Abnormally decreased renal Klotho is linked to endoplasmic reticulum-associated degradation in mice.

Aim: Endoplasmic reticulum-associated degradation (ERAD), which involves degradation of improperly folded proteins retained in the ER, is implicated in various diseases including chronic kidney disease. This study is aimed to determine the role of ERAD in Klotho deficiency of mice and human kidney tubular epithelial cells (HK-2) with renal interstitial fibrosis (RIF). Methods: Following establishment of a mouse RIF model by unilateral ureteral obstruction (UUO), a specific ERAD inhibitor, Eeyarestatin I (EerI), was administered to experimental animals by intraperitoneal injection. Serum and kidney samples were collected for analysis 10 days after operation. Soluble Klotho levels were measured by enzyme-linked immunosorbent assay, while the degree of kidney injury was assessed by renal histopathology. Renal Klotho expression was determined by quantitative real-time PCR, immunohistochemical and western blotting analyses. ERAD and unfolded protein response (UPR) were evaluated by detecting associated components such as Derlin-1, glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4) and protein disulfide isomerase (PDI). HK-2 cells were exposed to transforming growth factor (TGF)-ß1 with or without EerI, and expressions of related proteins including Klotho, Derlin-1, GRP78, ATF4 and PDI were determined by western blotting analyses. Results: UUO induced severe kidney injuries and RIF. Klotho expression in both serum and kidney tissue was obviously downregulated, while Derlin-1 was notably upregulated, indicating that ERAD was activated to potentially degrade improperly folded Klotho protein in this model. Intriguingly, treatment with EerI led to significantly increased Klotho expression, especially soluble (functional) Klotho. Furthermore, specific inhibition of ERAD increased expression of GRP78, ATF4 and PDI compared with the UUO group. The consistent results in vitro were also obtained in TGF-ß1-treated HK-2 cells exposed to EerI. These observations suggest that UPR was remarkably enhanced in the presence of ERAD inhibition and compensated for excess improperly folded proteins, subsequently contributing to the additional production of mature Klotho protein. Conclusion: ERAD is involved in Klotho deficiency in RIF and its specific inhibition significantly promoted Klotho expression, possibly through enhanced UPR. This may represent a novel regulatory mechanism and new therapeutic target for reversing Klotho deficiency.

Procaspase-Activating Compound-1 Synergizes with TRAIL to Induce Apoptosis in Established Granulosa Cell Tumor Cell Line (KGN) and Explanted Patient Granulosa Cell Tumor Cells In Vitro.

Granulosa cell tumors (GCT) constitute only ~5% of ovarian neoplasms yet have significant consequences, as up to 80% of women with recurrent GCT will die of the disease. This study investigated the effectiveness of procaspase-activating compound 1 (PAC-1), an activator of procaspase-3, in treating adult GCT (AGCT) in combination with selected apoptosis-inducing agents. Sensitivity of the AGCT cell line KGN to these drugs, alone or in combination with PAC-1, was tested using a viability assay. Our results show a wide range in cytotoxic activity among the agents tested. Synergy with PAC-1 was most pronounced, both empirically and by mathematical modelling, when combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This combination showed rapid kinetics of apoptosis induction as determined by caspase-3 activity, and strongly synergistic killing of both KGN as well as patient samples of primary and recurrent AGCT. We have demonstrated that the novel combination of two pro-apoptotic agents, TRAIL and PAC-1, significantly amplified the induction of apoptosis in AGCT cells, warranting further investigation of this combination as a potential therapy for AGCT.

In vitro metabolic characterization of orbitazine, a novel derivative of the PAC-1 anticancer agent.

