肝萎缩增生复合征及肝萎缩病理和代谢功能研究进展

肝萎缩增生复合征(atrophy-hypertrophy complex,AHC)是指肝组织萎缩和代偿性增生的一种临床病理特征,常见的病因有门静脉流入受阻、肝静脉流出受阻、胆道梗阻等。AHC常伴有区域性肝组织的解剖、病理、代谢功能的改变,包括肝脏沿肝门轴的旋转、萎缩肝叶的纤维化和门管区小门静脉的狭窄或血栓形成等。肝萎缩-增生复合征萎缩肝组织仍具有部分代谢功能和生物转化功能,并可能对维持病变肝脏的正常肝功能具有重要的作用,萎缩肝组织仍具有部分代谢功能和生物转化功能,对萎缩肝组织的代谢分区和代谢功能的进一步研究具有重要意义。本文通过分析近年来国内外有关AHC的文献,探讨AHC的病因、病理变化及萎缩肝组织的代谢功能分化特征的研究进展。     

Cellular cholesterol loss by DHCR24 knockdown leads to Aβ production by changing APP intracellular localization

For the past 20 years, the majority of cell culture studies reported that increasing cholesterol level increases amyloid-β (Aβ) production. Conversely, other studies and genetic evidences support that cellular cholesterol loss leads to Aβ generation. As a highly controversial issue in Alzheimer’s disease pathogenesis, the apparent contradiction prompted us to again explore the role of cellular cholesterol in Aβ production. Here, we adopted new neuronal and astrocytic cell models induced by 3β-hydroxysterol-Δ24 reductase (DHCR24), which obviously differ from the widely used cell models with overexpressing amyloid precursor protein (APP) in the majority of previous studies. In neuronal and astrocytic cell model, we found that deficiency of cellular cholesterol by DHCR24 knockdown obviously increased intracellular and extracellular Aβ generation. Importantly, in cell models with overexpressing APP, we found that APP overexpression could disrupt cellular cholesterol homeostasis and affect function of cells, coupled with the increase of APP β-cleavage product, 99-residue transmembrane C-terminal domain. Therefore, we suppose the results derived from the APP knockin models will need to be re-evaluated. One rational explanation for the discrepancy between our outcomes and the previous studies could be attributed to the two different cell models. Mechanistically, we showed that cellular cholesterol loss obviously altered APP intracellular localization by affecting cholesterol-related trafficking protein of APP. Therefore, our outcomes strongly support cellular cholesterol loss by DHCR24 knockdown leads to Aβ production.     

Identification of the actin and plasminogen binding regions of group B streptococcal phosphoglycerate kinase

Phosphoglycerate kinase (PGK), present on the surface of group B streptococcus (GBS), has previously been demonstrated to bind the host proteins actin and plasminogen. The actin and plasminogen binding sites of GBS-PGK were identified using truncated GBS-PGK molecules, followed by peptide mapping. These experiments identified two actin and plasminogen binding sites located between amino acids 126-134 and 204-208 of the 398-amino acid-long GBS-PGK molecule. Substitution of the lysine residues within these regions with alanine resulted in significantly reduced binding to both actin and plasminogen. In addition, conversion of the glutamic acid residue at amino acid 133 to proline, the amino acid found at this position for the PGK protein of Streptococcus pneumoniae, also resulted in sign ificantly reduced binding to actin and plasminogen. These results demonstrate that the lysine residues at amino acid positions 126, 127, 130, 204, and 208 along with the glutamic acid residue at amino acid position 133 are necessary for actin and plasminogen binding by GBS-PGK.     

