Antioxidant nanoparticles have recently gained tremendous attention for their enormous potential in biomedicine. However, discrepant reports of either medical benefits or toxicity, and lack of ...reproducibility of many studies, generate uncertainties delaying their effective implementation. Herein, the case of cerium oxide is considered, a well‐known catalyst in the petrochemistry industry and one of the first antioxidant nanoparticles proposed for medicine. Like other nanoparticles, it is now described as a promising therapeutic alternative, now as threatening to health. Sources of these discrepancies and how this analysis helps to overcome contradictions found for other nanoparticles are summarized and discussed. For the context of this analysis, what has been reported in the liver is reviewed, where many diseases are related to oxidative stress. Since well‐dispersed nanoparticles passively accumulate in liver, it represents a major testing field for the study of new nanomedicines and their clinical translation. Even more, many contradictory works have reported in liver either cerium‐oxide‐associated toxicity or protection against oxidative stress and inflammation. Based on this, finally, the intention is to propose solutions to design improved nanoparticles that will work more precisely in medicine and safely in society.
The burgeoning potential of antioxidant nanoparticles in theranostic applications faces apparently contradictory reports of either medical benefits or toxicity. This delays translation to clinical practice. Sources of those discrepancies are summarized focusing on the paradigmatic case of cerium oxide in liver disease. This analysis contributes to overcoming similar discrepancies of other nanoparticles and will enable the design of improved nanomedicines.
Kidney biomarkers appear to be useful in differential diagnosis between acute tubular necrosis (ATN) and other types of acute kidney injury (AKI) in cirrhosis, particularly hepatorenal syndrome ...(HRS‐AKI). Distinction is important because treatment is different. However, kidney biomarkers are still not used in clinical practice. The aim of the current study was to investigate the accuracy of several biomarkers in differential diagnosis of AKI and in predicting kidney outcome and patient survival. This was a prospective study of 320 consecutive cases of AKI in patients hospitalized for decompensated cirrhosis. Evaluation of AKI was made with a diagnostic algorithm that included identification and removal/treatment of precipitating factors and albumin administration (1 g/kg for 2 days) to patients with AKI stage 1B or greater. Urinary neutrophil gelatinase–associated lipocalin (NGAL), monomeric NGAL (mNGAL), interleukin‐18, and standard biomarkers were measured at diagnosis and on days 3, 7, and 14. Of the 320 cases, 153 were hypovolemia‐induced AKI (48%), 93 were HRS‐AKI (29%), 39 were ATN (12%), and 35 were due to miscellaneous causes (11%). Among all biomarkers, urinary NGAL measured at day 3 had the greatest accuracy for differential diagnosis between ATN and other types of AKI (area under the receiver operating characteristic curve, 0.87; 95% confidence interval, 0.78‐0.95). The cutoff with the best predictive accuracy for ATN diagnosis was 220 µg/g creatinine. Progression of AKI during hospitalization was associated with persistently high NGAL levels, and NGAL was an independent predictive factor of AKI progression. Likewise, NGAL was also an independent predictive factor of 28‐day mortality together with Model for End‐Stage Liver Disease score. Conclusion: These results support the use of NGAL in clinical practice within the context of a diagnostic algorithm for differential diagnosis of AKI and outcome prediction in cirrhosis.
Background
Several lines of evidence indicate that decompensated cirrhosis is characterized by the presence of systemic inflammation. Hepatorenal syndrome (HRS‐AKI) is a unique type of renal failure ...that occurs at late stages of cirrhosis. However, confirmation of the presence and significance of such inflammatory response in HRS‐AKI is lacking.
Aim and Methods
To characterize the systemic inflammatory response, as estimated by measuring a large number of cytokines, in 161 patients hospitalized for an acute decompensation of cirrhosis: 44 patients without acute kidney injury (AKI), 63 patients with hypovolaemia‐induced AKI and 58 patients with HRS‐AKI.
Results
HRS‐AKI was characterized by an altered cytokine profile compared to the other two groups, particularly IL‐6, IL‐8, TNF‐α, VCAM‐1, fractalkine and MIP‐1α. The inflammatory response was not related to presence of bacterial infection, concomitant acute‐on‐chronic liver failure or severity of renal dysfunction. Patients who responded to terlipressin and albumin had only a decrease in TNF‐α and RANTES after treatment without changes in other cytokines. Interestingly, patients with persistent HRS‐AKI had higher levels of IP‐10 and VCAM‐1 compared to those with resolution of HRS‐AKI. VCAM‐1 was also an independent predictor of 3‐month mortality. A systems biology analysis approach showed that the inflammatory status of HRS‐AKI was similar to that of chronic nonhepatic inflammatory conditions, such as lupus erythematosus or inflammatory bowel disease.
Conclusion
Hepatorenal syndrome is characterized by a marked systemic inflammatory state, reminiscent of that of nonhepatic inflammatory diseases, that correlates with patient outcomes.
