Interactions between age,sex, and hormones in experimental ischemic stroke

Age, sex, and gonadal hormones have profound effects on ischemic stroke outcomes, although how these factors impact basic stroke pathophysiology remains unclear. There is a plethora of inconsistent data reported throughout the literature, primarily due to differences in the species examined, the timing and methods used to evaluate injury, the models used, and confusion regarding differences in stroke incidence as seen in clinical populations vs. effects on acute neuroprotection or neurorepair in experimental stroke models. Sex and gonadal hormone exposure have considerable independent impact on stroke outcome, but these factors also interact with each other, and the contribution of each differs throughout the lifespan. The contribution of sex and hormones to experimental stroke will be the focus of this review. Recent advances and our current understanding of age, sex, and hormone interactions in ischemic stroke with a focus on inflammation will be discussed.     

Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency

X-linked lymphoproliferative syndrome (XLP) is a rare primary immunodeficiency characterized by increased vulnerability to Epstein–Barr virus infection. XLP type 1 is caused by mutations in SH2D1A, whereas X-linked inhibitor of apoptosis (XIAP) encoded by XIAP/BIRC4 is mutated in XLP type 2. In XIAP deficiency, hemophagocytic lymphohistiocytosis (HLH) occurs more frequently and recurrence is common. However, the underlying mechanisms remain mostly unknown. We describe the characteristics of the cytokine profiles of serum samples from 10 XIAP-deficient patients. The concentration of interleukin (IL)-18 was strikingly elevated in the patients presented with HLH, and remained high after the recovery from HLH although levels of other pro-inflammatory cytokines approached the normal range. Longitudinal examination of two patients demonstrated marked exacerbation of IL-18 levels during every occasion of HLH. These findings may suggest the association between HLH susceptibility and high serum IL-18 levels in XIAP deficiency.     

二苯乙烯苷通过上调XIAP抑制人脐静脉内皮细胞凋亡

目的:二苯乙烯苷(2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside,TSG)具有抗炎、抗氧化、抗动脉粥样硬化(atherosclerosis,As)等作用。课题组前期研究表明TSG对过氧化氢(H2O2)诱导损伤的内皮细胞具有保护作用,并抑制内皮细胞的凋亡,但机制尚未完全明确。本研究目的在于探讨TSG是否通过影响X连锁凋亡抑制蛋白(X-linked inhibitor of apoptosis protein,XIAP)、Caspase-9的表达来抑制细胞凋亡。方法:体外培养人脐静脉内皮细胞,实验分为正常对照组、模型组(300μmol·L-1H2O2)、TSG预处理组(10μmol·L-1TSG+300μmol·L-1H2O2)、Embelin与TSG联合处理组(30μmol·L-1Embelin+10μmol·L-1TSG+300μmol·L-1H2O2)、TSG单独处理组(10μmol·L-1TSG)、Embelin组(30μmol·L-1Embelin)。采用MTT法检测细胞增殖率,Hoechst 33258染色观察凋亡细胞核形态,RT-PCR和Western blot检测XIAP、Caspase-9的表达。结果:与空白对照组相比,H2O2组内皮细胞增殖率降低,核损伤明显,XIAP表达显著性下降,Caspase-9表达显著增加(P0.01);与H2O2组比较,经TSG预处理后,细胞增殖率增加,核损伤减轻,XIAP的表达上升,Caspase-9表达减少,差异均有显著性(P0.01)。与TSG预处理组比较,用XIAP阻断剂Embelin与TSG联合处理后,内皮细胞活力下降,XIAP表达显著降低,Caspase-9表达增加(P0.01)。结论:TSG具有抑制H2O2诱导的人脐静脉内皮细胞凋亡作用,其机制与增加XIAP的表达,抑制Caspase-9的表达有关。     

XIAP 基因在肿瘤中的研究进展

XIAP(X链锁凋亡抑制蛋白,X-linked inhibitor-of-apoptosis protain)是凋亡抑制蛋白(IAPs)家族中最有效力的caspase抑制物,具有抑制细胞凋亡,参与肿瘤的发生、发展。本文就XIAP在肿瘤中的作用机制、表达及治疗情况做一综述,有望为肿瘤的诊断及治疗提供一个新方法。     

The phosphatonins and the regulation of phosphate transport and vitamin D metabolism

