Organ-protective Effects Research Articles

Central hemodynamic and splanchnic circulation in children with meningococcal septic shock

Meningococcal infection is caused by the bacterium Neisseria meningitidis (also termed meningococcus). Invasive meningococcal disease remains a rare infectious disease not only with high mortality but also with important morbidity and remains as a leading cause of sepsis and septic shock. The pathogenic mechanisms of microcirculatory disorders in meningococcal septic shock have been subject to controversy. This article presents the results of a study of 11 paediatric patients’ (4 boys and 7 girls) with meningococcal septic shock (Group I) who were hospitalized at the Regional Children's Infectious Hospital from 2009 to 2011. The average age of the patients was 37.4 ± 8.4 mo. Septic shock was diagnosed according to International Pediatric Sepsis Consensus Conference: definitions of criteria for sepsis and organ dysfunction in paediatrics. Heart rate, respiratory rate, systolic blood pressure, diastolic blood pressure, average blood pressure, SpO2 were monitored. The cardiac output, ejection fraction, fraction shortening, stroke volume were measured by ultrasound in M-mode by Teichholz method. Blood circulation in the a. mesenterica, a. hepatica, a. lienalis, a. renal sinister, v. porta, v. lienalis, v. renal sinister was determined by impulse Doppler’s wave. Acid-base and electrolytes level in serum, nitric oxide (NO), endothelin I, creatinine, C-reactivity protein and lactate blood level were measured. The control group consisted of 21 healthy children (9 boys and 12 girls), aged 37.5 ± 5.4 mo. in average (Group II). We used t-criteria (Student’s) and correlation with R-criteria (Spearmen) for statistical analysis. The data showed a statistically significant lower fraction of ejection, fraction of shortening, stroke volume in Group I. Moreover, our data showed a statistically high level of mesenterial and portal blood flow rate and high pulse index in v. renal sinister compared to healthy children. The blood level of NO was increased in Group I as well as in Group II. Direct correlations were determined between the level of NO and mesenteric, hepatic arterial and venous blood flow rate. Statistically significant inverse correlations between the level of NO and pulse resistive index in splanchnic vessels were discovered as well as inverse correlations between the NO level and the indicator of the severity of condition on PRISM scale (r = –0.952). At the same time, we have found no correlation between splanchnic circulation value and cardiac output. Based on the results of this study, we consider that NO has organ protective effects in children with meningococcal sepsis. Future research should aim to introduce new strategies of intensive care for patients with meningococcal septic shock with early use of inotrope and NO-donor therapy in fluid restriction combination.

Hepatoprotective Effects of Corilagin Following Hemorrhagic Shock are Through Akt-Dependent Pathway.

ABSTRACTCorilagin, a component of Phyllanthus urinaria extract, possesses antioxidant, thrombolytic, antiatherogenic, and hepatoprotective properties, but the mechanism underlying these effects remains unclear. Previous studies showed that the Akt (protein kinase B) signaling pathway exerts anti-inflammatory and organ protective effects. The aim of this study was to investigate the mechanism of action of corilagin and determine whether these effects are mediated through the Akt-dependent pathway in a trauma-hemorrhagic shock-induced liver injury rodent model. Hemorrhagic shock was induced in male Sprague–Dawley rats; mean blood pressure was maintained at 35 mm Hg to 40 mm Hg for 90 min, followed by fluid resuscitation. During resuscitation, three doses of corilagin alone (1 mg/kg, 5 mg/kg, or 10 mg/kg, intravenously) were administered. Furthermore, a single dose of corilagin (5 mg/kg) with and without Wortmannin (1 mg/kg, PI3K inhibitor), Wortmannin alone, or vehicle was administered. Twenty-four hours after resuscitation, plasma alanine aminotransferase and aspartate aminotransferase concentration and hepatic parameters were measured. One-way ANOVA was used for statistical analysis. Hepatic myeloperoxidase activity and the concentrations of plasma alanine aminotransferase and aspartate aminotransferase, interleukin-6, tumor necrosis factor-α, intercellular adhesion molecule-1, and cytokine-induced neutrophil chemoattractant-1 (CINC-1) and CINC-3 increased following hemorrhagic shock. These parameters were significantly attenuated in corilagin-treated rats following hemorrhagic shock. Hepatic phospho-Akt expression was also higher in corilagin-treated rats than in vehicle-treated rats. The elevation of phospho-Akt was abolished by combined treatment with Wortmannin and corilagin. Our results suggest that corilagin exerts its protective effects on hemorrhagic shock-induced liver injury, at least, via the Akt-dependent pathway.

