Cholesterol and oxygenated cholesterol concentrations are markedly elevated in peripheral tissue but not in brain from mice with the Niemann–Pick type C phenotype

Niemann–Pick disease type C (NP-C) is a rare genetic disorder characterized by progressive neurodegeneration, frequent developmental delay and early death. Tissues of affected individuals accumulate large quantities of free cholesterol in lysosomes. Because cytotoxic oxygenated derivatives of cholesterol are known to form readily when cholesterol concentrations are elevated, we searched for these compounds in liver, kidney, spleen and brain from mice with the NP-C phenotype. In order of abundance, we identified 7- and 7-hydroxycholesterol, 5,6-epoxycholestan-3-ol, 4-hydroxycholesterol, cholest-4-en-3,7-diol and cholest-4-en-3,6-diol in most tissue samples. Cholesterol concentrations in affected mice were increased 3-fold in kidney and 7- to 8-fold in spleen and liver compared to controls (all p<0.001) but were unchanged in brain. Although oxysterol levels were markedly elevated in non-brain tissue, the oxysterol and cholesterol concentrations increased proportionally so that oxysterols expressed as percentage of total sterols were the same for all animals (0.34±0.19% averaged over all organs in affected animals vs 0.40±0.42% in control mice). In contrast to peripheral tissue, we could not detect any increase in either absolute or relative oxysterol levels in the brains of affected and control mice (49±61 vs 53±43 g/g wet weight and 0.45±0.52 vs 0.47±0.37%, respectively). Thus, brain sterols are normal in NP-C mice and it is unlikely that an accumulation of cytotoxic oxygenated derivatives of cholesterol could account for the progressive neuropathology seen in the disease.     

Serum levels of the adipokine zinc-α2-glycoprotein are increased in chronic hemodialysis

Zinc-α2-glycoprotein (ZAG) has recently been proposed as a new adipokine involved in body weight control. In the current study, we investigated renal elimination of this adipokine by comparing circulating ZAG levels in patients on chronic hemodialysis (CD) with controls. Sixty CD patients and 60 controls with a glomerular filtration rate greater than 50 mL/min were included. Serum concentrations of ZAG were determined by enzyme-linked immunosorbent assay; and its relationship with renal function, glucose and lipid metabolism, as well as inflammation was studied in both groups. Median ZAG serum levels were almost 2-fold higher in CD patients (94.4 ± 29.4 mg/L) as compared with controls (48.3 ± 23.5 mg/L) (P < .001). Furthermore, circulating ZAG was negatively correlated with fasting insulin, homeostasis model assessment of insulin resistance, and leptin in controls in univariate analysis. Moreover, CD independently predicted ZAG concentrations in multiple regression analysis. Renal filtration appears to be an important route of ZAG elimination, and markers of renal function should be included in studies on ZAG physiology.     

Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor β ligand

An estrogen receptor (ER) β ligand (LY3201) with a preference for ERβ over ERα was administered in s.c. pellets releasing 0.04 mg/d. The brains of these mice were examined 3 d after treatment had begun. Although estradiol-17β is known to increase spine density and glutaminergic signaling, as measured by Golgi staining, a clear reduction in spines was evident on the dendritic branches in LY3201-treated mice but no morphological alteration and no difference in the number of dendritic spines on dendritic stems were observed. In the LY3201-treatment group, there was higher expression of glutamic acid decarboxylase (GAD) in layer V of cortex and in the CA1 of hippocampus, more GAD(+) terminals surrounding the pyramidal neurons and less glutamate receptor (NMDAR) on the neurons in layer V. There were no alterations in expression of Iba1 or in Olig2 or CNPase. However, GFAP(+) astrocytes were increased in the LY3201-treatment group. There were also more projections characteristic of activated astrocytes and increased expression of glutamine synthetase (GS). No expression of ERβ was detectable in the nuclei of astrocytes. Clearly, LY3201 caused a shift in the balance between excitatory and inhibitory neurotransmission in favor of inhibition. This shift was due in part to increased synthesis of GABA and increased removal of glutamate from the synaptic cleft by astrocytes. The data reveal that treatment with a selective ERβ agonist results in changes opposite to those reported in estradiol-17β-treated mice and suggests that ERα and ERβ play opposing roles in the brain.     

Interleukin-27 enhances the production of tumour necrosis factor-α and interferon-γ by bone marrow T lymphocytes in aplastic anaemia

Aplastic anaemia (AA) is considered as an immune-mediated bone marrow failure syndrome. The mechanism is involved with a variety of immune molecules including interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α) and interleukins (ILs). IL-27 is a novel member of the IL-12 family, which mediates T cell response and enhances the production of IFN-γ. However, little is known about the role of IL-27 in the development of AA. This study investigated the role of IL-27 and its receptor IL-27R in the pathogenesis of AA. Both the mRNA expression of IL-27/IL-27R subunits in the bone marrow mononuclear cells (BMMNCs) and the levels of IL-27 in the marrow plasma in AA were found to be higher than in controls. Increased IL-27 correlated with the disease severity of AA. Subsequently, we stimulated marrow T lymphocytes with recombinant human (rh)IL-27 and found that rhIL-27 enhanced the production of TNF-α and IFN-γ in both CD4(+) and CD8(+) T lymphocytes from AA patients. We also detected increased TNF-α and IFN-γ in the supernatants of BMMNCs from AA patients after IL-27 stimulation. In conclusion, our data suggest that elevated IL-27 and IL-27-induced TNF-α and IFN-γ overproduction might be involved in the pathogenesis of AA.     

