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Cadmium (Cd), a type of heavy metal that accumulates in the body because of smoking, mediates the toxic effect of smoking in many diseases, such as cardiovascular disease, osteoarthritis, and osteoporosis. However, the toxic effect of Cd on intervertebral disc tissues have not been reported. In the current study, we demonstrated that Cd induced the apoptosis of annulus fibrosus (AF) cells, which contributed to intervertebral disc degeneration (IVDD). Specifically, Cd induced the nuclear translocation of FoxO1a, which drives AF cells apoptosis through mitochondrial‐related pathway. Phosphatidylinositol 3‐kinase/protein kinase B (PI3K/AKT) signal pathway is also involved in this process. The combined use of LY29002, an inhibitor of PI3K, and small interfering RNA‐targeting FoxO1a confirmed the relationship between the PI3K/AKT signal pathway and FoxO1a. In summary, present research explores the mechanism behind the contribution of smoking to IVDD and finds a new feasible target for preventing IVDD in smoking., Cadmium (Cd), a type of heavy metal that accumulates in the body because of smoking, mediates the occurrence of intervertebral disc (IVD) degeneration. Specifically, Cd induced the nuclear translocation of FoxO1a, which drives annulus fibrosus (AF) cells apoptosis through mitochondrial related pathway. It was the first time to explore the mechanism behind the contribution of smoking to IVD first and finds a feasible target for preventing IVD in smoking.

PurposeGermline nonsense and frameshift mutations in the adenomatous polyposis coli (APC) gene are found in approximately 90% of individuals affected by familial adenomatous polyposis (FAP) and a genotype-phenotype relationship has been observed. Missense mutations have also been found in a few cases, even if their role in FAP is still unknown. An association between a missense mutation, APC I1307K, and the risk of sporadic colorectal cancer (CRC) has been reported. In order to improve the knowledge about the genetic effect of APC I1307K on the phenotype, we tried a new approach using matrix-assisted laser desorption/ionization mass spectrometry (MALDI/MS).Experimental designAn APC mutation (I1307K) was found in an index case of a non-Jewish woman and her son with attenuated familial adenomatous polyposis (A-FAP) and no family history of cancer. In order to evaluate whether the presence and abundance of the ionic species are related to the presence of cancer or the presence of mutation, comparative analyses of 11 healthy clean-colon subjects, 59 patients with CRC (stage II n=19, stage III n=23, stage IV n=17) without polyps, and 9 FAP patients, carriers of a nonsense mutation in the APC gene, were evaluated.ResultsComparative analysis of serum protein profiles of the index patient and her healthy son, FAP and sporadic CRC patients, and subjects with preneoplastic lesions showed a characteristic abundance of ionic species at m/z 905, which was not present in healthy controls. Two peptides were identified from MALDI/MS/MS spectra of m/z 905 belonging to the kininogen-1 precursor and the human forkhead box protein 01A (FOXO1A). FOXO1A was present in only two subjects carrying I1307K, but not in other patients.ConclusionsOur findings seem to suggest a relationship between m/z 905, FOXO1A and the development and growth of colorectal cancer. FOXO1A fragment determination in serum with MALDI/MS might be a promising approach for early detection of colon carcinoma or for the development of targeted therapies.

Rhabdomyosarcoma (RMS) is a common paediatric soft tissue sarcoma that resembles developing foetal skeletal muscle. Tumours of the alveolar subtype frequently harbour one of two characteristic translocations that juxtapose PAX3 or PAX7, and the forkhead-related gene FKHR (FOXO1A). The embryonal subtype of RMS is not generally associated with these fusion genes. Here, we have quantified the relative levels of chimaeric and wild-type PAX transcripts in various subtypes of RMS (n=34) in order to assess the relevance of wild-type PAX3 and PAX7 gene expression in these tumours. We found that upregulation of wild-type PAX3 is independent of the presence of either fusion gene and is unlikely to contribute to tumorigenesis. Most strikingly, upregulated PAX7 expression is almost entirely restricted to cases without PAX3-FKHR or PAX7-FKHR fusion genes and may contribute to tumorigenesis in the absence of chimaeric PAX transcription factors. Furthermore, as myogenic satellite cells are known to express PAX7, this pattern of PAX7 expression suggests this cell type as the origin of these tumours. This is corroborated by the detection of MET (c-met) expression, a marker for the myogenic satellite cell lineage, in all RMS samples expressing wild-type PAX7.

International audience; After incomplete spinal cord injury (SCI), patients and animals may ă exhibit some spontaneous functional recovery which can be partly ă attributed to remodeling of injured neural circuitry. This post-lesion ă plasticity implies spinal remodeling but increasing evidences suggest ă that supraspinal structures contribute also to the functional recovery. ă Here we tested the hypothesis that partial SCI may activate ă cell-signaling pathway(s) at the supraspinal level and that this ă molecular response may contribute to spontaneous recovery. With this ă aim, we used a rat model of partial cervical hemisection which injures ă the bulbospinal respiratory tract originating from the medulla oblongata ă of the brainstem but leads to a time-dependent spontaneous functional ă recovery of the paralyzed hemidiaphragm. We first demonstrate that after ă SCI the PI3K/Akt signaling pathway is activated in the medulla oblongata ă of the brainstem, resulting in an inactivation of its pro-apoptotic ă downstream target, forkhead transcription factor (FKHR/FOXO1A). ă Retrograde labeling of medullary premotoneurons including respiratory ă ones which project to phrenic motoneurons reveals an increased FKHR ă phosphorylation in their cell bodies together with an unchanged cell ă number. Medulla infusion of the PI3K inhibitor, LY294002, prevents the ă SCI-induced Akt and FKHR phosphorylations and activates one of its ă death-promoting downstream targets, Fas ligand. Quantitative EMG ă analyses of diaphragmatic contractility demonstrate that the inhibition ă of medulla PI3K/Akt signaling prevents spontaneous respiratory recovery ă normally observed after partial cervical SCI. Such inhibition does not ă however affect either baseline contractile frequency or the ventilatory ă reactivity under acute respiratory challenge. Together, these findings ă provide novel evidence of supraspinal cellular contribution to the ă spontaneous respiratory recovery after partial SCI. (C) 2014 Elsevier ă Inc All rights reserved.

Objective IUGR re-programs hepatic gene expression, leading to alterations in perinatal mRNA levels that persist postnatally. Forkhead bos protein O1a (FoxO1a) is a nclear transcription factor, which is an important regulator of the in vivo metabolism of energetic substance, and play an important role in stabilizing the hepatocyte glucose metabolism and maintaining blood glucose levels in the body. Recent study investigated FoxO1a expression can stimulate key enzymes of gluconeogenesis pathway phosphoenolpyruvate carboxylase kinases (PEPCK), peroxisome proliferator-activated receptor g auxiliary activating factor1a (PGC-1a) and glucose 6 phosphatase (G-6-Pase) gene expression. The effect of IUGR upon hepatic FoxO1a expression is unknown. So in this study we investigate the persistent changes in hepatic FoxO1a expression caused by IUGR, which could initiate and maintain the obesity, insulin resistance and type 2 diabetes, and explore whether the changes in FoxO1a expression are gender specific.