See Editorial on Page 1199
Background and Aims
Despite the availability of new‐generation drugs, hepatocellular carcinoma (HCC) is still the third most frequent cause of cancer‐related deaths worldwide. Cerium oxide ...nanoparticles (CeO2NPs) have emerged as an antioxidant agent in experimental liver disease because of their antioxidant, anti‐inflammatory, and antisteatotic properties. In the present study, we aimed to elucidate the potential of CeO2NPs as therapeutic agents in HCC.
Approach and Results
HCC was induced in 110 Wistar rats by intraperitoneal administration of diethylnitrosamine for 16 weeks. Animals were treated with vehicle or CeO2NPs at weeks 16 and 17. At the eighteenth week, nanoceria biodistribution was assessed by mass spectrometry (MS). The effect of CeO2NPs on tumor progression and animal survival was investigated. Hepatic tissue MS‐based phosphoproteomics as well as analysis of principal lipid components were performed. The intracellular uptake of CeO2NPs by human ex vivo perfused livers and human hepatocytes was analyzed. Nanoceria was mainly accumulated in the liver, where it reduced macrophage infiltration and inflammatory gene expression. Nanoceria treatment increased liver apoptotic activity, while proliferation was attenuated. Phosphoproteomic analysis revealed that CeO2NPs affected the phosphorylation of proteins mainly related to cell adhesion and RNA splicing. CeO2NPs decreased phosphatidylcholine‐derived arachidonic acid and reverted the HCC‐induced increase of linoleic acid in several lipid components. Furthermore, CeO2NPs reduced serum alpha‐protein levels and improved the survival of HCC rats. Nanoceria uptake by ex vivo perfused human livers and in vitro human hepatocytes was also demonstrated.
Conclusions
These data indicate that CeO2NPs partially revert the cellular mechanisms involved in tumor progression and significantly increase survival in HCC rats, suggesting that they could be effective in patients with HCC.
The modeling and prediction of chaotic time series require proper reconstruction of the state space from the available data in order to successfully estimate invariant properties of the embedded ...attractor. Thus, one must choose appropriate time delay τ∗ and embedding dimension
for phase space reconstruction. The value of τ∗ can be estimated from the Mutual Information, but this method is rather cumbersome computationally. Additionally, some researchers have recommended that τ∗ should be chosen to be dependent on the embedding dimension
by means of an appropriate value for the time delay τw=(p-1)τ∗, which is the optimal time delay for independence of the time series. The C-C method, based on Correlation Integral, is a method simpler than Mutual Information and has been proposed to select optimally τw and τ∗. In this paper, we suggest a simple method for estimating τ∗ and τw based on symbolic analysis and symbolic entropy. As in the C-C method, τ∗ is estimated as the first local optimal time delay and τw as the time delay for independence of the time series. The method is applied to several chaotic time series that are the base of comparison for several techniques. The numerical simulations for these systems verify that the proposed symbolic-based method is useful for practitioners and, according to the studied models, has a better performance than the C-C method for the choice of the time delay and embedding dimension. In addition, the method is applied to EEG data in order to study and compare some dynamic characteristics of brain activity under epileptic episodes.
Biomarkers are potentially useful in assessment of outcomes in patients with cirrhosis, but information is very limited. Given the large number of biomarkers, adequate choice of which biomarker(s) to ...investigate first is important.
Analysis of potential usefulness of a panel of urinary biomarkers in outcome assessment in cirrhosis.
Fifty-five patients with acute decompensation of cirrhosis were studied: 39 had Acute Kidney Injury (AKI) (Prerenal 12, type-1 HRS (hepatorenal syndrome) 15 and Acute Tubular Necrosis (ATN) 12) and 16 acute decompensation without AKI. Thirty-four patients had Acute-on-chronic liver failure (ACLF). A panel of 12 urinary biomarkers was assessed, using a multiplex assay, for their relationship with ATN, ACLF and mortality.
Biomarker with best accuracy for ATN diagnosis was NGAL (neutrophil-gelatinase associated lipocalin): 36 26-125, 104 58-208 and 1807 494-3,716 μg/g creatinine in Prerenal-AKI, type-1 HRS and ATN, respectively; p<0.0001 (AUROC 0.957). Other attractive biomarkers for ATN diagnosis were IL-18, albumin, trefoil-factor-3 (TFF-3) and glutathione-S-transferase-π (GST-π) Biomarkers with less accuracy for ATN AUCROC<0.8 were β2-microglobulin, calbindin, cystatin-C, clusterin and KIM-1 (kidney injury molecule-1). For ACLF, the biomarker with the best accuracy was NGAL (ACLF vs. No-ACLF: 165 67-676 and 32 19-40 μg/g creatinine; respectively; p<0.0001; AUROC 0.878). Interestingly, other biomarkers with high accuracy for ACLF were osteopontin, albumin, and TFF-3. Biomarkers with best accuracy for prognosis were those associated with ACLF.