Возможности фиксированной комбинации высокоселективного бета-адреноблокатора бисопролола и антагониста кальция амлодипина (Конкор АМ) в лечении артериальной гипертонии у больных с метаболическими нарушениями

Introduction. Combination therapy is widely used in treatment of patients with arterial hypertension (AH) of high and very high cardiovascular risk. Fixed combinations (FC) of medications are preferable and it is important to develop new effective and safe ones. Organ-protective effects are also significant. Objective. To study antihypertensive effectiveness of new FC of highly selective β-adrenoblocker bisoprolol and calcium antagonist amlodipine (Concor® AM), its influence on cardiometabolic risk factors and target lesions in metabolic disorder patients with AH of stages 1 or 2. Materials and methods. The study included 30 patients (13 male, 17 female, mean age 47.20±0.22 years) with AH of stages 1 or 2 and metabolic syndrome (MS). All patients underwent clinical assessment of blood pressure (BP); levels of serum cholesterol (SCL), high density lipoprotein (HDL), low density lipoprotein (LDL), triglyceride, creatinine, and glucose in oral glucose tolerance test; 24-hour blood pressure monitoring; central systolic blood pressure (CSBP); carotid-femoral pulse wave velocity (cfPWV), and intima-media complex thickness which were determined initially and after 6 months of therapy with FC. Results. The target level of BP was reached by 88% patients after treatment with Concor® AM. Significant deceleration of heart rate (from 74.95±2.20 to 68.81±1.13 bpm) and CSBP (from 151.7 to 132.6 mm Hg) were observed. Treatment with Concor® AM led to artery stiffness decrease evaluated by cfPWV decrease (from 14.21±0.45 to 12.1±0.23 m/s, p≤0.05). Conclusion. FC of highly selective β-adrenoblocker bisoprolol and calcium antagonist amlodipine (Concor® AM) was shown effective for AH treatment in patients with MS. Future research is recommended to investigate the effectiveness of FC therapy in a larger cohort of patients.

Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest

Background: In-hospital mortality in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) is ≈50%. In OHCA patients, the leading cause of death is neurological injury secondary to ischemia and reperfusion. Glucagon-like peptide-1 analogs are approved for type 2 diabetes mellitus; preclinical and clinical data have suggested their organ-protective effects in patients with ischemia and reperfusion injury. The aim of this trial was to investigate the neuroprotective effects of the glucagon-like peptide-1 analog exenatide in resuscitated OHCA patients. Methods: We randomly assigned 120 consecutive comatose patients resuscitated from OHCA in a double-blind, 2-center trial. They were administered 17.4 μg exenatide (Byetta) or placebo over a 6-hour and 15-minute infusion, in addition to standardized intensive care including targeted temperature management. The coprimary end points were feasibility, defined as initiation of the study drug in >90% patients within 240 minutes of return of spontaneous circulation, and efficacy, defined as the geometric area under the neuron-specific enolase curve from 24 to 72 hours after admission. The main secondary end points included a composite end point of death and poor neurological function, defined as a Cerebral Performance Category score of 3 to 5 assessed at 30 and 180 days. Results: The study drug was initiated within 240 minutes of return of spontaneous circulation in 96% patients. The median blood glucose 8 hours after admission in patients receiving exenatide was lower than that in patients receiving placebo (5.8 [5.2–6.7] mmol/L versus 7.3 [6.2–8.7] mmol/L, P <0.0001). However, there were no significant differences in the area under the neuron-specific enolase curve, or a composite end point of death and poor neurological function between groups. Adverse events were rare with no significant difference between groups. Conclusions: Acute administration of exenatide to comatose patients in the intensive care unit after OHCA is feasible and safe. Exenatide did not reduce neuron-specific enolase levels and did not significantly improve a composite end point of death and poor neurological function after 180 days. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02442791.