OBJECTIVES: The in vitro evaluation of new drugs is an important step in the drug development pipeline. Orbitazine is a derivative of PAC-1 that has substituted the functional group homopiperazine ring with a piperazine ring. The purpose of this study was to assess the metabolic profile of orbitazine. METHODS: Metabolism was characterized in vitro by incubating liver microsomes with metabolize orbitazine or the classical metabolic enzyme substrates. High performance liquid chromatography (HPLC) and LC-MS/MS were used to identify the parent drugs and metabolites of orbitazine or metabolic enzyme substrates. KEY FINDINGS: There was no difference in metabolic stability or metabolites across different species. The metabolites included a debenzyl compound and several hydroxyl compounds, defined as M1(316), M2(440), M3(422), M4(422) and M5(422). We found that orbitazine was metabolized by CYP3A4, CYP2C9 and CYP2D6 in a human liver microsomes incubation system. Orbitazine had no significant inhibitory effect on CYP1A2, CYP2B6, CYP2C9, or CYP2C19 in human liver microsomes, but showed a dose-dependent inhibition of CYP2C8, CYP2D6 and CYP3A4; and there was no orbitazine-mediated induction of CYP1A2, CYP2B6, CYP3A4 or mRNA expression in hepatocytes. CONCLUSIONS: This in vitro data on the metabolism of orbitazine may provide valuable information to support further clinical progression as a potential therapeutic molecule.

Effect of postdose fasting duration on hetrombopag olamine pharmacokinetics and pharmacodynamics in healthy volunteers.

AIMS: Hetrombopag olamine is a novel small-molecule, nonpeptide thrombopoietin receptor agonist developed for immune thrombocytopenia treatment. This study aims to determine the safety and the effect of fasting duration after administration of hetrombopag on pharmacokinetics and pharmacodynamics in Chinese healthy subjects. METHODS: A randomized, open-label, single-dose, 3-period crossover, self-control trial was conducted. 15 eligible subjects were enrolled and received hetrombopag 7.5 mg at day 1 of each period followed by a standard meal 4 hours postdose (treatment A/fasting condition), or a high-calorie, high-fat meal 1 hour postdose (treatment B), or a high-calorie, high-fat meal 2 hours postdose (treatment C). The plasma concentrations of hetrombopag were determined by validated liquid chromatography-tandem mass spectrometry, platelet counts were quantified by blood test. Analysis was performed using a mixed model, including treatment, period as fixed effects and participant as a random effect. RESULTS: Compared with treatment A, peak concentration and area under concentration-time curve extrapolated to infinity decreased by 56 and 74.6%, and 44 and 61% in treatments B and C, respectively. The mean platelet number on day 6 increased by 15.8, 6.96 and 10.26%, respectively, in treatments A, B and C in comparison with baseline platelet level. No severe adverse events happened in any of the 3 treatments. CONCLUSION: Hetrombopag was well tolerated in healthy male subjects under fasted/fed conditions. The shorter fasting duration resulted in lower hetrombopag exposure, corresponding to a lower level of platelet elevation. Therefore, we recommended oral administration of hetrombopag on an empty stomach (fasting condition) or at least 2 hours before a meal to achieve maximum bioavailability.

Resveratrol analogues present effective antileishmanial activity against promastigotes and amastigotes from distinct Leishmania species by multitarget action in the parasites.

OBJECTIVES: The in vitro antileishmanial effect of analogues of resveratrol (AR) present in the N-aryl imines and N-aryl hydrazones series was investigated. In addition, possible parasite targets were evaluated. METHODS: Antipromastigote activity of Leishmania amazonensis, L. braziliensis and L. infantum, as well as the cytotoxicity on macrophages was determined by MTT assay and L. braziliensis-infected macrophages effect by Giemsa stain. After staining, effects on the parasite targets were analysed by flow cytometry or by fluorescence microscopy. KEY-FINDINGS: Among the tested compounds, the derivative AR26 showed the best effect against promastigotes of all Leishmania species (IC50  < 3.0 µg/ml), being more active than miltefosine, the control drug. AR26 was also effective against amastigotes of L. braziliensis (IC50  = 15.9 µg/ml), with low toxicity to mammalian cells. The evaluation of mechanism of action of AR26 on L. braziliensis promastigotes indicates mitochondrial potential depolarization, plasma membrane permeabilization, interference in the progression of the cell cycle and accumulation of autophagic vacuoles. In addition, any increase of the reactive oxygen species levels was detected in the treated L. braziliensis-macrophages. CONCLUSIONS: Data indicate that the antileishmanial activity of AR26 is related to multitarget action, and the resveratrol analogues could be used in future studies as antileishmanial agent.