A number of biomarkers appear promising for differential diagnosis between ATN and other types of AKI. The most interesting biomarkers for ACLF and prognosis are NGAL, osteopontin, albumin, and TFF-3. These results support the role of major inflammatory reaction in the pathogenesis of ACLF.
Objectives This study sought to evaluate the efficacy of enalapril and carvedilol to prevent chemotherapy-induced left ventricular systolic dysfunction (LVSD) in patients with hematological ...malignancies. Background Current chemotherapy may induce LVSD. Angiotensin-converting enzyme inhibitors and beta-blockers prevent LVSD in animal models of anthracycline-induced cardiomyopathy. Methods In this randomized, controlled study, 90 patients with recently diagnosed acute leukemia (n = 36) or patients with malignant hemopathies undergoing autologous hematopoietic stem cell transplantation (HSCT) (n = 54) and without LVSD were randomly assigned to a group receiving enalapril and carvedilol (n = 45) or to a control group (n = 45). Echocardiographic and cardiac magnetic resonance (CMR) imaging studies were performed before and at 6 months after randomization. The primary efficacy endpoint was the absolute change from baseline in LV ejection fraction (LVEF). Results The mean age of patients was 50 ± 13 years old, and 43% were women. At 6 months, LVEF did not change in the intervention group but significantly decreased in controls, resulting in a −3.1% absolute difference by echocardiography (p = 0.035) and −3.4% (p = 0.09) in the 59 patients who underwent CMR. The corresponding absolute difference (95% confidence interval CI) in LVEF was −6.38% (95% CI: −11.9 to −0.9) in patients with acute leukemia and −1.0% (95% CI: −4.5 to 2.5) in patients undergoing autologous HSCT (p = 0.08 for interaction between treatment effect and disease category). Compared to controls, patients in the intervention group had a lower incidence of the combined event of death or heart failure (6.7% vs. 22%, p = 0.036) and of death, heart failure, or a final LVEF <45% (6.7% vs. 24.4%, p = 0.02). Conclusions Combined treatment with enalapril and carvedilol may prevent LVSD in patients with malignant hemopathies treated with intensive chemotherapy. The clinical relevance of this strategy should be confirmed in larger studies. (Prevention of Left Ventricular Dysfunction During Chemotherapy OVERCOME; NCT01110824 )
Since its appearance, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), the causal agent of Coronavirus Disease 2019 (COVID-19), represents a global problem for human health that ...involves the host lipid homeostasis. Regarding, lipid rafts are functional membrane microdomains with highly and tightly packed lipid molecules. These regions enriched in sphingolipids and cholesterol recruit and concentrate several receptors and molecules involved in pathogen recognition and cellular signaling. Cholesterol-rich lipid rafts have multiple functions for viral replication; however, their role in SARS-CoV-2 infection remains unclear. In this review, we discussed the novel evidence on the cholesterol-rich lipid rafts as a platform for SARS-CoV-2 entry, where receptors such as the angiotensin-converting enzyme-2 (ACE-2), heparan sulfate proteoglycans (HSPGs), human Toll-like receptors (TLRs), transmembrane serine proteases (TMPRSS), CD-147 and HDL-scavenger receptor B type 1 (SR-B1) are recruited for their interaction with the viral spike protein. FDA-approved drugs such as statins, metformin, hydroxychloroquine, and cyclodextrins (methyl-β-cyclodextrin) can disrupt cholesterol-rich lipid rafts to regulate key molecules in the immune signaling pathways triggered by SARS-CoV-2 infection. Taken together, better knowledge on cholesterol-rich lipid rafts in the SARS-CoV-2-host interactions will provide valuable insights into pathogenesis and the identification of novel therapeutic targets.
Summary
Flavivirus infections are a public health threat in the world that requires the development of safe and effective vaccines. Therefore, the understanding of the anti‐flavivirus humoral immune ...response is fundamental to future studies on flavivirus pathogenesis and the design of anti‐flavivirus therapeutics. This review aims to provide an overview of the current understanding of the function and involvement of flavivirus proteins in the humoral immune response as well as the ability of the anti‐envelope (anti‐E) antibodies to interfere (neutralizing antibodies) or not (non‐neutralizing antibodies) with viral infection, and how they can, in some circumstances enhance dengue virus infection on Fc gamma receptor (FcγR) bearing cells through a mechanism known as antibody‐dependent enhancement (ADE). Thus, the dual role of the antibodies against E protein poses a formidable challenge for vaccine development. Also, we discuss the roles of antibody binding stoichiometry (the concentration, affinity, or epitope recognition) in the neutralization of flaviviruses and the “breathing” of flavivirus virions in the humoral immune response. Finally, the relevance of some specific antibodies in the design and improvement of effective vaccines is addressed.
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