miR-34a-/- mice are susceptible to diet-induced obesity

Objective: MicroRNA (miR)−34a regulates inflammatory pathways, and increased transcripts have been observed in serum and subcutaneous adipose of subjects who have obesity and type 2 diabetes. Therefore, the role of miR-34a in adipose tissue inflammation and lipid metabolism in murine diet-induced obesity was investigated. Methods: Wild-type (WT) and miR-34a−/− mice were fed chow or high-fat diet (HFD) for 24 weeks. WT and miR-34a−/− bone marrow-derived macrophages were cultured in vitro with macrophage colony-stimulating factor (M-CSF). Brown and white preadipocytes were cultured from the stromal vascular fraction (SVF) of intrascapular brown and epididymal white adipose tissue (eWAT), with rosiglitazone. Results: HFD-fed miR-34a−/− mice were significantly heavier with a greater increase in eWAT weight than WT. miR-34a−/− eWAT had a smaller adipocyte area, which significantly increased with HFD. miR-34a−/− eWAT showed basal increases in Cd36, Hmgcr, Lxrα, Pgc1α, and Fasn. miR-34a−/− intrascapular brown adipose tissue had basal reductions in c/ebpα and c/ebpβ, with in vitro miR-34a−/− white adipocytes showing increased lipid content. An F4/80high macrophage population was present in HFD miR-34a−/− eWAT, with increased IL-10 transcripts and serum IL-5 protein. Finally, miR-34a−/− bone marrow-derived macrophages showed an ablated CXCL1 response to tumor necrosis factor-α. Conclusions: These findings suggest a multifactorial role of miR-34a in controlling susceptibility to obesity, by regulating inflammatory and metabolic pathways

The role of microRNAs in glucocorticoid action - literature review

Glucocorticoids (GCs) are steroids with profound anti-inflammatory and immunomodulatory activities. Synthetic GCs are widely used for managing chronic inflammatory and autoimmune conditions, as immunosuppressants in transplantation, and as antitumor agents in certain hematological cancers. However, prolonged GC exposure can cause adverse effects. A detailed understanding of GCs' mechanisms of action may enable harnessing of their desirable actions while minimizing harmful effects. Here, we review the impact on GC biology of microRNAs, small noncoding RNAs that posttranscriptionally regulate gene expression. Emerging evidence indicates that microRNAs modulate GC production by the adrenal glands and cells' responses to GCs. Furthermore, GCs influence cell proliferation, survival, and function at least in part by regulating microRNA expression. We propose that the beneficial effects of GCs may be enhanced through combination with reagents targeting specific microRNAs

Tectonic control on the distribution of onshore mud volcanoes in parts of the Upper Benue Trough, northeastern Nigeria

Onshore mud volcanoes are rare geological phenomena, which in Nigeria were reported for the first time few years ago in the Upper Benue Trough. In this study a detail geological mapping of the area of mud volcanoes occurrence was carried out, with the primary aim of defining their relationship, if any, to the structural geology there. The systematic field reconnaissance included field observations of the structural features, as well as analysis of the location and distribution of the onshore mud volcanoes, marking their locations on the topographic and geological maps, analysis of the aerial photographs and satellite images. The study area covered the central part of the Upper Benue Trough where the onshore mud volcanoes were found. The study area is the part of a sedimentary basin comprising Cretaceous clastic rocks that have been deformed intensively by a network of faults often embedded in the underlying Precambrian basement. This network of faults underwent a rejuvenation period from the Aptian to the Palaeocene. The most prominent tectonic structure in the study area is the NE - SW trending Kaltungo Fault Zone, however, there are other minor faults with N - S and NW - SE trends. This study shows that the mud volcanoes found in the study area are usually located near or within fault zones, within the outcropping Upper Cretaceous Yolde Formation and Upper Bima Sandstone, both of which were deformed by the Kaltungo faults, as well as by other minor faults. Worldwide, incidences of onshore mud volcano formation are usually attributed to areas of tectonic activity, rapid sedimentation or hydrocarbon occurrence. In this study, the interpretation of the field observations and mapping results, combined with information on the structural evolution of the study area and seismic pattern (very scarce), have led to the conclusion that the location of onshore mud volcanoes in the Upper Benue Trough, being located along the fault zones, is structurally controlled. The close relationship between mud volcano location and the structural framework of the area may be interpreted as one of several possible subsurface geological responses to present tectonic activity

MiR-155 has a protective role in the development of non-alcoholic hepatosteatosis in mice