Dynasore suppresses cell proliferation, migration, and invasion and enhances the antitumor capacity of cisplatin via STAT3 pathway in osteosarcoma.

Osteosarcoma (OS) is the most common malignant bone tumor. The prognosis of metastatic and recurrent OS patients still remains unsatisfactory. Cisplatin reveals undeniable anti-tumor effect while induces severe side effects that threatening patients' health. Dynasore, a cell-permeable small molecule that inhibits dynamin activity, has been widely studied in endocytosis and phagocytosis. However, the anti-tumor effect of dynasore on OS has not yet been ascertained. In the present study, we suggested that dynasore inhibited cell proliferation, migration, invasion, and induced G0/G1 arrest of OS cells. Besides, dynasore repressed tumorigenesis of OS in xenograft mouse model. In addition, we demonstrated that dynasore improved the anti-tumor effect of cisplatin in vitro and in vivo without inducing nephrotoxicity and hepatotoxicity. Mechanistically, dynasore repressed the expression of CCND1, CDK4, p-Rb, and MMP-2. Furthermore, we found that dynasore exerts anti-tumor effects in OS partially via inhibiting STAT3 signaling pathway but not ERK-MAPK, PI3K-Akt or SAPK/JNK pathways. P38 MAPK pathway served as a negative regulatory mechanism in dynasore induced anti-OS effects. Taken together, our study indicated that dynasore does suppress cell proliferation, migration, and invasion via STAT3 signaling pathway, and enhances the antitumor capacity of cisplatin in OS. Our results suggest that dynasore is a novel candidate drug to inhibit the tumor growth of OS and enhance the anti-tumor effects of cisplatin.

Encapsulation of Isoniazid-conjugated Phthalocyanine-In-Cyclodextrin-In-Liposomes Using Heating Method.

Liposomes are reputed colloidal vehicles that hold the promise for targeted delivery of anti-tubercular drugs (ATBDs) to alveolar macrophages that host Mycobacterium tuberculosis. However, the costly status of liposome technology, particularly due to the use of special manufacture equipment and expensive lipid materials, may preclude wider developments of therapeutic liposomes. In this study, we report efficient encapsulation of a complex system, consisting of isoniazid-hydrazone-phthalocyanine conjugate (Pc-INH) in gamma-cyclodextrin (γ-CD), in liposomes using crude soybean lecithin by means of a simple organic solvent-free method, heating method (HM). Inclusion complexation was performed in solution and solid-state, and evaluated using UV-Vis, magnetic circular dichroism, 1H NMR, diffusion ordered spectroscopy and FT-IR. The HM-liposomes afforded good encapsulation efficiency (71%) for such a large Pc-INH/γ-CD complex (PCD) system. The stability and properties of the PCD-HM-liposomes look encouraging; with particle size 240 nm and Zeta potential -57 mV that remained unchanged upon storage at 4 °C for 5 weeks. The release study performed in different pH media revealed controlled release profiles that went up to 100% at pH 4.4, from about 40% at pH 7.4. This makes PCD-liposomes a promising system for site-specific ATBD delivery, and a good example of simple liposomal encapsulation of large hydrophobic compounds.

Cardioprotective effects of (E)-4-hydroxy-N'-(1-(3-oxo-3H-benzo[f]chromen-2-yl)ethylidene)benzohydrazide: a newly synthesized coumarin hydrazone against isoproterenol-induced myocardial infarction in a rat model.

