鸟氨酸脱羧酶的生理病理特点及其药物研究概况

鸟氨酸脱羧酶(ornithinedecarboxylase,ODC)是多胺代谢中的关键酶,广泛存在于人体和动物各组织细胞内,其中对肠细胞的增生、移行和分化起重要作用.机体调节因素比较复杂.在黏膜损伤性疾病及某些癌前病变等细胞大量增生的病理情况下ODC的表达发生改变,可以作为这些疾病分期、预后及药物作用靶点或疗效的指标.寻找对ODC有作用的药物对于治疗其相关疾病是非常有意义的.     

Nerve dysfunction leads to muscle morphological abnormalities in chronic inflammatory demyelinating polyneuropathy assessed by MRI

Neuropathic features of chronic inflammatory demyelinating polyneuropathy (CIDP) have been well documented, however very little is known about the implication of this neuropathy on skeletal muscle, and whether nerve lesions in CIDP lead to uniform disruptions in skeletal muscles. In this study, we assessed the triceps surae complex, using magnetic resonance imaging (MRI) in a group (n = 10) of CIDP patients compared with a healthy age-matched control group (n = 9). MRI (T1 and T2) of the leg musculature as well as plantar flexion strength measurements were obtained from both groups. CIDP patients compared with controls had ∼28% lower plantar flexion strength and ∼19% less total muscle volume (T1) of the triceps surae. When strength was normalized to fat corrected triceps surae volume CIDP patients were ∼30% weaker than controls. Relaxation times from the T2 scans were significantly longer in CIDP with the soleus, medial head of gastrocnemius and lateral head of gastrocnemius showing ∼37%, ∼38% and ∼26% longer relaxation times, respectively. CIDP patients were significantly weaker compared to controls and despite normalizing strength to total triceps surae contractile tissue volume this difference remained. CIDP patients had significantly longer T2 times, reflecting increased noncontractile tissue infiltration. These results indicate reduced muscle quantity and quality as a result of alterations in axonal function. Furthermore, when present study results are considered together with a prior report on the anterior compartment (Gilmore et al. 2016, Muscle Nerve 3:413–420), it is clear that both anterior and posterior leg compartments are affected similarly in CIDP despite different terminal nerve innervation and functional properties. Clin. Anat. 32:77–84, 2019. © 2019 Wiley Periodicals, Inc.     

The diversity of dolichol-linked precursors to Asn-linked glycans likely results from secondary loss of sets of glycosyltransferases

The vast majority of eukaryotes (fungi, plants, animals, slime mold, and euglena) synthesize Asn-linked glycans (Alg) by means of a lipid-linked precursor dolichol-PP-GlcNAc2Man9Glc3. Knowledge of this pathway is important because defects in the glycosyltransferases (Alg1-Alg12 and others not yet identified), which make dolichol-PP-glycans, lead to numerous congenital disorders of glycosylation. Here we used bioinformatic and experimental methods to characterize Alg glycosyltransferases and dolichol-PP-glycans of diverse protists, including many human pathogens, with the following major conclusions. First, it is demonstrated that common ancestry is a useful method of predicting the Alg glycosyltransferase inventory of each eukaryote. Second, in the vast majority of cases, this inventory accurately predicts the dolichol-PP-glycans observed. Third, Alg glycosyltransferases are missing in sets from each organism (e.g., all of the glycosyltransferases that add glucose and mannose are absent from Giardia and Plasmodium). Fourth, dolichol-PP-GlcNAc2Man5 (present in Entamoeba and Trichomonas) and dolichol-PP- and N-linked GlcNAc2 (present in Giardia) have not been identified previously in wild-type organisms. Finally, the present diversity of protist and fungal dolichol-PP-linked glycans appears to result from secondary loss of glycosyltransferases from a common ancestor that contained the complete set of Alg glycosyltransferases.     

Thrombospondin mediates the cytoadherence of Plasmodium falciparum- infected red cells to vascular endothelium in shear flow conditions

Cerebral malaria is thought to involve specific attachment of Plasmodium falciparum-infected knobby red cells to venular endothelium. The nature of surface ligands on host endothelial cells that may mediate cytoadherence is poorly understood. We have investigated the effects of soluble thrombospondin, rabbit antiserum raised against thrombospondin, and human immune serum on cytoadherence of parasitized erythrocytes in ex vivo mesocecum vasculature. Preincubation of infected red cells with soluble thrombospondin or human immune serum inhibits binding of infected red cells to rat venular endothelium. Infusion of the microcirculatory preparation with rabbit antithrombospondin antibodies before perfusion of parasitized erythrocytes also resulted in decreased cytoadherence. In addition, incubation of infected cells with human immune sera obtained from malaria patients significantly inhibited the observed cytoadherence. Our results indicate that thrombospondin mediates binding of infected red cells to venular endothelium and may thus be involved in the pathogenesis of cerebral malaria.     

Multilamelled structures from the lungs of patients with pulmonary alveolar proteinosis

Multilamellated structures (MS), which accumulate in the lungs of patients with pulmonary alveolar proteinosis, were examined under the electron microscope. MS, in general, consisted of alternating light and dark lamellae arranged concentrically about membranous vesicles or electron-dense bodies. The darker osmiophilic lamellae consisted of trilaminar membranes 80 to 100 A thick, and the lighter lamellae, which varied from 150 to 300 A in width, appeared amorphous. MS made up 42.6 +/- 12.4% (n = 4) of the total particulate volume present in the pulmonary lavage effluents. MS resembled tubular myelin structures from the lungs of patients, although these latter structures accounted for only 1.6 +/- 2.3% (n = 4) of the total particulate volume. Abnormalities, such as polygonal tubules, irregular tubule dimensions, and large size potential, indicated that tubular myelin structures in the lungs of patients were variable in structure. MS appear to be a form of tubular myelin structure. MS were treated with a variety of disruptive agents and then examined under the electron microscope. Information was obtained about the composition of the MS and the intermolecular forces involved in their three-dimensional organization. Extraction of the MS with acetone or treatment of the structures with phospholipase c resulted in loss of membranes from the structures without a concomitant loss of the intermembranous amorphous material, indicating that phospholipids were a major membrane component. Analysis of phospholipids in the acetone extracts of the MS revealed that the membranes consisted of 45% phosphatidylcholine and that the major fatty acid of the phosphatidylcholine was palmitate (76%). The amorphous material of the intermembranous spaces consisted primarily of protein, since it was destroyed by the proteases trypsin and pronase without loss of the membranes. Reducing agents such as mercaptoethanol and dithiothreitol were disruptive, indicating the importance of disulfide bridges between the protein constituents in maintaining the integrity of the MS. The significance of hydrophobic interactions between the protein constituents was demonstrated by the disruptive action of chaotropic agents according to the sequence KSCN greater than KI greater than KCl. These data indicate that MS consist of phospholipid membranes organized in a protein matrix maintained by intermolecular disulfide bridges and hydrophobic interactions.