Serum levels of the bone turnover markers dickkopf-1, osteoprotegerin,and TNF-α in knee osteoarthritis patients

Clinical Rheumatology - Knee osteoarthritis (KOA) is a common degenerative joint disease causing pain, stiffness, reduced motion, swelling, crepitus, and disability. Several inflammatory markers...     

Serum lipid concentrations among persons with spinal cord injury – A systematic review and meta-analysis of the literature

Background

Lipid optimization comprises a therapeutic cornerstone of primary and secondary cardiovascular disease prevention. This systematic review and meta-analysis sought to clarify patterns of lipid profiles in spinal cord injury (SCI) patients compared to able-bodied individuals as well as among subgroups of SCI patients stratified by sex, activity level, race, and level of injury.

Methods

Searches were conducted in PubMed, CINAHL, PsycINFO, and EMBASE. The initial literature search broadly identified peer-reviewed studies that examined cardiovascular risk factors in SCI. A total of 50 studies were ultimately identified that focused on lipid levels in SCI. Demographic data (including subject age, duration of injury, height, weight, and body mass index [BMI]) and lipid values were extracted for able-bodied individuals and subjects with SCI. Statistical analyses included t-testing and analysis of variance (ANOVA).

Results

Compared with controls, individuals with SCI had significantly lower total cholesterol (TC) (183.4 mg/dL versus 194.9 mg/dL, p = 0.019) and high-density lipoprotein cholesterol (HDL-C) (41.0 mg/dL versus 49.6 mg/dL, p < 0.001) and higher TC/HDL-C ratios (4.5 versus 4.0, p = 0.002), though no significant differences were found for triglyceride (TG) and non-HDL-C values.

Conclusions

SCI represents an increasingly common chronic condition, now secondarily characterized by heightened CVD risk potentially in part due to unique lipid profiles characterized primarily by low HDL-C and an increased TC/HDL-C ratio. As other at-risk patient populations have received increased acknowledgment with more stringent lipid panel screening at earlier ages and increased frequency, we would propose that the same be implemented for the SCI population until more-specific CVD risk stratification guidelines are established for this population.     

Simultaneous donor bone marrow and cardiac transplantation: can tolerance be induced with the development of chimerism?

Mixed bone marrow chimerism (mixed chimerism) is defined by the coexistence of two genetically different bone marrow stem cells in an individual. The chimeric immune system recognizes donor antigen as self, yet is capable of mounting a normal response to third-party antigens. In animal models, mixed chimerism confers donor-specific tolerance for solid-organ and cellular grafts: tissue from the bone marrow donor is permanently accepted by mixed chimeras in the absence of conventional immunosuppressive agents. Clinical application of mixed chimerism to induce transplantation tolerance requires novel approaches to safely and reliably achieve engraftment of donor bone marrow in transplant recipients. Recent advances offer potential solutions to these obstacles and suggest that the application of mixed chimerism to induce tolerance to transplanted organs may soon be a clinical reality.     

Role of MKK3–p38 MAPK signalling in the development of type 2 diabetes and renal injury in obese db/db mice

Aims/hypothesis  Obesity and diabetes are associated with increased intracellular p38 mitogen-activated protein kinase (MAPK) signalling, which may promote tissue inflammation and injury. Activation of p38 MAPK can be induced by either of the immediate upstream kinases, MAP kinase kinase (MKK)3 or MKK6, and recent evidence suggests that MKK3 has non-redundant roles in the pathology attributed to p38 MAPK activation. Therefore, this study examined whether MKK3 signalling influences the development of obesity, type 2 diabetes and diabetic nephropathy. Methods  Wild-type and Mkk3 (also known as Map2k3) gene-deficient db/db mice were assessed for the development of obesity, type 2 diabetes and renal injury from 8 to 32 weeks of age. Results   Mkk3 ^+/+ db/db and Mkk3 ^−/− db/db mice developed comparable obesity and were similar in terms of incidence and severity of type 2 diabetes. At 32 weeks, diabetic Mkk3 ^+/+ db/db mice had increased kidney levels of phospho-p38 and MKK3 protein. In comparison, kidney levels of phospho-p38 in diabetic Mkk3 ^−/− db/db mice remained normal, despite a fourfold compensatory increase in MKK6 protein levels. The reduced levels of p38 MAPK signalling in the diabetic kidneys of Mkk3 ^−/− db/db mice was associated with protection against the following: declining renal function, increasing albuminuria, renal hypertrophy, podocyte loss, mesangial cell activation and glomerular fibrosis. Diabetic Mkk3 ^−/− db/db mice were also significantly protected from tubular injury and interstitial fibrosis, which was associated with reduced Ccl2 mRNA expression and interstitial macrophage accumulation. Conclusions/interpretation  MKK3–p38 MAPK signalling is not required for the development of obesity or type 2 diabetes, but plays a distinct pathogenic role in the progression of diabetic nephropathy in db/db mice.     

