine, and sophoridine, have received considerable research attention in experimental models of CRC in vivo and in vitro. This review found that extracts of S. flavescens and/or its constituent compounds have been reported to inhibit CRC cell proliferation by inducing cell-cycle arrest at the G1 phase, inducing apoptosis via the intrinsic pathway, interfering in cancer metabolism, inhibiting metastasis and angiogenesis, regulating senescence and telomeres, regulating the tumour microenvironment and down-regulating cancer-related inflammation. In addition, matrine and oxymatrine reversed multi-drug resistance and enhanced the effects of chemotherapies. These anti-cancer effects were associated with regulation of several cellular signalling pathways including: MAPK/ERK, PI3K/AKT/mTOR, p38MAPK, NF-κB, Hippo/LATS2, TGF-ß/Smad, JAK/STAT3, RhoA/ROC, and Wnt/ ß-catenin pathways. These multiple actions in CRC suggest the alkaloids of S. flavescens may be therapeutic candidates for CRC management. Nevertheless, there remains considerable scope for future research into its flavonoid constituents, the effects of combinations of compounds, and the interaction between these compounds and anti-cancer drugs. In addition, more research is needed to investigate likely drug ligand-receptor interactions for each of the bioactive compounds.

High-volume hemofiltration reduces short-term mortality with no influence on the incidence of MODS, hospital stay, and hospitalization cost in patients with severe-acute pancreatitis: A meta-analysis.

This study aimed to investigate the efficiency, safety and cost-efficiency of blood purification (BP) in treating patients with severe-acute pancreatitis (SAP). A literature search was conducted using PubMed, OVID, International Clinical Trials Register (ICTRP), and Cochrane Central Register of Controlled Trials (CENTRAL). A total of 11 prospective studies and 6 retrospective studies, which reported the mortality of 1279 SAP patients, were included for analysis. Decreased short-term mortality and incidence rate of infection were observed in the high-volume hemofiltration (HVHF) group, but not in patients treated with other types of BP. There was no significant difference in the incidence of multiple-organ dysfunction (MODS), duration of hospital stay, or cost of hospitalization between the BP and non-BP groups. The starting time point, substitution fluid flow rate, filter membrane type, hemofilter change interval, anticoagulation, and sustaining times of BP varied across studies. In conclusion, HVHF may reduce the short-term mortality (<4 weeks), not long-term mortality, of SAP patients by decreasing the incidence of infection, while other types of BP did not show a significant beneficial effect. Neither HVHF nor other BP patterns affect the duration of hospital stay, cost of hospitalization, or incidence of MODS in SAP patients.

Genome-Wide Meta-Analysis Identifies Three Novel Susceptibility Loci and Reveals Ethnic Heterogeneity of Genetic Susceptibility for IgA Nephropathy.

BACKGROUND: Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk. METHODS: Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny. RESULTS: Identification of three novel loci (rs6427389 on 1q23.1 [P=8.18×10-9, OR=1.132], rs6942325 on 6p25.3 [P=1.62×10-11, OR=1.165], and rs2240335 on 1p36.13 [P=5.10×10-9, OR=1.114]), implicates FCRL3, DUSP22.IRF4, and PADI4 as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of PADI4, and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on FCRL3. Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and DEFA showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119). CONCLUSIONS: A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs.  These variants may explain susceptibility differences between Chinese and European populations.

Survival outcomes and adverse events in patients with chronic kidney disease after coronary artery bypass grafting and percutaneous coronary intervention: a meta-analysis of propensity score-matching studies.

