Neuroinflammation in acute liver failure: Mechanisms and novel therapeutic targets

It is increasingly evident that neuroinflammatory mechanisms are implicated in the pathogenesis of the central nervous system (CNS) complications (intracranial hypertension, brain herniation) of acute liver failure (ALF). Neuroinflammation in ALF is characterized by microglial activation and arterio-venous difference studies as well as studies of gene expression confirm local brain production and release of proinflammatory cytokines including TNF-α and the interleukins IL-1β and IL-6. Although the precise nature of the glial cell responsible for brain cytokine synthesis is not yet established, evidence to date supports a role for both astrocytes and microglia. The neuroinflammatory response in ALF progresses in parallel with the progression of hepatic encephalopathy (HE) and with the severity of brain edema (astrocyte swelling). Mechanisms responsible for the relaying of signals from the failing liver to the brain include transduction of systemic proinflammatory signals as well as the effects of increased brain lactate leading to increased release of cytokines from both astrocytes and microglia. There is evidence in support of a synergistic effect of proinflammatory cytokines and ammonia in the pathogenesis of HE and brain edema in ALF. Therapeutic implications of the findings of a neuroinflammatory response in ALF are multiple. Removal of both ammonia and proinflammatory cytokines is possible using antibiotics or albumen dialysis. Mild hypothermia reduces brain ammonia transfer, brain lactate production, microglial activation and proinflammatory cytokine production resulting in reduced brain edema and intracranial pressure in ALF. N-Acetylcysteine acts as both an antioxidant and anti-inflammatory agent at both peripheral and central sites of action independently resulting in slowing of HE progression and prevention of brain edema. Novel treatments that directly target the neuroinflammatory response in ALF include the use of etanercept, a TNF-α neutralizing molecule and minocycline, an agent with potent inhibitory actions on microglial activation that are independent of its antimicrobial properties; both agents have been shown to be effective in reducing neuroinflammation and in preventing the CNS complications of ALF. Translation of these findings to the clinic has the potential to provide rational targeted approaches to the prevention and treatment of these complications in the near future.     

Nanopore detection of antibody prion interactions

In nanopore analysis, peptides and proteins can be detected by the change in current when single molecules interact with an α-hemolysin pore embedded in a lipid membrane. A prion peptide, PrP(143-169), can readily translocate through the pore, but on the addition of monoclonal antibody M2188, which binds the peptide, the number of translocations is reduced because the complex is too large to translocate. At a peptide-to-immunoglobulin G (IgG) ratio of 2:1, only bumping events were observed. The event profile of a control peptide that does not bind the antibody was unchanged. Similarly, the presence of the antibody prevents translocation of the full-length prion protein. Because a nanopore can detect a single molecule, these experiments represent an important first step towards the development of a sensitive prion detector.     

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that typically develops as a result of acute liver failure or chronic liver disease. Brain edema is a common feature associated with HE. In acute liver failure, brain edema contributes to an increase in intracranial pressure, which can fatally lead to brain stem herniation. In chronic liver disease, intracranial hypertension is rarely observed, even though brain edema may be present. This discrepancy in the development of intracranial hypertension in acute liver failure versus chronic liver disease suggests that brain edema plays a different role in relation to the onset of HE. Furthermore, the pathophysiological mechanisms involved in the development of brain edema in acute liver failure and chronic liver disease are dissimilar. This review explores the types of brain edema, the cells, and pathogenic factors involved in its development, while emphasizing the differences in acute liver failure versus chronic liver disease. The implications of brain edema developing as a neuropathological consequence of HE, or as a cause of HE, are also discussed.     

亚临床肝性脑病患者肠道菌群和血清炎症因子水平变化及益生菌的干预作用

目的探讨亚临床肝性脑病(SHE)患者肠道菌群及血清炎症因子水平的变化及益生菌对该病的干预作用。方法选取2015年1月至2018年10月在我院就诊的40例SHE患者为观察组。选择同期我院体检中心检查无明显肝胆胃肠道病变和急慢性炎症性疾病的30例健康者为对照组。观察组患者在低盐饮食和护肝降转氨酶基础上加用双歧杆菌三联活菌胶囊630 mg/次,2次/d,温开水送服,连用6周。观察两组对象肠道菌群数量及血清炎症因子水平的变化。结果观察组患者治疗前肠道双歧杆菌和乳杆菌的数量少于对照组,而大肠埃希菌数量多于对照组(均P0.05)。治疗6周后,观察组患者肠道双歧杆菌和乳杆菌的数量较治疗前明显上升,而大肠埃希菌数量较治疗前明显下降(均P0.05);同时观察组患者治疗前血清IL-6和TNF-α水平高于对照组,IL-10水平低于对照组(均P0.05)。治疗6周后,观察组患者血清IL-6和TNF-α水平较治疗前明显下降,而IL-10水平较治疗前明显上升(均P0.05)。结论双歧杆菌三联活菌胶囊能调节SHE患者肠道菌群紊乱,重建肠道菌群屏障,同时能调节患者血清炎症因子水平,控制局部炎症反应。     