Investigation into Iron Chelating and Antioxidant Potential of Melilotus officinalis in Iron Dextran Induced Iron Overloaded Sprague Dawley Rat Model.

Excess of iron leads to generates free radicals, causes organ damage. Melilotus officinalis (Fabaceae) reported to have various pharmacological activities. It contains flavonoids and phenolic compounds which have iron chelating and antioxidant property. Hence, present study was designed to investigate the beneficial effects of different fractions of M. officinalis for the management of iron overload disease and its complications. Iron overload was induced by 6 IP injections of iron dextran (12.5 mg/100 g) uniformly distributed over the period of 30 days. The different fractions of M. officinalis were given orally and Deferoxamine (DFO) subcutaneously for 30 days. The iron chelating and various biochemical parameters were estimated on 15th and 30th day. The different fractions of M. officinalis demonstrated dose dependant in-vitro iron chelating ability. There were significant (P<0.01) iron chelating potential shows in rats treated with methanolic fraction of methanolic extract (MFME) and methanolic fraction of aqueous extract (MFAE) of M. officinalis as compared to disease control (DC) rats. The rats treated with MFME and MFAE of M. officinalis shows significant (P<0.01) antioxidant and vital organ protective effect as compared to DC rats. Better iron chelation was observed on 30th day and at higher dose (300 mg/kg) as compared to 15th day and at lower dose (150 mg/kg). The present study concludes that MFME and MFAE of M. officinalis have reversible iron chelating and antioxidant potential in rats. The study also proves the possible mechanism of action, as an iron chelator by increasing the excretion of iron in urine and feces.

Maresin 1 Maintains the Permeability of Lung Epithelial Cells In Vitro and In Vivo.

Previous reports showed that Maresin 1 (MaR1) possessed organ protection effects and could attenuate acute lung injury. Here, we aim to figure out whether MaR1 can maintain the permeability of lung epithelial cells by regulating the expression of tight junction protein during lung injury. Monolayer of murine lung epithelial cells was stimulated by lipopolysaccharide (LPS) with or without MaR1 and the permeability was evaluated. The expression of Claudin-1 and ZO-1 in lung epithelial cells was analyzed by immunofluorescence staining and western blotting. MaR1 was given to the mice after LPS induced acute lung injury. The permeability of lung was assessed by Evans Blue extravasation, lung wet/dry ratio and protein concentration in bronchoalveolar lavage fluid. Lung injury score was also evaluated. The expression of Claudin-1 and ZO-1 in the lung was analyzed by immunofluorescence staining. Results showed that MaR1 maintained the permeability of lung epithelial cells and upregulated the expression of Claudin-1 and ZO-1 after LPS stimulation. In acute lung injury mice, MaR1 upregulated the expression of Claudin-1 and ZO-1, decreased lung permeability, and reduced lung injury. In summary, this study suggests that MaR1 can maintain the permeability of lung epithelial cells by upregulating the expression of Claudin-1 and ZO-1 in acute lung injury.

The Efficacy of Noble Gases in the Attenuation of Ischemia Reperfusion Injury: A Systematic Review and Meta-Analyses.