BACKGROUND: The present meta-analysis of propensity score-matching studies aimed to compare the long-term survival outcomes and adverse events associated with coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in patients with chronic kidney disease (CKD). METHODS: Electronic databases were searched for studies comparing CABG and PCI in patients with CKD. The search period extended to 13 February 2021. The primary outcome was all-cause mortality, and the secondary endpoints included myocardial infarction, revascularization, and stroke. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were used to express the pooled effect. Study quality was assessed using the Newcastle-Ottawa scale. The analyses were performed using RevMan 5.3. RESULTS: Thirteen studies involving 18,005 patients were included in the meta-analysis. Long-term mortality risk was significantly lower in the CABG group than in the PCI group (HR: 0.76, 95% CI: 0.70-0.83, p < .001), and similar results were observed in the subgroup analysis of patients undergoing dialysis and for different estimated glomerular filtration rate ranges. The incidence rates of myocardial infarction (OR: 0.25, 95% CI: 0.12-0.54, p < .001) and revascularization (OR: 0.17, 95% CI: 0.08-0.35, p < .001) were lower in the CABG group than in the PCI group, although there were no significant differences in the incidence of stroke between the two groups (OR: 1.24; 95% CI: 0.89-1.73, p > .05). Subgroup analysis among patients on dialysis yielded similar results. CONCLUSIONS: Our propensity score matching analysis revealed that, based on long-term follow-up outcomes, CABG remains superior to PCI in patients with CKD.

Pomelo peel oil suppresses TNF-α-induced necroptosis and cerebral ischaemia-reperfusion injury in a rat model of cardiac arrest.

CONTEXT: Pomelo peel oil (PPO) [Citrus maxima (Burm.) Merr. (Rutaceae)] is reported to possess antioxidant and antimelanogenic activities. OBJECTIVE: To investigate the effect of PPO [Citrus maxima (Burm.) Merr. cv. Shatian Yu] on tumour necrosis factor-α (TNF-α)-induced necroptosis in cerebral ischaemia-reperfusion injury (CIRI) after cardiac arrest (CA). MATERIALS AND METHODS: Male Sprague Dawley rats were randomly assigned to six groups: sham group, PP0-L (10 mg/kg), PPO-M (20 mg/kg), PPO-H (40 mg/kg) and two control groups (CA, 0.9% saline; Gly, 10% glycerol). All drugs were administered intravenously to the CA/CPR rats within 10 min after return of spontaneous circulation (ROSC). After 24 h, rats were assessed for neuronal injury via the neurological deficit score (NDS), cerebral cortex staining and transmission electron microscopy (TEM) and expression levels of TNF-α and necroptosis-related proteins by immunoreactivity staining and western blotting. RESULTS: Compared to those in the sham group (survival rate, 100% and NDS, 80), the survival rate and NDS were significantly reduced in the model groups (CA, 56.25%, 70; Gly, 62.5%, 71; PPO-L, 75%, 72; PPO-M, 87.5%, 75; PPO-H, 81.25%, 74). In the PPO-M group, Nissl bodies were significantly increased (43.67 ± 1.906 vs. 17 ± 1.732), the incidence of pathomorphological injury was lower and the necroptosis markers (TNF-α, RIPK1, RIPK3, p-MLKL/MLKL) expression was downregulated compared to those in the CA group (p < 0.05). DISCUSSION AND CONCLUSIONS: The neuroprotective effects of PPO in the CA rats suggested that PPO possibility as a health product enhances the resistance ability against brain injury for humans.

High-potassium preconditioning enhances tolerance to focal cerebral ischemia-reperfusion injury through anti-apoptotic effects in male rats.

Imbalances between cellular K+ efflux and influx are considered to be involved in cerebral ischemia-reperfusion (I/R) injury. High-potassium pretreatment alleviates this injury, but the underlying molecular mechanism is unclear. In this study, we sought to investigate whether high-potassium preconditioning enhances cerebral tolerance to I/R injury through an anti-apoptotic mechanism. Adult male Sprague-Dawley rats were randomly divided into four groups (n = 40/group): a sham-operated group, normal saline group (3.2 ml/kg saline, intravenous (IV)), and low-dose and high-dose potassium chloride (KCl) groups (40 and 80 mg/kg KCl solution, IV, respectively). Subsequently, the rats underwent 90 min of middle cerebral artery occlusion (MCAO) followed by 24 hr of reperfusion (MCAO/R). Neurological deficit scores, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin and eosin staining, and TUNEL assay were used to assess neural injury. The expression of apoptotic proteins, brain potassium levels, mitochondrial function and oxidative stress were detected to explore the potential mechanism. After 24 hr of reperfusion, in both KCl treatment groups, neurological deficits and the cerebral infarct volume were reduced, and the apoptosis index of neurons was decreased. Furthermore, high-potassium preconditioning increased brain K+ , adenosine triphosphate (ATP), cytochrome c oxidase (COX) levels, reduced malondialdehyde level, improved Na+ /K+ -ATPase, succinic dehydrogenase and superoxide dismutase activities, upregulated anti-apoptotic protein expression, and downregulated pro-apoptotic protein expression. This study suggests that high-potassium preconditioning enhanced cerebral tolerance to I/R injury in a rat MCAO/R model. The protective mechanism may involve apoptosis inhibition via preservation of intracellular K+ and improvement of mitochondrial function.