细胞分裂素生物合成基因在调节一组烟草病理相关蛋白基因表达中的作用

对一组病理相关蛋白基因在烟草 ( N icotiana tabacum cv. Wisconsin 38)中的表达情况进行了研究 ,包括 :碱性几丁质酶、β- 1 ,3-葡萄糖苷酶、渗透蛋白及伸展蛋白。RNA杂交实验表明在正常烟草植株中上述 4个基因具有发育和器官专一性的表达。在含有细胞分裂素生物合成基因的转基因烟草丛生芽中 ,这 4个基因的表达受过量合成的内源细胞分裂素和载体效应的共同调节 ,细胞分裂素降低这些基因的表达 ,而载体效应则促进它们的表达。热激处理也明显降低这 4种基因的表达水平。上述结果表明这些病理相关蛋白基因具有复杂的调控系统     

Role of serine/threonine phosphatase (SP-STP) in Streptococcus pyogenes physiology and virulence

Reversible phosphorylation is the key mechanism regulating several cellular events in prokaryotes and eukaryotes. In prokaryotes, signal transduction is perceived to occur primarily via the two-component signaling system involving histidine kinases and cognate response regulators. Although an alternative regulatory pathway controlled by the eukaryote-type serine/threonine kinase (Streptococcus pyogenes serine/threonine kinase; SP-STK) has been shown to modulate bacterial growth, division, adherence, invasion, and virulence in group A Streptococcus (GAS; S. pyogenes), the precise role of the co-transcribing serine/threonine phosphatase (SP-STP) has remained enigmatic. In this context, this is the first report describing the construction and characterization of non-polar SP-STP mutants in two different strains of Type M1 GAS. The STP knock-out mutants displayed increased bacterial chain lengths in conjunction with thickened cell walls, significantly reduced capsule and hemolysin production, and restoration of the phenotypes postcomplementation. The present study also reveals important contribution of cognately regulated-reversible phosphorylation by SP-STK/SP-STP on two major response regulators of two-component systems, WalRK and CovRS. We also demonstrate a distinct role of SP-STP in terms of expression of surface proteins and SpeB in a strain-specific manner. Further, the attenuation of virulence in the absence of STP and its restoration only in the complemented strains that were generated by the use of a low copy plasmid and not by a high copy one emphasize not only the essential role of STP in virulence but also highlight the tightly regulated SP-STP/SP-STK-mediated cognate functions. SP-STP thus is an important regulator of GAS virulence and plays a critical role in GAS pathogenesis.     

糖尿病肾病发病机制研究进展

糖尿病肾病(DN)是糖尿病(DM)最常见的慢性并发症,也是终末期肾病(ESRD)的主要原因,其治疗费用巨大。其发病机制主要涉及遗传易感性、糖代谢紊乱、肾血流动力学的改变、细胞因子、炎症机制已及氧化应激等方面。本文就以上作用机制的最新研究进展作一综述。     

Identification of a novel Francisella tularensis factor required for intramacrophage survival and subversion of innate immune response

Francisella tularensis, the causative agent of tularemia, is one of the deadliest agents of biological warfare and bioterrorism. Extremely high virulence of this bacterium is associated with its ability to dampen or subvert host innate immune response. The objectives of this study were to identify factors and understand the mechanisms of host innate immune evasion by F. tularensis. We identified and explored the pathogenic role of a mutant interrupted at gene locus FTL_0325, which encodes an OmpA-like protein. Our results establish a pathogenic role of FTL_0325 and its ortholog FTT0831c in the virulent F. tularensis SchuS4 strain in intramacrophage survival and suppression of proinflammatory cytokine responses. This study provides mechanistic evidence that the suppressive effects on innate immune responses are due specifically to these proteins and that FTL_0325 and FTT0831c mediate immune subversion by interfering with NF-κB signaling. Furthermore, FTT0831c inhibits NF-κB activity primarily by preventing the nuclear translocation of p65 subunit. Collectively, this study reports a novel F. tularensis factor that is required for innate immune subversion caused by this deadly bacterium.     

Low Activity of Angiotensin-Converting Enzyme in Cerebral Microvessels of Young Spontaneously Hypertensive Rats

Angiotensin-converting enzyme (ACE) activity was measured in microvessels prepared from cerebral cortices of 4-week-old spontaneously hypertensive rats (SHR). The Vmax value of the ACE activity in the cerebral microvessels of SHR was lower than that of Wistar Kyoto controls of the same age by 25% without difference in Km value for substrate. The low activity of ACE in the cerebral microvessels of young SHR indicates that in this animal model of hypertension the function of ACE is genetically altered in the cerebral microvessels, which may be correlated with the alteration of the cerebral microcirculation and pathogenesis of hypertension.