The current study was carried out to evaluate the effect of pretreatment and co-treatment with a newly synthesized coumarin hydrazone, (E)-4-hydroxy-N'-(1-(3-oxo-3H-benzo[f]chromen-2-yl)ethylidene)benzohydrazide (hereinafter EK6), against isoproterenol-induced myocardial infarction in rats. Changes in biochemistry, cardiac biomarkers, electrocardiography, and histopathology after treatment with EK6 or acenocoumarol (Sintrom) were studied. Animals were randomly divided into 4 groups: vehicle control (C), isoproterenol + Sintrom (ISO + Sin), isoproterenol + EK6 (ISO + EK6), and isoproterenol (ISO). Myocardial infarction was induced by subcutaneous ISO administration at a dose of 85 mg·kg-1·day-1 with a drug-free interval of 24 h on days 6 and 7. Treatment with ISO led to significant elevation (p < 0.05) in serum levels of cardiac injury biomarkers, namely cardiac troponin-T, lactate dehydrogenase, creatine kinase-MB, alanine aminotransferase, and aspartate aminotransferase compared with levels in the vehicle control. A change in the lipid profile was also observed as a significant increase in total cholesterol and triglycerides. Furthermore, ISO caused significant alterations in the electrocardiogram pattern, including significant ST-segment elevation, significant decreased R wave amplitude, and significant increase in heart rate (16%) as well as marked changes in the histopathology of the heart tissue. Pretreatment and co-treatment with newly synthesized coumarin hydrazone restored all ISO-induced biochemical, lipid, cardiac, and histopathological changes in rats with myocardial infarction.

Dynasore Suppresses mTORC1 Activity and Induces Autophagy to Regulate the Clearance of Protein Aggregates in Neurodegenerative Diseases.

Autophagy is an important cellular protein control process, which plays a key role in the regulation of cell homeostasis and pathogenesis of many human diseases including neurodegenerative diseases. Reduced autophagic activity and abnormal protein aggregation are common features of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Therefore, pharmacological regulation of overall autophagy may be helpful for effective treatment of neurodegenerative diseases. In the present study, we find Dynasore, a potent inhibitor of dynamin, can repress the lysosomal localization of mTOR and block the activity of mTORC1, which in turn enhances the nuclear translocation of the master regulators of autophagy including TFE3 and TFEB. We find that autophagic flux is upregulated in Dynasore-treated cells. Moreover, treatment of Dynasore significantly promotes the clearance of protein aggregates formed by mutant huntingtin protein containing expanded polyglutamine (polyQ), but not damaged mitochondria. In contrast, treatment with Dynasore has no effect on the clearance of polyQ aggregates of mutant huntingtin in ATG5-depleted cells, in which autophagy is defective. Taken together, our results indicate that Dynasore affects autophagic degradation of neurodegenerative disease-associated proteins by regulating mTORC1-TFEB signaling.

Effects of SC99 on cerebral ischemia-perfusion injury in rats: Selective modulation of microglia polarization to M2 phenotype via inhibiting JAK2-STAT3 pathway.

Inhibition of Janus kinases 2-Signal transducers and activators of transcription3 (JAK2-STAT3) pathway has been shown to exert anti-inflammatory actions. SC99, a novel specific inhibitor targeting JAK2-STAT3 pathway, has been verified to negatively modulate platelet activation and aggregation in vitro. In current study, a middle cerebral artery occlusion and reperfusion (MCAO/R) model was established in Sprague Dawley rats and primary cultured microglia was exposed to oxygen and glucose deprivation (OGD/R) in vitro. Different dosages were employed to detect the effects of SC99 on cerebral ischemia-perfusion (I/R) injury and evaluate the underlying mechanisms. Our results showed that intracerebroventricular injection of SC99 (10 mmol/L, 15 µL) produced an effective inhibitory effect on the phosphorylation of JAK2 and STAT3. Correspondingly, SC99 ameliorated neuronal apoptosis and degeneration, neurobehavioral deficits, inflammatory response and brain edema. And SC99 promoted microglia polarization to an anti-inflammatory M2 phenotype. We concluded that SC99 could alleviate brain damage and play an anti-inflammatory action by promoting microglia polarization to an anti-inflammatory phenotype after I/R injury, which provides an emerging and promising alternative to protect the brain against MCAO/R injury in the future investigations.

A phase I study of the safety and tolerability of VLX600, an Iron Chelator, in patients with refractory advanced solid tumors.