Noble gases have been attributed to organ protective effects in ischemia reperfusion injury in a variety of medical conditions, including cerebral and cardiac ischemia, acute kidney injury, and transplantation. The aim of this study was to appraise the available evidence by systematically reviewing the literature and performing meta-analyses. PubMed, EMBASE, and the Cochrane Library. Inclusion criteria specified any articles on noble gases and either ischemia reperfusion injury or transplantation. In vitro studies, publications without full text, review articles, and letters were excluded. Information on noble gas, organ, species, model, length of ischemia, conditioning and noble gas dose, duration of administration of the gas, endpoints, and effects was extracted from 79 eligible articles. Study quality was evaluated using the Jadad scale. Effect sizes were extracted from the articles or retrieved from the authors to allow meta-analyses using the random-effects approach. Argon has been investigated in cerebral, myocardial, and renal ischemia reperfusion injury; helium and xenon have additionally been tested in hepatic ischemia reperfusion injury, whereas neon was only explored in myocardial ischemia reperfusion injury. The majority of studies show a protective effect of these noble gases on ischemia reperfusion injury across a broad range of experimental conditions, organs, and species. Overall study quality was low. Meta-analysis for argon was only possible in cerebral ischemia reperfusion injury and did not show neuroprotective effects. Helium proved neuroprotective in rodents and cardioprotective in rabbits, and there were too few data on renal ischemia reperfusion injury. Xenon had the most consistent effects, being neuroprotective in rodents, cardioprotective in rodents and pigs, and renoprotective in rodents. Helium and xenon show organ protective effects mostly in small animal ischemia reperfusion injury models. Additional information on timing, dosing, and comparative efficacy of the different noble gases, as well as confirmation in large animal models, is needed before designing clinical trials.

Hydrogen-rich saline mediates neuroprotection through the regulation of endoplasmic reticulum stress and autophagy under hypoxia-ischemia neonatal brain injury in mice

Hydrogen as a new medical gas exerts organ-protective effects through regulating oxidative stress, inflammation and apoptosis. Multiple lines of evidence reveal the protective effects of hydrogen in various models of brain injury. However, the exact mechanism underlying this protective effect of hydrogen against hypoxic-ischemic brain damage (HIBD) is not fully understood. The present study was designed to investigate whether hydrogen-rich saline (HS) attenuates HIBD in neonatal mice and whether the observed protection is associated with reduced endoplasmic reticulum (ER) stress and regulated autophagy. The results showed that HS treatment significantly improved brain edema and decreased infarct volume. Furthermore, HS significantly attenuated HIBD-induced ER stress responses, including the decreased expression of glucose-regulated protein 78, C/EBP homologous protein, and down-regulated transcription factor. Additionally, we demonstrated that HS induced autophagy, including increased LC3B and Beclin-1 expression and decreased phosphorylation of mTOR and Stat3, as well as phosphorylation of ERK. Taken together, HS exerts neuroprotection against HIBD in neonatal mouse, mediated in part by reducing ER stress and increasing autophagy machinery.

Nuclear factor erythroid 2-related factor 2 is a critical target for the treatment of glucocorticoid-resistant lupus nephritis.

BackgroundDimethyl fumarate (DMF), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, has been proven effective for the systemic treatment of multiple sclerosis. The aim of this study is to evaluate the anti-inflammatory effects of Nrf2 activators on human renal mesangial cells (HRMCs) and the development of lupus nephritis (LN) in mice.MethodsTo assess Nrf2 activation in vitro, HRMCs were treated with safe doses of Nrf2 activators and prednisolone. The expression levels of Nrf2 and its target genes were measured using quantitative reverse transcription PCR and enzyme-linked immunosorbent assay. The anti-inflammatory effects of these compounds were assessed by measuring tumor necrosis factor alpha-induced cytokine secretion. Experimental LN was induced in female BALB/c mice by a single intraperitoneal injection of pristane. The urine albumin-to-creatinine ratio was measured at 20 weeks after injection. Pathological changes as well as protein and mRNA expression levels were assessed in the kidney obtained at the experimental end point. Oral administration of DMF or prednisolone to these mice was initiated after pristane injection.ResultsNrf2 activators such as sulforaphane and DMF showed anti-inflammatory effects in HRMCs, whereas glucocorticoid (prednisolone) showed partial effects. Moreover, DMF ameliorated the development of kidney diseases in pristane-induced LN mice, whereas glucocorticoid had no effect.ConclusionsNrf2 activators showed stronger anti-inflammatory and organ-protective effects than glucocorticoid in the kidney. Thus, Nrf2 activators are potential therapeutic targets in glucocorticoid-resistant LN in humans.