Hepatic steatosis is a global epidemic that is thought to contribute to the pathogenesis of type 2 diabetes. MicroRNAs (miRs) are regulators that can functionally integrate a range of metabolic and inflammatory pathways in liver. We aimed to investigate the functional role of miR-155 in hepatic steatosis. Male C57BL/6 wild-type (WT) and miR-155−/− mice were fed either normal chow or high fat diet (HFD) for 6 months then lipid levels, metabolic and inflammatory parameters were assessed in livers and serum of the mice. Mice lacking endogenous miR-155 that were fed HFD for 6 months developed increased hepatic steatosis compared to WT controls. This was associated with increased liver weight and serum VLDL/LDL cholesterol and alanine transaminase (ALT) levels, as well as increased hepatic expression of genes involved in glucose regulation (Pck1, Cebpa), fatty acid uptake (Cd36) and lipid metabolism (Fasn, Fabp4, Lpl, Abcd2, Pla2g7). Using miRNA target prediction algorithms and the microarray transcriptomic profile of miR-155−/− livers, we identified and validated that Nr1h3 (LXRα) as a direct miR-155 target gene that is potentially responsible for the liver phenotype of miR-155−/− mice. Together these data indicate that miR-155 plays a pivotal role regulating lipid metabolism in liver and that its deregulation may lead to hepatic steatosis in patients with diabetes

An essential role of human Ada3 in p53 acetylation.

The p53 tumor suppressor protein functions as a critical component of genotoxic stress response by regulating the expression of effector gene products that control the fate of a cell following DNA damage. Unstressed cells maintain p53 at low levels through regulated degradation, and p53 levels and activity are rapidly elevated upon genotoxic stress. Biochemical mechanisms that control the levels and activity of p53 are therefore of great interest. We and others have recently identified hAda3 (human homologue of yeast alteration/deficiency in activation 3) as a p53-interacting protein and enhancer of p53 activity. Here, we show that endogenous levels of p53 and Ada3 interact with each other, and by using inducible overexpression and short hairpin RNA-mediated knockdown strategies we demonstrate that hAda3 stabilizes p53 protein by promoting its acetylation. Use of a p53 mutant with mutations of known p300/CREB-binding protein acetylation sites demonstrated that hAda3-dependent acetylation is required for increase in p53 stability and target gene induction. Importantly, we demonstrate that endogenous hAda3 is essential for DNA damage-induced acetylation and stabilization of p53 as well as p53 target gene induction. Overall, our results establish hAda3, a component of coactivator complexes that include histone acetyltransferase p300/CREB-binding protein, as a critical mediator of acetylation-dependent stabilization and activation of p53 upon genotoxic stress in mammalian cells

Jakość życia a sprawność funkcjonalna chorych na stwardnienie rozsiane

Background. Multiple sclerosis is a chronic disease and the most common one influencing central nervous system. It is a con­dition that significantly impairs the patient’s life. It deteriorates functional abilities in all aspects of daily life, and thus worsens the quality of life.Aim. The aim of the study was to evaluate functional capacity in patients with multiple sclerosis and its impact on quality of life.Materials and methods. The study was covered by 50 people. The tests were carried out using a diagnostic survey. Usedresearch tools were interview questionnaires for socio-demographic data and standardized research tools: ADL and IADL scale and the scale of Quality of Life WHOQOL-BREF. For statistical analysis of the correlation the coefficient test Spearman’s rho-test and Kolmogorov-Smirnov were used. Statistical significance of differences was determined at a confidence level of p<0.05.Results. The study included men and women. Women accounted for the majority of the study population — 64%, andonly 33% of the respondents were men. The vast majority of respondents lived with the family — 78%. Among the respondents, 86% had suffered over 20 years, only 14% of respondents had suffered no more than 10 years. Analyses have shown that the test people were more efficient in terms of basic and complex activities of daily living, the higher they assessed the quality of their own lives.Conclusions.1.A statistically significant correlation was shown between the assessment of quality of life and the exercise of the basic activities of daily living for people with multiple sclerosis.2.Statistically significant differences were observed between the assessment of quality of life and performance ofcomplex activities of daily living for people with multiple sclerosis.3.No statistically significant relationship was observed between the duration of the disease and the assessment ofthequality of life in various fields according to scale WHOQOL-Bref. (PNN 2013; 2(5): 188–194)Wprowadzenie. Stwardnienie rozsiane to przewlekła i najczęstsza choroba ośrodkowego układu nerwowego. Jest schorzeniem, które znacznie zaburza życie chorego. Pogarsza sprawność funkcjonalną we wszystkich aspektach życia codziennego, a co za tym idzie, pogarsza także jakość życia.Cel. Celem pracy była ocena sprawności funkcjonalnej chorych na stwardnienie rozsiane i jej wpływ na jakość życia.Materiał i metody. Badaniem zostało objętych 50 osób. Badania zostały przeprowadzone metodą sondażu diagnostycznego. Użyte narzędzia badawcze to kwestionariusz wywiadu dla danych socjodemograficznych oraz standaryzowane narzędzia badawcze: skala ADL i IADL, a także Skala Jakości Życia WHOQOL-BREF. Do analizy statystycznej wykorzystano test współczynnika korelacji rho-Spearmana i test Kołmogorowa-Smirnowa. Istotność statystyczną różnic określono na poziomie ufności p<0,05.Wyniki. W badaniu brali udział mężczyźni i kobiety. Kobiety stanowiły większość badanej populacji — 64%, a tylko 33% badanych stanowili mężczyźni. Zdecydowana większość badanych osób mieszkała z rodziną — 78%. Wśród badanych86% chorowało powyżej 20 lat, tylko 14% respondentów chorowało nie dłużej niż 10 lat. Analizy wykazały, że im badane osoby były bardziej sprawne w zakresie podstawowych i złożonych czynności życia codziennego, tym wyżej oceniały jakość własnego życia.Wnioski.1.Wykazano istotną statystycznie zależność pomiędzy oceną jakości życia a wykonywaniem podstawowych czynności życia codziennego przez osoby chore na stwardnienie rozsiane.2.Wykazano istotne statystycznie różnice między oceną jakości życia a wykonywaniem złożonych czynności życia codziennego przez osoby chore na stwardnienie rozsiane.3.Nie wykazano istotnych statystycznie zależności pomiędzy czasem trwania choroby a oceną jakości życia w poszczególnych dziedzinach skali WHOQOL-Bref. (PNN 2013; 2(5): 188–194