Introduction VLX600 is a novel iron chelator designed to interfere with intracellular iron metabolism, leading to inhibition of mitochondrial respiration and bioenergetic catastrophe and resultant tumor cell death. Methods We conducted a multicenter, phase 1, dose escalation study to determine the safety and adverse event profile and the maximum tolerated dose and recommended phase 2 dose of VLX600. Other endpoints included pharmacokinetics, and preliminary evidence of anti-cancer efficacy as assessed according to RECIST 1.1 criteria. VLX600 was administered intravenously on days 1, 8, and 15 of each 28-day treatment cycle. Results Nineteen patients were enrolled, and seventeen received at least one dose of VLX600. Dose increments were reduced to 50% after dose level 3 (40 mg) due to the occurrence of a grade 3 pulmonary embolism. The study was then closed early due to slow recruitment. No maximum tolerated dose (MTD) nor RP2D had been identified at the time of study closure. Overall, the drug was well tolerated and no DLTs were observed. Fourteen patients experienced drug-related adverse events of any grade. The most frequently reported drug-related AEs were fatigue, nausea, constipation, vomiting, increased alkaline phosphatase, anemia, and decreased appetite. No formal efficacy or survival analyses were performed. No objective responses were observed, though six patients (32%) had stable disease as best response. Conclusion VLX600 was reasonably well tolerated and, together with preclinical data, there is support for further efforts to explore its activity as single agent and in combination with drugs or radiation.

Assessment of the effects of levosimendan and thymoquinone on lung injury after myocardial ischemia reperfusion in rats.

AIM: The aim of this study was to investigate the effects of levosimendan and thymoquinone (TQ) on lung injury after myocardial ischemia/reperfusion (I/R). MATERIALS AND METHODS: Twenty-four Wistar albino rats were included in the study. The animals were randomly assigned to 1 of 4 experimental groups. In Group C (control group), left anterior descending artery was not occluded or reperfused. Myocardial I/R was induced by ligation of the left anterior descending artery for 30 min, followed by 2 h of reperfusion in the I/R, I/R-levosimendan (24 µg/kg) (IRL) group, and I/R-thymoquinone (0.2 mL/kg) (IRTQ) group. Tissue samples taken from the lungs of rats were histochemically stained with H&E and immunohistochemically stained with p53, Bcl 2, Bax, and caspase 3 primer antibodies. RESULTS: Increased expression of p53 and Bax was observed (4+), especially in the I/R group. In IRTQ and IRL groups, expression was also observed at various locations (2+, 3+). H&E staining revealed that that the lungs were severely damaged and the walls of the alveoli were too thick, the number of areas examined was increased during the evaluation. Caspase 3 expression was observed to be at an (1+, 2+) intensity that was usually weak and diffuse in multiple areas. Bcl 2 was not found to be expressed in any of the tissues. H&E staining revealed that that the lungs were severely damaged in the I/R group, with the walls of the channels and alveoli thickened and edematous, and also an intense inflammatory cell migration was observed. Immunohistochemical staining was more prominent in inflammatory areas and structures around the terminal bronchioles. CONCLUSION: The findings in our study have shown that administration of levosimendan and TQ during I/R increases expression of caspase 3, p53, and Bax in lung tissue and has a protective effect on lung as distant organ. We suggest that findings of this study be elucidated with further large-scale clinical studies.

Effects of levosimendan on mortality in patients undergoing cardiac surgery: A systematic review and meta-analysis.

PURPOSE: We sought to determine the impact of levosimendan on mortality following cardiac surgery based on large-scale randomized controlled trials (RCTs). METHODS: We searched PubMed, Web of Science, Cochrane databases, and ClinicalTrials.gov for RCTs published up to December 2017, on levosimendan for patients undergoing cardiac surgery. RESULTS: A total of 25 RCTs enrolling 2960 patients met the inclusion criteria; data from 15 placebo-controlled randomized trials were included for meta-analysis. Pooled analysis showed that the all-cause mortality rate was 6.4% (71 of 1106) in the levosimendan group and 8.4% (93 of 1108) in the placebo group (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.55-1.04; P = 0.09). There were no significant differences between the two groups in the rates of myocardial infarction (OR: 0.91; 95% CI, 0.68-1.21; P = 0.52), serious adverse events (OR: 0.84; 95% CI, 0.66-1.07; P = 0.17), hypotension (OR: 1.69; 95% CI, 0.94-3.03; P = 0.08), and low cardiac output syndrome (OR: 0.47; 95% CI, 0.22-1.02; P = 0.05). CONCLUSION: Levosimendan did not result in a reduction in mortality in adult cardiac surgery patients. Well designed, adequately powered, multicenter trials are necessary to determine the role of levosimendan in adult cardiac surgery.