Fimasartan: A New Angiotensin Receptor Blocker.

Fimasartan is the ninth, and most recent, angiotensinII receptor antagonist approved as an antihypertensive agent. Fimasartan, a pyrimidin-4(3H)-one derivative of losartan with the imidazole ring replaced, which enables higher potency and longer duration than losartan. Fecal elimination and biliary excretion are the predominant elimination pathways of fimasartan and the urinary excretion was found to be less than 3% 24h after administration. Fimasartan is primarily catabolized by cytochrome P450 isoform 3A and no significant drug interaction was observed when used in combination with hydrochlorothiazide, amlodipine, warfarin, or digoxin. Fimasartan at a dosage range of 60-120mg once daily showed an antihypertensive effect over 24h. In a large, population-based observational study, fimasartan showed an excellent safety profile. Anti-inflammatory and organ-protecting effects of fimasartan have been shown in various preclinical studies, including aortic balloon injury, myocardial infarct ischemia/reperfusion, doxorubicin cardiotoxicity, and ischemic stroke models.

FIRST-IN-HUMAN SINGLE-ASCENDING-DOSE STUDY OF IW-1973, A NEW SOLUBLE GUANYLATE CYCLASE STIMULATOR

IW-1973 is an orally active soluble guanylate cyclase (sGC) stimulator that reduces blood pressure (BP) and exhibits anti-fibrotic, anti-inflammatory and organ-protective effects in animal models of systemic hypertension, pulmonary hypertension and heart failure. A Phase 1a first-in-human clinical

Антигипертензивные и органопротективные эффекты торасемида

Антигипертензивные и органопротективные эффекты торасемида

Angiotensin II during Experimentally Simulated Central Hypovolemia.

Central hypovolemia, defined as diminished blood volume in the heart and pulmonary vascular bed, is still an unresolved problem from a therapeutic point of view. The development of pharmaceutical agents targeted at specific angiotensin II receptors, such as the non-peptidergic AT2-receptor agonist compound 21, is yielding many opportunities to uncover more knowledge about angiotensin II receptor profiles and possible therapeutic use. Cardiovascular, anti-inflammatory, and neuroprotective therapeutic use of compound 21 have been suggested. However, there has not yet been a focus on the use of these agents in a hypovolemic setting. We argue that the latest debates on the effect of angiotensin II during hypovolemia might guide for future studies, investigating the effect of such agents during experimentally simulated central hypovolemia. The purpose of this review is to examine the role of angiotensin II during episodes of central hypovolemia. To examine this, we reviewed results from studies with three experimental models of simulated hypovolemia: head up tilt table test, lower body negative pressure, and hemorrhage of animals. A systemic literature search was made with the use of PubMed/MEDLINE for studies that measured variables of the renin–angiotensin system or its effect during simulated hypovolemia. Twelve articles, using one of the three models, were included and showed a possible organ-protective effect and an effect on the sympathetic system of angiotensin II during hypovolemia. The results support the possible organ-protective vasodilatory role for the AT2-receptor during hypovolemia on both the kidney and the splanchnic tissue.