The incidence of acute kidney injury following cardiac arrest and cardiopulmonary resuscitation in a rat model.

OBJECTIVE: In the current study, we investigated the incidence of acute kidney injury (AKI) induced by cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) and whether such an AKI can recover spontaneously in rats. METHODS: We used transesophageal alternating current stimulation to establish 7 min of CA rat model followed by conventional CPR. The experimental rats were randomly divided into three groups (n = 20 per group) according to the different time points after restoration spontaneous circulation (ROSC): the ROSC 24 h, ROSC 48 h, and ROSC 72 h group. The diagnosis of rat AKI refers to the 2012 KDIGO adult AKI diagnostic criteria. The severity of AKI quantified by the serum creatinine (SCR), blood urea nitrogen (BUN) levels and histological features of renal tissue. RESULTS: The incidence rates of AKI in ROSC 24 h, ROSC 48 h, and ROSC 72 h group were 65%, 45%, and 42.9%. Moreover, the values of SCR and BUN were highest at ROSC 24 h, and then gradually decreased with the time of ROSC. The histological changes of the renal tissues such as glomerular collapse, renal tubular cell swelling, and inflammatory cell infiltration had also observed. CONCLUSION: The incidence of AKI in rats was high after suffering from CA and CPR, but renal function improved with the prolongation of ROSC time, indicating the ability of the kidney to self-repair.

Elevated Serum Potassium Concentration Alleviates Cerebral Ischemia-Reperfusion Injury via Mitochondrial Preservation.

BACKGROUND/AIMS: The anti-apoptotic effect of an increase in the extracellular concentration of potassium ([K+]) has been confirmed in vitro. However, it is not yet known whether elevated serum [K+] exerts a cerebroprotective effect in vivo. In this study, we aimed to explore the effect of elevated serum [K+] in a rat model of middle cerebral artery occlusion and reperfusion (MCAO/R). METHODS: Rats subjected to 90-min MCAO received 2.5% KCL, 1.25% KCL, or a normal saline solution at a dose of 3.2 mL/kg at the onset of reperfusion. Rats that were subjected to vascular exposure and ligation without MCAO were defined as the Sham group. Serum [K+] was determined using a blood gas analyzer at 1 min after medicine administration. At 24 h post-reperfusion, rat brains were harvested and processed for 2% 2,3,5-triphenyltetrazolium chloride staining, terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling staining, detection of caspase-3 and cleaved-caspase-3 by western blotting, detection of reactive oxygen species (ROS) by dihydroethidium staining, and observation of mitochondrial structure by electron microscopy. In addition, malondialdehyde (MDA), adenosine triphosphate (ATP), total superoxide dismutase (T-SOD), cytochrome C oxidase (COX) activity, and mitochondrial permeability transition pore (MPTP) opening were measured using detection kits. RESULTS: The results showed that elevated serum [K+] decreased cerebral injury and apoptosis, reduced ROS and MDA levels and MPTP opening, increased ATP levels and cytochrome C oxidase activity, and improved mitochondrial ultrastructural changes, although there was no significant difference in T-SOD activity. CONCLUSION: These findings suggested that elevated serum [K+] could alleviate cerebral ischemia-reperfusion injury and the mechanism may be associated with the preservation of mitochondrial function.