Is axonal degeneration a key early event in Parkinson’s disease?

Author Posting. © The Author(s), 2016. This is the author's version of the work. It is posted here by permission of IOS Press for personal use, not for redistribution. The definitive version was published in Journal of Parkinson's Disease 6 (2016): 703-707, doi:10.3233/JPD-160881.Recent research suggests that in Parkinson’s disease the long, thin and unmyelinated axons of dopaminergic neurons degenerate early in the disease process. We organized a workshop entitled ‘Axonal Pathology in Parkinson’s disease’, on March 23rd, 2016, in Cleveland, Ohio with the goals of summarizing the state-of-the-art and defining key gaps in knowledge. A group of eight research leaders discussed new developments in clinical pathology, functional imaging, animal models, and mechanisms of degeneration including neuroinflammation, autophagy and axonal transport deficits. While the workshop focused on PD, comparisons were made to other neurological conditions where axonal degeneration is well recognized

The inhibitor of differentiation-2 promotes synovial fibroblast-dependent osteoclastogenesis in rheumatoid arthritis

Objectives: Despite indirect evidence suggesting that low oxygen levels might occur in the rheumatoid arthritis (RA) synovium, direct proof of the presence of hypoxia in the arthritic synovium as well as the relevance of low oxygen levels for joint destruction is lacking. The aim of this study was to analyse the distribution of hypoxia in arthritic joints and to evaluate the molecular effects of the hypoxic environment on the phenotype of RA synovial fibroblasts (SF).<p></p> Methods: The hypoxia marker EF-5 was applied in mice with the collagen-induced arthritis (CIA). Expression profile analysis with hypoxic and normoxic SF was performed using subtractive hybridization and microarray. The expression of the inhibitor of differentiation-2 (Id-2), CD68 (macrophage marker) and prolyl hydroxylase (fibroblast marker) was evaluated by immunohistochemistry on synovial tissues from RA, osteoarthritis patients and CIA mice. To evaluate the function of Id-2 in SF, cells were transfected with the pcDNA3.1 containing cDNA for Id-2 or Id-2-specific siRNA or mock controls. The expression of Id-2 and genes regulated by Id-2 in transfected SF was evaluated by SYBR Green real-time PCR and western blot. SF stably transfected with Id-2 were cocultured with bone marrow cells in a transwell system. The expression of the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin were measured by real-time PCR. The development of osteoclasts was evaluated by visualization of the activity of tartrate-resistant acid phosphatase.<p></p> Results: Using the hypoxia marker EF-5 we found that in mice with CIA, synovial cells invading bone and cartilage are exposed to reduced oxygen levels. Expression profile studies identified Id-2 as being upregulated under low oxygen conditions. In addition, IL-1beta stimulation increased the expression of Id-2 in these cells. Histological studies of RA synovium and CIA synovium showed strong expression of Id-2 in SF at sites of synovial invasion into bone. Overproduction of Id-2 in SF by stable transfection triggered the expression of several genes promoting osteoclastogenesis, including BMP-2, PTHrP, Wnt5a and vascular endothelial growth factor. Conversely, the suppression of endogenous Id-2 led to the downregulation of the expression of these molecules. Consistent with these findings coculture of Id-2 transfected SF with bone marrow cells increased the expression of the osteoclast differentiation factor RANKL, and decreased the expression of the osteoclast inhibitory factor osteoprotegerin in bone marrow stromal cells, which was followed by an increase in the number of osteoclasts.<p></p> Conclusion: Taken together, our data provide evidence that hypoxia is present at sites of synovial invasion in RA and that Id-2 induced by hypoxia contributes at these sites to joint destruction by promoting SF-dependent osteoclastogenesis