Plasma concentrations of soluble IL-2 receptor α (CD25) are increased in type 1 diabetes and associated with reduced C-peptide levels in young patients

Aims/hypothesis

Type 1 diabetes is a common autoimmune disease that has genetic and environmental determinants. Variations within the IL2 and IL2RA (also known as CD25) gene regions are associated with disease risk, and variation in expression or function of these proteins is likely to be causal. We aimed to investigate if circulating concentrations of the soluble form of CD25, sCD25, an established marker of immune activation and inflammation, were increased in individuals with type 1 diabetes and if this was associated with the concentration of C-peptide, a measure of insulin production that reflects the degree of autoimmune destruction of the insulin-producing beta cells.

Methods

We used immunoassays to measure sCD25 and C-peptide in peripheral blood plasma from patient and control samples.

Results

We identified that sCD25 was increased in patients with type 1 diabetes compared with controls and replicated this result in an independent set of 86 adult patient and 80 age-matched control samples (p?=?1.17?×?10^?3). In 230 patients under 20 years of age, with median duration-of-disease of 6.1 years, concentrations of sCD25 were negatively associated with C-peptide concentrations (p?=?4.8?×?10^?3).

Conclusions/interpretation

The 25% increase in sCD25 in patients, alongside the inverse association between sCD25 and C-peptide, probably reflect the adverse effects of an on-going, actively autoimmune and inflammatory immune system on beta cell function in patients.     

Serum levels of the regulatory cytokines transforming growth factor-β and interleukin-10 are reduced in patients with discoid lupus erythematosus

T-lymphocytes are believed to play an important role in the pathogenesis of discoid lupus erythematosus (DLE). However, the reasons that lead to loss of tolerance and to development of autoimmunity in DLE remain unclear. In the present paper, we investigated serum levels of the regulatory cytokines transforming growth factor (TGF)-β and interleukin (IL)-10 in 25 newly diagnosed patients with DLE, 15 with systemic lupus erythematosus (SLE), 10 with psoriasis, 10 with atopic dermatitis (AD) and 20 healthy controls (HC). TGF-β serum levels were significantly lower in patients with DLE compared with patients with psoriasis and HC, while no differences were found between DLE, SLE and AD (medians: DLE: 28.49?ng/ml; psoriasis: 42.77?ng/ml; HC: 43.71?ng/ml; DLE vs. psoriasis: p?相似文献   

Normalized levels of red blood cells expressing phosphatidylserine,their microparticles,and activated platelets in young patients with β-thalassemia following bone marrow transplantation

Bone marrow transplantation (BMT) serves as the only curative treatment for patients with β-thalassemia major; however, hemostatic changes have been observed in these BMT patients. Aggregability of thalassemic red blood cells (RBCs) and increased red blood cell-derived microparticles (RMPs) expressing phosphatidylserine (PS) are thought to participate in thromboembolic events by initially triggering platelet activation. To our knowledge, there has been no report providing quantitation of these circulating PS-expressing RBCs and RMPs in young β-thalassemia patients after BMT. Whole blood from each subject was fluorescently labeled to detect RBC markers (CD235a) and annexin-V together with the known number TruCount? beads. PS-expressing RBCs, RMPs, and activated platelets were identified by flow cytometry. In our randomized study, we found the decreased levels of three aforementioned factors compared to levels in patients receiving regular blood transfusion (RT). This study showed that BMT in β-thalassemia patients decreases the levels of circulating PS-expressing RBCs, their MPs, and procoagulant platelets when compared to patients who received RT. Normalized levels of these coagulation markers may provide the supportive evidence of the effectiveness of BMT for curing thalassemia.     

Effects of estrogen receptor α and β gene deletion on estrogenic induction of progesterone receptors in the locus coeruleus in female mice

Locus coeruleus (LC) is involved in the LHRH regulation by gonadal steroids. We investigated the expression of progesterone and estrogen receptors (PR; ER) in LC neurons of ERα (αERKO) or ERβ (βERKO) knockout mice, and their wild-type (αWT and βWT). Immunocytochemical studies showed that LC expresses PR and both ERs, although ERβ was more abundant. Estradiol benzoate (EB) decreased ERα-positive cells in WT and βERKO mice, and progesterone caused a further reduction, whereas none of the steroids influenced ERβ expression. ERβ deletion increased ERα while ERα deletion did not alter ERβ expression. In both WT mice, EB increased PR expression, which was diminished by progesterone. These steroid effects were also observed in αERKO animals but to a lesser extent, suggesting that ERα is partially responsible for the estrogenic induction of PR in LC. Steroid effects on PR in βERKO mice were similar to those in the αERKO but to a lesser extent, probably because PR expression was already high in the oil-treated group. This expression seems to be specific of LC neurons, since it was not observed in other areas studied, the preoptic area and ventromedial nucleus of hypothalamus. These findings show that LC in mice expresses αER, βER, and PR, and that a balance between them may be critical for the physiological control of reproductive function.