Aldoxorubicin: a tumor-targeted doxorubicin conjugate for relapsed or refractory soft tissue sarcomas.

Despite available therapies after initial systemic therapy, prognosis remains poor in relapsed or refractory soft tissue sarcomas (STS). The rational and clinical development of novel agents to improve outcomes in this area of high unmet need is desperately warranted. Aldoxorubicin is a prodrug of doxorubicin that binds to serum albumin immediately after administration through an acid-sensitive hydrazone linker and is subsequently transported to tumor tissues where the acidic environment cleaves the linker and facilitates delivery of a tumor-targeted drug payload. In clinical studies to date, there has been evidence of efficacy and mitigated cardiac toxicity. In this review, we comprehensively detail the clinical development of aldoxorubicin in STS to date. Specifically, we highlight available data on the pharmacokinetics and efficacy from Phase I, Phase II, and Phase III trials in advanced or metastatic STS. We conclude with considerations for future directions of investigation for this promising antitumor agent.

Prophylactic preoperative levosimendan for off-pump coronary artery bypass grafting in patients with left ventricular dysfunction: Single-centered randomized prospective study.

BACKGROUND: Off-pump coronary artery bypass surgery (OPCAB) is often complicated by hemodynamic instability, especially in patients with prior left ventricular (LV) dysfunction and appropriate choice of inotrope plays a vital role in perioperative management of these patients. AIM AND OBJECTIVE: To study hemodynamic effects and immediate outcome of prophylactic infusion of levosimendan in patients with the LV dysfunction undergoing OPCAB surgery and whether this strategy helps in successful conduct of OPCAB surgery. MATERIALS AND METHODS: After Institutional Ethics Committee approval, 60 patients posted for elective OPCAB surgery were randomly divided into two groups (n = 30 each). Patients with the LV ejection fraction <30% were included. Study group was started on injection levosimendan (@ 0.1 µg/kg/min) in the previous night before surgery and continued for 24 h including intraoperative period. Hemodynamic monitoring included heart rate, invasive blood pressure, cardiac index (CI), pulmonary capillary wedge pressure (PCWP), pulse oximetry, and arterial blood gases with serum lactates at as T0 (baseline), T1 (15 min after obtuse marginal and/or PDA anastomoses), T2 (at end of surgery), T3 (6 h after surgery in Intensive Care Unit [ICU]), T4 (12 h after surgery), and T5 (24 h after surgery in ICU). Vasopressor was added to maintain mean arterial pressure >60 mmHg. Chi-square/Fisher's exact/Mid P exact test and Student's t-tests were applied for categorical and continuous data. RESULTS: CI was greater and PCWP reduced significantly in Group L during intraoperative and early postoperative period. Serum lactate concentration was lower in patients pretreated with levosimendan. Incidence of postoperative atrial fibrillation (POAF) (36.6 vs. 6.6%; P = 0.01), low cardiac output syndrome (LCOS) (30% vs. 6%; P = 0.02), and acute kidney injury (23.3% vs. 6.7%; P = 0.04) was less in Group L. Three patients (10%) in control group required conversion to cardiopulmonary bypass (CPB) as compared to none in the study group. There was no difference regarding ICU or hospital stay and mortality in both groups. CONCLUSION: Preoperative levosimendan helps in successful conduct of OPCAB and reduces the incidence of LCOS, POAF, conversion to CPB, and requirement of intra-aortic balloon pump.

Comparative Efficacy of Drugs for Preventing Acute Kidney Injury after Cardiac Surgery: A Network Meta-Analysis.