The organ protective effects and timing of continuous blood purification in the treatment of severe sepsis：a double-blind randomized controlled trial

To investigate the organ protective effects and the timing of continuous blood purification (CBP) in the treatment of severe sepsis. A double-blind randomized controlled trial was conducted. Seventy-four patients with severe sepsis aged between 35 years and 80 years with acute physiology and chronic health evaluation Ⅱ (APACHEⅡ) scores over 20 admitted to Department of Critical Care Medicine of the First Hospital of Wuhan from January 2013 to January 2015 were enrolled. They were divided into control group (n = 37) and treatment group (n = 37) by random number table method. All patients in these two groups received conventional therapy following the guidelines for management of severe sepsis in 2012. In addition the patients in treatment group received continuous veno-venous hemofiltration (CVVH). The critical score, liver and kidney function indexes, etc., levels of pro-inflammatory cytokines in plasma and ultra filtrate before and 24, 48, and 72 hours after treatment, and the clinical picture 2 weeks after treatment in two groups were observed. APACHE Ⅱ scores, multiple organ dysfunction syndrome (MODS) scores, Murray scores of acute lung injury, and systemic inflammatory response syndrome (SIRS) scores of the patients of the above two groups were gradually declined after the treatment. The levels of white blood cell count (WBC), procalcitonin (PCT), lactate (Lac), tumor necrosis factor-α (TNF-α), interleukins (IL-6 and IL-8), and endotoxin gradually lowered. Levels of blood urea nitrogen (BUN), serum creatinine (SCr), alanine transaminase (ALT) and the oxygenation index (PaO2/FiO2) showed a tendency of lowering. There were statistically significant differences in scores of critical illness, WBC, PCT, Lac, pro-inflammatory cytokine, liver and kidney function indexes, etc. between treatment group and control group 48 hours after treatment (APACHE Ⅱ score: 15.5±4.7 vs. 20.3±5.3, MODS score: 4.6±1.4 vs. 7.3±2.2, Murray score: 1.4±0.5 vs. 1.7±0.6, SIRS score: 2.9±0.8 vs. 3.7±1.0, WBC (×109/L): 1.1±0.5 vs. 1.6±0.5, PCT (μg/L): 26.7±12.0 vs. 32.4±14.1, Lac (mmol/L): 7.6±2.2 vs. 9.3±2.8, TNF-α (μg/L): 96.3±17.4 vs. 153.4±24.2, IL-6 (μg/L): 146.8±20.6 vs. 213.8±29.2, IL-8 (μg/L): 287.1±43.6 vs. 354.5±56.2, endotoxin (kEU/L): 1.4±0.5 vs. 2.6±0.8, BUN (mmol/L): 8.7±3.6 vs. 18.5±6.4, SCr (μmol/L): 143±39 vs. 197±42, ALT (U/L): 141±27 vs. 183±34, PaO2/FiO2 (mmHg, 1 mmHg = 0.133 kPa): 150.3±45.4 vs. 124.7±32.1, all P < 0.05], and the difference was significant up to 72 hours. In the treatment group, TNF-α, IL-6, IL-8, and endotoxin could be decreased in the filtrate 24 hours and 48 hours after treatment and they correlated with the lowering tendency of their plasma levels. Compared with the control group, CVVH based on conventional treatment of severe sepsis could significantly reduce the incidence of MODS (10.8% vs. 29.7%, χ2 = 4.423, P = 0.038) and mortality (5.4% vs. 13.5%, χ2 = 4.674, P = 0.032), and remarkably shortened the duration of mechanical ventilation (days: 3.1±0.6 vs. 5.3±1.7, t = 2.103, P = 0.045), and the length of intensive care unit (ICU) stay (days: 8.5±1.7 vs. 13.2±2.4, t = 2.245, P = 0.042). Early CBP can decrease the level of pro-inflammatory cytokines, prevent MODS, and remarkably improve the prognosis of patients with severe sepsis.