Phosphate homeostasis is preserved during variations in phosphate intake by short-term intrinsic renal and intestinal adaptations in transport processes, and by more long-term hormonal mechanisms, which regulate the efficiency of phosphate transport in the kidney and intestine. Recently, several phosphaturic peptides such as fibroblast growth factor 23 (FGF-23), secreted frizzled-related protein-4 (sFRP-4), extracellular phosphoglycoprotein (MEPE) and fibroblast growth factor 7 (FGF-7) have been shown to play a pathogenic role in several hypophosphatemic disorders such as tumor-induced osteomalacia (TIO), autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemic rickets (XLH), the McCune-Albright syndrome (MAS) and fibrous dysplasia (FD). These proteins induce phosphaturia and hypophosphatemia in vivo, and inhibit sodium-dependent renal phosphate transport in cultured renal epithelial cells. Interestingly, despite the induction of hypophosphatemia by FGF-23 and sFRP-4 in vivo, serum 1, 25-dihydroxyvitamin D (1alpha,25(OH)(2)D) concentrations are decreased or remain inappropriately normal, suggesting an inhibitory effect of these proteins on 25-hydroxyvitamin D 1alpha-hydroxylase activity. In FGF-23 knockout mice, 25-hydroxyvitamin D 1alpha-hydroxylase expression is increased and elevated serum 1alpha,25(OH)(2)D levels cause significant hypercalcemia and hyperphosphatemia. MEPE, however, increases circulating 1alpha,25(OH)(2)D. Circulating or local concentrations of these peptides/proteins may regulate 25-hydroxyvitamin D 1alpha-hydroxylase activity in renal tissues under physiologic circumstances.     

Structural Basis for Bivalent Smac-Mimetics Recognition in the IAP Protein Family

XIAP is an apoptotic regulator protein that binds to the effector caspases -3 and -7 through its BIR2 domain, and to initiator caspase-9 through its BIR3 domain. Molecular docking studies suggested that Smac-DIABLO may antagonize XIAP by concurrently targeting both BIR2 and BIR3 domains; on this basis bivalent Smac-mimetic compounds have been proposed and characterized. Here, we report the X-ray crystal structure of XIAP-BIR3 domain in complex with a two-headed compound (compound 3) with improved efficacy relative to its monomeric form. A small-angle X-ray scattering study of XIAP-BIR2BIR3, together with fluorescence polarization binding assays and compound 3 cytotoxicity tests on HL60 leukemia cell line are also reported. The crystal structure analysis reveals a network of interactions supporting XIAP-BIR3/compound 3 recognition; moreover, analytical gel-filtration chromatography shows that compound 3 forms a 1:1 stoichiometric complex with a XIAP protein construct containing both BIR2 and BIR3 domains. On the basis of the crystal structure and small-angle X-ray scattering, a model of the same BIR2-BIR3 construct bound to compound 3 is proposed, shedding light on the ability of compound 3 to relieve XIAP inhibitory effects on caspase-9 as well as caspases -3 and -7. A molecular modeling/docking analysis of compound 3 bound to cIAP1-BIR3 domain is presented, considering that Smac-mimetics have been shown to kill tumor cells by inducing cIAP1 and cIAP2 ubiquitination and degradation. Taken together, the results reported here provide a rationale for further development of compound 3 as a lead in the design of dimeric Smac mimetics for cancer treatment.     

ABCD1 mutations and phenotype distribution in Chinese patients with X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder resulting from mutations within the ABCD1 gene. Adrenomyeloneuropathy (AMN) and childhood cerebral ALD (CCALD) are most common phenotypes in the Western ALD patients. Here we performed mutation analysis of ABCD1 in 10 Chinese ALD families and identified 8 mutations, including one novel deletion (c.1477_1488 + 11del23) and 7 known mutations. Mutations c.1772G>A and c.1816T>C were first reported in the Chinese patients. Mutations c.1661G>A and c.1679C>T were demonstrated to be de novo mutations. The dinucleotide deletion 1415_16delAG, described as a mutational hotspot in different ethnic groups, was identified in two families. In addition, we performed a retrospective nation-wide mutation study of X-linked ALD in China based on a literature review. The retrospective study further confirmed the hypothesis that exon 6 is a potential mutation cluster region in the Asian populations. Furthermore, it suggested that CCALD is the most common phenotype in China.