BACKGROUND: Acute kidney injury (AKI) occurs frequently after cardiac surgery and has been associated with increased hospital length of stay, mortality, and costs. OBJECTIVE: We aimed to evaluate the efficacy of pharmacologic strategies for preventing AKI after cardiac surgery. METHODS: We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) up to 6 May 2017 and the reference lists of relevant articles about trials. The outcome was the occurrence of AKI. This is the first network meta-analysis of the different prevention strategies using Bayesian methodology. RESULTS: The study included 63 articles with 19,520 participants and evaluated the effect of ten pharmacologic strategies to prevent AKI in patients undergoing cardiac surgery. Compared with placebo, the odds ratio (OR) for the occurrence of AKI was 0.24 [95% confidence interval (CI) 0.16-0.34] with natriuretic peptide, 0.33 (95% CI 0.14-0.70) with fenoldopam, 0.54 (95% CI 0.31-0.84) with dexmedetomidine, 0.56 (95% CI 0.29-0.95) with low-dose erythropoietin, 0.63 (95% CI 0.43-0.88) with levosimendan, 0.76 (95% CI 0.52-1.10) with steroids, 0.83 (95% CI 0.48-1.40) with high-dose erythropoietin, 0.85 (95% CI 0.64-1.14) with N-acetylcysteine, 0.96 (95% CI 0.69-1.29) with sodium bicarbonate, and 1.05 (95% CI 0.70-1.41) with statins. The surface under the cumulative ranking curve probabilities indicated that natriuretic peptide was the best treatment therapy and that fenoldopam ranked second. CONCLUSIONS: Natriuretic peptide is probably the preferred pharmacologic strategy to prevent AKI in adult patients undergoing cardiac surgery, especially in those at high risk of AKI.

Systolic mitral annulus velocity is a sensitive index for changes in left ventricular systolic function during inotropic therapy in patients with acute heart failure.

BACKGROUND: Echocardiography is recommended for assessment of left ventricular systolic function in patients with acute heart failure but few randomised trials have validated techniques like tissue Doppler (TDI) and speckle tracking (STE) in patients with acute heart failure following ST-elevation myocardial infarction. METHODS: This was a substudy from the LEAF (LEvosimendan in Acute heart Failure following myocardial infarction) trial (NCT00324766 ), which randomised 61 patients developing acute heart failure, including cardiogenic shock, within 48 hours after ST-elevation myocardial infarction, double-blind to a 25-hour infusion of levosimendan or placebo. TDI-derived systolic mitral annulus velocity (S'), STE-derived global longitudinal strain (Sl) and strain rate (SRl) were measured at baseline, day 1, day 5 and after 42 days. RESULTS: Datasets rejected for analyses were 2% (TDI) and 17% (STE). S' increased by 23% in the levosimendan group versus 8% in the placebo group from baseline to day 1 ( p= 0.011) and by 30% vs. 3% from baseline to day 5 ( p <0.0005). Significant, but less pronounced, improvements in global Sl ( p = 0.025 and p = 0.032) and in global SRl ( p = 0.046 and p = 0.001) in favour of levosimendan were also present. CONCLUSION: S' by TDI and STE-derived Sl and SRl were sensitive indices for changes in left ventricular systolic function related to treatment with levosimendan. However, S' by TDI was more feasible and sensitive and might be preferred for assessment of changes in left ventricular systolic function in critically ill patients with acute heart failure receiving inotropic therapy.

Efficacy and safety of a calcium sensitizer, levosimendan, in patients with right heart failure due to pulmonary hypertension.