Short-term preconditioning enhances the therapeutic potential of adipose-derived stromal/stem cell-conditioned medium in cisplatin-induced acute kidney injury

The development of new strategies to preserve renal function after acute kidney injury (AKI) is necessary due to limited clinical intervention options. The organ-protective effects of mesenchymal stromal/stem cells (MSCs) and their conditioned medium (CM) have been investigated demonstrating that both separately promoted tubular recovery and ameliorated the outcome of AKI. Nevertheless, strategies to optimise the regenerative potential of both are highly needed. Here we investigated the effects of CM from adipose-derived MSCs (ASCs) preincubated in a hypoxic environment (Hyp). Protective factors were investigated by PCR analysis and a protein array in vitro. The expression of 64 of the 308 proteins assayed was found to be more than two-fold increased after Hyp. CM of Hyp-pretreated ASCs (pCM) was used to enhance regeneration in a mouse model of cisplatin-induced AKI (cisAKI). Renal function was assessed by measurements of markers for AKI and serum cytokine levels. The pCM significantly ameliorated serum creatinine and neutrophil gelatinase-associated lipocalin values, and also the levels of inflammatory cytokines IL-1β and IL-6 in the serum of mice with AKI. Our work clearly showed that a Hyp preconditioning significantly increases the release of protective factors in ASCs and enhances the therapeutic effects of CM in cisAKI in mice.

Nitrite attenuated peroxynitrite and hypochlorite generation in activated neutrophils

Oxidative stress is usually considered as an important factor to the pathogenesis of various diseases. Peroxynitrite (ONOO−) and hypochlorite (OCl−) are formed in immune cells as a part of the innate host defense system, but excessive reactive oxygen species generation can cause progressive inflammation and tissue damage. It has been proven that through mediating nitric oxide (NO) homeostasis, inorganic nitrite (NO2-) shows organ-protective effects on oxidative stress and inflammation. However, the effects of NO2- on the function of immune cells were still not clear. The potential role of NO2- in modulating ONOO− and OCl− generation in neutrophil cells was investigated in this study. As an immune cell activator, lipopolysaccharide (LPS) increased both ONOO− and OCl− production in neutrophils, which was significantly attenuated by NO2-. NO2- reduced superoxide (O2·-) generation via a NO-dependent mechanism and increased NO formation in activated neutrophils, suggesting a crucial role of O2·- in NO2--mediated reduction of ONOO−. Moreover, the reduced effect of NO2- on OCl− production was attributed to that NO2- reduced H2O2 production in activated neutrophils without influencing the release of myeloperoxidase (MPO), thus limiting OCl− production by MPO/H2O2 system. Therefore, NO2- attenuates ONOO− and OCl− formation in activated neutrophils, opening a new direction to modulate the inflammatory response.

Effects of Adrenomedullin on Doxorubicin-Induced Cardiac Damage in Mice.

Doxorubicin (DOX) is one of the best known anticancer drugs, and is used in the treatment of lymphoma, lung cancer, stomach cancer, and a number of other cancers. However, DOX has some serious side effects, the worst being lethal heart failure. Occasionally, its side effects result in the cessation of the anticancer treatment, thus having a serious adverse influence on prognosis. Agents that can be administered as alternative prophylactics or to ameliorate the side effects of DOX will be useful in increasing the safety and efficacy of anticancer therapy. Adrenomedullin (AM) is a peptide hormone secreted by many organs, including the heart; it has an organ-protective effect, including antiapoptotic, anti-inflammatory, and antioxidative stress. Blood AM levels increase with heart failure; endogenic AM has been suggested in order to protect the heart. Furthermore, exogenous AM administration has shown therapeutic effects for heart failure in patients. However, it is unclear whether AM can protect the heart against drug-induced cardiac injury in vivo. The present study was performed in order to investigate the effects of AM on DOX-induced cardiac damage. Male BALB/c mice were treated with DOX and/or AM. Exogenous AM improved the survival ratio of DOX-treated mice. In addition, AM reduced serum lactate dehydrogenase (LDH) levels following DOX treatment. On pathological examination, AM was shown to inhibit DOX-induced cardiac tissue damage, mitochondrial abnormality, and cell death. These findings suggest that AM has a protective effect against DOX-induced cardiac damage.

Non-steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease.