双歧杆菌四联活菌片联合乳果糖对轻微型肝性脑病患者炎症性肠黏膜损伤的保护作用

目的探讨双歧杆菌四联活菌片联合乳果糖对轻微型肝性脑病(MHE)患者炎症性肠黏膜损伤的保护作用,为该类患者的治疗提供参考。方法选择2018年1月至2019年12月我院内科住院治疗的90例MHE患者,随机分为联用组和单用组各45例。两组患者给予低盐饮食、护肝降转氨酶、维持水电解质平衡及防治并发症等基础治疗。单用组患者给予乳果糖口服液20 mL/次,3次/d,口服。联用组患者在单用组基础上加用双歧杆菌四联活菌片1.5 g/次,3次/d,温开水送服。两组患者连用8周。观察两组患者治疗前后血清丙氨酸转氨酶(ALT)、数字连接试验(NCT)时间、血清炎症因子[白介素(IL) 6、肿瘤坏死因子(TNF) α]和肠黏膜损伤指标[血清肠脂肪酸结合蛋白(IFABP)、中晚期糖基化终末产物(AGEs)]水平变化,并比较临床型肝性脑病(HE)的进展率。结果治疗8周后,两组患者ALT、IL 6、TNF α、IFABP、AGEs水平和NCT时间均较治疗前明显下降,且联用组患者下降幅度大于单用组(均P<0.05)。联用组患者临床型HE的进展率为8.89%(4/45),明显低于单用组的24.44%(11/45),差异有统计学意义(χ²=3.920,P=0.047 1)。结论双歧杆菌四联活菌片联合乳果糖能改善MHE患者肝功能和智力测验结果,降低临床型HE的进展率,其作用机制可能与其能抑制IL 6、TNF α水平,保护肠黏膜相关。     

Prion's Progress: Patterns and Rates of Molecular Evolution in Relation to Spongiform Disease

Modification of the cellular prion protein has been correlated with the acquisition of several neurodegenerative diseases, including kuru, scrapie, bovine spongiform encephalopathy (BSE), and Creutzfeldt–Jakob disease (CJD). Sequence conservation and amino acid identity are known to influence the efficacy of interspecific transmission. We analyzed patterns of interspecific genetic variation with a view toward identifying features related to disease transmission. The reconstructed gene trees and amino acid tree were compared with the species tree, and all discordances observed were related to the species barrier of disease transmission. The rates of synonymous substitution, nonsynonymous substitution, and nucleotide content were determined for the protein-coding gene. Substitutions implicated in each of the prion diseases were found to occur in regions of the protein that are least variable across all species—opposite to the pattern of variability expected from interaction with an infectious pathogen. Amino acid residues related to the species barrier form a single cluster associated with the first alpha-helical domain of the protein. Residues related to sporadic and hereditary human prion disease form two separate clusters, associated with the second and third alpha-helical domains. Taken together, these results are consistent with the view that prion diseases arise from accidents in protein folding, rather than infection with an undiscovered virus-like particle. We speculate that the differences in disease phenotype between transmissable and hereditary forms could result from interactions between different parts of the protein during propagation. Received: 18 April 1997 / Accepted: 17 October 1997     

Extraordinary Changes in Excitatory Amino Acid Levels in Cerebrospinal Fluid of Influenza-Associated Encephalopathy of Children

The correlation between the glutamate-glutamine cycle and nitric oxide (NO) production in the central nervous system (CNS) of a new type of influenza-associated encephalopathy in children is discussed. When measurements of several amino acids and NOx (nitrite/nitrate) levels in the cerebrospinal fluid (CSF) using HPLC-fluorescence and -UV methods, respectively, were made. the CSF glutamate levels of patients with the new type of encephalitis were significantly lower, and both glutamine and NOx levels were significantly higher than those of the control group and the patients of the meningitis group. Results indicate that the turnover rate of glutamate in CNS, particularly in the brain, increases in the influenza-associated encephalopathy. The high mortality in the disease may correlate with the hyperactivity of supra-spinal glutamate neurons and the subsequent high activity levels of NOx in CNS.     

可溶性细胞间粘附分子-1在新生儿缺氧缺血性脑病血清中的表达及临床意义

目的：探讨可溶性细胞间粘附分子-1（ICAM-1）在新生儿缺氧缺血性脑病（HIE）血清中的表达及其与病情严重程度的关系。方法：采用酶联免疫吸附双抗体夹心法（ELISA）检测45例HIE新生儿和50例健康新生儿血清中可溶性ICAM-1水平。结果：HIE组血清可溶性ICAM-1浓度为（159．25±25．62）ng／ml,对照组血清可溶性ICAM-1浓度为（53．35±12．42）ng／ml,两组相比较有显著性并差异（P〈0．05）;轻、中、重度HIE患儿血清可溶性ICAM-1浓度与对照组比较显著升高（P〈0．05）,在HIE各组中可溶性ICAM-1浓度为重度〉中度〉轻度,各组相比较有显著性差异（P〈0．05）;HIE患儿血清可溶性ICAM-1水平与临床分度呈正相关相关（r=0．652,P〈0．01）。结论：可溶性ICAM-1在HIE新生儿血清中呈高表达,可溶性ICAM-1的水平与病情严重程度密切相关。可溶性ICAM-1在新生儿缺氧缺血性脑损伤中起着重要作用：     

Instability of familial spongiform encephalopathy-related prion mutants

We examined the influence of D177N (D178N in humans) mutation on the conformational stability of the S2 region of moPrP^C with varying pHs by using the SDSL-ESR technique. The ESR spectrum of D177N at pH 7.5 was narrower than that of Y161R1, referred to as WT^∗. The ESR spectrum of D177N did not change when pH in the solution decreased to pH 4.0. Our results suggested that the disappearance of a salt bridge (D177-R163) induced the increase in the instability of S2 region. Moreover, the line shape of the ESR spectrum obtained from H176S neighboring the salt bridge linked to the S2 region was similar to D177N. These results indicate that the protonation of H176 is strongly associated with the stability of S2 region. These findings are important for understanding the mechanism by which the disruption of the salt bridge in the S2 region forms the pathogenic PrP^Sc structure in hereditary prion disease.