BACKGROUND: Despite using vasoactive and pulmonary hypertension (PH) specific therapies, the in-hospital mortality of severe PH with right heart failure (RHF) is high. We conducted a prospective analysis evaluating the efficacy and safety of levosimendan in PH patients with severe acute RHF. METHODS: Forty-five PH patients hospitalized between January 2016 and November 2016 were recruited into a single arm, prospective, open-label study. Levosimendan was administered at the rate of .05-0.1 µg/kg/min, up to a total dose of 12.5 mg. The primary endpoints were changes of World Health Organization Function Class (WHO-FC) and Borg dyspnoea scores. Secondary endpoints included changes in 6-min walk distance (6-MWD), biochemical markers and right heart structure and function together with adverse events on day 7 and incidence of major cardiovascular events (death or readmission due to RHF) on day 30. RESULTS: Forty-five PH patients were enrolled. On the 7th day after levosimendan infusion, seven out of 13 PH patients with WHO-FC IV improved by one class (P = .008). Borg dyspnoea scores, 6-MWD and NT-proBNP improved significantly (P < .001). Compared with baseline, the right atrial transverse dimension, end-systolic eccentricity index and tricuspid annular plane systolic excursion improved significantly (58.8 ± 13.1 mm vs 53.7 ± 12.4 mm; 1.50 ± 0.27 vs 1.38 ± 0.23; 15.0 (13.0, 16.0) mm vs 15.8 (14.0, 17.4) mm, P < .005, respectively). One patient occurred sudden death after discharge during follow-up. CONCLUSIONS: Intravenous levosimendan can effectively improve severe RHF of PH patients in hospital and well tolerated.

Mitochondrial Inhibition Augments the Efficacy of Imatinib by Resetting the Metabolic Phenotype of Gastrointestinal Stromal Tumor.

Purpose: Imatinib dramatically reduces gastrointestinal stromal tumor (GIST) 18F-FDG uptake, providing an early indicator of treatment response. Despite decreased glucose internalization, many GIST cells persist, suggesting that alternative metabolic pathways are used for survival. The role of mitochondria in imatinib-treated GIST is largely unknown.Experimental Design: We quantified the metabolic activity of several human GIST cell lines. We treated human GIST xenografts and genetically engineered KitV558del/+ mice with the mitochondrial oxidative phosphorylation inhibitor VLX600 in combination with imatinib and analyzed tumor volume, weight, histology, molecular signaling, and cell cycle activity. In vitro assays on human GIST cell lines were also performed.Results: Imatinib therapy decreased glucose uptake and downstream glycolytic activity in GIST-T1 and HG129 cells by approximately half and upregulated mitochondrial enzymes and improved mitochondrial respiratory capacity. Mitochondrial inhibition with VLX600 had a direct antitumor effect in vitro while appearing to promote glycolysis through increased AKT signaling and glucose transporter expression. When combined with imatinib, VLX600 prevented imatinib-induced cell cycle escape and reduced p27 expression, leading to increased apoptosis when compared to imatinib alone. In KitV558del/+ mice, VLX600 alone did not induce tumor cell death, but had a profound antitumor effect when combined with imatinib.Conclusions: Our findings show that imatinib alters the metabolic phenotype of GIST, and this may contribute to imatinib resistance. Our work offers preclinical proof of concept of metabolic targeting as an effective strategy for the treatment of GIST. Clin Cancer Res; 24(4); 972-84. ©2017 AACR.

Dynasore suppresses proliferation and induces apoptosis of the non-small-cell lung cancer cell line A549.

Lung cancer is the leading cause of cancer death worldwide, and most of all cases are non-small-cell lung cancer. Lung cancer is associated with dysregulation of mitochondrial fusion and fission, and inhibition of the fission regulator Dynamin-related protein 1 (Drp1) reduces proliferation and increases apoptosis of lung cancer cells. Dynasore is a small molecule non-selective inhibitor of the GTPase activity of dynamin 1, dynamin 2, and Drp1 in vivo and in vitro. Here, we investigated the effects of dynasore on the proliferation and apoptosis of A549 lung cancer cells, alone and in combination with the chemotherapeutic drug cisplatin. We found that cisplatin increased mitochondrial fission and dynamin 2 expression, whereas dynasore had the opposite effects. However, both cisplatin and dynasore independently induced mitochondrial oxidative stress, leading to mitochondrial dysfunction, reduced cell proliferation, and enhanced apoptosis. Importantly, dynasore significantly augmented the anti-cancer effects of cisplatin. To the best of our knowledge, this is the first report that dynasore inhibits proliferation and induces apoptosis of lung cancer cells, and enhances the inhibitory effects of cisplatin.