Pharmaceutical antagonism of the mineralocorticoid receptor (MR) can protect against organ damage caused by elevated aldosterone levels in patients experiencing heart failure (HF), chronic kidney disease (CKD), primary aldosteronism, and hypertension. While traditional steroid-based MR antagonists effectively reduce mortality rates and extend patient survival, their broad application has been limited by significant side effects, most notably hyperkalaemia. Recently, finerenone (BAY 94-8862) has emerged as a next-generation non-steroidal dihydropyridine-based MR antagonist designed to minimize off-target effects while maintaining potent efficacy. In this review, the outcomes of finerenone therapy in several diseases associated with MR activity are explored. The (pre-) clinical efficacy of finerenone is compared with that of traditional steroid-based MR antagonists. Finally, recent and ongoing clinical trials using finerenone to treat chronic HF, CKD, and diabetic nephropathy are discussed. Taken together, pre-clinical and clinical evidence suggests that finerenone may achieve equivalent organ-protective effects with reduced levels of electrolyte disturbance compared with traditional steroid-based MR antagonists. This supports further clinical development of finerenone for the treatment of cardiovascular and renal disease.

Adipose Tissue-Derived Stem Cells Reduce Acute and Chronic Kidney Damage in Mice.

Acute and chronic kidney injuries (AKI and CKI) constitute syndromes responsible for a large part of renal failures, and are today still associated with high mortality rates. Given the lack of more effective therapies, there has been intense focus on the use stem cells for organ protective and regenerative effects. Mesenchymal stem cells (MSCs) have shown great potential in the treatment of various diseases of immune character, although there is still debate on its mechanism of action. Thus, for a greater understanding of the role of MSCs, we evaluated the effect of adipose tissue-derived stem cells (AdSCs) in an experimental model of nephrotoxicity induced by folic acid (FA) in FVB mice. AdSC-treated animals displayed kidney functional improvement 24h after therapy, represented by reduced serum urea after FA. These data correlated with cell cycle regulation and immune response modulation via reduced chemokine expression and reduced neutrophil infiltrate. Long-term analyses, 4 weeks after FA, indicated that AdSC treatment reduced kidney fibrosis and chronic inflammation. These were demonstrated by reduced interstitial collagen deposition and tissue chemokine and cytokine expression. Thus, we concluded that AdSC treatment played a protective role in the framework of nephrotoxic injury via modulation of inflammation and cell cycle regulation, resulting in reduced kidney damage and functional improvement, inhibiting organ fibrosis and providing long-term immune regulation.

Serial Changes in Serum ACE 2 and Plasma Ang (1-7) Concentration of Acute Heart Failure Syndrome Patients with Standard Therapy

Recently the existence of the ACE2-Ang(1-7)-Mas receptor-axis and the organ-protective effect by activating this axis have been revealed. We reported that serum ACE2 concentration level is higher and plasma Ang(1-7) concentration level is lower in AHFS-patients than healthy volunteers. Although there are no reports about its serial changes. To evaluate the serial changes of serum ACE2 concentration and plasma Ang(1-7) concentration for hospitalized AHFS-patients. Seventy-three patients hospitalized with acute heart failure at our institute between Nov. 2012 and May 2014. Plasma renin activity, serum ACE, plasma Ang II, serum ACE2, plasma Ang(1-7), and plasma aldosterone concentrations were measured immediately after the patient were able to sit up, and then one and three months after the onset of the standard therapy then evaluated the serial changes. Average age was 63±14 years old, 22% male, and the cause of acute AHFS was 29 ischemic heart disease, 43 non-ischemic heart disease. There were no serial changes in plasma renin activity, serum ACE, plasma Ang II, serum ACE2 and plasma aldosterone concentration. Plasma Ang(1-7) concentration significantly increased (2.43±1.18 ng/ml vs 3.02±1.98 ng/ml vs 3.35±2.01 ng/ml, p±0.05). Plasma Ang(1-7) concentration increased in AHFS patients with standard therapy.