Acute kidney injury in China: a cross-sectional survey.

BACKGROUND: Acute kidney injury (AKI) has become a worldwide public health problem, but little information is available about the disease burden in China. We aimed to evaluate the burden of AKI and assess the availability of diagnosis and treatment in China. METHODS: We launched a nationwide, cross-sectional survey of adult patients who were admitted to hospital in 2013 in academic or local hospitals from 22 provinces in mainland China. Patients with suspected AKI were screened out on the basis of changes in serum creatinine by the Laboratory Information System, and we reviewed medical records for 2 months (January and July) to confirm diagnoses. We assessed rates of AKI according to two identification criteria: the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) AKI definition and an increase or decrease in serum creatinine by 50% during hospital stay (expanded criteria). We estimated national rates with data from the 2013 report by the Chinese National Health and Family Planning Commission and National Bureau of Statistics. FINDINGS: Of 2,223,230 patients admitted to the 44 hospitals screened in 2013, 154,950 (7·0%) were suspected of having AKI by electronic screening, of whom 26,086 patients (from 374,286 total admissions) were reviewed with medical records to confirm the diagnosis of AKI. The detection rate of AKI was 0·99% (3687 of 374,286) by KDIGO criteria and 2·03% (7604 of 374,286) by expanded criteria, from which we estimate that 1·4-2·9 million people with AKI were admitted to hospital in China in 2013. The non-recognition rate of AKI was 74·2% (5608 of 7555 with available data). Renal referral was done in 21·4% (1625 of 7604) of the AKI cases, and renal replacement therapy was done in 59·3% (531 of 896) of those who had the indications. Delayed AKI recognition was an independent risk factor for in-hospital mortality, and renal referral was an independent protective factor for AKI under-recognition and mortality INTERPRETATION: AKI has become a huge medical burden in China, with substantial underdiagnosis and undertreatment. Nephrologists should take the responsibility for leading the battle against AKI. FUNDING: National 985 Project of China, National Natural Science Foundation of China, Beijing Training Program for Talents, International Society of Nephrology Research Committee, and Bethune Fund Management Committee.

Coronary artery bypass surgery compared with percutaneous coronary interventions in patients with insulin-treated type 2 diabetes mellitus: a systematic review and meta-analysis of 6 randomized controlled trials.

BACKGROUND: Data regarding the long-term clinical outcomes in patients with insulin-treated type 2 diabetes mellitus (ITDM) revascularized by either coronary artery bypass surgery (CABG) or percutaneous coronary intervention (PCI) are still controversial. We sought to compare the long-term (≥1 year) adverse clinical outcomes in patients with ITDM who underwent revascularization by either CABG or PCI. METHODS: Randomized Controlled Trials (RCTs) comparing the long-term clinical outcomes in patients with ITDM and non-ITDM revascularized by either CABG or PCI were searched from electronic databases. Data for patients with ITDM were carefully retrieved. Odd Ratio (OR) with 95 % confidence interval (CI) was used to express the pooled effect on discontinuous variables and the pooled analyses were performed with RevMan 5.3. RESULTS: Six RCTs involving 10 studies, with a total of 1297 patients with ITDM were analyzed (639 patients from the CABG group and 658 patients from the PCI group). CABG was associated with a significantly lower mortality rate compared to PCI with OR: 0.59, 95 % CI 0.42-0.85; P = 0.004. Major adverse cardiovascular and cerebrovascular events as well as repeated revascularization were also significantly lower in the CABG group with OR: 0.51, 95 % CI 0.27-0.99; P = 0.03 and OR 0.34, 95 % CI 0.24-0.49; P < 0.00001 respectively. However, compared to PCI, the rate of stroke was higher in the CABG group with OR: 1.41, 95 % CI 0.64-3.09; P = 0.40, but this result was not statistically significant. CONCLUSION: CABG was associated with significantly lower long-term adverse clinical outcomes compared to PCI in patients with ITDM. However, due to an insignificantly higher rate of stroke in the CABG group, further researches with a larger number of randomized patients are required to completely solve this issue.